Single Technology Appraisal

Belzutifan for treating tumours associated with von Hippel-Lindau disease [ID3932]

Committee Papers

NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

SINGLE TECHNOLOGY APPRAISAL

Belzutifan for treating tumours associated with von Hippel-Lindau disease [ID3932]

Contents:

The following documents are made available to stakeholders:

Access the final scope and final stakeholder list on the NICE website.

1. Company submission from Merck Sharp & Dohme :

• a. Full submission

• b. Summary of Information for Patients (SIP)

2. Clarification questions and company responses

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

• a. Action Kidney Cancer

• b. UK Kidney Association

• c. VHL UK

4. External Assessment Report prepared by Kleijnen Systematic Reviews Ltd

5. External Assessment Report – factual accuracy check

6. Technical engagement response from company

7. Technical engagement responses and statements from experts:

• a. Clinical expert, nominated by UK Kidney association

• b. Patient expert, nominated by VHL UK/Ireland

• c. Patient expert, nominated by VHL UK/Ireland

8. External Assessment Group critique of company response to technical engagement prepared by Kleijnen Systematic Reviews Ltd

• 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

Belzutifan for treating tumours associated with von Hippel-Lindau disease (ID3932)

Document B

Company evidence submission

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June 2023

Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

© Merck Sharp & Dohme (UK) Limited (2023). All rights reserved

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Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

© Merck Sharp & Dohme (UK) Limited (2023). All rights reserved

Contents

Tables and figures ................................................................................................................... 4 Abbreviations ......................................................................................................................... 14 Definitions and descriptions of key terms used in the submission ................................ 16 B.1 Decision problem, description of the technology and clinical care pathway ......... 19 B.2 Clinical effectiveness ..................................................................................................... 39 B. 3 Cost effectiveness ....................................................................................................... 121 B.4 References .................................................................................................................... 259 B.5 Appendices ................................................................................................................... 270 Appendix C: Summary of product characteristics (SmPC) and UK public assessment report ..................................................................................................................................... 271 Appendix D: Identification, selection and synthesis of clinical evidence .................... 272 Appendix E: Subgroup analysis ........................................................................................ 301 Appendix F: Adverse reactions ......................................................................................... 302 Appendix G: Published cost-effectiveness studies ........................................................ 310 Appendix H: Health-related quality-of-life studies .......................................................... 338 Appendix I: Cost and healthcare resource identification, measurement and valuation ................................................................................................................................................ 377 Appendix J: Clinical outcomes, base-case analysis inputs and disaggregated results from the model ..................................................................................................................... 377 Appendix K: Price details of treatments included in the submission ........................... 398 Appendix L: Checklist of confidential information .......................................................... 399 Appendix M: MK-6482-004 study statistical analysis details ....................................... 400 Appendix N: Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST 1.1) definitions of best overall response .......................................................................... 408 Appendix O: MK-6482-004 study results from other data cut-off dates ..................... 412 Appendix P: Additional MK-6482-004 study results ...................................................... 417 Appendix Q: VHL Natural History Study summary of key details ................................ 424

Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

© Merck Sharp & Dohme (UK) Limited (2023). All rights reserved

Tables and figures

Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

© Merck Sharp & Dohme (UK) Limited (2023). All rights reserved

Table 25 MK-6482-004 summary of best overall tumour response for pancreatic neuroendocrine tumours (RECIST 1.1) – independent review committee (efficacy analysis set) ............................................................................................................. 89 Table 26 MK-6482-004 summary of duration of response for pancreatic neuroendocrine tumours (RECIST 1.1) – independent review committee (efficacy analysis set) ............................................................................................................. 92 Table 27 MK-6482-004 summary of time to response for pancreatic neuroendocrine tumours (RECIST 1.1) – independent review committee (efficacy analysis set) ...... 94 Table 28 MK-6482-004 summary of progression-free survival for pancreatic neuroendocrine tumours (RECIST 1.1) – independent review committee (efficacy analysis set) ............................................................................................................. 94 Table 29 Sample selection process: Trial Population Subgroup ............................ 101 Table 30 Baseline characteristics of the VHL Natural History Study and MK-6482-004 trial populations before – VHL RCC cohort ............................................................ 102 Table 31 Baseline characteristics of the VