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Single Technology Appraisal

Lu vipivotide tetraxetan for treating PSMApositive hormone-relapsed metastatic prostate cancer after 2 or more therapies [ID3840]

Committee Papers

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NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

SINGLE TECHNOLOGY APPRAISAL

Lu vipivotide tetraxetan for treating PSMA-positive hormone-relapsed metastatic prostate cancer after 2 or more therapies [ID3840]

Contents:

The following documents are made available to consultees and commentators:

The final scope and final stakeholder list are available on the NICE website.

1. Company submission from Novartis Pharmaceuticals

2. Clarification questions and company responses

3. Patient group, professional group and NHS organisation submissions from:

• a. British Nuclear Medicine Society

• b. Prostate Cancer UK

• c. TACKLE Prostate Cancer

4. Evidence Review Group report prepared by ScHARR

5. Evidence Review Group report – factual accuracy check

6. Technical engagement response from company

7. Technical engagement responses and statements from experts:

• a. Prof. Amit Bahl, Consultant Oncologist – clinical expert, nominated by Novartis Pharmaceuticals

• b. Dr Amarnath Challipalli, Consultant Clinical Oncologist – clinical expert, nominated by Prostate Cancer UK

• c. Dr Stephen Allen, Acting Chairman – patient expert, nominated by Tackle Prostate Cancer

• d. Mr Peter Isard – patient expert, nominated by Tackle Prostate Cancer

• e. Prof. Sabina Dizdarevic, Research Lead and Principal Lead Consultant in Imaging and Nuclear Medicine – clinical expert, nominated by the British Nuclear Medicine Society (see item 8b)

8. Technical engagement responses from consultees and commentators:

• a. Bayer

• b. British Nuclear Medicine Society c. Prostate Cancer UK

9. Evidence Review Group critique of company response to technical engagement prepared by ScHARR

Any information supplied to NICE which has been marked as confidential, has been redacted. All personal information has also been redacted.

NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

Single technology appraisal

177Lu vipivotide tetraxetan for treating PSMApositive hormone-relapsed metastatic prostate cancer after 2 or more therapies [ID3840]

Document B

Company evidence submission

15 March 2022

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Contents

Contents ........................................................................................................................................... 2 List of Abbreviations ......................................................................................................................... 7 B.1 Decision problem, description of the technology and clinical care pathway ........................... 11 B.1.1 Decision problem .............................................................................................................. 11 B.1.2 Description of the technology being appraised ................................................................ 17 B.1.3 Health condition and position of the technology in the treatment pathway ..................... 19 B.1.4 Equality considerations .................................................................................................... 32 B.2 Clinical effectiveness ............................................................................................................... 33 B.2.1 Identification and selection of relevant studies ................................................................ 35 B.2.2 List of relevant clinical effectiveness evidence ................................................................ 35 B.2.3 Summary of methodology of the relevant clinical effectiveness evidence ...................... 36 B.2.4 Quality assessment of the relevant clinical effectiveness evidence ................................ 49 B.2.5 Clinical effectiveness results of the relevant trials ........................................................... 50 B.2.6 Subgroup analysis ............................................................................................................ 58 B.2.7 Meta-analysis ................................................................................................................... 60 B.2.8 Indirect and mixed treatment comparisons ...................................................................... 60 B.2.9 Adverse reactions ............................................................................................................. 70 B.2.10 Ongoing studies ............................................................................................................. 78 B.2.11 Innovation ....................................................................................................................... 78 B.2.12 Interpretation of clinical effectiveness and safety evidence ........................................... 81 B.3 Cost effectiveness ................................................................................................................... 85 B.3.1 Published cost-effectiveness studies ............................................................................... 86 B.3.2 Economic analysis ............................................................................................................ 91 B.3.3 Clinical parameters and variables .................................................................................... 95 B.3.4 Measurement and valuation of health effects ................................................................ 126 B.3.5 Cost and healthcare resource use identification, measurement and valuation ............. 131 B.3.6 Summary of base-case analysis inputs and assumptions ............................................. 141 B.3.7 Base-case results (pairwise) .......................................................................................... 150 B.3.8 Sensitivity analyses ........................................................................................................ 151 B.3.9 Subgroup analysis .......................................................................................................... 170 B.3.10 Validation ...................................................................................................................... 170 B.3.11 Interpretation and conclusions of economic evidence ................................................. 171 References ................................................................................................................................... 174 Appendices .................................................................................................................................. 187

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Tables and Figures Table 1: The decision problem ...................................................................................................... 12 Table 2: Technology being appraised............................................................................................ 17 Table 3: Incidence of AEs (any Grade and Grade 3–4) according to Phase 3 RCTs ................... 30 Table 4: Clinical effectiveness evidence ........................................................................................ 36 Table 5: Summary of the trial design for VISION .......................................................................... 37 Table 6: Summary of the VISION trial methodology ..................................................................... 38 Table 7: Definitions for outcome measures used in VISION ......................................................... 40 Table 8: Analysis sets used in the analysis of outcomes in VISION ............................................. 42 Table 9: Statistical methods for the primary analysis of VISION ................................................... 44 Table 10: Baseline characteristics for PFS-FAS and FAS in VISION ........................................... 46 Table 11: Concomitant medications indicated as SOC that were taken by ≥10% of patients in either treatment arm (FAS SAS) .................................................................................................... 47 Table 12: OS in VISION (FAS) ...................................................................................................... 50 Table 13: rPFS in VISION per independent central review (PFS-FAS) ........................................ 53 Table 14: Time to first SSE (PFS-FAS) ......................................................................................... 55 Table 15: Analyses of ORR, DCR and DOR per independent central review (Response evaluable analysis set) ................................................................................................................................... 57 Table 16: Baseline characteristics for RWE analysis .................................................................... 61 Table 17: Patients receiving cabazitaxel in the RWE analysis ...................................................... 62 Table 18: Summary of studies included in the NMA ..................................................................... 65 Table 19: DIC and residual deviance values for OS using fixed effects and random effects models ............................................................................................................................................ 67 Table 20: DIC and residual deviance values for rPFS using fixed effects and random effects models ............................................................................................................................................ 67 Table 21: Duration of exposure to randomised treatment based upon trial arm (FAS safety analysis set) ................................................................................................................................... 70 Table 22: Duration of exposure to[177] Lu vipivotide tetraxetan and summary of cycles (FAS safety analysis set) ................................................................................................................................... 71 Table 23: Overview of AEs during randomised treatment (FAS safety analysis set) ................... 71 Table 24: AEs by primary SOC and maximum grade during randomised treatment occurring it at least 5% of patients in either arm during randomised treatment (FAS safety analysis set) ......... 72 Table 25: AEs occurring in at least 5% of patients in either arm during randomised treatment with suspected relationship by preferred term and maximum grade (FAS-SAS) ................................. 73 Table 26: SAEs occurring in at least 1% of patients in either arm during randomised treatment (FAS-SAS) ..................................................................................................................................... 73 Table 27: On-treatment deaths during randomised treatment (FAS-SAS) ................................... 74 Table 28: AEs leading to permanent discontinuation of[177] Lu vipivotide tetraxetan during randomised treatment (FAS-SAS) ................................................................................................. 75 Table 29: AEs leading to interruption or dose reduction of[177] Lu vipivotide tetraxetan occurring in at least 0.5% of the patients during randomised treatment (FAS-SAS) ........................................ 77 Table 30: Overview of treatment-emergent adverse events of interest during randomised treatment (FAS-SAS) ..................................................................................................................... 78 Table 31: End-of-life criteria ........................................................................................................... 84 Table 32: Summary list of published cost-effectiveness studies identified in the SLR ................. 87 Table 33: Summary of previous TAs identified in the SLR ............................................................ 89 Table 34: Summary of the features of the economic analysis ...................................................... 93 Table 35: Patient baseline characteristics in the model ................................................................ 95 Table 36: Predicted mean rPFS versus SOC for selected survival extrapolations ..................... 103 Table 37: Predicted difference in mean rPFS versus cabazitaxel for selected survival extrapolations ............................................................................................................................... 104 Table 38: Identified publications presenting Kaplan–Meier OS registry data for patients with mCRPC ........................................................................................................................................ 106 Table 39: Predicted difference in mean OS versus SOC for selected survival extrapolations ... 114 Table 40: Predicted difference in mean OS versus cabazitaxel for selected survival extrapolations ............................................................................................................................... 115

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Table 41: Predicted difference in mean time-to-first SSE versus SOC for selected survival extrapolations ............................................................................................................................... 124 Table 42: SSE incidence and rates applied in a scenario analyses............................................ 125 Table 43: Distribution of SSEs ..................................................................................................... 126 Table 44: Incidence of Grade ≥3 AEs occurring in at least 2% of patients ................................. 126 Table 45: Utility decrements associated with SSEs .................................................................... 127 Table 46: Utility decrements and duration of disutility associated with AEs ............................... 128 Table 47: Numbers of patients who provided EQ-5D scores at each treatment cycle in VISION ...................................................................................................................................................... 129 Table 48: Descriptive statistics for EQ-5D health state utility values derived from VISION ....... 129 Table 49: EQ-5D health state utilities derived from generalised linear mixed model ................. 130 Table 50: EQ-5D health state utilities derived from NICE TA391 ............................................... 130 Table 51: Base case health state utility inputs ............................................................................ 131 Table 52: Drug acquisition and administration costs ................................................................... 133 Table 53: Treatment duration and costs for[177] Lu vipivotide tetraxetan and cabazitaxel ............ 135 Table 54: SOC resource utilisation .............................................................................................. 135 Table 55: Resource utilisation for cabazitaxel ............................................................................. 136 Table 56: Therapeutic interventions resource utilisation ............................................................. 137 Table 57: Distribution of subsequent treatments ......................................................................... 138 Table 58: Costs associated with appointments and diagnostic procedures/ tests ...................... 139 Table 59: Healthcare resource utilisation for appointments and diagnostic procedures/ tests ... 140 Table 60: Costs associated with Grade ≥ 3 adverse events ....................................................... 140 Table 61: Costs associated with SSEs ........................................................................................ 141 Table 62: Summary of variables applied in the cost effectiveness analysis ............................... 141 Table 63: Key assumptions of the cost effectiveness analysis ................................................... 144 Table 64: Base-case results at[177] Lu vipivotide tetraxetan list price (deterministic) ................... 150 Table 65: Base-case results at[177] Lu vipivotide tetraxetan PAS price (deterministic) ................. 150 Table 66: Base-case results at[177] Lu vipivotide tetraxetan list price (probabilistic) ..................... 151 Table 67: Base-case results at[177] Lu vipivotide tetraxetan PAS price (probabilistic) .................. 155 Table 68: Results from scenario analyses – Impact of utilising the stratified flexible Weibull (1 knot) model for rPFS extrapolation (list price for[177] Lu vipivotide tetraxetan) ............................. 163 Table 69: Results from scenario analyses – Impact of utilising the stratified flexible Weibull (1 knot) model for rPFS extrapolation (PAS for[177] Lu vipivotide tetraxetan) ................................... 164 Table 70: Results from scenario analyses – Impact of utilising interval imputation of missing data with flexible 2-knot Weibull model for the rPFS analysis in VISION (list price for[177] Lu vipivotide tetraxetan) .................................................................................................................................... 164 Table 71: Results from scenario analyses – Impact of utilising interval imputation of missing data with flexible 2-knot Weibull model for the rPFS analysis in VISION (PAS price for[177] Lu vipivotide tetraxetan) .................................................................................................................................... 164 Table 72: Results from scenario analyses – Impact of utilising the Gamma model for OS extrapolation (list price for[177] Lu vipivotide tetraxetan) ................................................................ 165 Table 73: Results from scenario analyses – Impact of utilising the Gamma model for OS extrapolation (PAS price for[177] Lu vipivotide tetraxetan) ............................................................. 165 Table 74: Results from scenario analyses – Impact of utilising the application of NMA HR to the 177Lu vipivotide tetraxetan + SOC arm of VISION to inform OS (list price for 177Lu vipivotide tetraxetan) .................................................................................................................................... 165 Table 75: Results from scenario analyses – Impact of utilising the application of NMA HR to the 177Lu vipivotide tetraxetan + SOC arm of VISION to inform OS (PAS price for 177Lu vipivotide tetraxetan) .................................................................................................................................... 165 Table 76: Results from scenario analyses – Impact of utilising IPCW adjustment with stratified flexible Weibull (2 knots) model to inform OS (list price for[177] Lu vipivotide tetraxetan) ............. 166 Table 77: Results from scenario analyses – Impact of utilising IPCW adjustment with stratified flexible Weibull (2 knots) model to inform OS (PAS price for[177] Lu vipivotide tetraxetan) .......... 166 Table 78: Results from scenario analyses – Impact of using total incidence to model SSEs (list price for[177] Lu vipivotide tetraxetan) ............................................................................................. 166

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Table 79: Results from scenario analyses – Impact of using total incidence to model SSEs (PAS price for[177] Lu vipivotide tetraxetan) ............................................................................................. 167 Table 80: Results from scenario analyses – Impact of applying SOC SSE rate to cabazitaxel treatment arm (list price for[177] Lu vipivotide tetraxetan) .............................................................. 167 Table 81: Results from scenario analyses – Impact of applying SOC SSE rate to cabazitaxel treatment arm (PAS price for[177] Lu vipivotide tetraxetan) ........................................................... 167 Table 82: Results from scenario analyses – Impact of applying concomitant SOC treatment costs to the[177] Lu vipivotide tetraxetan and cabazitaxel treatment arm (list price for[177] Lu vipivotide tetraxetan) .................................................................................................................................... 167 Table 83: Results from scenario analyses – Impact of applying concomitant SOC treatment costs to the[177] Lu vipivotide tetraxetan and cabazitaxel treatment arm (PAS price for[177] Lu vipivotide tetraxetan) .................................................................................................................................... 168 Table 84: Results from scenario analyses – Impact of applying SOC therapeutic intervention use to the cabazitaxel treatment arm (list price for[177] Lu vipivotide tetraxetan) ................................. 168 Table 85: Results from scenario analyses – Impact of applying SOC therapeutic intervention use to the cabazitaxel treatment arm (PAS price for[177] Lu vipivotide tetraxetan) .............................. 168 Table 86: Results from scenario analyses – Impact of assuming that proportion of patients treated with cabazitaxel receiving subsequent carboplatin and radiotherapy equals the VISION SOC population (list price for[177] Lu vipivotide tetraxetan) ........................................................... 169 Table 87: Results from scenario analyses – Impact of assuming that proportion of patients treated with cabazitaxel receiving subsequent carboplatin and radiotherapy equals the VISION SOC population (PAS price for[177] Lu vipivotide tetraxetan) ........................................................ 169 Table 88: Results from scenario analyses – Impact of applying the overall pre-progressed health state utility value from VISION to the cabazitaxel treatment arm (list price for[177] Lu vipivotide tetraxetan) .................................................................................................................................... 169 Table 89: Results from scenario analyses – Impact of applying the overall pre-progressed health state utility value from VISION to the cabazitaxel treatment arm (PAS price for[177] Lu vipivotide tetraxetan) .................................................................................................................................... 169 Table 90: Results from scenario analyses – Impact of applying treatment-independent health state utility values (list price for[177] Lu vipivotide tetraxetan) ........................................................ 170 Table 91: Results from scenario analyses – Impact of applying treatment-independent health state utility values (PAS price for[177] Lu vipivotide tetraxetan) ..................................................... 170

Figure 1: Mechanism of action for[177] Lu vipivotide tetraxetan ....................................................... 17 Figure 2: Treatment pathways for patients with mCRPC and the proposed positioning of[177] Lu vipivotide tetraxetan ....................................................................................................................... 28 Figure 3: Overview of the study design for VISION ....................................................................... 37 Figure 4: CONSORT diagram showing participant flow in VISION ............................................... 49 Figure 5: Kaplan–Meier plot of OS (FAS) ...................................................................................... 52 Figure 6: Kaplan–Meier plot of rPFS per independent central review (PFS-FAS) ........................ 54 Figure 7: Kaplan–Meier plot of time to first SSE (PFS-FAS) ......................................................... 56 Figure 8: Subgroup analyses of OS – Forest plot of HR with 95% CI (FAS) ................................ 59 Figure 9: Subgroup analyses of rPFS per independent central review – forest plot of HR with 95% CI (PFS-FAS) ......................................................................................................................... 60 Figure 10: OS for patients in the RWE analysis following receipt of cabazitaxel .......................... 62 Figure 11: OS network (based on HR) .......................................................................................... 66 Figure 12: Base-case NMA results – OS (fixed-effects model) ..................................................... 68 Figure 13: Base-case NMA results – rPFS (fixed-effects model) .................................................. 69 Figure 14: Partitioned survival model structure ............................................................................. 92 Figure 15: Radiographic progression free survival: Standard parametric models ........................ 98 Figure 16: Radiographic progression free survival: Standard parametric models: Long-term extrapolations ................................................................................................................................. 99 Figure 17: Radiographic progression free survival: Royston-Palmar spline-based models ....... 100 Figure 18: Radiographic progression free survival: Royston-Palmar spline-based models: Longterm extrapolations....................................................................................................................... 101

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Figure 19: Radiographic progression free survival model fit: Akaike’s information criterion (A) and Bayesian information criterion (B) ................................................................................................ 102 Figure 20: Cabazitaxel rPFS curves applied in the base case and scenario analyses generated from reference[177] Lu vipivotide tetraxetan survival curves .......................................................... 104 Figure 21: Selected distributions for extrapolating rPFS for[177] Lu vipivotide tetraxetan, SOC (VISION) and cabazitaxel (via HR) .............................................................................................. 105 Figure 22: Comparison of OS from the VISION SOC arm with OS data presented in Mehtala et al. (original data) .......................................................................................................................... 107 Figure 23: Comparison of OS from the VISION SOC arm with OS data presented in Mehtala et al. (time accelerated adjusted data) ............................................................................................. 107 Figure 24: Comparison of OS from the VISION SOC arm with OS data presented in Notohardjo et al. (original data) ...................................................................................................................... 108 Figure 25: Overall survival: Standard parametric models ........................................................... 109 Figure 26: Overall survival: Standard parametric models: Long-term extrapolations ................. 110 Figure 27: Overall survival: Royston-Palmar spline-based models ............................................. 111 Figure 28: Overall survival: Royston-Palmar spline-based models: Long-term extrapolations .. 112 Figure 29: Overall survival model fit: Akaike’s information criterion (A) and Bayesian information criterion (B) ................................................................................................................................... 113 Figure 30: Ensemble predictions for overall survival ................................................................... 114 Figure 31: Cabazitaxel OS curves applied in the base case and scenario analyses ................. 116 Figure 32: Selected distributions for extrapolating OS for[177] Lu vipivotide tetraxetan, SOC (VISION) and cabazitaxel (UK RWE) .......................................................................................... 116 Figure 33: Time-to-first SSE data from VISION........................................................................... 117 Figure 34: Time-to-first SSE: Parametric Models Fitted to the VISION Trial Data ..................... 118 Figure 35: Time-to-first SSE: Long-Term Extrapolations Fitted to the VISION Trial Data .......... 119 Figure 36: Time-to-first SSE: Flexible Spline-Based Models Fitted to the VISION Trial Data .... 120 Figure 37: Time-to-first SSE: Long-term Extrapolations Based on the Flexible Spline-Based Models Fitted to the VISION Trial Data ....................................................................................... 121 Figure 38: Time-to-first SSE: Model Fit Statistics – A (AIC) and B (BIC) .................................... 122 Figure 39: Time-to-first SSE: Ensemble Models ......................................................................... 123 Figure 40: Comparison of time-to-first SSE in VISION and CARD ............................................. 125 Figure 41: Scatter plot of probabilistic results on the cost-effectiveness plane for[177] Lu vipivotide tetraxetan at list price ([177] Lu vipivotide tetraxetan vs. cabazitaxel) ............................................. 152 Figure 42: Scatter plot of probabilistic results on the cost-effectiveness plane for[177] Lu vipivotide tetraxetan at list price ([177] Lu vipivotide tetraxetan vs. SOC) ....................................................... 153 Figure 43: Cost-effectiveness acceptability curves for[177] Lu vipivotide tetraxetan at list price([177] Lu vipivotide tetraxetan vs. cabazitaxel) ........................................................................................... 154 Figure 44:Cost-effectiveness acceptability curves for[177] Lu vipivotide tetraxetan at list price([177] Lu vipivotide tetraxetan vs. SOC) ..................................................................................................... 155 Figure 45: Scatter plot of probabilistic results on the cost-effectiveness plane for[177] Lu vipivotide tetraxetan at PAS price ([177] Lu vipivotide tetraxetan vs. cabazitaxel) .......................................... 156 Figure 46: Scatter plot of probabilistic results on the cost-effectiveness plane for[177] Lu vipivotide tetraxetan at PAS price ([177] Lu vipivotide tetraxetan vs. SOC) .................................................... 157 Figure 47: Cost-effectiveness acceptability curves for[177] Lu vipivotide tetraxetan at PAS price ([177] Lu vipivotide tetraxetan vs. cabazitaxel) ................................................................................. 158 Figure 48: Cost-effectiveness acceptability curves for[177] Lu vipivotide tetraxetan at PAS price([177] Lu vipivotide tetraxetan vs. SOC) ................................................................................... 159 Figure 49: Tornado plot (ICER) of deterministic sensitivity analysis for[177] Lu vipivotide tetraxetan at list price ([177] Lu vipivotide tetraxetan vs. cabazitaxel) .............................................................. 160 Figure 50: Tornado plot (ICER) of deterministic sensitivity analysis for[177] Lu vipivotide tetraxetan at list price ([177] Lu vipivotide tetraxetan vs. SOC)......................................................................... 161 Figure 51: Tornado plot (ICER) of deterministic sensitivity analysis for[177] Lu vipivotide tetraxetan at PAS price ([177] Lu vipivotide tetraxetan vs. cabazitaxel) ........................................................... 162 Figure 52: Tornado plot (ICER) of deterministic sensitivity analysis for[177] Lu vipivotide tetraxetan at PAS price ([177] Lu vipivotide tetraxetan vs. SOC) ...................................................................... 163

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List of Abbreviations

Company evidence submission template for[177] Lu vipivotide tetraxetan for treating PSMApositive hormone-relapsed metastatic prostate cancer after 2 or more therapies [ID3840]

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Company evidence submission template for[177] Lu vipivotide tetraxetan for treating PSMApositive hormone-relapsed metastatic prostate cancer after 2 or more therapies [ID3840]

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Company evidence submission template for[177] Lu vipivotide tetraxetan for treating PSMApositive hormone-relapsed metastatic prostate cancer after 2 or more therapies [ID3840]

© Advanced Accelerator Applications (2022). All rights reserved

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B.1 Decision problem, description of the technology and clinical care pathway

B.1.1 Decision problem

This submission covers the technology’s full anticipated marketing authorisation for [[177] Lu]LuPSMA 617 (hereinafter[177] Lu vipivotide tetraxetan) “for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive, metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition (ARPI) and taxane-based chemotherapy or who are not medically suitable for taxanes”. The decision problem addressed within this submission is broadly consistent with the NICE final scope for this appraisal with respect to the population, intervention, outcomes and comparators (with the exception of docetaxel rechallenge, radium-223, and olaparib), and the NICE reference case. The differences between the decision problem addressed within this submission and the NICE final scope are outlined in Table 1.

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Table 1: The decision problem

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Company evidence submission template for[177] Lu vipivotide tetraxetan for treating PSMA-positive hormone-relapsed metastatic prostate cancer after 2 or more therapies [ID3840]

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Company evidence submission template for[177] Lu vipivotide tetraxetan for treating PSMA-positive hormone-relapsed metastatic prostate cancer after 2 or more therapies [ID3840]

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Company evidence submission template for[177] Lu vipivotide tetraxetan for treating PSMA-positive hormone-relapsed metastatic prostate cancer after 2 or more therapies [ID3840]

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aThe terminology ‘Standard of Care (SOC)’ is used throughout this submission to align with the lexicon from the VISION trial. SOC should be considered equivalent to the other widely used terminology of ‘Best Standard of Care (BSoC)’.

Abbreviations:[177] Lu: Lutetium-177; ARPI: androgen receptor pathway inhibitor; BRCA1/2: breast cancer genes 1 and 2; DCR: disease control rate; DOR: duration of response; HSPC: hormone-sensitive prostate cancer; mCRPC: metastatic castration-resistant prostate cancer; MHRA: Medicines and Healthcare products Regulatory Agency; mHSPC: metastatic hormone-sensitive prostate cancer; NA: not applicable; NHS: National Health Service; NICE: National Institute for Health and Care Excellence; ORR: overall response rate; OS: overall survival; PFS: progression-free survival; PSA: prostate-specific antigen; PSMA: prostate-specific membrane antigen; QALY: quality-adjusted life year; rPFS: radiographic progression-free survival; SOC: standard of care; SSE: symptomatic skeletal event. Source: NICE final scope document [ID3840]

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B.1.2 Description of the technology being appraised

A summary of the mechanism of action, marketing authorisation status, costs and administration requirements of[177] Lu vipivotide tetraxetan in the treatment of mCRPC is presented in Table 2.

Table 2: Technology being appraised

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==> picture [421 x 341] intentionally omitted <==

----- Start of picture text -----
o The following laboratory tests should be performed before and
during treatment with [177] Lu vipivotide tetraxetan. These are in
line with standard monitoring requirements for existing
treatments in mCRPC. [16, 17] Dosing should be modified as per
the SmPC based on the results of laboratory results. [15]
▪ Haematology (haemoglobin, white blood cell count,
absolute neutrophil count, platelet count).
▪ Kidney function (serum creatinine or calculated
creatinine clearance).
▪ Liver function (alanine aminotransferase, aspartate
aminotransferase, alkaline phosphatase, blood serum
albumin, total blood bilirubin).
List price and The proposed list price of one single dose vial of [177] Lu vipivotide

average cost of tetraxetan is .
a course of
treatment
Patient access This submission includes the confidential simple patient access
scheme (if scheme (PAS) for [177] Lu vipivotide tetraxetan, representing a discount

applicable) to the list price of %.
The proposed PAS price of one single dose vial of [177] Lu vipivotide
****
tetraxetan is .
A confidential PAS is known to be in place for cabazitaxel. [10] As this
information is not publicly available, it has not been included in the
submission.
----- End of picture text -----

Abbreviations:[177] Lu: lutetium-177; CHMP: Committee for Medicinal Products for Human Use; DNA: deoxyribonucleic acid; MBq: megabecquerel; mCi: millicurie; mCRPC: metastatic castration-resistant prostate cancer; MHRA: Medicines and Healthcare products Regulatory Agency; NICE: National Institute for Health and Care Excellence; PAS: patient access scheme; PSMA: prostate-specific membrane antigen; UK: United Kingdom.

B.1.3 Health condition and position of the technology in the

treatment pathway

Summary of the health condition

• Prostate cancer is the most common cancer in males in the UK, with an incidence of 52,280 cases diagnosed in the UK between April 2018 and March 2019.[18] The incidence of PC in the UK has increased steadily over the past decade, and is projected to rise to 233 cases per 100,000 males by 2035 (12% increase 2014–2035).[19]

• • PC is the second most common cause of cancer death amongst men in the UK[20] Due to the insidious nature of the symptoms of early stage PC, patients may often present with advanced/metastatic disease.[18]

• • Metastatic PC causes a wide range of physical and psychological symptoms that significantly impact upon patients’ lives,[21, 22] imposing considerable burden on patients, their families, and society.[23]

• • PC is the second most common cause of cancer death amongst men in the UK.[20] The population for this submission is patients with advanced disease, that has progressed despite prior therapies.

• • Clinical trials in patients with mCRPC who have progressed despite docetaxel have reported median OS in their control arms of 11.2–13.6 months.[24] Considered together, alongside the fact that patients who have progressed despite also receiving ARPI are likely to have even

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shorter OS, the estimated prognosis for patients considered in this submission is under 12 months. The median OS for patients in the SOC arm of VISION, the primary source of evidence for[177] Lu vipivotide tetraxetan in this submission, was only 11.3 months.[25]

• PSMA-positivity is an independent poor prognostic indicator for progression-free survival and overall survival in CRPC.[26]

Summary of the treatment pathway

• Patients with mCRPC are currently treated with taxane-based chemotherapy, ARPIs, and radium-223 (if they have bone metastases but no visceral metastases), alongside SOC supportive treatments. With the advent of new therapies, as well as the diversifying use of existing therapies such as ARPIs and docetaxel, the treatment pathway for mCRPC is becoming increasingly complex and lacks definitive evidence for sequencing of specific therapies.[2]

• Physicians rely on published guidelines and clinical expertise to consider the risk-to-benefit profile of therapeutic options, as well as considering patient characteristics, prior therapies (as above), and patient preferences to make treatment decisions.[27, 28]

• Treatment options are severely limited by factors such as a patients’ functional performance status, treatment-related toxicities, treatments previously received earlier in the disease course, disease resistance to ARPIs, and the presence of visceral metastases (which precludes the use of radium-223). Therefore, there remains a considerable unmet need for additional effective and well-tolerated, targeted therapeutic options for those with mCRPC who have progressed despite multiple prior non-targeted therapies.[27-30]

Position of[177] Lu vipivotide tetraxetan

• [177] Lu vipivotide tetraxetan is positioned for the treatment of adult patients with PSMA-positive, mCRPC who have been treated with an ARPI and a taxane-based chemotherapy, or who are not medically suitable for taxanes.

• As such,[177] Lu vipivotide tetraxetan represents a much-needed treatment option with a novel mechanism of action for patients with mCRPC. This is reflected by the Promising Innovative Medicines (PIM) designation granted by the MHRA for[177] Lu vipivotide tetraxetan.[31]

B.1.3.1 Disease overview and epidemiology

Prostate cancer (PC) is a type of cancer that originates in the gland cells of the prostate where excessive and aberrant cell growth leads to the formation of tumours. These tumours may remain confined to the prostate but often eventually extend beyond the prostate’s capsule and spread to local or distant sites in the body as metastases.[32] The vast majority of PCs originate from the prostate’s glandular cells and the most common subtype of PC is acinar adenocarcinoma, which accounts for 90–95% of PC cases.[32, 33] The majority of remaining cases of PC are generally classified as ductal adenocarcinoma (originating in cells lining the prostate gland ducts) or neuroendocrine carcinoma (originating from neuroendocrine cells in the prostate).

The cause of PC is thought to be a complex interplay of genetic factors, environmental factors and hormonal imbalances, which collectively drive chronic inflammation and abnormal proliferation of PC cells. The majority of PC cases in the UK are sporadic (non-hereditary) in – nature, while approximately 5 9% of men have hereditary disease.[34] Notably, the most frequently mutated DNA repair genes in PC are BRCA1/2 and these convey more aggressive disease and earlier onset.[35] Certain environmental and lifestyle factors (such as dietary carcinogens, infectious agents and obesity) have been implicated as risk factors for PC; however, no definitive link has been established between PC and preventable risk factors.[32]

Prostate cancer may present as either localised, locally advanced, or advanced/metastatic and is the most common cancer in males in the UK, with an incidence of 52,280 cases diagnosed in England between April 2018 and March 2019.[18] As of 2018, the World Cancer Research Fund reported the UK to have the 16[th] highest PC rate worldwide (age-standardised incidence of 80.7 Company evidence submission template for[177] Lu vipivotide tetraxetan for treating PSMApositive hormone-relapsed metastatic prostate cancer after 2 or more therapies [ID3840]

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per 100,000).[36] The overall incidence of PC in the UK has increased steadily over the past decade, and is projected to rise to 233 cases per 100,000 males by 2035 (12% increase 2014– 2035).[19] Age is a major risk factor in the development of PC and age-specific incidence rates rise sharply from around age 50–54 years (70 cases per 100,000), with the highest rates found at ages 75–79 years (819 cases per 100,000).[19]

In England during 2018, the proportion of patients diagnosed with stage I, II, III, and IV PC were 35.5% (n=17,670), 13.6% (n=6,758), 23.9% (n=11,889), and 17% (n=8,442); 10.1% (n=5,051) newly diagnosed patients were of unknown stage.[37] There proportions remained broadly stable from 2013–2018.[37] Of all patients diagnosed with PC in England and Wales during 2020, 14% presented with metastatic disease.[18] Furthermore, although incidence data specific to mCRPC is not widely reported for the UK, a longitudinal analysis of the UK-based General Practice Research Database (GPRD) revealed that 28% of PC patients that had undergone androgen deprivation therapy (ADT) developed CRPC between 1999–2009 (8.3 per 100 person years in all PC patients).[38] These figures are in line with an international systematic review of prevalence studies, which indicated that 10–20% of patients with PC developed CRPC over a 5-year followup period.[39] The same study indicated that almost all patients had bone metastases (84–95%) at the point of mCRPC diagnosis.[39]

PSMA positivity in PC

PSMA is a 750-amino-acid type II transmembrane protein encoded by the folate hydrolase 1 gene.[13] PSMA is expressed in benign prostate tissue at modest levels as well as demonstrating some limited expression in other tissues.[13] However, in prostate adenocarcinoma, PSMA expression increases substantially. Furthermore, expression of PSMA has been shown to be higher in more aggressive disease, including more advanced tumour staging, and in cases of biochemical recurrence or CRPC.[13] Due to the specificity of PSMA expression on cancerous prostate tissue, particularly in advanced or recurrent PC, imaging using PSMA-targeted radioligands has become an important modality to detect nodal or distant metastases and inform clinical decision making.[40] The vast majority of patients with mCRPC are PSMA-positive, with the VISION trial (which represents the key source of clinical evidence for[177] Lu vipivotide tetraxetan in this submission) reporting 86.6% of screened patients meeting criteria for PSMA-positivity. In a retrospective analysis of 1,007 consecutive patients in a single-centre who underwent assessment for PSMA-status over a 3-year period, PSMA-positivity was on average detected in 79.5% of patients with PC.[41] However, this proportion was noted to markedly increase in patients with an elevated PSA (46% in patients with PSA ≤0.2 ng/ml – 96% in patients with PSA >10.0 ng/ml).[41] Given that patients with progressive mCRPC are expected to have an elevated PSA (mean PSA of patients in VISION was 77.5 ng/ml in the treatment arm and 74.6 ng/ml in the standard of care arm), it is reasonable to expect the proportion of PSMA-positivity to be approximately 90% in the patient population covered within this submission.[25]

B.1.3.2 Disease burden

Patients with early stage, non-metastatic PC often do not experience any symptoms from their disease.[42] However, symptoms may develop when the cancer grows large enough to press against the urethra and interfere with urinary habits. Possible early symptoms of localised or locally advanced PC include difficulty in commencing urination or emptying the bladder, a weak urinary flow, urinary frequency, urinary urgency, haematuria, and nocturia.[42] The insidious nature of early PC and the non-specific symptoms which present with early disease can often result in a

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delayed diagnosis, which leads to a considerable proportion of patients presenting with metastatic disease, as described in Section B.1.3.1.

Metastatic PC on the other hand causes a wide range of symptoms that can significantly impact upon patients’ lives.[21, 22] In addition to the urinary symptoms experienced in early disease, patients may experience constitutional symptoms such as unexplained weight loss, generalised fatigue, sleep disturbance and anxiety.[22] Disease burden in the pelvis can lead to pelvic or back pain, as well as colorectal dysfunction in the form of constipation and/or diarrhoea.[22] Additionally, bone metastases can lead to significant skeletal morbidity (often known as “symptomatic skeletal events”), such as pain, pathological fractures, spinal cord compression, or hypercalcaemia and its associated complications (nausea and vomiting, polydipsia, myalgia, delirium, renal impairment, and cardiac arrythmias).[22] Visceral metastases can also cause a variety of symptoms, depending on the site and extent of the metastases.[43] For instance, lung metastases can lead to shortness of breath whereas liver metastases can lead to jaundice, pruritis, abdominal swelling and pain.[44]

Due to the wide range or debilitating symptoms, patients with mCRPC experience a substantial impact on their physical, mental, and social well-being, which leads to a negative impact on health-related quality of life (HRQoL) that deteriorates further in more advanced cases.[45-47] In a UK-based survey of chemotherapy naïve-patients with mCRPC (n=163), EuroQoL 5 Dimension (EQ-5D) utility scores were significantly lower in symptomatic patients (0.63; standard deviation [SD]: 0.17) than asymptomatic/mildly symptomatic patients (0.83; SD: 0.13).[47] A European observational study of patients with mCRPC (n=602), which included patients based in the UK (n=79), further demonstrated the impaired HRQoL for patients with mCRPC both prechemotherapy (EQ-5D utility: 0.70; SD: 0.02) and post-chemotherapy (EQ-5D utility: 0.60; SD: 0.03).[46] Mean EQ-5D utility scores for mCRPC patients ranged from 0.59 to 0.84 across six studies of patients in centres in Europe (including the UK) and Asia Pacific.[46-51] In the advanced stages of mCRPC, patients can also experience a profound psychological impact. According to a survey of patients with mCRPC, 72% highlighted the emotional impact of a metastatic diagnosis, reporting worry/anxiety/fear, low mood/depression, shock, increased burden on carers and strain on relationships.[52] As confirmed by UK clinical experts, very few patients with mCRPC receive three lines of treatment, as there is a lack of effective treatments beyond second-line, likely contributing to the emotional impact of progressive mCRPC.[5]

Bone metastases, which are commonly observed for patients with mCRPC, carry a further negative impact on HRQoL for patients.[53] Symptomatic skeletal events (SSEs), comprising of spinal cord compression, pathological fractures, radiation to bone, and surgery to bone, have been associated with poorer HRQoL. There is a lack of data concerning the utility detriment of bone metastases in PC patients in the UK. However, global studies document a significant burden of disease. A multinational study of HRQoL in PC patients (n=3,477) in five major European countries (UK, France, Germany, Spain, and Italy) found that patients with CRPC and bone metastases had significantly lower EQ-5D and FACT-P scores than CRPC patients without bone metastases but at high risk of developing bone metastases in the future. EQ-5D scores for these groups were 0.59 and 0.77, and FACT-P scores were 82.99 and 99.54, respectively. Furthermore, in a cross-sectional study of patients with mCRPC and bone metastasis (n=125) in Asia Pacific, although the incidence of skeletal-related events (SREs) was 3.0% (95% CI 2.26, 3.78), bone pain was reported by 39.2% of patients.[48] Patients experiencing bone pain faced significant burden on their lives including: hospitalisation (26.5% of patients; mean [SD] length of stay 16.0 [21.67] days), surgeries (14.3%), and emergency department attendance (18.4%). In

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contrast with mCRPC patients as a whole, patients with SREs had an EQ-5D utility score of 0.34 (SD: 0.32), which is indicative of higher humanistic burden.[48]

Mortality

PC is the second most common cause of cancer death amongst men in the UK, and accounted for 13% of all cancer deaths in 2018 (11,890 deaths; age-standardised mortality of 45.9 per 100,000 males).[20] PC mortality is strongly correlated with age and almost three-quarters of deaths occur in men aged ≥75 years, with age-specific mortality rates rising steeply in patients over 55 years old.[20]

While survival rates are initially high in patients with localised to locally advanced disease (Stages 1–3), prognosis worsens when patients progress to advanced/metastatic PC (Stage 4). Among patients diagnosed between 2013 and 2017 in England, the 1-year survival rate decreased from 100% for those diagnosed at Stages 1–3, to 88% at Stage 4.[54] Five-year survival rates also decreased substantially, from 100% for Stage 1–2 disease, to 96% for Stage 3 and 49% for Stage 4 disease.[54] However, these figures are not sub-divided by hormone-sensitivity status, nor by response to initial lines of therapy, and thus are not representative of the target population of this submission who have mCRPC uncontrolled by initial lines of therapy.

A summary of recent clinical trials in mCRPC patients with recurrent disease despite ADT and docetaxel treatment identified three trials (TROPIC, NCT00417079; COU-301, NCT00638690; AFFIRM, NCT00974311).[24] These trials reported a median OS of 15.1, 15.8 and 18.4 months for intervention arms and 12.7, 11.2, and 13.6 months for their control arms, respectively. Overall, this suggests that the OS for patients with mCRPC that progress despite docetaxel is approximately 12–13 months, although is likely shorter for patients who have also experienced further disease progression despite ARPI treatment. The median OS for patients in the SOC arm of VISION, the primary source of evidence for[177] Lu vipivotide tetraxetan in this submission, was only 11.3 months (Section B.2.5.2).[25]

The link between high PSMA expression and mCRPC means that survival outcomes are particularly poor in patients with a high level of PSMA expression.[55, 56] According to a retrospective study of patients with mCRPC who were treated with various life-prolonging therapies and underwent baseline PSMA imaging (n=238), patients with high PSMA expression had significantly shorter OS compared with those with low PSMA expression (15.8 months [95% CI 13.0, 18.1] versus 22.7 months [95% CI 17.7, 30.7 months]; p=0.002).[57] After accounting for life-prolonging therapies and prognostic groups, high PSMA expression was identified as an independent prognostic factor for a reduction in OS (HR 1.7 [95% CI 1.2, 2.2]; p=0.003).[57]

B.1.3.3 Current treatment pathway for patients with mCRPC

Guidelines for the treatment of patients with prostate cancer in the UK are available from the National Institute for Health and Care Excellence, NG131.[2] Other key guidelines for management of prostate cancer are available from the European Association of Urology and the European Society for Medical Oncology.[58, 59] These guidelines contain largely congruent treatment recommendations.

Diagnosis

If there is clinical or radiographic suspicion of advanced/metastatic PC (e.g. concerning symptoms such as bone pain or evidence of prostatic capsular breach on magnetic resonance Company evidence submission template for[177] Lu vipivotide tetraxetan for treating PSMApositive hormone-relapsed metastatic prostate cancer after 2 or more therapies [ID3840]

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imaging [MRI]), imaging procedures such as an isotope bone scan using single photon emission computed tomography (SPECT), further MRI, CT, or PET, may be recommended to diagnose, locate, and stage metastatic disease.[2, 34, 60, 61] In particular, PET scanning with choline-based radiotracers ([11] Carbon [C]-Choline, and[18] Fluorine [F]-Choline) provides greater detail than conventional methods (CT or bone scans) to offer a more accurate picture of PC metastases,[62, ] 63 although currently available PET methods offer limited sensitivity in patients with low prostatespecific antigen (PSA) levels and/or lymph node metastases.[34, 64, 65]

PSMA testing in the UK

PSMA scanning represents a highly sensitive and accurate method for the staging of metastatic PC and is currently being used in selected NHS centres for patients who require more accurate staging of disease than can be achieved with bone scanning and MRI. Determination of PSMApositivity should be radiotracer agnostic, meaning that healthcare professionals who wish to determine the PSMA-status of a patient with mCRPC may use any suitable gamma-emitting radiotracer linked to an appropriate PSMA ligand to do so. In general, once products with marketing authorisation are available from any manufacturer, these products should be used in preference to unlicenced products. This is in accordance with the SmPC for[177] Lu vipivotide tetraxetan, which does not specify the determination method for PSMA-status.[15]

There are multiple modalities for assessing PSMA-status, including PET–CT and SPECT scans. Currently[68] Ga PET–CT scanning is accessible in five cities in England. An MHRA marketing authorisation application for the AAA[68] Ga gozetotide compound was submitted in ** ****, with approval expected in **** ****. The diagnostic molecule[68] Ga gozetotide will offer an additional option for imaging at these centres. Another commercial[68] Ga radiotracer manufactured by University of California, Los Angeles, has been approved by the Food and Drug Administration (FDA), with potential future MHRA approval. This radiotracer is for imaging of PSMA-positive lesions in patients with suspected PC metastases who are potentially curable by surgery or radiation therapy and therefore is anticipated to become the SOC for diagnosis and staging in patients with advanced prostate cancer.[66] Furthermore, a technetium-99m[[99m] Tc]-labelled PSMA radiotracer is currently in development, with an open-label Phase I trial having commenced in April 2021 sponsored by Jonsson Comprehensive Cancer Centre, University of California, Los Angeles.[67] This radiotracer is for use with single photon emission computed tomography– computed tomography (SPECT–CT) scanning.[68, 69] It is important to note that these imaging techniques can be used at various points in the prostate cancer pathway, for instance if a patient experiences biochemical recurrence, for disease staging, or when more sensitive imaging is required compared to conventional imaging, and as such are not solely to support the treatment decision with a PSMA-targeted therapy such as[177] Lu vipivotide tetraxetan.

Expansion of existing services has been addressed through the NHS Levelling Up agenda and the future expansion of PET–CT facilities is eagerly anticipated by the clinical community. It is also anticipated the commercialisation of[18] F fluorinated PSMA radiotracers for use with PET–CT infrastructure will provide further options for the identification of PSMA-positive patients with mCRPC.

VISION, the pivotal trial providing clinical evidence for[177] Lu vipivotide tetraxetan, defined PSMApositivity as[68] Ga gozetotide uptake greater than that of liver parenchyma in one or more metastatic lesions of any size in any organ system.[25 ] Furthermore, in the context using[68] Ga gozetotide, PSMA-negativity may be defined as[68] Ga gozetotide uptake equal to or lower than that of liver parenchyma in any lymph node with a short axis of at least 2.5 cm, in any metastatic

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solid-organ lesions with a short axis of at least 1.0 cm, or in any metastatic bone lesion with a soft-tissue component of at least 1.0 cm in the short axis.[25]

PC treatment pathway

The treatment of PC is dependent upon disease location, stage, grade, PSA level and other patient-related considerations.[2, 70] Treatment for patients with localised or locally advanced prostate cancer (Stages I–III) may have a curative intent, whereas there are no curative pharmacological treatment options for patients with metastatic PC (Stage IV), and treatment instead focuses on extending survival, as well as relieving symptoms and preserving quality of life.[2]

Localised or locally advanced PC

Patients with newly diagnosed localised or locally advanced PC undergo risk stratification and discussion by a urological cancer multidisciplinary team (MDT).[2] Patients are categorised into either low-, intermediate-, or high-risk disease based upon their PSA level, Gleason score, and clinical disease stage.[2] Patients with high-risk or locally-advanced disease are offered radical treatment if it is likely their disease can be controlled in the long term.[2] Otherwise, docetaxel chemotherapy alongside long-term ADT is offered to patients who have no significant comorbidities.

ADT is a standard treatment that can be used to lower androgen levels (such as testosterone) to slow growth or even shrink PC tumours.[71, 72] ADT can be performed with drugs in the form of luteinising hormone-releasing hormone agonists/antagonists, anti-androgen therapies such as bicalutamide and flutamide, or alternatively by surgery to remove the testicles (orchidectomy).[71] Patients with localised or locally-advanced PC may be eligible for ADT in combination with radiotherapy when they have an intermediate to high risk of disease recurrence, or ADT alone when surgery or radiotherapy are not appropriate.[71] In cases of non-metastatic CRPC, one of two ARPIs (darolutamide or apalutamide) may be offered alongside ADT.[73, 74]

Metastatic hormone-sensitive PC

For patients with metastatic PC (stage IV), the cancer has spread to distant sites beyond the prostate and no curative treatment options remain and the aim of therapy should be to prolong life and to maintain patients’ HRQoL for as long as possible.[75]

Patients diagnosed with hormone-sensitive metastatic PC may undergo ADT to prolong survival, palliate symptoms and reduce the risk for potentially serious sequelae of advanced disease (such as spinal cord compression, pathological fractures and ureteral obstruction).[76] Patients with advanced/metastatic PC may receive ADT monotherapy, ADT and ARPI therapies together, or a combination of ADT plus chemotherapy (docetaxel).[72]

First-line therapy for metastatic PC is docetaxel chemotherapy (alongside ADT).[2] Docetaxel chemotherapy may be offered to patients who do not have significant comorbidities and should be commenced within 12 weeks of starting ADT. Docetaxel may be used for six 3-weekly cycles at a dose of 75 mg/m[2] , with or without daily prednisolone. Docetaxel is frequently used whilst a patient’s disease is hormone-sensitive, rather than following confirmation of CRPC. During 2019, the National Prostate Cancer Audit found that 36% of UK patients with newly diagnosed hormone-sensitive metastatic PC received docetaxel (alongside ADT) as upfront therapy.[18] However, during 2020 there was a marked fall by 74% in mHSPC patients receiving docetaxel

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with a concomitant rise in the use of enzalutamide, in line with NICE’s interim guidance on systemic anti-cancer therapies during the COVID-19 pandemic to reduce potential patient exposure to coronavirus.[77] Furthermore, work by Prostate Cancer UK highlighted that the proportion of patients with newly diagnosed metastatic PC who received first-line docetaxel significantly varied by age.[11] For men aged under 70, 63.6% received docetaxel first-line. This proportion fell significantly to 21.9% of those men aged over 70 and declined further still to 5.7% in men aged 80 and older. Given that docetaxel was only added to the NICE guidelines as a treatment option for newly diagnosed hormone-sensitive PC in 2019, it is possible that the proportion of patients in this setting receiving docetaxel will increase over time, especially with emerging evidence for triplet therapy (a combination of docetaxel, ADT and ARPI).[4]

A further option for treatment of metastatic hormone-sensitive PC is ARPI therapy in combination with ADT. Both enzalutamide and apalutamide have recently each been individually recommended by NICE as options for treatment alongside ADT in this setting.[74, 78] However, despite available therapies, after some months or years, patients usually develop hormonerelapse, at which point patients are classified as having mCRPC.[79]

Metastatic castration-resistant PC

Hormone-relapse (otherwise known as ’castration-resistance’) is broadly defined as the point of failure of primary ADT in the treatment of a patient’s PC,[2] or specifically defined as a patient with a testosterone level of <50 ng/dL (<1.7 nM/L) plus either biochemical progression (three consecutive rises in PSA at least one week apart resulting in two 50% increases over the nadir and a PSA >2 ng/ml) or radiological progression (the appearance of new lesions: either ≥2 bone lesions or a soft tissue lesion using Response Evaluation Criteria in Solid Tumours).[28] mCRPC is sometimes referred to as ‘hormone-relapsed’ disease, however throughout this submission mCRPC is used to align with the most commonly used terminology in medical literature and other Health Technology Assessment (HTA) appraisals.

If chemotherapy is not yet felt to be clinically indicated, then a patient may initially be treated with corticosteroids (e.g. dexamethasone 0.5 mg daily) or an ARPI (abiraterone or enzalutamide) in combination with prednisone or prednisolone in patients who have no or mild symptoms after primary failure of ADT. It is important to note that ARPIs may not be used in sequence under NICE guidelines and should only be used once within the entire PC treatment pathway due to limited evidence of the efficacy of re-challenge with ARPIs.[80] Thus, the expanding use of ARPIs in earlier stages of PC management (e.g. in hormone-sensitive disease) will preclude their use in mCRPC.[73, 74, 78, 81] This changing landscape has been particularly noted during the COVID-19 pandemic in 2020, with a marked rise in ARPI (enzalutamide) use (3 patients in 2019 vs. 1,011 patients in 2020), in line with NICE’s interim systemic anticancer therapy guidance.[77]

In patients where chemotherapy is clinically indicated, the NICE guidelines state that mCRPC patients’ first-line treatment option is docetaxel.[2] Docetaxel is recommended, within its licensed indications, as a treatment option for people with mCRPC only if their Karnofsky performancestatus score is 60% or more. Docetaxel treatment should be discontinued after a maximum of 10 cycles, if a severe adverse event occurs, or if the patient shows evidence of disease progression. Repeat treatment with docetaxel is not recommended if the patient experiences disease recurrence following completion of previously completed docetaxel treatment. Patients who receive docetaxel in earlier hormone-sensitive disease are highly unlikely to receive repeat treatment with docetaxel in the mCRPC setting. This has been confirmed by UK clinical experts within an advisory board setting.[5 ]

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For patients with mCRPC who progress despite docetaxel, those who are not medically suitable for docetaxel, or those who have previously been treated with docetaxel earlier in the treatment pathway, remaining options are limited:

• Cabazitaxel, another taxane chemotherapy, is recommended in patients who maintain an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and have previously received 225 mg/m[2] or more of docetaxel. Treatment with cabazitaxel should be continued for a maximum of 10 cycles or until disease progression.[10]

• An ARPI, either abiraterone or enzalutamide, may be used following failure of docetaxel or in patients in whom docetaxel was not suitable.[82, 83] However, if any ARPI has been used previously at any stage in the treatment pathway, further use of ARPIs is not commissioned.

• Radium-223 is recommended in patients with mCRPC who have already received docetaxel and who have symptomatic bone metastases. Its use is precluded in patients with visceral metastases.[84]

Importantly, some patients are medically unsuitable for taxane-based chemotherapy. It has been acknowledged in previous NICE appraisals that creating an exhaustive list of reasons for a patient being medically unsuitable for taxanes is particularly challenging,[81] reasons for medical unsuitability may include but are not limited to: hypersensitivity to active substance or excipients, neutropenia <1,500 cells/mm[3] , severe hepatic impairment, poor performance status (ECOG ≥3, ECOG ≥2 with substantial comorbidities, and lack of social support or impaired cognitive understanding sufficient to impact upon treatment compliance or toxicity monitoring.[84] These ineligibility criteria may apply to patients after they have received treatment with ARPI and prior to a first taxane, or after ARPI treatment and subsequent treatment with a taxane, at the point of treatment decision for a second taxane (e.g., cabazitaxel).

In UK clinical practice, it has been estimated that of the patients with mCRPC who receive firstline treatment with docetaxel, approximately 55% are eligible to receive second-line chemotherapy.[10] As discussed previously, UK clinical experts have advised that retreatment with docetaxel is highly unusual in UK clinical practice, occurring in as low as 2% of patients,[5] and thus the vast majority of patients who do receive further chemotherapy currently receive cabazitaxel and not retreatment with docetaxel.

Additional palliative interventions can be used at any point during the treatment pathway and are considered SOC. These may include supportive measures (pain medication, hydration, blood product transfusion, etc), ADT, corticosteroids, 5-alpha reductases (finasteride or dutasteride), targeted radiotherapy for SREs (e.g. malignant spinal cord compression or painful bone metastases), bone-targeted therapies aimed at providing symptomatic relief (zoledronic acid, bisphosphonates), or surgical intervention (e.g. ureteric stenting for obstructive nephropathy), as well as emotional and psychological support.

An overview of the clinical pathway for mCRPC in UK clinical practice including the proposed positioning of[177] Lu vipivotide tetraxetan is provided in Figure 2.

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Figure 2: Treatment pathways for patients with mCRPC and the proposed positioning of[177] Lu vipivotide tetraxetan

==> picture [552 x 255] intentionally omitted <==

ARPIs may only be used a single time during a patient’s PC treatment pathway. In addition to the places in therapy shown here, ARPIs may also be used earlier in the PC treatment pathway in cases of non-metastatic CRPC.

aFor patients who do not have significant comorbidities. Commenced within 12 weeks of starting ADT. Six 3-weekly cycles at a dose of 75 mg/m2 (with or without daily prednisolone).[b] Either enzalutamide or apalutamide are recommended for use in this hormone-sensitive, metastatic setting alongside ADT.[c] Either enzalutamide or abiraterone are recommended for use in this castration-resistant, metastatic setting. ARPIs may only be used once during a patient’s PC treatment pathway.[d] Recommended as an option for patients with a Karnofsky performance-status score of 60% or more. Treatment should be stopped at a maximum of 10 cycles, if a severe adverse event occurs, or if disease progression occurs. Repeat cycles are not advised in the case of disease recurrence following prior docetaxel.[e] Recommended as an option for patients with an ECOG performance score of 0 or 1 who have received 225 mg/m[2] or more of docetaxel. Retreatment with docetaxel is permitted according to NICE guidelines but is not typical, occurring in as low as 2% of patients,[6] and thus is not represented in this pathway.[f] Positioned as a treatment for patients with PSMA-positive mCRPC who have progressed on previous ARPI and taxane-based chemotherapy or who are not medically suitable for taxanes.[g] Bone targeted agents include zolendronic acid (recommended as an options for patients with bone metastases to reduce the risk of skeletal-related events), bisphosphonates (recommended as an option for pain relief in patient with bone metastases when other analgesics and palliative radiotherapy have not been sufficient), and radium-223 (recommended as an option for patients with symptomatic bone metastases who do not have visceral metastases and who have already received docetaxel or in who docetaxel is contraindicated or not suitable).

Abbreviations :[177] Lu: lutetium-177; ADT: androgen deprivation therapy; ARPI: androgen receptor pathway inhibitor; ECOG: Eastern Cooperative Oncology Group; KP: Karnofsky performance-status; mCRPC: metastatic castration-resistant prostate cancer; PSMA: prostate-specific membrane antigen; SOC: standard of care. Source : NICE Prostate Cancer, Diagnosis and Management[2] Company evidence submission template for[177] Lu vipivotide tetraxetan for treating PSMA-positive hormone-relapsed metastatic prostate cancer after 2 or more therapies [ID3840]

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B.1.3.4 Unmet need in mCRPC

Limited therapeutic options available

Treating patients with mCRPC presents a clinical challenge, with a considerable unmet need in terms of treatment options beyond palliative care for patients with symptomatic mCRPC that has progressed despite multiple prior therapies.[29, 30] Cabazitaxel represents an additional treatment option for patients who are able to tolerate further chemotherapy. However, a proportion of patients who have progressed despite multiple prior therapies would not be suitable for further chemotherapy due to these patients being elderly and/or frail with significant disease, prior treatment-related comorbidities and a higher tumour burden.[85] Furthermore, with the expanding indications for docetaxel and ARPIs, multiple lines of treatment may be exhausted in the metastatic hormone-sensitive setting, prior to developing mCRPC, even if patients maintain a good performance score.[2] Thus, for many patients with mCRPC who have progressed on ARPIs and taxane treatment, palliative care is often the only available treatment option.[30] This results in patients with mCRPC facing very poor prognoses while suffering from a significant quality of life deterioration caused by rapid disease progression, highlighting a significant unmet need for new treatments that prolong life and preserve HRQoL.

Furthermore, only one in three men with newly diagnosed metastatic prostate cancer were prescribed docetaxel therapy in the UK, despite NICE recommendations that this be offered to all men at this stage, with this proportion falling by 74% during 2020 due to the COVID-19 pandemic.[18, 77] Furthermore, the majority of these patients are likely to have hormone-sensitive PC and will not yet have developed mCRPC. Although it is unclear why docetaxel uptake is this low, clinical leads for this audit suggested patient choice may play a part.[86] In addition, there was widespread variability across NHS providers in England for those who received docetaxel, ranging from 0% to 39%.[18] The National Cancer Registration and Analysis Service (NCRAS) have addressed the disparities in prescription of chemotherapy across the UK, and the reasons for this are complex, but there are some factors which were been established such as age and comorbidity.[87] Therefore, with a shift of recommended non-taxane based therapies to earlier in the prostate cancer pathway, and the detrimental effect of multiple lines of treatment, by the time patients progress to mCRPC, if taxanes are not suitable patients are left with little or potentially no further options (i.e., if ARPIs have already been utilised).

Patients with visceral metastases

Currently available treatments are limited in their ability to treat visceral metastases, which are found in 22–33% of patients with mCRPC.[88-90 ] Patients with visceral metastases are wellestablished to have a worse prognosis than those with non-visceral metastases.[91] According to a prognostic model based on Phase 3 data (N=1,050), patients with mCRPC that received first-line chemotherapy are at increased risk of death when they have visceral disease compared to those with lymph node metastases (hazard ratio [HR] 1.27; 95% confidence interval [CI] 0.96–1.51).[92] In a separate Phase 3 study, men treated with chemotherapy (docetaxel or mitoxantrone [a chemotherapy that is no longer a treatment option in the UK][2] ) who had visceral liver metastases had a significantly shorter OS (10.0 months; 95% CI 5.4–11.5) than those with bone metastases only (19.0 months; 95% CI 14.4–17.2) and those with lymph node metastases only (26.7 months; 95% CI 22.3–34.2).[93] Moreover, a dual-centre retrospective observational study showed that patients treated with cabazitaxel for mCRPC had a significantly shorter OS when they had visceral disease (8.7 months; 95% CI 5.9–11.5) compared to those who had bone or lymph node metastases only (11.7 months; 95% CI 7.5–15.9; p=0.042).[94]

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Visceral metastases are a similarly important prognostic factor for patients treated with an ARPI. In a small study of patients treated with abiraterone (N=265), a significantly shorter median OS was associated with liver metastases than other sites of metastasis (10.5 months vs 18.5 months, respectively; p=0.006).[95] Similar findings have been found in a Phase 3 study of enzalutamide, whereby patients with mCRPC visceral metastases had a substantially shorter median OS (13.4 months; 95% CI 10.4–16.5) than those with non-visceral metastases (median OS not reached; 95% CI 18.3–not reached).[91] Furthermore, radium-223 is only recommended for mCRPC patients with bone metastases and no known visceral metastases, further reducing available treatment options.[84] mCRPC patients with visceral metastases represent a substantial subgroup of unmet need in the current treatment landscape.

Safety and tolerability of current treatment options

Both safety and tolerability of treatments become increasingly important in patients with PC who have progressed despite prior treatments. The majority of patients with mCRPC, especially those who are medically unsuitable for taxane-based chemotherapy, are elderly and frail, rendering them less able to tolerate treatment-related toxicities.[85] Advanced age and a higher comorbidity burden are associated with increased risk of death in patients with PC.[96] In this advanced disease stage, patients need options that improve OS, PFS, and HRQoL without serious AEs.

Taxanes are cytotoxic agents and are associated with higher rates of toxicity and higher-grade AEs than other treatments.[30] Across Phase 3 randomised controlled trials (RCTs), the incidence of all-grade AEs is over 90% in mCRPC patients treated with taxanes, while the incidence of Grade 3–4 AEs ranges from 66% to 75% (summarised in Table 3).[89, 97-100] In particular, high rates of Grade 3–4 haematological AEs have been reported for taxane-based chemotherapies, including leukopenia (docetaxel: 17.1%;[97 ] cabazitaxel: 68.2%[90] ) and neutropenia (docetaxel: 57.7%;[97] cabazitaxel: 81.7%[90] ), predisposing vulnerable patients to severe and life-threatening infections.

Table 3: Incidence of AEs (any Grade and Grade 3–4) according to Phase 3 RCTs

Abbreviations : AE: adverse event; IV: intravenous; RCT: randomised controlled trial.

Though ARPI is generally better-tolerated than taxanes, it is not without risk: enzalutamide has been associated with both falls and fractures,[101] and abiraterone acetate has a warning for hepatotoxicity.[102] In a clinical study of enzalutamide, higher incidence of fatigue, diarrhoea, hot flashes, musculoskeletal pain, and headache were reported in the enzalutamide group compared with placebo.[89] In a clinical study evaluating abiraterone acetate plus prednisolone, AEs including oedema, hypokalaemia, and cardiac disorders were more common in the group that received abiraterone acetate plus prednisone compared to the prednisone-only arm.[103]

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A recent trial of radium-223 plus abiraterone acetate and prednisolone versus placebo plus abiraterone acetate and prednisolone was unblinded due to increased fractures and deaths in the intervention arm, and thus due to safety concerns these two therapies are contraindicated for concurrent usage.[8, 104]

Overall, the significant toxicity associated with successive lines of therapy for patients with mCRPC limits their routine use, both through progressive comorbidities (secondary to advancing age and prior treatment) and through patient choice when considering the benefits of treatment against potential adverse events. As such, there is a significant unmet need for patients who have progressed through or are medically unsuitable for currently available therapies and who would be otherwise only eligible for SOC. Accordingly, compared with mCRPC patients more broadly, prognosis is particularly poor for patients who have progressed through or are medically unsuitable for currently available therapies; patients receiving standard of care (SOC) in the VISION trial (which provides the key clinical evidence for[177] Lu vipivotide tetraxetan in this indication) included patients previously treated with ARPI and one or more taxane-based chemotherapies. The patients in VISION receiving SOC alone had a median OS of only 11.3 months (see Section B.2.5), emphasising the significant unmet need for patients with mCRPC who have progressed despite currently available life-prolonging therapies.

Need for novel targeted therapies

Additional treatment options with novel targeted mechanisms of action able to improve survival and preserve HRQoL in patients with mCRPC are urgently needed, given the currently poor prognosis experienced by mCRPC patients who have progressed through available treatment options. Despite NICE appraising several technologies in the mCRPC and advanced prostate cancer setting during the previous few years, these compounds all fall within the ARPI drug class (which can only be commissioned once in the pathway), or the taxane drug class (cabazitaxel – for use after docetaxel). In part, limitations in efficacy and safety for currently available therapies may be due to their non-targeted mode of action. In recent years, major steps have been taken to develop radioligand therapies (RLT) which offer the possibility to treat the cancer lesions in a specific and tumour-selective manner by exploiting cell surface receptors mainly expressed on malignant cells.[34, 105] In particular, PSMA is a potential target for RLT due to high expression on the surface of PC cells and limited expression on normal tissues,[55, 106-109] allowing PSMAtargeted radiotherapeutics to bind with high-affinity to PSMA[107] and deliver radiation locally to tumour cells while minimising radioactivity-related side effects.[110] Whilst radium-223 targets bone metastases through mimicking calcium, there are no currently available PC treatments that specifically target primary tumour cells This approach offers a key advantage in patient selection over conventional therapies. As such,[177] Lu vipivotide tetraxetan represents a much-needed treatment option with a novel mechanism of action for patients with mCRPC. This is reflected by the Promising Innovative Medicines (PIM) designation granted by the MHRA for[177] Lu vipivotide tetraxetan.[31]

Using PSMA scanning (PET/CT or SPECT), PSMA-positive patients can be identified, allowing clinicians to identify those patients which may benefit from the PSMA-targeted RLT.[34] Patients who are not PSMA-positive and may not benefit from PSMA-targeted RLT can also avoid unnecessary exposure to a treatment without significant benefit, an approach not currently available for more conventional treatment strategies such as taxane-based chemotherapy. In particular, the European Association of Urology highlights[177] Lu vipivotide tetraxetan as the PSMA therapeutic radiopharmaceutical with the most robust supporting data and compassionate usage is already widespread.[34, 111][177] Lu vipivotide tetraxetan therefore represents an important

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development in the treatment of patients with mCRPC, providing a more selective and targeted approach with a superior risk-to-benefit ratio, compared to currently available treatments.[177] Lu vipivotide tetraxetan has the potential to improve survival outcomes alongside a more tolerable side-effect profile for patients with mCRPC, a disease which currently carries a very poor prognosis.

B.1.4 Equality considerations

There are a currently a limited number of clinical centres in the UK which would be able to conduct the required assessment for PSMA positivity and then subsequently deliver treatment with[177] Lu vipivotide tetraxetan. The limited number of centres may have an impact on equal access for patients across the country, based on ability to travel. At present, due to the substantial disease burden of mCRPC, patients are currently actively seeking treatment with 177Lu vipivotide tetraxetan through private healthcare in the UK, thus emphasising the current unmet need in this patient cohort and potentially exacerbating socioeconomic health inequalities.[112]

In addition, there is a need for additional therapeutic options for prostate cancer progression in patients who are not medically suitable to receive taxanes. It has been reported that approximately 50% of mCRPC patients do not receive treatment with a taxane, mostly due to specific safety concerns, frailty, and/or patient refusal (due to the side effect profile of taxanes).[10] Thus, limiting the eligibility of[177] Lu vipivotide tetraxetan to only those patients who have received taxanes would create significant inequality in the management of patients with mCRPC. Both safety concerns and side effects are data-driven and largely non-overlapping with[177] Lu vipivotide tetraxetan (i.e., patients not medically suitable for taxanes can benefit from[177] Lu vipivotide tetraxetan). The phase III VISION study was designed to specifically select patients who had previously received taxanes to demonstrate that[177] Lu vipivotide tetraxetan provides clinical benefit in patients that have tried all available treatments known to influence OS.[25] However, mechanistically, there is no reason that the efficacy and safety of[177] Lu vipivotide tetraxetan would be significantly different in patients who have not previously received taxanes compared to patients who have previously received taxanes. Thus, patients who are not medically suitable to receive taxanes for PSMA-positive mCRPC are still likely to derive clinical benefit from[177] Lu vipivotide tetraxetan. Therefore, the clinical effectiveness and safety demonstrated in the phase III VISION study could be clinically and mechanistically extrapolated to encompass the unmet medical need in patients who would not be medically suitable to receive taxanes.

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B.2 Clinical effectiveness

• The efficacy and safety of[177] Lu vipivotide tetraxetan has been demonstrated in VISION, an international, prospective, open-label, randomised Phase III trial investigating the[177] Lu vipivotide tetraxetan + SOC vs SOC only in patients with mCRPC previously treated with ARPI and taxane-based chemotherapy.

• As VISION did not include a direct comparison of[177] Lu vipivotide tetraxetan to cabazitaxel, the clinical effectiveness of[177] Lu vipivotide tetraxetan has been compared against cabazitaxel using real-world database analyses, with further supporting information from an indirect treatment comparison (ITC), and data from the head-to-head TheraP Phase 2 study. This robust and comprehensive set of data support the benefit of[177] Lu vipivotide tetraxetan compared to cabazitaxel, and was gathered to reduce uncertainty and inform decision-making

Efficacy

• VISION trial compared[177] Lu vipivotide tetraxetan + SOC, (n=551) to SOC only (n=280). The data-cut for the final analyses of VISION was 27[th] January 2021.

• In VISION patients receiving treatment with[177] Lu vipivotide tetraxetan + SOC demonstrated a significant extension in both of primary endpoints (OS and rPFS) compared to patients receiving SOC (p<0.001).

  • [177] Lu vipivotide tetraxetan + SOC reduced the risk of death by 38% vs SOC alone (p<0.001).

    • Median OS was significantly improved with[177] Lu vipivotide tetraxetan + SOC compared with SOC alone (15.3 vs 11.3 months).

  • [177] Lu vipivotide tetraxetan + SOC reduced the risk of radiographic disease progression or death (rPFS) by 60% versus SOC alone (p<0.001).

    • Median rPFS was significantly improved with[177] Lu vipivotide tetraxetan + SOC versus SOC alone (8.7 vs 3.4 months).

• In VISION patients receiving treatment with[177] Lu vipivotide tetraxetan + SOC demonstrated significant improvement across all key secondary outcomes compared with SOC.

  • [177] Lu vipivotide tetraxetan + SOC significantly reduced the risk of SSEs or death by 50% relative to SOC alone (p<0.001).

  • [177] Lu vipivotide tetraxetan + SOC significantly prolonged the median time to first SSE versus SOC alone (11.5 vs 6.8 months).

  • [177] Lu vipivotide tetraxetan + SOC improved patients’ QoL vs. SOC alone by delaying the time to FACT-P, BPI-SF (pain intensity) and EQ-5D-5L score deterioration by 3.5, 3.7 and 0.5 months, respectively (all p<0.001).

• VISION demonstrated significant improvements for[177] Lu vipivotide tetraxetan + SOC across multiple secondary endpoints including an increased rate of ORR (p<0.001) and DCR (p<0.001)

• Subgroup analysis, although limited by low patient numbers in certain subgroups, demonstrated that the benefit of[177] Lu vipivotide tetraxetan extended across multiple key subgroups such as patients aged ≥65 and those with liver metastases, which represent some of the frailer cohorts of patients with mCRPC.

• Similar efficacy was demonstrated for patients receiving[177] Lu vipivotide tetraxetan + SOC regardless of whether ARPI was included as part of SOC. This emphasises the applicability of the VISION results to UK clinical practice in which multiple courses of ARPI treatment are not permitted.

  • The VISION study was a global trial, with SOC varying between countries according to physician discretion and local guidelines. The consistency of treatment effect across subgroups such as those receiving or not receiving ARPI as a component of SOC provides confidence in the generalisability of VISION to UK clinical practice, and this generalisability has been confirmed by UK clinicians in an advisory board setting.[5]

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Real-world evidence

• In order to further understand the mCRPC patient population within the UK healthcare system, a retrospective real-world evidence (RWE) study of patients with mCRPC was carried out using linked healthcare datasets from Public Health England (PHE) and NHS Digital, including records from 1[st] January 2009 to 31[st] December 2018.

  • This data was collected in an effort to provide the most relevant data possible for cabazitaxel in UK clinical practice, and to address the paucity of UK RWE available in the mCRPC setting

• Baseline characteristics for mCRPC patients in VISION closely align with those in UK clinical practice in terms of age, ethnicity, and ECOG status, highlighting the generalisability of VISION trial results to UK clinical practice.

• • Patients receiving cabazitaxel in UK clinical practice are expected to most closely resemble the VISION trial population in that in the UK, cabazitaxel can only be prescribed post-docetaxel, and is highly likely to be given in the post-ARPI setting.[10] The median OS for patients receiving cabazitaxel in the UK RWE analysis was **** months.

Indirect treatment comparison

• The only head-to-head evidence comparing[177] Lu vipivotide tetraxetan to cabazitaxel is the TheraP trial. TheraP demonstrated a benefit for[177] Lu vipivotide tetraxetan versus cabazitaxel in terms of rPFS (1.59 [95% CI: 1.16–2.17]).

• • However, TheraP was not powered to robustly investigate overall survival and has not yet published any results for this endpoint. The trial utilised an on-site, non-official synthesised version of[177] Lu vipivotide tetraxetan (not provided by the company) and differed in inclusion criteria due to the requirement for a fluorodeoxyglucose (FDG) PET-CT scan in addition to gallium PET-CT imaging. For these reasons, TheraP does not provide an appropriate head-tohead comparison to inform efficacy in the economic model.

• • Given the lack of suitable head-to-head efficacy data to compare[177] Lu vipivotide tetraxetan and cabazitaxel, an indirect treatment comparison was explored to generate relative efficacy estimates for these two treatment options.

• • The NMA demonstrated a significant benefit in terms of OS (** **** **** **** ***** *****) and rPFS (** **** **** **** ***** *****) for[177] Lu vipivotide tetraxetan compared to cabazitaxel. The rPFS result from the NMA was validated by close alignment to the rPFS HR reported in TheraP.

Adverse reactions

• [177] Lu vipivotide tetraxetan demonstrated a very manageable safety profile compared to protocolpermitted SOC alone with the most common grade 3+ TEAEs experienced by >5% of patients treated with[177] Lu vipivotide tetraxetan relating to bone marrow suppression - lymphopenia (7.8% vs 0.5%), anemia (12.9% vs 4.9%), and thrombocytopenia (7.9% vs 1.0%) - and fatigue (7.0% vs 2.4); these adverse events did not severely impact patient QoL and less than 12% of patients randomised to[177] Lu vipivotide tetraxetan discontinued treatment due to TEAEs.

• • Although rates of AEs were higher across multiple categories in the[177] Lu vipivotide tetraxetan + SOC arm compared with the SOC arm, these AEs were likely at least in part contributed to be a longer mean exposure to treatment in the intervention arm (*** vs. *** ******), due to extended OS.

• The rate of AEs leading to death were similar between intervention and control arms (3.6% vs. 2.9%).

• • The most common category of AEs leading to dose reduction or interruption of[177] Lu vipivotide tetraxetan was myelosuppression, representing a category of AEs that can be addressed prophylactic measures. Despite the lack of required G-CSF prophylaxis in VISION, rates of grade ≥3 leukopenia and neutropenia were 2.3% and 3.2% respectively. In contrast, CARD, the pivotal trial that investigated the efficacy of cabazitaxel in mCRPC patients having progressed despite docetaxel and ARPI, required all patients receiving cabazitaxel to receive primary prophylaxis G-CSF. Despite this, CARD still high reported rates of grade ≥3 leukopenia and

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neutropenia with cabazitaxel treatment, 32.0% and 44.7% respectively.[113]

End of life criteria

• Given the short life-expectancy for patients with mCRPC previously treated with ARPI and taxane-based chemotherapy, and the extension to life compared to current treatment (cabazitaxel or SOC) that is offered by[177] Lu vipivotide tetraxetan treatment,[177] Lu vipivotide tetraxetan should be considered to meet the end of life criteria for this patient population.

B.2.1 Identification and selection of relevant studies

A systematic literature review (SLR) was conducted December 2019, with subsequent updates conducted in April 2021 and November 2021, to identify relevant clinical evidence on the efficacy and safety data of treatment for patients with mCRPC, and to specifically identify evidence related to efficacy and safety of[177] Lu vipivotide tetraxetan in the patient population relevant to this submission. The searches identified 9,099 records that were considered relevant for the review, of these, 26 publications reporting on 18 unique clinical trials were included in the SLR. Full details of the SLR search strategy, methodology and results can be found in Appendix D. Of the included studies, one study, VISION, presented relevant data to inform the direct evidence for[177] Lu vipivotide tetraxetan + SOC versus SOC in the patient population considered in this submission.

B.2.2 List of relevant clinical effectiveness evidence

The clinical evidence to support the efficacy and safety of[177] Lu vipivotide tetraxetan in this submission derives from VISION, the pivotal trial comparing[177] Lu vipivotide tetraxetan + SOC against SOC only. VISION is a Phase III, international, prospective, open-label, randomised controlled trial. VISION was designed from a global perspective and as such, the study may not capture all country-specific comparators or components of SOC. However, subgroup analyses were performed to ensure generalisability of results (Section B.2.6). Data from VISION has been published in the New England Journal of Medicine by Sartor et al. (2021).[25] The patient populations in VISION is aligned with the population of relevance for this submission. A summary of VISION is presented below in Table 4.

A summary of the clinical evidence for the efficacy and safety of currently available treatments in UK clinical practice, namely cabazitaxel, the relevant active comparator for[177] Lu vipivotide tetraxetan, is presented in Section B.2.8. This includes a real-world evidence (RWE) analysis, which was undertaken to understand the mCRPC patient population within the UK healthcare system.

A further source of supportive clinical effectiveness evidence for[177] Lu vipivotide tetraxetan is Thera-P, a multicentre, unblinded, randomised (1:1), phase II trial that compared[177] Lu vipivotide tetraxetan monotherapy (n=99) to cabazitaxel (n=101) in patients with mCRPC who had progressed despite prior treatments with docetaxel and ARPI.[114] The TheraP trial was not captured by SLR criteria as it is Phase II, hence falling outside the inclusion requirement of Phase III. Despite not offering sufficiently robust head-to-head evidence between[177] Lu vipivotide tetraxetan and cabazitaxel to inform the economic analysis in this submission, TheraP is described in further detail in Section B.2.8.

A summary of the clinical evidence for the efficacy and safety of currently available treatments in UK clinical practice, namely cabazitaxel, the relevant active comparator for[177] Lu vipivotide

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tetraxetan, is presented in Section B.2.8. This includes a real-world evidence (RWE) analysis, which was undertaken to understand the mCRPC patient population within the UK healthcare system.

Table 4: Clinical effectiveness evidence

Outcomes in bold indicate those used in the economic model. Abbreviations:[177] Lu: lutetium-177; ARPI: androgen receptor pathway inhibitor; DCR: disease control rate; DOR: duration of response; mCRPC: metastatic castration-resistant controlled trial; ORR: overall response rate; OS: overall survival; PFS: progression-free survival; PSMA: prostate-specific membrane antigen; RCT: randomised controlled trial; rPFS: radiographic progression-free survival; SOC: standard of care; SSE: symptomatic skeletal event. Source : Sartor et al. (2021).[25]

B.2.3 Summary of methodology of the relevant clinical

effectiveness evidence

B.2.3.1 Trial design

An overview of the study design of VISION is presented in Figure 3.

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Figure 3: Overview of the study design for VISION

==> picture [452 x 92] intentionally omitted <==

aPatients who had received only 1 prior taxane treatment were eligible only if they were unwilling to receive a further taxane treatment or their physician deemed the patient medically unsuitable to receive a second regimen. VISION OS data were mature by the time of the first rPFS data analysis. Abbreviations :[ 177] Lu: lutetium-177; ARPI: androgen receptor pathway inhibitor; mCRPC: metastatic castrationresistant controlled trial; PSMA: prostate-specific membrane antigen; SOC: standard of care. Source : Sartor et al. (2021).[25]

Patients were initially selected based on the eligibility criteria described below (Section B.2.3.2).[25] Eligible patients were assigned in a 2:1 ratio to receive either the interventional arm ([177] Lu vipivotide tetraxetan + SOC) or the control arm (SOC only). Randomisation was stratified by baseline lactate dehydrogenase (LDH) [≤260 U/mL or >260 U/mL], presence of liver metastases (yes or no), ECOG performance status (0–1 or 2), and inclusion of an ARPI in protocol-permitted standard care at the time of randomisation (yes or no).[25] Patients continued treatment in either arm of the trial until either disease progression based upon radiological assessment as measured by PCWG3 criteria, the investigator feels there was a lack of clinical benefit or unacceptable toxicity, a prohibited treatment is clinically required, patient is non-adherent to the trial regimen, consent to continue with treatment is withdrawn, or at the sponsor’s or investigator’s discretion.[25] A summary of the full trial design is presented in Table 5.

Table 5: Summary of the trial design for VISION

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Abbreviations:[177] Lu: lutetium-177;[68] Ga: gallium-68; ARPI: androgen receptor pathway inhibitor; BPI-SF: Brief Pain Inventory – Short Form; CT: computerised tomography; ECOG: Eastern Cooperative Oncology Group; EQ5D-5L: EuroQoL-5 Dimension-5 Level; FACT-P: Functional Assessment of Cancer Therapy – Prostate; ITT: intention to treat; LDH: lactate dehydrogenase; OS: overall survival; PET–CT: positron emission tomography – computerised tomography; PFS: progression-free survival; PFS-FAS: progression-free survival full analysis set; PSA: prostate-specific antigen; PSMA: prostate-specific membrane antigen; rPFS: radiographic progression-free survival; SOC: standard of care. Source : Sartor et al. (2021).[25]

B.2.3.2 Trial methodology

A summary of the methodology of VISION is presented in Table 6.

Table 6: Summary of the VISION trial methodology

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Company evidence submission template for[177] Lu vipivotide tetraxetan for treating PSMApositive hormone-relapsed metastatic prostate cancer after 2 or more therapies [ID3840]

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aThe inclusion and exclusion criteria presented here represent a summary of the full eligibility criteria, which is presented in Appendix M.

bIf a patient had only received one taxane regimen, the patient was only eligible if they were not willing to receive a second taxane regimen or the patient’s physician deemed him unsuitable to receive a second taxane regimen. Abbreviations:[177] Lu: lutetium-177;[68] Ga: gallium-68; ARPI: androgen receptor pathway inhibitor; BPI-SF: Brief Pain Inventory – Short Form; CT: computerised tomography; DCR: disease control rate; DOR: duration of response; ECOG: Eastern Cooperative Oncology Group; EQ-5D-5L: EuroQoL-5 Dimension-5 Level; FACT-P: Functional Assessment of Cancer Therapy – Prostate; GBq: gigabecquerel; G-CSF: granulocyte colony stimulating-factor; GM-CSF: granulocyte macrophage colony-stimulating factor; HRQoL: health-related quality of life; ITT: intention to treat; LDH: lactate dehydrogenase; mCi: millicurie; MRI: magnetic resonance imaging; ORR: overall response rate; OS: overall survival; PET–CT: positron emission tomography – computerised tomography; PFS: progression-free survival; PFS-FAS: progression-free survival full analysis set; PSA: prostate-specific antigen; PSMA: prostate-specific membrane antigen; rPFS: radiographic progression-free survival; SOC: standard of care; SSE: symptomatic skeletal event . Source : Sartor et al. (2021).[25]

Definitions for efficacy outcome measures used in VISION are presented in Table 7.

Table 7: Definitions for outcome measures used in VISION

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The following rules were taken into account to define the BOR: CR = at least 2 determinations of CR at least 4 weeks apart; PR = at least 2 determinations of PR or better (i.e. CR) at least 4 weeks apart (and not qualifying for CR); Stable disease = at least 1 Stable disease assessment or better (i.e. CR or PR) > 6 weeks after first dose of randomised treatment (and not qualifying for CR or PR); PD = PD at first evaluable scan after first dose of randomised treatment (and not qualifying for CR, PR or Stable disease).

Abbreviations : AE: adverse event; BOR: best overall response; BPI-SF: Brief Pain Inventory – Short Form; CR: complete response; CT: computerised tomography; EQ-5D-5L: EuroQol 5-dimensions 5-level; FACT-P: Functional Assessment of Cancer Therapy – Prostate; HRQoL: health-related quality of life; MRI: magnetic resonance imaging; ORR: overall response rate; OS: overall survival; PCWG3: Prostate Cancer Working Group 3; PD: progressed disease; PR: partial response; PRO: patient reported outcome; PSA: prostate specific antigen; RECIST: Response Evaluation Criteria in Solid Tumours; rPFS: radiographic progression-free survival; SAE: serious adverse event; SSE: symptomatic skeletal event. Source : Sartor et al. (2021),[25] Scher et al (2016).[115]

B.2.3.3 Statistical analysis and definition of study groups in the relevant clinical effectiveness evidence

Trial Populations

The trial was originally designed to randomise 750 patients. However, shortly after commencement of the trial, a high, early dropout rate amongst those randomised to SOC became evident (47 of 84; 56%) with the majority of these dropouts withdrawing consent to follow-up.[25] The root cause of this was identified as disappointment among those not randomly Company evidence submission template for[177] Lu vipivotide tetraxetan for treating PSMApositive hormone-relapsed metastatic prostate cancer after 2 or more therapies [ID3840]

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assigned to receive[177] Lu vipivotide tetraxetan. This dropout meant that rPFS data could not be collected for these patients, unlike for OS data that could become available through mCRPC registries, which consequently could result in bias in the analysis of rPFS. To address this, remedial measures were put in place on 5[th] March 2019 following discussions with the FDA, including:

• Regular contact with sites to discuss management of patients in the control arm

• Production of a patient information tool to guide pre-screening discussions of expectations

• Limiting reimbursement for patients to discourage long-distance travel

To address potential bias created by the initial high dropout rate disproportionately affecting the SOC arm, the primary analysis of rPFS was altered to focus on patients prospectively randomised on or after 5[th] March 2019. This patient cohort comprises the progression-free survival full analysis set (PFS-FAS).

Furthermore, at time of the rPFS primary analysis, a planned interim analysis of OS was performed on an ITT basis and included all randomised patients (i.e., including those randomised before 5[th] March 2019). This planned interim analysis became the final OS analysis, as sufficient events had accrued by this time point for the data to be mature. To achieve these analyses, the total number of patients randomised into the trial was increased from N=750 to N=814.

Table 8: Analysis sets used in the analysis of outcomes in VISION

Abbreviations : DCR: disease control rate; FAS: full analysis set; ITT: intention to treat; ORR: overall response rate; OS: overall survival; PFS: progression-free survival; rPFS: radiographic progression-free survival. Source : Advanced Accelerator Applications Data on File (VISION Clinical Study Report).[116]

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Summary of clinical data cut-off dates

The analyses presented in this assessment submission are based on cumulative data generated in VISION up to the data cut-off date of 27[th] January 2021, at which time 530 OS events were reached in the main study, triggering the primary OS analysis and the primary analysis of rPFS.[25]

Primary efficacy analysis

The primary objectives of VISION were to evaluate if[177] Lu vipivotide tetraxetan + SOC improved rPFS and/or OS versus SOC in patients with mCRPC who had progressed after receipt of previous treatment with one or more ARPIs and with either one or two taxane chemotherapy regimens.[25] Full details of the statistical analyses used for the primary endpoints in VISION are presented in Table 9.

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Table 9: Statistical methods for the primary analysis of VISION

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Abbreviations : FAS: full analysis set; CI: confidence interval; HR: hazard ratio; ITT: intention to treat; OS: overall survival; PFS-FAS: progression free survival full analysis set; rPFS: radiographic progression free survival; Source : Sartor et al. (2021).[25]

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B.2.3.4 Baseline characteristics

The baseline characteristics of the VISION study population are presented in Table 10. Patient demographic characteristics were well balanced between analysis sets and between treatment arms. Patients exhibited high levels of bone (>90%) and lymph node (~50%) metastases, with lower levels of visceral metastases: lung (~10%) and liver (~12%). Over half of all patients had received only a single line of ARPI therapy, reflecting current UK practice guidelines. Notably, the vast majority of patients had received docetaxel (~97%), which aligns with current UK guidelines where docetaxel is recommended in hormone-sensitive PC as well as mCRPC and thus patients can receive docetaxel prior to developing hormone-relapse. The baseline characteristics for patients in VISION are closely aligned to those of mCRPC patients in UK clinical practice (Section B.2.8), which provides assurance that VISION results are generalisable to UK clinical practice.

Table 10: Baseline characteristics for PFS-FAS and FAS in VISION

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Abbreviations :[177] Lu: Lutetium-177; ARPI: androgen receptor pathway inhibitor; ECOG: Eastern Cooperative Oncology Group; FAS: full analysis set; IU: international unit; PFS-FAS: progression-free survival full analysis set; LDH: lactate dehydrogenase; PSA: prostate specific antigen; PSMA: prostate-specific membrane antigen; SOC standard of care. Source : Sartor et al. (2021).[25]

B.2.3.5 Concomitant medications

Concomitant medications that were indicated as SOC and taken by ≥10% of patients in either treatment arm are presented in Table 11. Medications used in SOC were predominantly used for symptom control at the discretion of treating physicians, as they would be used in UK clinical practice, and are not expected to impact on OS. The exception to this is ARPIs, which are not expected to be used concurrently with[177] Lu vipivotide tetraxetan in UK clinical practice. This is because multiple uses of ARPI treatments at different stages of disease (sequencing) is not commissioned in the UK. However, as VISION was a global study and sequencing of ARPIs is permitted in other countries, ARPIs were included as part of SOC at the treating physician’s discretion. To account for this difference in SOC a subgroup analysis was performed on the VISION data based on whether ARPIs were included as part of SOC, with results presented in Section B.2.6.

Table 11: Concomitant medications indicated as SOC that were taken by ≥10% of patients in either treatment arm (FAS SAS)

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aATC levels are presented alphabetically; preferred terms within ATC level are sorted by descending frequency, as reported in the 'Lu vipivotide tetraxetan + SOC’ column. A medication/therapy can appear in more than one ATC level. Every patient is counted a single time for each applicable specific medication category. bConcomitant medications indicated as SOC are all medications indicated as SOC (per sponsor pre-specified list) starting on or after the start of randomised treatment or starting prior to and continuing after the start of randomised treatment but not more than 30 days after end of randomised treatment Abbreviations :[177] Lu: Lutetium-177; 5HT3: 5-hydroxytryptamine; ARPI: androgen receptor pathway inhibitor; ATC: anatomical therapeutic chemical; FAS: full analysis set; PSMA: prostate-specific membrane antigen; SAS: safety analysis set; SOC: standard of care. Source : Sartor et al. (2021),[25] Advanced Accelerator Applications Data on File (VISION Clinical Study Report).[116]

B.2.3.6 Participant flow

1,179 patients were initially screened for eligibility for VISION and 1,003 (85.1%) went on to receive a[68] Ga gozetotide PET-CT scan.[25] Of those scanned, 869 (86.6%) of patients met the eligibility criteria based on PSMA-status (one or more PSMA-positive lesion and no PSMAnegative lesions).[25] A total of 831 (82.9%) met all eligibility criteria for VISION and were included in the trial. Patients were randomised in a 2:1 ratio between 4[th] June 2018 and 23[rd] October 2019. 551 patients were assigned to the intervention arm ([177] Lu vipivotide tetraxetan + SOC) whilst 280 were assigned to the control arm (SOC).[25] The data-cut for the final analyses of VISION was 27[th] January 2021.[25] A full CONSORT diagram of participant flow in VISION is presented below in Figure 4.

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Figure 4: CONSORT diagram showing participant flow in VISION

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The numbers in parentheses indicate the numbers of patients who underwent randomisation on or after March 5, 2019, which was the date on which trial-site education measures were implemented to reduce the incidence of withdrawal from the trial in the control group (see Document B, Section B.2.3.3 for further details). Abbreviations : 177Lu: Lutetium-177; PET: positron emission tomography; PSMA: prostate-specific membrane antigen; SOC: standard of care. Source : Sartor et al. (2021).[25]

B.2.4 Quality assessment of the relevant clinical effectiveness

evidence

Full details of the SLR, including methods and results of the quality assessment can be found in Appendix D.

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A quality assessment of VISION was performed using the University of York’s Centre for Reviews and Dissemination (CRD) checklist for RCTs (as per recommendations in the NICE user guide), and is presented in Appendix D.[117] Overall, VISION is considered to be of high quality with low risk of bias.

B.2.5 Clinical effectiveness results of the relevant trials

B.2.5.1 Overview of results

The following section of the submission presents results for patients receiving[177] Lu vipivotide tetraxetan + SOC or SOC only from the 27[th] January 2021 data-cut of the VISION trial. At this time, the median follow-up was 20.9 months.[25] This section details results for VISION’s alternative primary endpoints (OS and rPFS) and secondary endpoints (time to first SSE, HRQoL, overall response rate [ORR], duration of response [DOR], and disease control rate [DCR]).

VISION met its alternative primary endpoints of demonstrating significant improvements in OS and in rPFS with[177] Lu vipivotide tetraxetan + SOC compared with SOC.[25] Treatment with[177] Lu vipivotide tetraxetan+ SOC was also associated with significant improvements in ORR, DOR, time to first SSE, as well as significantly delaying time to deterioration across multiple HRQoL measures compared with treatment with SOC alone.[25, 116]

B.2.5.2 Overall survival (OS)

At the 27[th] January 2021 data-cut, VISION met both of its alternative primary objectives. Firstly, VISION demonstrated a statistically significant improvement in OS for patients receiving[177] Lu vipivotide tetraxetan + SOC compared with patients receiving SOC only (p<0.001, Table 12).[25] There was an estimated 38% reduction in the risk of death in the[177] Lu vipivotide tetraxetan + SOC arm compared with the SOC only arm (HR=0.62; 95% CI: 0.52, 0.74) and patients receiving 177Lu vipivotide tetraxetan + SOC benefited from a median extension to OS of 4 months (15.3 versus 11.3 months).[25] Highly similar results were obtained through an alternative analysis of OS using PFS-FAS, presented in Appendix M, with[177] Lu vipivotide tetraxetan + SOC extending OS by *** ****** ********* compared with SOC only. The benefit to OS became rapidly apparent and was found to be significant within six months of commencing[177] Lu vipivotide tetraxetan (Figure 5), furthermore, this benefit was maintained throughout the follow-up duration of approximately 20 months.[25] Additionally, the number and types of post-treatment cancer-related therapies were generally well-balanced between the two randomised arms ([177] Lu vipivotide tetraxetan + SOC, 28.1%; SOC, 34.6%) with proportions remaining similar across the most common cancer-related therapies. Therefore, receipt of post-treatment cancer-related therapies were not considered to have a substantial influence on the OS of trial participants.

In summary, considering the poor prognosis and lack of effective treatment options for patients with mCRPC following treatment with ARPI and taxane-based chemotherapy, extension of OS of greater than 4 months represents an important improvement for these patients (Section B.2.12).

Table 12: OS in VISION (FAS)

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aHazard Ratio of 177Lu vipivotide tetraxetan + SOC vs. SOC from stratified Cox PH model. bStratified Log-rank Test one-sided p-value.[c] Both Cox PH model and Log-rank test are stratified for LDH (≤ 260 IU/L vs. > 260 IU/L); presence of liver metastases (yes vs. no); ECOG score (0 or 1 vs. 2); and inclusion of ARPI in best supportive/standard of care at time of randomisation (yes vs no). IRT data for stratification are used.[d] Follow-up time = (Date of event or censoring - randomisation date + 1)/30.4375 (months) censoring for deaths. Abbreviations :[177] Lu: Lutetium-177; CI: confidence interval; FAS: full analysis set; IRT: interactive response technology; NE: not evaluable; OS: overall survival; PH: proportional hazards; PSMA: prostate-specific membrane antigen; SE: standard error. Source : Sartor et al. (2021),[25] Advanced Accelerator Applications Data on File (VISION Clinical Study Report).[116]

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Figure 5: Kaplan–Meier plot of OS (FAS)

==> picture [453 x 328] intentionally omitted <==

Stratified log-rank test and stratified Cox model using strata per Interactive Response Technology defined by LDH level, presence of liver metastases, ECOG score and inclusion of ARPI in SOC at time of randomisation. n/N: number of events/number of patients in treatment arm. Abbreviations :[177] Lu: Lutetium-177; ARPI: androgen receptor pathway inhibitor; CI: confidence interval; ECOG: Eastern Cooperative Oncology Group; FAS: full analysis set; LDH: lactate dehydrogenase; OS: overall survival; PSMA: prostate-specific membrane antigen; SOC: standard of care. Source : Sartor et al. (2021).[25]

B.2.5.3 Radiographic progression-free survival (rPFS)

At the 27[th] January 2021 data-cut, VISION also met its other alternative primary objective of demonstrating a statistically significant improvement in PFS for patients receiving[177] Lu vipivotide tetraxetan + SOC compared with patients receiving SOC only (p<0.001,

Table 13).[25] There was an estimated 60% reduction in the risk of radiographic progression in the 177Lu vipivotide tetraxetan + SOC arm compared with the SOC only arm (HR=0.40; 95% CI: 0.29, 0.57). Patients receiving[177] Lu vipivotide tetraxetan + SOC benefited from a median extension to rPFS of 5.3 months, equivalent to an approximately 2.5-fold extension to radiographic progression-free survival.[25] As with OS, the benefit to rPFS became rapidly apparent and was found to be significant within three months of commencing[177] Lu vipivotide tetraxetan (Figure 6). This result is of importance as it translates into patients receiving[177] Lu vipivotide tetraxetan + SOC delaying the considerable reduction in HRQoL associated with disease progression.[45-47]

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Table 13: rPFS in VISION per independent central review (PFS-FAS)

aHazard Ratio of 177Lu vipivotide tetraxetan + SOC vs. SOC only. bBoth Cox PH model and Log-rank test are stratified for LDH (≤ 260 IU/L vs. > 260 IU/L); presence of liver metastases (yes vs. no); ECOG score (0 or 1 vs. 2); and inclusion of ARPI in SOC at time of randomisation (yes vs no). IRT data for stratification are used.[c] Patients censored without adequate post-baseline evaluations or adequate baseline assessment.[d] Follow-up time = (Date of event or censoring - randomisation date + 1)/30.4375 (months) censoring for death or radiographic progression. Abbreviations :[177] Lu: Lutetium-177; CI: confidence interval; IRT: interactive response technology; NE: not evaluable; PFS-FAS: progression-free survival full analysis set; PH: proportional hazards; PSMA: prostate-specific membrane antigen; rPFS: radiographic progression-free survival; SE: standard error. Source : Sartor et al. (2021),[25] Advanced Accelerator Applications Data on File (VISION Clinical Study Report).[116]

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Figure 6: Kaplan–Meier plot of rPFS per independent central review (PFS-FAS)

==> picture [452 x 328] intentionally omitted <==

Stratified log-rank test and stratified Cox model using strata per IRT defined by LDH level, presence of liver metastases, ECOG score and inclusion of ARPI in SOC at time of randomisation. n/N: number of events/number of patients in treatment arm. Abbreviations :[177] Lu: Lutetium-177; ARPI: androgen receptor pathway inhibitor; CI: confidence interval; ECOG: Eastern Cooperative Oncology Group; IRT: interactive response technology; PFS-FAS: progression-free survival full analysis set; LDH: lactate dehydrogenase; PSMA: prostate-specific membrane antigen; rPFS: radiographic progression-free survival; SOC: standard of care. Source : Sartor et al. (2021).[25]

B.2.5.4 Time to first symptomatic skeletal event (SSE)

At the 27[th] January 2021 data-cut, VISION demonstrated a statistically significantly prolonged time to first SSE for patients receiving[177] Lu vipivotide tetraxetan + SOC compared with patients receiving SOC only, with an estimated 50% reduction in the risk of experiencing an SSE (p<0.001, Figure 7).[25] As with the alternate primary endpoints, the effect on time to first SSE became rapidly apparent following just three months of treatment (equivalent to two doses). The median time to first SSE was extended by 4.7 months (

Table 14). Given the significant morbidity associated with SSEs (pain, radiation therapy, surgical intervention, spinal cord compression and associated functional disability),[49] a prolonged time to first SSE is a meaningful result for patients with mCRPC of whom the vast majority already have established bone metastasis.[25]

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Table 14: Time to first SSE (PFS-FAS)

aHazard Ratio of 177Lu vipivotide tetraxetan + BSC/BSoC vs. BSC/BSoC.

bCox PH model is stratified for LDH (≤ 260 IU/L vs. > 260 IU/L); presence of liver metastases (yes vs. no); ECOG score (0 or 1 vs. 2); and inclusion of NAAD in best supportive/standard of care at time of randomisation (yes vs no). IRT data for stratification are used.

cFollow-up time = (Date of event or censoring - randomisation date + 1)/30.4375 censoring for death or SSE. Abbreviations :[177] Lu: Lutetium-177; CI: confidence interval; IRT: interactive response technology; NAAD: novel androgen axis drug; NE: not evaluable; PFS-FAS: progression-free survival full analysis set; PH: proportional hazards; PSMA: prostate-specific membrane antigen; SE: standard error; SSE: symptomatic skeletal event. Source : Sartor et al. (2021),[25] Advanced Accelerator Applications Data on File (VISION Clinical Study Report).[116]

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Figure 7: Kaplan–Meier plot of time to first SSE (PFS-FAS)

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Stratified log-rank test and stratified Cox model using strata per IRT defined by LDH level, presence of liver metastases, ECOG score and inclusion of ARPI in SOC at time of randomisation. n/N: number of events/number of patients in treatment arm. Abbreviations :[177] Lu: Lutetium-177; ARPI: androgen receptor pathway inhibitor; CI: confidence interval; ECOG: Easter Cooperative Oncology Group; IRT: interactive response technology; LDH: lactate dehydrogenase; PFSFAS: progression-free survival full analysis set; PSMA: prostate-specific membrane antigen; SSE: symptomatic skeletal event. Source : Sartor et al. (2021).[25]

B.2.5.5 Health-related quality of life (HRQoL)

VISION measured HRQoL using three validated questionnaires: BPI-SF, FACT-P, and EQ-5D5L. The results of each of these analyses at the 27[th] January 2021 data-cut are discussed below. Kaplan Meier curves for time-to-deterioration in these HRQoL outcomes are presented in Appendix M.

Time to worsening in Brief Pain Inventory – Short Form (BPI-SF)

Time to worsening in BPI-SF was defined as the earliest occurrence of a ≥30% increase or ≥2 point increase relative to baseline, clinical progressive disease or death. VISION demonstrated a statistically significantly prolonged time to worsening in BPI-SF for patients receiving[177] Lu vipivotide tetraxetan + SOC compared with patients receiving SOC only **** **** **** *** ***** ****** ******** **** ******* *** ************ ****** *** ***** ******* ** **** ******** **** *** ******* **** .[25]

********** **** ************* *** ***** **** ********** Patients in the intervention arm experienced an increase in median time to worsening in BPI-SF of 3.7, **** *** *** months for pain intensity, pain interference, and worst pain intensity, respectively.[116]

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Time to worsening in FACT-P was defined as the earliest occurrence of a ≥10 point decrease relative to baseline, clinical progressive disease or death. VISION demonstrated a statistically significantly prolonged time to worsening in FACT-P for patients receiving[177] Lu vipivotide tetraxetan + SOC compared with patients receiving SOC only **** **** **** *** ***** ****** ******** ******** ******** ******* ***** .[25] This benefit was demonstrated across FACT-P total score, ******* ****** *** ***** ******* ***** ***** *****. Patients in the intervention arm experienced an

increase in median time to worsening of 3.5, **** *** *** months for FACT-P total score, PSI-8 score, and TOI score, respectively.[116]

EuroQoL-5 Dimension-5 Level (EQ-5D-5L)

Time to worsening in EQ-5D-5L was defined as the earliest occurrence of no change or any decrease relative to baseline. VISION demonstrated * ************* ************* ********* **** ** ********* ** ******** for patients receiving[177] Lu vipivotide tetraxetan + SOC compared with **** ******* ******* ******* patients receiving SOC only .[116] Patients in the intervention arm *** ****** experienced an increase in median time to worsening in EQ-5D-5L utility scores of , equivalent to a **** *********** in time to worsening compared with SOC only.[116]

B.2.5.6 ORR, DCR and DOR

The ORR and DCR were analysed using the response evaluable analysis set, as described in Section B.2.3.3 (Table 8). At the 27[th] January 2021 data-cut, VISION demonstrated a statistically significant improvements in ORR and DCR with[177] Lu vipivotide tetraxetan + SOC compared with SOC only (Table 15).[25] ORR was ***** in the[177] Lu vipivotide tetraxetan + SOC arm vs. **** SOC ***** ***** ****** only arm, with an odds ratio of (95% CI: ).

The DCR was also statistically significant in favour of the[177] Lu vipivotide tetraxetan + SOC arm (stratified, two-sided Wald’s Chi-square test p<0.001).[25] DCR was 89.0% in the[177] Lu vipivotide tetraxetan + SOC arm vs. ***** in the SOC only arm, with and odds ratio of **** (95% CI: ***** ***** ).

These results are significant for patients with mCRPC as they indicate that[177] Lu vipivotide tetraxetan + SOC significantly increases the chance of an individual remaining free from disease progression compared with SOC only.

Table 15: Analyses of ORR, DCR and DOR per independent central review (Response evaluable analysis set)

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aOdds Ratio of 177Lu vipivotide tetraxetan + SOC vs. SOC based on logistic regression model stratifying for the randomisation stratification factors, LDH (≤ 260 IU/L vs. > 260 IU/L); presence of liver metastases (yes vs. no); ECOG score (0 or 1 vs. 2); and inclusion of an ARPI in SOC at time of randomisation (yes vs no). IRT data for stratification are used. P-value based on Wald’s Chi-Square test.[b] Patient censored without adequate post-baseline evaluations or adequate baseline assessment per RECIST 1.1. Abbreviations :[177] Lu: Lutetium-177; BOR: best overall response; CI: confidence interval; CR: complete response; DCR: disease control rate; DOR: duration of response in responding patients (months); EDOR: expected duration of response (months) (=mean DOR multiplied by ORR); IRT: interactive response technology; ORR: overall response rate; PR: partial response; PSMA: prostate-specific membrane antigen; SE: standard error. Source : Sartor et al. (2021).[25]

B.2.6 Subgroup analysis

Pre-specified subgroup analyses were conducted for OS and rPFS, the primary outcomes accessed in VISION, to assess the efficacy of[177] Lu vipivotide tetraxetan + SOC in key patient sub-populations.[25] These pre-specified subgroups are listed in Table 6 and include: ARPI as part of assigned SOC at the start of the study, presence of liver metastasis at baseline, baseline LDH level, baseline ECOG score, age, and race. It should be noted that across these categories a number of subgroups had low sample sizes (Asian, African American or Black; ECOG score of 2; presence of liver metastases; and patients aged below 65 years), leading to wide confidence intervals. Results should be interpreted with caution for these subgroups. However, overall, the results of subgroup analyses were consistent with, and supportive of, the results from the primary analysis of OS and rPFS.[25]

Post-hoc analysis of VISION results demonstrated that patients who had received one line of taxane chemotherapy prior to entry into VISION had ** *********** ******** advantage compared with patients who had received two prior lines of taxane chemotherapy (Appendix M). This further supports the generalisability of VISION’s results to UK clinical practice in which docetaxel retreatment is highly uncommon and patients would only be expected to receive a single line of taxane-based chemotherapy prior to cabazitaxel.[118]

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Subgroup analyses of OS per independent central review

For all subgroups, with the exception of Asian patients which had a very low patient numbers and thus had extremely wide confidence intervals, the analyses showed a favourable trend for the 177Lu vipivotide tetraxetan + SOC arm vs. the SOC only arm with HRs centred near the study's overall OS HR of 0.6.[25] Notably, OS for the greater than 65 years of age subgroup showed a marked improvement with narrow confidence intervals for[177] Lu vipivotide tetraxetan + SOC.[25] This subgroup is important as patients older than 65 years of age are more likely to be unsuitable for taxane treatment or may refuse treatment due to expected adverse events. Furthermore, the inclusion of ARPI as part of SOC did not significantly alter the benefit to OS, with both arms of this subgroup favouring[177] Lu vipivotide tetraxetan + SOC. A forest plot of HRs for the subgroup analyses on OS is presented in Figure 8.

Figure 8: Subgroup analyses of OS – Forest plot of HR with 95% CI (FAS)

==> picture [456 x 186] intentionally omitted <==

n/N: number of events/number of patients in treatment arm. Vertical line shows HR for the overall population. Abbreviations :[177] Lu: Lutetium-177; ARPI: androgen receptor pathway inhibition; CI: confidence interval; ECOG: Easter Cooperative Oncology Group; HR: hazard ratio; LDH: lactate dehydrogenase; PFS-FAS: progression-free survival full analysis set; PS: performance score; PSMA: prostate-specific membrane antigen; SOC: standard of care. Source : Sartor et al. (2021).[25]

Subgroup analyses of rPFS per independent central review

As with OS subgroup analyses, all subgroups, with the exception of Asian patients, showed a favourable trend for the[177] Lu vipivotide tetraxetan + SOC arm vs. the SOC only arm with HRs centred near the study's overall rPFS HR of 0.4.[25] Consistent with results for OS, rPFS for the greater than 65 years of age subgroup showed a marked improvement with narrow confidence intervals for[177] Lu vipivotide tetraxetan + SOC.[25] Furthermore, the inclusion of ARPI as part of SOC did not significantly alter the benefit to rPFS, with both of these subgroups favouring[177] Lu vipivotide tetraxetan + SOC. A forest plot of HRs for the subgroup analyses on rPFS is presented in

Figure 9.

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Figure 9: Subgroup analyses of rPFS per independent central review – forest plot of HR with 95% CI (PFS-FAS)

==> picture [450 x 183] intentionally omitted <==

n/N: number of events/number of patients in treatment arm. Vertical line shows HR for the overall population. Abbreviations :[177] Lu: Lutetium-177; ARPI: androgen receptor pathway inhibition; CI: confidence interval; ECOG: Easter Cooperative Oncology Group; HR: hazard ratio; LDH: lactate dehydrogenase; PFS-FAS: progression-free survival full analysis set; PS: performance score; PSMA: prostate-specific membrane antigen; SOC: standard of care. Source : Sartor et al. (2021).[25]

B.2.7 Meta-analysis

As VISION represents the only Phase III study evaluating the safety and efficacy of[177] Lu vipivotide tetraxetan for the treatment of adult patients with PSMA-positive mCRPC who have been treated with ARPI and taxane-based chemotherapy (see Section B.2.2), no meta-analysis was performed.

B.2.8 Indirect and mixed treatment comparisons

Direct evidence for the comparison of[177] Lu vipivotide tetraxetan to SOC is available from VISION. However, for cabazitaxel there is no direct, Phase III RCT data available. As described in Section B.1.1, based on clinical guidelines cabazitaxel is the appropriate comparator to assess cost-effectiveness. Therefore, to assess the relative efficacy of[177] Lu vipivotide tetraxetan and cabazitaxel, three separate sources of data have been considered: a real-world database analysis, TheraP, and a network meta-analysis (NMA).

B.2.8.1 Supportive evidence for 177Lu vipivotide tetraxetan comparators

Real-World Evidence from UK clinical practice

In order to further understand the relevant mCRPC patient population within the UK healthcare system, a retrospective RWE study of patients with mCRPC was carried out using linked healthcare datasets from Public Health England (PHE) and NHS Digital. The analysis included records from 1[st] January 2009 to 31[st] December 2018, and used combined data from major UK databases including the National Cancer Regsitry (NCR), Systemic Anticancer Therapy Dataset

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(SACT), Hospital Episode Statistics (HES), Diagnostic Imaging Dataset (DID), and Radiotherapy Dataset (RTDS).

The objective of this real-world database analysis was to assess the clinical characteristics, current standard of care, clinical outcomes, and healthcare resource usage and associated costs of patients with mCRPC in England. This data was generated in order to understand the survival of patients in UK clinical practice (focusing on cabazitaxel), as well as to assess the similarity of the VISION patient population to mCRPC patients captured in the dataset.

Challenges were encountered in identifying which patients had received and progressed despite ADT within the available data, and as such, clearly defining the population as containing only mCRPC and not also including mHSPC. However, patients who have received cabazitaxel are expected to be most closely aligned with the population of relevance to this submission (postARPI, post-taxane) and would be expected to be composed of exclusively patients with mCRPC. ***** *** Therefore, particular focus was placed upon this cohort of patients (n= ). patients in the RWE cabazitaxel cohort had no recorded follow-up and hence were censored from further survival analysis. Further details of the RWE study methodology provided in Appendix N.

Baseline characteristics of patients identified in the RWE analysis are presented in Table 16. The baseline characteristics from this real-world database analysis are closely aligned to VISION, and as such this analysis provides highly relevant real-word data on the current outcomes for patients in the UK who would be considered eligible for treatment with[177] Lu vipivotide tetraxetan (Section B.2.3.4). As such, matching of VISION patients to RWE baseline characteristics is not expected to substantially impact results. As the main clinical comparator is cabazitaxel, the characteristics of this subset of patients is reported in order to demonstrate the overall similarity with the VISION population.

Table 16: Baseline characteristics for RWE analysis

a*** patients in the RWE cabazitaxel cohort had no recorded follow-up and hence were censored from subsequent survival analysis.[b] Age in the RWE cohort was reported as age at mCRPC diagnosis, not age at cabazitaxel initiation, and thus is not directly comparable to age reported for VISION.[c] Ethnicity in VISION was specified as ‘White’, not ‘White British,[116][d] ECOG status as reported at the point of cabazitaxel initiation. This data were available for ***** patients in total, with *** patients of unknown ECOG status. Abbreviations : ECOG: Eastern Cooperative Oncology Group; FAS: full analysis set; RWE: real-world evidence. Source: Sartor et al. 2021[25]

The RWE database analysis reviewed the OS of patients with mCRPC. Of particular relevance to the comparison between[177] Lu vipivotide tetraxetan and cabazitaxel, data are available for the OS of patients following receipt of cabazitaxel (Table 17; Figure 10). Median OS for patients ** ****** ***** ****** receiving cabazitaxel was , with a restricted mean OS of . Disease progression, rPFS or PFS, is challenging to capture in database analyses, and often relies on the commencement of a new treatment to act as a proxy for progression. However, in mCRPC that has already progressed despite multiple prior therapies, this proxy becomes inconsistent,

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especially when patients do not go on to receive another therapy leading to high levels of censored data. Thus, this RWE analysis was not able to capture data on rPFS, only OS.

It was noted that the OS for cabazitaxel in the RWE analysis was shorter than the median OS for the SOC arm of VISION (**** months vs. 11.3 months). However, patients in clinical trials receive enhanced monitoring through more frequent visits to physicians and imaging. Therefore, patients in clinical trials may have longer OS compared to what would be anticipated in real-world practice. This effect is likely greater for patients in the control arms of trials, who are expected to receive less regular oncological follow-up and imaging in real-world practice than patients receiving active oncological therapy. Therefore, it is expected that patients in real-world practice receiving SOC would experience shorter OS than that observed in VISION.

Table 17: Patients receiving cabazitaxel in the RWE analysis

Abbreviations : OS: overall survival; RWE: real-world evidence.

Figure 10: OS for patients in the RWE analysis following receipt of cabazitaxel

==> picture [432 x 300] intentionally omitted <==

*** patients in the total RWE cabazitaxel cohort (n=*****) had no recorded follow-up and hence were censored from subsequent survival analysis. This survival analysis was performed on the remaining ***** patients. Abbreviations : OS: overall survival; RWE: real-world evidence

TheraP

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TheraP is a Phase II, multicentre, unblinded, randomised trial conducted at 11 centres in Australia which directly compared[177] Lu vipivotide tetraxetan to cabazitaxel in patients with mCRPC for whom cabazitaxel was considered the next appropriate standard of treatment.[110] In TheraP, 200/291 men met screening criteria for inclusion into the trial with 98 receiving[177] Lu vipivotide tetraxetan monotherapy, and 85 receiving cabazitaxel.[110]

TheraP was primarily designed to evaluate PSA response (defined as a reduction of PSA ≥50% from baseline). The study observed significantly higher rates of PSA response in the[177] Lu vipivotide tetraxetan arm compared with the cabazitaxel arm by intention to treat (66% vs. 37%, corresponding to a difference of 29% [95% CI: 16%, 42%, p<0.0001]). Secondary objectives measured in TheraP are also supportive of superior efficacy for[177] Lu vipivotide tetraxetan compared with cabazitaxel. For example, patients receiving[177] Lu vipivotide tetraxetan had significantly longer rPFS than patients receiving cabazitaxel (HR: 0.64 [95% CI 0.44, 0.83, P=0.007]).[110] The results for rPFS are consistent in terms of point estimate and confidence intervals with the results from the network meta-analysis (Section B.2.8.6), providing further certainty in the benefit of[177] Lu vipivotide tetraxetan in comparison to cabazitaxel.

Furthermore, Grade 3–4 AEs occurred in only 33% of men in the[177] Lu vipivotide tetraxetan arm compared with 53% of the cabazitaxel arm. In particular, grade 3–4 neutropenia was less common with[177] Lu vipivotide tetraxetan (4% vs 13%), with no episodes of febrile neutropenia (0% vs 8%). Dose reductions due to AEs were reported in fewer men receiving[177] Lu vipivotide tetraxetan compared with cabazitaxel (12% vs. 25%). No deaths were attributed to[177] Lu vipivotide tetraxetan.[110] Overall, the safety profile of[177] Lu vipivotide tetraxetan was notably superior to that of cabazitaxel.

Despite representing the only direct head-to-head study comparing[177] Lu vipivotide tetraxetan to cabazitaxel, a number of factors mean that TheraP is not suitable to inform efficacy in the economic model. Firstly, as TheraP is a Phase II trial, it did not meet eligibility criteria for inclusion in the ITC (Section B.2.8.3). Additional aspects of the trial that limit its role as a source of direct comparison include:

• The version of[177] Lu vipivotide tetraxetan used in the trial was ‘hospital compounded’ (i.e., not company-manufactured) and thus the molecule is potentially subject to variability from company-specific production

• Randomisation was stratified by disease burden (>20 sites vs. ≤20 sites), previous ARPI treatment, and study site. All of these differ from the stratification factors applied to randomisation in VISION

• Patients in the experimental arm of TheraP received a starting dose of 8.5 GBq of[177] Lu vipivotide tetraxetan, which reduced by 0.5 GBq per cycle. This differs from the recommended dose of[177] Lu vipivotide tetraxetan, which was used in VISION, of 7.4 GBq per cycle

• Patients in the TheraP study received[18] F-FDG PET/CT imaging at baseline (in addition to[68] Ga PET/CT) in order to exclude patients with FDG-positive disease sites with minimal PSMA expression

Therefore, TheraP does not provide sufficiently robust evidence to support a direct head-to-head comparison between[177] Lu vipivotide tetraxetan and cabazitaxel for the indication of relevance to

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this submission. Although not suitable for direct comparison, evidence from TheraP may be considered alongside the main body of evidence in this submission as a source of supporting evidence for patients medically suitable for taxane-based chemotherapy.

B.2.8.2 Identification and selection of relevant studies from the clinical SLR

As discussed in Section B.2.1, an interventional SLR was conducted to identify all relevant clinical evidence on the efficacy and safety of[177] Lu vipivotide tetraxetan and any potential comparators for the treatment of adult patients with PSMA-positive mCRPC who have been treated with ARPI and taxane-based chemotherapy. The SLR was originally conducted on 28[th] June 2019, with subsequent updates conducted on 6[th] April 2021 (Update 1) and 3[rd] November 2021 (update 2). In the original SLR 18 records were identified, with seven, and one additional records being subsequently identified at Update 1 and Update 2 respectively. Thus, a total of 26 records were included in the Interventional SLR, representing 20 Phase III RCTs. As the SLR was conducted from a global perspective, not all identified treatments are expected to align with NICE-specific guidance on management of mCRPC. Full details of the methodology and results of the SLR are presented in Appendix D.

For UK patients with mCRPC who have already received treatment with ARPI and taxane-based chemotherapy there are currently very limited viable options for further treatment. As previously discussed in Section B.1.1, cabazitaxel (for eligible patients) represents the only treatment option besides SOC. Patients may also have already received cabazitaxel prior to[177] Lu vipivotide tetraxetan under current positioning.

B.2.8.3 Eligibility criteria for the NMA

In the absence of suitable head-to-head studies, a Bayesian NMA was performed to determine the relative efficacy of[177] Lu vipivotide tetraxetan versus currently available mCRPC treatment options. To meet this objective, all RCTs identified as part of the SLR were reviewed against predefined eligibility criteria for the NMA. Any study that assessed the efficacy or safety of at least one intervention considered relevant and used in UK clinical practice was included in the NMA, including: ARPIs (abiraterone or enzalutamide), radium-223, and cabazitaxel. Of the 20 Phase III RCTs that were identified in the SLR, nine studies were ultimately included in the NMA (Table 18). Details of all 20 studies identified by the SLR, and the rationale for including or excluding these studies from the NMA are presented in Appendix D.

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Table 18: Summary of studies included in the NMA

Note: Progression on prior docetaxel was not a restriction in PROfound. Abbreviations : BSC: best supportive care; mCRPC: metastatic castration-resistant prostate cancer; SOC: standard of care.

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Including VISION, the NMA consisted of a total of eight RCTs that were connected through a common comparator arm of ARPI and mitoxantrone/placebo plus prednisone (Figure 11). To include VISION in the NMA, a distinct subpopulation of patients was analysed post-hoc. This subpopulation included those patients in the SOC arm who received an ARPI as a component of SOC at the time of initial randomisation. This cohort will henceforth be referred to as ‘SOC-ARPI’.

Figure 11: OS network (based on HR)

==> picture [451 x 254] intentionally omitted <==

Abbreviations : ARPI: androgen receptor pathway inhibitor; BSC: best supportive care; HR: hazard ratio; SOC: standard of care

B.2.8.4 Heterogeneity across studies included in the NMA

As per the best practice in evidence synthesis and NMA, studies included in the evidence network were assessed for imbalances in the distribution of treatment effect modifiers.[119] Various baseline parameters were evaluated to assess the clinical heterogeneity between the studies included in the NMA. These parameters included age, Gleason score, PSA values, prior treatment status, and ECOG performance status scores (Appendix D). Baseline characteristics were relatively similar between trials for median age and ECOG PS 0–1, with reported median PSA levels in PROfound, CARD, and VISION all being relatively similar and other trials generally reporting higher median PSAs in both intervention and placebo arms.

Furthermore, patient disease characteristics (e.g., PSMA-positivity, genetic characteristics), prior therapies, and trial duration differed substantially between trials. These differences across studies may include differences in stratification factors which could be effect modifiers. The absence of stratification at the time of randomisation could have generated some imbalances across the experimental arm and the comparator arm, which could confound the output of treatment effect in an NMA.

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B.2.8.5 NMA methods

The NMA was conducted using the summary results reported in study publications and included the HRs of OS and PFS. In this analysis, a linear model with normal likelihood distribution was used for these time-to-event outcomes (log HR and standard error [SE]). The NMA was performed using the Markov Chain Monte Carlo (MCMC) software (Rücker, 2012; Rücker and Schwarzer, 2014).[120, 121] This method includes the synthesis of all included data (direct and indirect comparisons), resulting in a single set of effective sizes.

The NMA model inputs included natural log of HR (logHR) and SE of logHR. The results of the NMA were based on a sufficient number of iterations (e.g., 80,000 iterations) on at least three chains, with a burn-in of 20,000 iterations. Convergence was assessed by visual inspection of trace plots (Presented in Appendix D). The accuracy of the posterior estimates was assessed using the Monte Carlo error for each parameter (Monte Carlo error <1% of the posterior standard deviation or Monte Carlo error divided by posterior standard deviations should be ≤0.05).

For each outcome, fixed and random effects models were evaluated based on the Deviance Information Criterion (DIC) value (Table 19 and Table 20). Although random effect modelling yielded a lower DIC, given the small size of the network and low total number of studies available for inclusion, there is limited information to estimate the heterogeneity standard deviation and the prior distribution may be too heavy-tailed. The heterogeneity parameter is therefore difficult to estimate, necessitating the use of the fixed effects model in the base case. The results based on random effects models are presented in Appendix D, but should be interpreted with caution.

Table 19: DIC and residual deviance values for OS using fixed effects and random effects models

Abbreviations : DIC: Deviance information criteria; Dbar: Posterior mean of the deviance; pD: Effective number of parameters.

Table 20: DIC and residual deviance values for rPFS using fixed effects and random effects models

Abbreviations : DIC: Deviance information criteria; Dbar: Posterior mean of the deviance; pD: Effective number of parameters.

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B.2.8.6 NMA results

The results of the NMA are presented in terms of ‘point estimates’ (median of posterior) for the comparative treatment effects, along with the 95% credible intervals (95% CrI).[177] Lu vipivotide tetraxetan demonstrated significant benefit in OS compared against cabazitaxel plus prednisone (Figure 12). Similarly,[177] Lu vipivotide tetraxetan showed significantly greater rPFS benefits compared against cabazitaxel plus prednisone (Figure 13).

The NMA results show a higher survival benefit as assessed by OS and rPFS with[177] Lu vipivotide tetraxetan + SOC compared with olaparib. However, statistical significance was not reached. PROfound, the trail investigating olaparib, enrolled patients with mCRPC who had progressed on prior ARPI and had variants in 1 of 15 homologous recombination repair genes. VISION included patients irrespective of any gene alterations. Progression on prior docetaxel was not a restriction in PROfound, as this study enrolled ~34% docetaxel-naïve patients in the experimental arm. VISION included patients with progressive PSMA-positive mCRPC. The PROfound study did not report PSMA positivity as the inclusion criteria and likely included patients irrespective of PSMA positivity. Median PSA level in the experimental group was lower in PROfound when compared to VISION (PROfound: 68 ng/mL [range, 24–294 ng/mL]; VISION: 77.5 [range, 0–6,988]). These differences across the studies could confound the output of an NMA and thus results are uncertain. Furthermore, Olaparib is only indicated in a minority subgroup of mCRPC patients and is not recommended by NICE at the time of this submission.

Figure 12: Base-case NMA results – OS (fixed-effects model)

==> picture [468 x 193] intentionally omitted <==

Abbreviations : ARPI: androgen receptor pathway inhibitor; CrI: credible interval; HR: hazard ratio; SoC: standard of care (protocol permitted)

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Figure 13: Base-case NMA results – rPFS (fixed-effects model)

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Abbreviations : ARPI: androgen receptor pathway inhibitor; CrI: credible interval; HR: hazard ratio; SoC: standard of care (protocol permitted)

B.2.8.7 Limitations of the NMA

There are several important limitations to keep in mind when interpreting the results of the NMA:

• The key limitation of this NMA was inter-trial heterogeneity between[177] Lu vipivotide tetraxetan and comparator populations in terms of disease severity. Patients included in VISION had more severe disease as indicated by a higher prior treatment count and at least 40% of patients in VISION previously receiving treatment with cabazitaxel. Due to limited available data, adjusting for these differences was not possible using metaregression techniques.

• There were differences across the included studies in terms of trial design and patient characteristics. In these trials, the assessment of reference arms may help eliminate potential unidentified confounders as the differences in reference can be adjusted using a baseline risk regression. However, limited studies and minimal statistical heterogeneity across the reference arms preclude any adjustment using baseline risk

• The small sample size and data immaturity of comparator trials limits the interpretation of the results

B.2.8.8 Conclusions of the NMA

In order to understand the relative efficacy of[177] Lu vipivotide tetraxetan compared to cabazitaxel, the most relevant comparator at this place in the treatment pathway, in adult patients with PSMApositive mCRPC who have been treated with ARPI and taxane-based chemotherapy, three key sources of data are available: a real world UK database analysis, TheraP, and NMA results. Although each source of evidence individually has specific limitations, they all support the conclusion that[177] Lu vipivotide tetraxetan has superior efficacy compared with cabazitaxel, with TheraP indicating a favourable safety profile. The RWE analysis of patients receiving cabazitaxel, considered the most similar cohort to patients in VISION, shows a median OS of ** ****** . The median survival for patients in VISION receiving[177] Lu vipivotide tetraxetan was 15.3 months, emphasising the benefit that treatment with[177] Lu vipivotide tetraxetan brings compared with cabazitaxel.

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Although rPFS data was not available from RWE, the rPFS results from TheraP demonstrate the significant superiority of[177] Lu vipivotide tetraxetan compared with cabazitaxel. Despite the intertrial heterogeneity noted in the NMA, the NMA rPFS results are closely aligned with the rPFS data from TheraP. In TheraP, the HR for the comparison of[177] Lu vipivotide tetraxetan compared with cabazitaxel was 0.64 (95% CI: 0.44, 0.83), which is noted to be very similar to the estimated **** **** **** ***** ***** HR from the NMA for this comparison: .[110] Thus, considered together, the results of the RWE, TheraP, and NMA provide substantial evidence for the superiority of[177] Lu vipivotide tetraxetan over cabazitaxel for both OS and rPFS.

Given the limitations of TheraP and the NMA, the OS data from the RWE analysis were considered to be most reflective of the efficacy of cabazitaxel in the population of relevance to this submission (post-ARPI, post-taxane), as they were reported directly from patients receiving cabazitaxel in UK clinical practice, where its positioning is in line with the intended positioning of 177Lu vipivotide tetraxetan. These data were therefore selected to inform OS for cabazitaxel in the economic model; given the similarity in baseline characteristics between VISION and the RWE cohort, these data were included without adjustment.

B.2.9 Adverse reactions

The following sections present treatment exposure and adverse event data from the FAS safety analysis set in VISION. AEs were graded according to common terminology criteria for adverse events (CTCAE) v5.0. All AE monitoring and SAE recording and reporting began at the time of patient consent and continued up to and including 30 days after the last dose of[177] Lu vipivotide tetraxetan or the date of deciding to end SOC, whichever was later. All AEs and abnormal test findings were recorded, regardless of suspected causal relationship to treatment. The assessment of AE causality was performed by individual investigators on a case-by-case basis.[25]

Treatment exposure

In VISION, patients randomised to the[177] Lu vipivotide tetraxetan + SOC arm received a minimum of 4 planned cycles of[177] Lu vipivotide tetraxetan 7.4 GBq (200 mCi), one cycle every six weeks, up to a maximum of six cycles. Mean duration of treatment exposure in the[177] Lu vipivotide tetraxetan + SOC arm was *** months, *** months and *** months for any randomised treatment (Table 21), for[177] Lu vipivotide tetraxetan (Table 22), and for SOC respectively.[116] Only **** of patients experienced a delay to one of their treatment cycles due to an AE.[116] On average, patients received *** **** **** cycles of treatment with each cycle lasting *** **** **** months, leading to a relative dose intensity of ****** **** ***** of the planned cycles of treatment.[25]

Table 21: Duration of exposure to randomised treatment based upon trial arm (FAS safety analysis set)

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This table presents mean duration of exposure to all treatment included in the allocated treatment arm, not just exposure to[177] Lu vipivotide tetraxetan in the intervention arm.

Abbreviations :[177] Lu: Lutetium-177; FAS: full analysis set; Max: maximum; Min: minimum; NA: not applicable; PSMA: prostate-specific membrane antigen; SD: standard deviation; SOC: standard of care. Source : Advanced Accelerator Applications Data on File (VISION Clinical Study Report).[116]

Table 22: Duration of exposure to[177] Lu vipivotide tetraxetan and summary of cycles (FAS safety analysis set)

A patient may be counted in more than one row for reason for delay of cycle. Abbreviations :[177] Lu: Lutetium-177; FAS: full analysis set; Max: maximum Min: minimum; PSMA: prostate-specific membrane antigen; SD: standard deviation; SOC: standard of care. Source : Advanced Accelerator Applications Data on File (VISION Clinical Study Report).[116]

Overview of adverse events (AEs)

In VISION, most patients experienced an AE, regardless of treatment arm (Table 23). For all categories except AEs leading to reduction of dose of SOC, AEs were more frequent in the[177] Lu vipivotide tetraxetan + SOC arm.[25] Post-hoc exposure-adjusted safety analyses showed that the higher incidence of AEs in the[177] Lu vipivotide tetraxetan + SOC arm was in part related to the longer exposure in this arm,[122] as emphasised by the observation that patients in the[177] Lu vipivotide tetraxetan + SOC arm experienced higher rates of AEs secondary to their primary SOC than those patients in the SOC only arm (Table 24).[25] Furthermore, the imbalance of drugrelated AEs should be interpreted with caution as the study was open label. Moreover, patients were already receiving SOC before randomisation and as such, SOC may have not been systematically considered as a Study Drug by investigators.[25]

Table 23: Overview of AEs during randomised treatment (FAS safety analysis set)

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Drug-related is related to any study drug ([177] Lu vipivotide tetraxetan or SOC), as assessed by the investigator. aFour patients randomised to 177Lu vipivotide tetraxetan + SOC arm received only SOC and therefore contribute to the FAS safety analysis set of the SOC arm

Abbreviations :[177] Lu: Lutetium-177; AE: adverse event; FAS: full analysis set; PSMA: prostate-specific membrane antigen; SOC: standard of care. Source : Sartor et al. (2021),[25] Advanced Accelerator Applications Data on File (VISION Clinical Study Report).[116]

Table 24: AEs by primary SOC and maximum grade during randomised treatment occurring it at least 5% of patients in either arm during randomised treatment (FAS safety analysis set)

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Abbreviations :[177] Lu: Lutetium-177; AE: adverse event; FAS: full analysis set; PSMA: prostate-specific membrane antigen; SOC: standard of care. Source : Sartor et al. (2021),[25] Advanced Accelerator Applications Data on File (VISION Clinical Study Report).[116]

Adverse events occurring in at least 5% of patients

AEs occurring is at least 5% of patients in either arm during randomised treatment that were suspected by the investigator to be related to study treatment are presented in Table 25.[25] Overall, treatment-related AEs were more frequent in the[177] Lu vipivotide tetraxetan + SOC arm compared with the SOC only arm. The grade ≥ 3 events that were reported with highest incidences in the intervention arm were anaemia (9.6%), thrombocytopenia and lymphopenia (6.8% each), all other grade ≥ 3 AEs were reported in less than 5% of patients in this arm.

Table 25: AEs occurring in at least 5% of patients in either arm during randomised treatment with suspected relationship by preferred term and maximum grade (FAS-SAS)

Abbreviations :[177] Lu: Lutetium-177; AE: adverse event; FAS: full analysis set; PSMA: prostate-specific membrane antigen; SAS: safety analysis set; SOC: standard of care. Source : Sartor et al. (2021).[25]

Serious adverse events occurring in at least 1% of patients

SAEs occurring in at least three patients in either arm are presented in Table 26. In either arm,

**** *** *** ******** **** * ********* ****** ****** *** ****** **** *********** ***** *** ******** ** **** ** ******** ** *** *** **** *** **** **** ** [] ** ********** ********** * *** *****[116]

Table 26: SAEs occurring in at least 1% of patients in either arm during randomised treatment (FAS-SAS)

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Abbreviations :[177] Lu: Lutetium-177; AE: adverse event; FAS: full analysis set; PSMA: prostate-specific membrane antigen; SOC: standard of care. Source : Advanced Accelerator Applications Data on File (VISION Clinical Study Report).[116]

Deaths occurring during randomised treatment

SAEs leading to fatal outcome during randomised treatment are presented in Table 27.[116] Per protocol, disease progression was not to be reported as an AE leading to fatal outcome, however this had not been fully clarified before *** such SAEs were reported by the investigators (*** in each arm).[116] *** **** ****** **** **** ******** **** **** **** ** ****** *** **** ****** ************ ***** *** ************ ************ ***** ** [] ** ********** ********** * *** ***.[116] No apparent patterns in the

nature SAEs with fatal outcomes were observed.[116]

Table 27: On-treatment deaths during randomised treatment (FAS-SAS)

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aOn-treatment deaths are deaths that occurred during randomised treatment or within 30 days of randomised treatment discontinuation. Abbreviations :[177] Lu: Lutetium-177; COVID-19: coronavirus disease 2019; FAS: full analysis set; PSMA: prostatespecific membrane antigen; SOC: standard of care. Source : Advanced Accelerator Applications Data on File (VISION Clinical Study Report).[116]

AEs leading to permanent discontinuation of[177] Lu vipivotide tetraxetan treatment

AEs leading to permanent discontinuation of[177] Lu vipivotide tetraxetan are presented in

Table 28. The most frequent events were related to cytopenias (ranging from 2.8% for thrombocytopenia and anaemia to 0.6% for pancytopenia). All other events were reported in less than 0.5% of the patients each.

Table 28: AEs leading to permanent discontinuation of[177] Lu vipivotide tetraxetan during randomised treatment (FAS-SAS)

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Abbreviations :[177] Lu: Lutetium-177; COVID-19: coronavirus disease 2019; FAS: full analysis set; PSMA: prostatespecific membrane antigen; SOC: standard of care.

Source : Advanced Accelerator Applications Data on File (VISION Clinical Study Report).[116]

AEs leading to interruption or dose reduction of[177] Lu vipivotide tetraxetan treatment

AEs leading to dose interruption or dose reduction of[177] Lu vipivotide tetraxetan are presented in Table 29.[116] The most frequent events that led to dose interruption or reduction of[177] Lu Company evidence submission template for[177] Lu vipivotide tetraxetan for treating PSMApositive hormone-relapsed metastatic prostate cancer after 2 or more therapies [ID3840]

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vipivotide tetraxetan were anaemia (interruption: ****, reduction: ****) and thrombocytopenia (interruption: **** and reduction: ****). All other events that led to dose interruption or reduction were reported for less than **** of the patients.[116]

Table 29: AEs leading to interruption or dose reduction of[177] Lu vipivotide tetraxetan occurring in at least 0.5% of the patients during randomised treatment (FAS-SAS)

Abbreviations :[177] Lu: Lutetium-177; COVID-19: coronavirus disease 2019; FAS: full analysis set; PSMA: prostatespecific membrane antigen; SOC: standard of care. Source : Advanced Accelerator Applications Data on File (VISION Clinical Study Report).[116]

Treatment-emergent adverse events of interest

An overview of treatment-emergent adverse events of interest during randomised treatment is presented in Table 30.[25]

• Fatigue was selected due to its high likelihood of being associated with active cancer treatment. Higher rates of fatigue in the[177] Lu vipivotide tetraxetan + SOC arm compared to the SOC arm were noted. However, this effect may in part be accounted for by the longer duration of treatment exposure in the[177] Lu vipivotide tetraxetan + SOC arm. Furthermore, fatiguerelated events leading to discontinuation of[177] Lu vipivotide tetraxetan were rare and only occurred in 2 patients (0.4%).

• Myelosuppression, considering the suppression of all blood cell lines, was selected due to its high likelihood of being associated with active cancer treatment, especially in the context of treatments involving radiation. Myelosuppression was commonly observed in the[177] Lu vipivotide tetraxetan arm (47.4%), with under half of these events being grade ≥3 (23.4%). As described previously, myelosuppressive events were the most common reasons for dose reduction, interruption, and discontinuation of[177] Lu vipivotide tetraxetan.

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• Dry mouth was selected due to the known distribution of PSMA in the salivary glands. Dry mouth in the[177] Lu vipivotide tetraxetan + SOC arm was higher than that observed in the SOC arm, as expected, given the known distribution of PSMA in the salivary glands. However, no grade ≥3 events were observed.

• Nausea and vomiting were selected due to their high likelihood of being associated with active cancer treatment. Nausea and vomiting were reported approximately twice as often in the[177] Lu vipivotide tetraxetan + SOC arm (39.3% of patients) as compared to the SOC only arm (17.1%), but grade ≥3 events were infrequent in either arm. Only one patient (0.2%) was withdrawn from[177] Lu vipivotide tetraxetan due to this category of events.

• Renal effects were selected due to the known distribution of PSMA in the proximal tubule and known renal route of excretion of[177] Lu vipivotide tetraxetan. Renal effects were similar in frequency for grade ≥3 AEs between arms (3.4% vs. 2.9%). SAEs were reported more frequently in the SOC only arm (3.4%) than in the[177] Lu vipivotide tetraxetan + SOC arm (1.7%). None of the events in this category were grade 4 in severity or above (no events had a fatal outcome) and only a single patient (0.2%) was withdrawn from[177] Lu vipivotide tetraxetan due to this category of events

• Review of the standard safety topics of hepatotoxicity and QTc prolongation did not reveal concern for any relationship with[177] Lu vipivotide tetraxetan.

Table 30: Overview of treatment-emergent adverse events of interest during randomised treatment (FAS-SAS)

Abbreviations :[177] Lu: Lutetium-177; COVID-19: coronavirus disease 2019; FAS: full analysis set; PSMA: prostatespecific membrane antigen; SOC: standard of care. Source : Sartor et al. (2021).[25]

B.2.10 Ongoing studies

No additional studies are expected to reach completion within 12 months of the submission date that would offer additional evidence for[177] Lu vipivotide tetraxetan in addition to the evidence presented here.

B.2.11 Innovation

In contrast to early localised PC where patients can be well managed with available treatment options,[2] therapeutic options available to mCRPC patients following progression despite ARPI Company evidence submission template for[177] Lu vipivotide tetraxetan for treating PSMApositive hormone-relapsed metastatic prostate cancer after 2 or more therapies [ID3840]

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and taxane-based chemotherapy are severely limited. Furthermore, those patients deemed medically unsuitable for taxanes who have also received an ARPI prior to developing mCRPC will be limited to supportive care alone. These patients experience significant unmet need, as discussed in Section B.1.3.4. Current real-world therapeutic options for the majority of patients are limited beyond palliative care with available therapies having significant toxicities limiting tolerability.[29, 30] Furthermore, patients who have progressed despite multiple prior therapies tend to be frail with significant disease, prior treatment-related comorbidities and a higher tumour burden.[85] Treatment options for patients with visceral metastases are limited even further, with radium-223 not being licensed for use in this subpopulation.[84] Furthermore, rates of AEs while receiving taxane-based chemotherapy are high, with correspondingly frequent dose reductions, interruptions, and discontinuation of therapy. Therefore, to meet this unmet need, new, tolerable, targeted therapies are required in this patient population, which have the potential to produce meaningful improvements in survival and preserve HRQoL.

177Lu vipivotide tetraxetan is a novel radioligand therapy with a unique, targeted mechanism of action that distinguishes it from other available therapies, targeting an unexploited biomarker (PSMA) to overcome disease resistance and drive predictable response. The innovative potential of[177] Lu vipivotide tetraxetan, as demonstrated though the VISION trial, is summarised as follows:

• 177Lu vipivotide tetraxetan offers a targeted approach to treating mCRPC .25 The PSMA receptor is highly expressed in prostate cancer cells and is tested for prior to initiation of therapy. Patients who are PSMA-positive can benefit from a treatment that localises to their disease, minimising off-target effects of potent radiotherapy (Section B.2.9). Whilst patients who are PSMA-negative can avoid undergoing an unnecessary therapy, which is unlikely to offer them any benefit, as may occur with untargeted chemotherapy. This approach offers a key advantage in patient selection over conventional therapies. Furthermore, despite patients with PSMA-positive PC having poorer outcomes with SOC, quantitative analysis of VISION demonstrated that patients with greater PSMA expression had statistically superior outcomes for both rPFS and OS when treated with[177] Lu vipivotide tetraxetan.[123]

  • 177

  • o Lu vipivotide tetraxetan selectively targets the primary prostate tumour, as well as any PSMA-positive metastatic lesions, unlike radium-223, which acts through mimicking calcium, localising to bone metastases but not the primary tumour or visceral metastases.

• 177Lu vipivotide tetraxetan is the first radioligand therapy in the treatment of prostate cancer .[2] For this reason,[177] Lu vipivotide tetraxetan offers a new treatment paradigm via its novel mechanism of action and biomarker-targeted approach (Section B.1.2), drawing experience from other disease areas that have benefitted from targeted radioligand therapies. As[177] Lu vipivotide tetraxetan does not act through modifying a hormonal pathway or through systemic cytotoxic effects, it offers patients who have progressed despite these therapies a new mechanism to combat their disease alongside an advantageous safety profile.

  • Radioligand therapy (RLT) represents an important future pillar of oncology treatment with life-enhancing potential. Currently, RLT is only available on the NHS for a small number of patients with rare neuroendocrine cancers.[124] However there are roughly 30 RLT molecules in phase II/III trials globally to treat a variety of cancer types, meaning the therapy platform will soon be able to improve the lives of thousands more patients with different cancers. Investing in capacity to deliver RLT

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treatments will generate value for the NHS through improved infrastructure, shared learnings, and logistical efficiencies for patients and clinicians.

• 177Lu vipivotide tetraxetan provides a significant extension to both OS and rPFS for patients currently eligible for cabazitaxel, as well as those with no other options besides SOC .[25] As such,[177] Lu vipivotide tetraxetan offers not only meaningful outcomes for patients but also offers new hope for patients, as evidenced by the high initial dropout rate in VISION for patients randomised not to receive[177] Lu vipivotide tetraxetan (Sections B.2.5.2 and B.2.5.3). The superiority of[177] Lu vipivotide tetraxetan compared with cabazitaxel is supported by the combined evidence of the RWE analysis, TheraP, and the NMA.

• 177Lu vipivotide tetraxetan leads to a delayed time to SSE .25 Given the known significant morbidity and HRQoL burden of symptomatic bone metastases in mCRPC, delaying time to SSE represents a significant benefit for improving patients’ HRQoL over their disease course (Section B.2.5.4).

• 177Lu vipivotide tetraxetan improved patient HRQoL compared to SOC. 98 The benefit to patients’ HRQoL was reflected in the delayed time to score deterioration for patients receiving 177Lu vipivotide tetraxetan compared with SOC, which was observed across all three HRQoL questionnaires completed by patients (BPI-SF, FACT-P, and EQ-5D-5L; Section B.2.5.5).

• The beneficial effects of[177] Lu vipivotide tetraxetan become rapidly apparent after ******** ******* **

• therapy initiation .[25, 116] Across all primary and key secondary outcomes, the ******[***] ** ********** ********** ** *** ****** ***** ****** *** ***** *** ****** ** ********** ** **** ** *** ***** *** ********** ********** ** ************ ***** *** **** ******* (Section B.2.5).

• 177Lu vipivotide tetraxetan is effective regardless of whether an ARPI is included as part of concurrent SOC.[25] Given the evolving roles of ARPIs earlier in PC treatment pathways alongside the scope of their role being constrained to single-use anywhere in the UK PC treatment pathway, it is key that[177] Lu vipivotide tetraxetan’s clinical benefits are not significantly altered by concurrent receipt of an ARPI, as patients may have received an ARPI earlier in their treatment and no longer be eligible for ARPI as part of SOC (Document B.2.6). Overall, components of SOC in VISION were designed to be used at treating physicians’ discretion, to help manage disease-related symptoms not to extend OS, in the same manner that SOC would be expected to be used in UK clinical practice.

• 177Lu vipivotide tetraxetan demonstrates good clinical efficacy in patients aged ≥65 .25 Although oncological management should not be based upon age alone,[85] as the central risk factor for developing PC is advancing age, it is paramount that any treatments for PC, especially those for mCRPC, are effective and applicable for an elderly population where there is an increased risk of clinical frailty (Section B.2.6).[125]

• 177Lu vipivotide tetraxetan addresses an unmet clinical need in mCRPC patients with liver metastases .[25] Although the sample size of this subgroup was low, leading to wide confidence intervals in subgroup analysis, both OS and rPFS were extended in this vulnerable group of patients. As patients with visceral metastases are known to experience poorer HRQoL (as discussed in Section B.1.3.4) and have limited treatment options (they are unable to receive radium-223), the benefit[177] Lu vipivotide tetraxetan brings to both OS and rPFS has the potential to address a key area of unmet need for these patients (Section B.2.6).

The potential value of[177] Lu vipivotide tetraxetan in clinical practice has also been recognised by the MHRA, with a Promising Innovative Medicine (PIM) designation having been granted in August 2021. This recognises the i) life-threatening nature of mCPRC; ii) high unmet need where

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there is no method of treatment available or existing methods have serious limitations; iii) the medicinal product is likely to offer major advantage over methods currently used in the UK and iv) the potential side effects are likely to be outweighed by the reasonable expectation of a positive risk balance.[126] AAA is awaiting a final decision on the Scientific Opinion that would allow for patients to enroll in the Early Access to Medicines Scheme until marketing authorisation.

In summary,[177] Lu vipivotide tetraxetan offers an innovative approach to treating patients with mCRPC who have progressed despite ARPI and taxane-based chemotherapy. Treatment with 177Lu vipivotide tetraxetan offers improvements to patients’ life expectancy and HRQoL that extend to key subgroups of especially frail patients. Furthermore,[177] Lu vipivotide tetraxetan’s novel mechanism of action and biomarker-targeted approach facilitate a tolerable side effect profile. For these reasons,[177] Lu vipivotide tetraxetan meets the significant unmet need experienced by the patient population relevant to this submission.

B.2.12 Interpretation of clinical effectiveness and safety evidence

Principal findings of the clinical evidence base

Clinical effectiveness

Patients with mCRPC suffer from significantly poorer OS than patients with non-metastatic or hormone-sensitive disease (Section B.1.3.4). Patients receiving SOC only in VISION had a median OS of 11.3 months (95% CI: 9.8, 13.5),[25] which is slightly lower than results reported for the control arm of recent clinical trials in patients with mCRPC who have progressed despite docetaxel, likely due to patients in VISION already having progressed despite receiving both docetaxel and ARPI.[24] Although new therapies have been introduced since this analysis, once patients have exhausted available options, prognosis remains poor with SOC only.[82, 83, 127] In particular, the role of ARPIs has been widely expanded to now include use earlier in the PC management pathway, including non-metastatic patients with high-risk disease as well as patients with metastatic hormone-sensitive PC.[82, 83, 127] Given that role of ARPIs are limited to single-use in a patients entire PC disease management pathway, the expanding earlier use of ARPI further compounds the lack of available treatment options once mCRPC is diagnosed, as an ARPI is highly likely to have already been exhausted. In this context, the importance of extending OS with new, innovative therapies is key to improving outcomes in patients with mCRPC.[177] Lu vipivotide tetraxetan represents a new line of therapy with the potential to significantly extend OS in this setting.

The burden of mCRPC on HRQoL for patients is significant and extends across multiple domains of health, affecting patients’ physical, mental, and emotional well-being (Section B.1.3.4). In particular, given the high prevalence of bone metastases in mCRPC, SSEs play a key role in causing detriment to HRQoL.[25] VISION demonstrated that[177] Lu vipivotide tetraxetan extended time to first SSE by 4.7 months, corresponding to an increase in time free from SSEs of 69.1%.[25] Furthermore, VISION demonstrated significant extensions to time-to-worsening across three HRQoL questionnaires (BPI-SF, FACT-P, EQ-5D-5L).[116] Importantly, these questionnaires collectively cover physical, mental, and emotional well-being, reflecting the broad benefit to HRQoL patients yield from treatment with[177] Lu vipivotide tetraxetan.[25] In particular, patients showed significant extensions in time-to-worsening for all three metrics of pain assessed by the BPI-SF (pain intensity, pain interference, and worst pain intensity), which is critical given the substantial burden of pain, especially bone pain, that patients with mCRPC can experience.[48] In

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summary,[177] Lu vipivotide tetraxetan extended patients’ survival whilst allowing them to experience less pain and maintain an overall better HRQoL during that time.

177Lu vipivotide tetraxetan also demonstrated benefit across a range of subgroups analysed in VISION. Of particular note were the extensions to OS and rPFS observed in patients aged ≥65, with an LDH elevated >260 IU/L, with liver metastases, and of ECOG performance status 2, as these characteristics represent some of the key vulnerabilities present in patients with mCRPC. The subgroup analyses in VISION, although should be interpreted with care due to some wide confidence intervals due to low sample sizes, provide encouraging initial evidence that[177] Lu vipivotide tetraxetan carries benefit even for some of the especially frail patients with mCRPC.

Safety

The safety profile of[177] Lu vipivotide tetraxetan as assessed in VISION demonstrated increased levels of adverse events compared to SOC only but rates of discontinuation were not proportionally raised (11.9%).[25] Furthermore, the key AEs that lead to discontinuation of[177] Lu vipivotide tetraxetan were cytopenias secondary to myelosuppression. It should be noted that CARD, the pivotal trial that investigated the efficacy of cabazitaxel in mCRPC patients having progressed despite docetaxel and ARPI, required all patients receiving cabazitaxel to receive primary prophylaxis G-CSF. Despite this, rates of any-grade leukopenia and neutropenia were 74.4% and 65.9%, respectively; rates of grade ≥3 leukopenia and neutropenia were 32.0% and 44.7% respectively.[113] .[113] In contrast, although prophylactic G-CSF was permitted in VISION, it was not encouraged. Despite this lack of required G-CSF prophylaxis, rates of any-grade leukopenia and neutropenia were 11.0% and 8.1%, respectively; rates of grade ≥3 leukopenia and neutropenia were 2.3% and 3.2% respectively.[25]

Besides AEs related to myelosuppression, all other grade ≥3 AEs were observed in <5% of patients receiving[177] Lu vipivotide tetraxetan alongside SOC. Furthermore,[177] Lu vipivotide tetraxetan did not substantially raise the proportion of AEs leading to an outcome of death (3.2% vs. 2.0%). Overall, these results reflect that although rates of AEs were high, likely contributed to by the frailty of the patient population and their prolonged exposure to treatment as compared with SOC only, the safety profile of[177] Lu vipivotide tetraxetan was consistent with that previously reported, with AEs for the vast majority of patients being tolerable and manageable with appropriate interventions.[25, 116]

Strengths and limitations of the clinical evidence base

The clinical evidence within this submission has been derived from an SLR of clinical trials investigating the efficacy and safety of a variety of treatment options, including[177] Lu vipivotide tetraxetan, in patients with mCRPC (see Section B.2.1). Evidence for[177] Lu vipivotide tetraxetan is provided by the VISION trial, a Phase III, randomised, controlled trial deemed to be of high quality, which was used as the basis of the submitted MHRA marketing authorisation application.

The VISION trial population is broadly consistent with the anticipated licenced indication for[177] Lu vipivotide tetraxetan and the population specified in the NICE final scope (see Section B.1). The trial baseline characteristics are consistent with the target patient population in the UK, and their generalisability has been validated by clinical experts.[5] The generalisability of VISION is further confirmed by alignment with the baseline characteristics observed in the RWE analysis.

One limitation of VISION is that ARPIs were included as a possible option within SOC due the fact it was a global study, with several countries allowing ARPI rechallenge. VISION was Company evidence submission template for[177] Lu vipivotide tetraxetan for treating PSMApositive hormone-relapsed metastatic prostate cancer after 2 or more therapies [ID3840]

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designed in this manner to provide physicians flexibility in how they choose to manage frail, heavily pre-treated patients, in order to help extend life and palliate symptoms. In the UK, ARPI usage is limited to once in the entire treatment-pathway for PC.[2] Given the earlier roles of ARPI in treating PC,[78, 83] it is possible that patients with mCRPC in the UK may no longer have ARPI as an available option for their SOC. However, subgroup analysis of VISION demonstrated that both alternative primary endpoints, extension of OS and rPFS, were met regardless of ARPI inclusion as part of SOC. Therefore, this limitation of VISION is not expected to limit the generalisability of results to the UK patient population.

A further strength of the evidence base is that the OS data from VISION are reasonably mature. At the most recent data cut (27[th] January 2021), 62.3% of patients in the[177] Lu vipivotide tetraxetan + SOC arm, and 66.8% of patients in the SOC arm had died (Section B.2.5.2). Analysis of OS demonstrated a significant HR (0.62, p<0.001) with established 95% CIs (0.52, 0.74). Likewise, for rPFS, 44.4% of patients in the[177] Lu vipivotide tetraxetan + SOC arm, and 30.1% of patients in the SOC arm showed radiographic disease progression (B.2.5.3). Analysis of rPFS also demonstrated a significant HR (0.40, p<0.001) with established 95% CIs (0.29, 0.57).

A limitation of the evidence base was the lack of a sufficiently robust head-to-head comparison for[177] Lu vipivotide tetraxetan compared to the relevant comparator cabazitaxel in patients considered medically suitable for taxane-based chemotherapy. However, three key sources of evidence are available to support this comparison. The RWE provides UK-specific data and confirms the generalisability of VISION data to mCRPC patients in UK clinical practice through close alignment of baseline and clinical characteristics. Furthermore, TheraP offers strong supporting evidence in the form a Phase II clinical trial, which demonstrates a significant benefit to rPFS when patients receive[177] Lu vipivotide tetraxetan compared with cabazitaxel. Additionally, the rPFS HR reported in TheraP closely resembles that generated through the NMA, adding support to its accuracy despite noted inter-trial heterogeneity. The NMA demonstrated the significant benefit of[177] Lu vipivotide tetraxetan in both OS and rPFS, compared with cabazitaxel. Therefore, when considered in conjunction, the RWE, TheraP and the NMA provide strong evidence to support the superiority of[177] Lu vipivotide tetraxetan compared with cabazitaxel.

A final limitation of the VISION trial was its open label design, which led to the initial high dropout rate in the SOC only arm due to disappointment at not receiving[177] Lu vipivotide tetraxetan (Section B.2.3.3). Blinding was not possible due to the ease with which patients and site personnel would be able to ascertain if a radioactive dose was being administered. However, trial site education measures alongside creation of the PFS-FAS allowed for equitable distribution between the interventional and control arms of the trial with subsequent analysis of rPFS not being affected by bias due to the early high drop-out rate disproportionately affecting the SOC only arm.

End-of-life criteria

177Lu vipivotide tetraxetan should be considered as an end-of-life treatment for adult patients with PSMA-positive mCRPC who have been treated with ARPI and taxane-based chemotherapy or who are not medically suitable for taxanes, given that (a) these patients have a limited expectancy, normally less than 2 years and (b) there is sufficient evidence to indicate that the 177Lu vipivotide tetraxetan offers an extension to life of at least an additional 3 months, compared with current NHS treatment (Table 31).

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Table 31: End-of-life criteria

Abbreviations:[177] Lu: Lutetium-177; ARPI: androgen receptor pathway inhibition; mCRPC: metastatic castrationresistant prostate cancer, NHS: National Health Service, OS: overall survival; PSMA: prostate-specific membrane antigen, SOC: standard of care. Source: Sartor et al. (2021).[25]

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B.3 Cost effectiveness

177Lu vipivotide tetraxetan (at PAS price) represents a cost-effective use of NHS resources compared to cabazitaxel, with a base case ICER below the £50,000 per QALY willingness-to-pay threshold for end-of-life treatments. Cabazitaxel represents the most relevant active comparator for 177Lu vipivotide tetraxetan in clinical practice, and thus forms the focus of the cost-effectiveness analysis. De novo cost-effectiveness model • A de novo cost-utility model was developed to evaluate the cost-effectiveness of[177] Lu vipivotide tetraxetan + SOC versus clinically relevant comparators (cabazitaxel and SOC) for the treatment of mCRPC. • The model which has been developed is a cohort-based partitioned survival model consisting of three mutually exclusive health states: (I) progression-free; (II) progressed; and (III) dead • For the[177] Lu vipivotide tetraxetan and SOC treatment arms, standard parametric distributions and spline models were used to extrapolate time-to-event data from VISION (rPFS and OS) for patients in the model. • For the cabazitaxel treatment arm, rPFS was informed by application of the HR from the NMA to the extrapolated time-to-event data for the[177] Lu vipivotide tetraxetan treatment arm, and OS was informed directly by RWE for patients who received cabazitaxel in UK clinical practice (see Section B.2.8). • Treatment-specific utility values for the ‘pre-progression’ and ‘progressed’ health states were derived from EQ-5D data from VISION for[177] Lu vipivotide tetraxetan and SOC. Based on feedback from clinical experts, the ‘pre-progression’ utility value for cabazitaxel was assumed to be equivalent to SOC, given its greater toxicity than[177] Lu vipivotide tetraxetan, and the utility value for the ‘progressed’ health state was sourced from NICE TA391. • Resource use and costs included in the model were based on costs taken from the British National Formulary (BNF) [2021][128] , the Drugs and pharmaceutical electronic market information tool (eMIT) [2021][129] and the National Schedule of NHS costs (2019-20).[130] • Feedback from UK clinicians was sought in an advisory board setting in order to validate assumptions and inputs included in the model. Base case cost-effectiveness results • Cabazitaxel represents the most relevant active comparator for[177] Lu vipivotide tetraxetan in clinical practice, forming the focus for the cost-effectiveness analysis. Given the substantial unmet need in clinical practice for patients who are not suitable for treatment with taxanes, results are also presented versus SOC. • Compared to cabazitaxel,[177] Lu vipivotide tetraxetan was associated with an increased number of life years () and QALYs gained (), but also higher total costs (). In the base case analysis the ICER for[177] Lu vipivotide tetraxetan versus cabazitaxel was ******** at[177] Lu vipivotide tetraxetan list price and £49,949 at[177] Lu vipivotide tetraxetan PAS price. • Compared to SOC,[177] Lu vipivotide tetraxetan was associated with an increased number of life years () and QALYs gained (), but also higher total costs (). In the base case analysis the ICER for[177] Lu vipivotide tetraxetan versus SOC was £* at[177] Lu vipivotide tetraxetan list price and £125,687 at[177] Lu vipivotide tetraxetan PAS price. Sensitivity analyses • The DSA results identified a small number of key influential parameters (pre-/post progression utility value, and exposure to[177] Lu vipivotide tetraxetan) with the model being largely robust to uncertainty in the majority of parameters. • Scenario analyses were conducted to address sources of uncertainty in the model (adjustment for informative censoring of OS/rPFS, health state utility values, concomitant treatment, subsequent treatment, therapeutic interventions).

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B.3.1 Published cost-effectiveness studies

An SLR was conducted to identify any relevant economic evaluations for the treatment of adult patients with pre-treated, progressive mCRPC. This population is broadly aligned to the anticipated licenced indication of adult patients with PSMA-positive mCRPC who have been treated with ARPI and taxane-based chemotherapy or who are not medically suitable for taxanes. Searches were performed on 3[rd] November 2021 and full details of the SLR search strategy, study selection process, results and quality assessment of included studies are reported in Appendix G.

The SLR identified 26 articles from 20 cost-effectiveness studies. Details of these studies are presented in Table 32. The SLR did not identify any economic evaluations or prior TAs which considered the specific population of interest to this submission, however, NICE TA391,[10] NICE TA316,[83] NICE TA259,[82] and the ongoing NICE TA ID1640,[11] as a whole have been considered to inform the structure of the de novo economic analysis presented in this submission, as well as various inputs utilised in the analysis.

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Table 32: Summary list of published cost-effectiveness studies identified in the SLR

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Abbreviations : BSC: best supportive care; ICER: incremental cost-effectiveness ratio; mCRPC: metastatic castration-resistant prostate cancer; NA: not applicable; NR: not reported; QALYs: quality-adjusted life years; SOC: standard of care; TDM: therapeutic drug monitoring.

Table 33: Summary of previous TAs identified in the SLR

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Abbreviations : BSC: best supportive care; ICER: incremental cost-effectiveness ratio; mCRPC: metastatic castration-resistant prostate cancer; NICE: National Institute of Care and Clinical Excellence; OS: overall survival; PFS: progression free survival; QALYs: quality-adjusted life years; SRE: skeletal related event; TA: technology appraisal.

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B.3.2 Economic analysis

Of the 18 cost-effectiveness studies and eight previous NICE TAs identified within the SLR, none evaluated the cost-effectiveness of[177] Lu vipivotide tetraxetan compared with cabazitaxel or SOC. For this reason, a de novo cost-effectiveness analysis has been conducted to inform the economic model presented in this submission. The cost-effectiveness model employed for this economic analysis was built in Microsoft Excel[® ] and the objective of this economic analysis was to assess the cost effectiveness of[177] Lu vipivotide tetraxetan compared with cabazitaxel or SOC in patients with PSMA-positive mCRPC.

In line with the NICE reference case, this analysis was conducted from the perspective of the NHS, including direct medical costs and Personal Social Services (PSS) over a lifetime time horizon.

B.3.2.1 Patient population

The patient population considered within this economic evaluation is adult patients with PSMApositive mCRPC who have been treated with ARPI and taxane-based chemotherapy or who are not medically suitable for taxanes. As set out in the decision problem in Section B.1.1 above (Table 1), the population for this economic evaluation is in line with the full anticipated marketing authorisation for[177] Lu vipivotide tetraxetan in mCRPC. Furthermore, the population for this economic evaluation largely aligns with the VISION trial population, aside from those patients not medically suitable for taxanes, who did not meet the inclusion criteria for VISION. This subpopulation is expected to represent only a small proportion of the overall patients eligible for 177Lu vipivotide tetraxetan, and for equity of access it is important to include these patients within the cost-effectiveness analysis.

B.3.2.2 Model structure

As noted in Section B.3.1, no prior health economic evaluations for[177] Lu vipivotide tetraxetan in adult patients with PSMA-positive mCRPC who have been treated with ARPI and taxane-based chemotherapy or who are not medically suitable for taxanes were identified by for published economic evaluations in this indication. Therefore, a de novo health economic model was constructed in Microsoft Excel to evaluate the cost-effectiveness of[177] Lu vipivotide tetraxetan versus clinically relevant comparators.

The model which has been developed is a cohort-based partitioned survival model consisting of three mutually exclusive health states:

• Progression-free (PF) – Defined as the period before the patient has experienced disease progression

• Progressed disease (PD) – Defined as the period where the patient remains alive following disease progression where patients may receive treatment with subsequent anticancer therapy and supportive care

• Dead – An absorbing state into which patients transition upon their death

A graphical depiction of the partitioned survival model approach is presented in Figure 14. Patients enter into the model upon commencing treatment, and then progress through the three health states for the time horizon of the model based on the survival functions associated with each treatment. The distribution of patients in each health state is governed by VISION-derived

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rPFS and OS curves. The model employed a one-week cycle length as this provided the greatest precision in the tracking of the number of patients in each health state in the early years of the model. This cycle length is relatively short compared to the model’s 10-year time horizon, and as such there were no half-cycle corrections applied in the model. Within the model there are no patients remaining alive in either treatment arm at 10 years, therefore, the 10-year time-horizon utilised within the model is considered to represent a life-time horizon for this patent population.

The partitioned survival approach was selected for this analysis as it is considered the most suitable for an oncology model in which patients are expected to unilaterally progress, and no cure or spontaneous remission are considered clinically plausible with current therapies. Thus, the model structure does not allow for patients to improve their health state, which reflects the progressive nature of their condition. The partitioned survival approach also allows for modelling of OS and rPFS based on study-observed events, which facilitates the replication of within-trial data and means that the model is expected to accurately reflect disease progression and the observed survival profile of patients treated with[117] Lu vipivotide tetraxetan and comparator therapies. Furthermore, a partitioned survival approach is consistent with previous NICE technology appraisals (TAs) in mCRPC, including NICE TA391,[10] NICE TA316,[83] NICE TA259,[82] and the ongoing NICE TA ID1640.[11]

Figure 14: Partitioned survival model structure

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The data in the figure are fictitious and used for illustrative purposes only. S(t) PFS is the survival function describing the probability that a patient remains in the progression-free health state beyond a specific time point (t) from model entry. S(t) OS is the survival function describing the probability that a patient survives in the progression-free or the progressed health states beyond a specific time point (t) from model entry. Membership in the progressed health state is determined by subtracting the progression-free state membership from the dead state membership. Abbreviations: OS: overall survival; PFS: progression-free survival.

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Features of the de novo analysis

Costs and health-related utilities were allocated to each health state and multiplied by state occupancy to calculate the weighted costs and QALYs per cycle. Cost components considered included: drug acquisition and administration costs for each treatment ([177] Lu vipivotide tetraxetan, cabazitaxel, concomitant treatments, therapeutic interventions given as part of SOC, and subsequent active cancer-related therapies), health state costs (capturing medical resource utilisation), and cost of individual SSEs and AEs. Effectiveness measures included life years (LYs) and QALYs. The incremental cost-effectiveness ratio (ICER) of[177] Lu vipivotide tetraxetan versus cabazitaxel and SOC was evaluated in terms of the incremental cost per QALY gained.

The analysis was conducted from the perspective of the NHS, including direct medical costs and Personal Social Services (PSS) costs over a lifetime time horizon (10 years) for the patient cohort from the initiation of treatment. A weekly cycle length was considered in the base case, and both costs and effects were discounted at 3.5% annually.[149] The economic analysis is conducted using the most recent estimates of resource use and treatment costs available from published sources (2020/2021). Costs quoted for other cost-years or in other currencies are inflated to the model cost-year and/or converted to UK, as applicable. A summary of the features of the economic analysis is presented in Table 34. This analysis is broadly consistent with the modelling approach taken in previous appraisals for therapies used earlier in the treatment pathway.[10, 82, 83]

Table 34: Summary of the features of the economic analysis

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Abbreviations: BNF: British National Formulary; eMIT: Drugs and pharmaceutical electronic market information tool; NICE: National Institute of Health and Care Excellence; NHS: National Health Service; PSS: personal social services; QALY: quality-adjusted life-year.

B.3.2.3 Intervention technology and comparators

Intervention technology

The intervention of interest is 7,400 MBq (200 mCi) of[177] Lu vipivotide tetraxetan (1,000 MBq/mL [27 mCi/mL]) administered intravenously via injection or infusion once every 6 weeks (±1 week) for a total of 6 doses. This is aligned to the draft SmPC for[177] Lu vipivotide tetraxetan and broadly in accordance with the dosing regimen used in VISION.[25] Data from the[177] Lu vipivotide tetraxetan + SOC arm of the VISION trial were used to inform the inputs in the economic analysis.[25]

Comparators

This cost-effectiveness evaluation considers 25 mg/m[2] of cabazitaxel administered via infusion every 3 weeks for a total of 10 doses, which represents the most relevant comparator for[177] Lu vipivotide tetraxetan for patients eligible for treatment with further chemotherapy following treatment with an ARPI and docetaxel. As described in Section B.1.3.3, it is expected that the vast majority of patients who do receive further chemotherapy currently receive cabazitaxel and therefore this is considered the most appropriate comparator for[177] Lu vipivotide tetraxetan. In the absence of appropriate head-to-head clinical data to inform a comparison between[177] Lu vipivotide tetraxetan and cabazitaxel, clinical inputs for cabazitaxel have been informed by data from the UK RWE analysis (see Section B.2.8.1), and HRs derived from the NMA (see Section B.2.8.6) which have been applied to the survival extrapolations for[177] Lu vipivotide tetraxetan.[25 ] Cabazitaxel is considered to represent the most relevant active comparator for[177] Lu vipivotide tetraxetan in clinical practice, and thus forms the focus for the cost-effectiveness analysis.

This cost-effectiveness analysis considers SOC as a relevant comparator for[177] Lu vipivotide tetraxetan in patients who are not eligible for treatment with cabazitaxel following treatment with an ARPI and docetaxel, or patients who are medically unsuitable for treatment with taxanes,

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given the substantial unmet need in this patient population. The comparison of[177] Lu vipivotide tetraxetan to SOC is in line with the comparison made in VISION, and therefore data from the SOC arm of VISION trial were used to inform the inputs in the economic analysis.[25 ] Although VISION was designed to specifically select patients who had previously received taxanes, mechanistically, there is no reason that the efficacy and safety of[177] Lu vipivotide tetraxetan would be significantly different in patients who have not previously received taxanes compared to patients who have previously received taxanes. Thus, the clinical efficacy and safety data from VISION is considered to be generalisable to those patients who are medically unsuitable for taxanes.

B.3.3 Clinical parameters and variables

B.3.3.1 Baseline characteristics

The baseline characteristics for the modelled cohort are provided in Table 35. These inputs were based on the baseline characteristics of patients in VISION. The baseline characteristics for the patients in VISION are consistent with the target patient population in the UK as evidenced through their similarity to those of the patients receiving cabazitaxel in the RWE analysis. Furthermore, the generalisability of the baseline characteristics has been validated by clinical experts.[153]

Table 35: Patient baseline characteristics in the model

Weight, heights and BSA are used for calculating dosing in derivation of treatment costs and are not model inputs. BSA calculated using the Mostellar formula.[154] Abbreviations: BSA: body surface area.

B.3.3.2 Radiographic Progression Free Survival (rPFS)

As described in Section B.3.2.2, the model is a cohort-based partitioned survival model consisting of three mutually exclusive health states: (i) PF, (ii) PD, and (iii) dead. The proportion of patients within each health state at each weekly model cycle was then determined for both treatment arm using cumulative survival probabilities which were derived from the VISION intention-to-treat OS and rPFS curves. As the follow-up of VISION was shorter than the model time horizon, extrapolation from the observed rPFS and OS data was required.

In accordance with the NICE Decision Support Unit (DSU) Technical Support Document (TSD) 14 and TSD21 guidance, a range of standard parametric distributions (e.g. exponential, Weibull, stratified Weibull, Gompertz, stratified Gompertz, log-normal, stratified log-normal, log-logistic, stratified log-logistic, gamma, stratified gamma, generalised gamma, and stratified generalised gamma) and flexible models (i.e. spline models) were explored for extrapolation.[155, 156]

The spline models explored were developed based on the algorithm by Royston and Parmar et al. (2002).[157] Stratified and unstratified one-, two-, and three-knot Weibull spline models were explored and the goodness-of-fit criteria (including the Akaike information criterion [AIC] and the Bayesian information criterion [BIC]) were then estimated for each parametric function. Stratified Company evidence submission template for[177] Lu vipivotide tetraxetan for treating PSMApositive hormone-relapsed metastatic prostate cancer after 2 or more therapies [ID3840]

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models refer to models in which all parameters can vary by treatment. These models relax the assumptions of proportional hazards (PH) or constant acceleration factors, and the use of stratified models allows model fit statistics to be used to compare the model fit across all models (unlike models fitted separately to each treatment arm, wherein model fit cannot be compared across all models).

In determining the choice of survival model for the base case, consideration was given to the following, as per the recommendations provided in NICE DSU TSD14 and TSD21.[155]

• AIC/ BIC tests: the AIC and the BIC provide useful statistical tests of the relative fit of different parametric survival models. These tests weight the improved fit of models with the potentially inefficient use of additional parameters. Lower AIC and BIC values indicate better fit of the selected model.

• Visual inspection: the visual inspection can evaluate how well a parametric survival model fits with the observed Kaplan–Meier curves. The parametric survival model that most closely follows the Kaplan–Meier curve could be considered the best fit.

• Clinical plausibility for both short-term and long-term estimates of survival.

Adjustments were also made in the model traces to ensure that logical inconsistencies, such as the proportion of patients alive being less than the proportion of patients alive and progressionfree, could not occur (i.e. rPFS and time-to-first SSE were bound by OS as a minimum).

In addition, the VISION trial was an open-label study, and patients could withdraw from the study at any time during follow-up. There is a risk that any imbalance between study arms in the number of patients that withdrew from the study could be associated with one or more prognostic effects. This could lead to informative censoring where the patients that withdrew from the study may not be representative of the intent-to-treat (ITT) population. As such, scenario analyses were explored to where inverse probability-of-censoring weighting (IPCW) was conducted to adjust for informative censoring; full details are presented in Appendix J.

177Lu vipivotide tetraxetan and SOC

The rPFS data from VISION (see Section B.2.5.3) was used to fit the parametric models. A range of parametric models were considered; however, the fit of these models were problematic because of the plateau (flat tails) to the curves in both arms. This plateau means it is difficult to fit curves that both fit the data well, and that produce plausible long-term extrapolations. Investigatory analyses were conducted to assess the proportional hazards assumption. These indicated that the proportional hazards assumption was not met (Chi-square = 15.1, 1 degree of freedom, P < 0.0001).

The original fit of the stratified Gompertz model produced flat curves in the extrapolation of the control arm. To make these extrapolations plausible the hazard rates in the SOC arm were constrained to be greater than or equal to those in the[177] Lu vipivotide tetraxetan arm after the maximum follow-up time for rPFS. The same rule was applied to the stratified flexible splinebased Weibull for 1 and 2-knot models. The knot positions of these 2 spline-based models were also manually altered to find models that gave plausible predictions, as the original models also produced flat curves for the extrapolations. A stratified flexible spline-based Weibull model with 3-knot was also attempted, but this model failed to converge.

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The fit of parametric models to the VISION trial data for rPFS data is shown in Figure 15 and long-term predictions in Figure 16. The fit of Royston-Palmar parametric models to the VISION trial data for rPFS data is shown in Figure 17 with long-term predictions shown in Figure 18.

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Figure 15: Radiographic progression free survival: Standard parametric models

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Abbreviations: BSC/BSoC: Standard of care; PSMA: prostate specific membrane antigen.

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Figure 16: Radiographic progression free survival: Standard parametric models: Long-term extrapolations

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Abbreviations: BSC/BSoC: Standard of care; PSMA: prostate specific membrane antigen.

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Figure 17: Radiographic progression free survival: Royston-Palmar spline-based models

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Abbreviations: BSC/BSoC: Standard of care; PSMA: prostate specific membrane antigen.

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Figure 18: Radiographic progression free survival: Royston-Palmar spline-based models: Long-term extrapolations

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Abbreviations: BSC/BSoC: Standard of care; PSMA: prostate specific membrane antigen

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Visual assessment of the standard parametric models compared to the VISION data indicated that all models provided a poor fit to initial survival. The stratified Gompertz and generalised gamma models appeared to give the best visual fit. However, the generalised gamma model had difficulty in capturing the uncertainty of the extrapolations. The stratified flexible spline-based models provided a good visual fit with data and appeared to capture the uncertainty well for the extrapolation. The model fit statistics for the models fitted to the OS data are presented in Figure 19.

Figure 19: Radiographic progression free survival model fit: Akaike’s information criterion (A) and Bayesian information criterion (B)

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Abbreviations: AIC: Akaike’s information criterion; BIC: Bayesian information criterion.

The stratified flexible spline-based Weibull with 2-knots was selected for the base-case analysis as this produced the best statistical fit according to AIC and BIC, good visual fit to the VISION data, and appeared to capture the uncertainty in the SOC arm well. Clinical experts confirmed the clinical predictions for[177] Lu vipivotide tetraxetan and SOC based on this model were

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plausible. In order to explore the impact of adjusting the survival extrapolations on the costeffectiveness analysis, a scenario analysis was conducted using the stratified flexible Weibull (1 knot) model, representing the next best fitting curve according to AIC and BIC and also aligning with clinical predictions for[177] Lu vipivotide tetraxetan and SOC.

The predicted mean rPFS for the models considered are presented in Table 36, estimated through simulations of survival curves based on the model parameters and variance covariance matrices.

Table 36: Predicted mean rPFS versus SOC for selected survival extrapolations

Abbreviations: CrI: credible interval; rPFS: radiographic progression free survival.

Cabazitaxel

In the absence of appropriate clinical or real-world data to inform rPFS for the patient population of relevance to this economic analysis, a HR of **** **** *** ************ for cabazitaxel vs.[177] Lu vipivotide tetraxetan , representing the inverse of the HR presented in the NMA described in Section B.2.8 ***** **** *** *********** was applied to the extrapolated rPFS data from the[177] Lu vipivotide tetraxetan + SOC arm of the VISION. Despite uncertainty in the NMA (as described in Section B.2.8.4 and Section B.2.8.7) this HR is very similar to the HR derived from the TheraP trial for the comparison of[177] Lu vipivotide tetraxetan compared with cabazitaxel (1.59 [95% CI: 1.16–2.17]), which provides external validation for the use of the NMA results within the model.[110] Clinical experts also considered the rPFS HR for cabazitaxel vs[177] Lu vipivotide tetraxetan to be reasonable. The resulting curves applied in the base case and scenario analyses for cabazitaxel are presented in Figure 20, and the predicted mean rPFS for the models considered are presented in Table 37.

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Figure 20: Cabazitaxel rPFS curves applied in the base case and scenario analyses generated from reference[177] Lu vipivotide tetraxetan survival curves

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Abbreviations: rPFS: radiographic progression free survival.

Table 37: Predicted difference in mean rPFS versus cabazitaxel for selected survival extrapolations

aThe mean rPFS for cabazitaxel has been determined from the area under curve of the model trace (assuming a 10-year time horizon) and as such 95% CrI are not available. Abbreviations: CrI: credible interval; rPFS: radiographic progression free survival.

Summary of base case rPFS assumptions

The base case rPFS extrapolations for[177] Lu vipivotide tetraxetan, cabazitaxel and SOC are shown in Figure 21. It should be acknowledged that the rPFS curve for cabazitaxel falls below that of SOC. As described above, many of the extrapolations for the VISION control arm produced flat curves that were not clinically plausible. This included the stratified flexible splinebased Weibull 2-knot model used in the base case, which was by far the best fitting model according to AIC and BIC. As a result, the hazard rates in the SOC arm were constrained to be greater than or equal to those in the[177] Lu vipivotide tetraxetan arm after the maximum follow-up time for rPFS. These difficulties in extrapolating the SOC arm may explain this logical inconsistency between the cabazitaxel and SOC rPFS curves.

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Figure 21: Selected distributions for extrapolating rPFS for[177] Lu vipivotide tetraxetan, SOC (VISION) and cabazitaxel (via HR)

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Abbreviations: HR: hazard ratio; KM: Kaplan-Meier; PSMA: prostate-specific membrane antigen; rPFS: radiographic progression free survival; SOC: standard of care.

B.3.3.3 Overall Survival (OS)

The survival models for the base case were selected in line with the approach outlined for rPFS (Section B.3.3.2)

177Lu vipivotide tetraxetan and SOC

The OS data from VISION (see Section B.2.5.2) was used to fit the parametric models. The OS data showed less complicated survival curves compared with the rPFS data. There was a possible departure from the proportional hazards assumption between 0 and 9 months, although this appeared to be relatively minor and may potentially be captured with accelerated failure time models. The test for proportional hazards was inconclusive (Chi-squared = 2.76; degrees of freedom = 1; p = 0.097).

The OS data in VISION is not completely mature, which can make survival extrapolation problematic. As such, a targeted literature search was performed to identify registry studies presenting Kaplan–Meier graphs for OS in populations of mCRPC patients. The purpose of this search was to identify data that could guide survival extrapolation model choice for patients receiving SOC only. Six suitable studies were identified, and the findings of this literature search are summarised in Table 38.

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Table 38: Identified publications presenting Kaplan–Meier OS registry data for patients with mCRPC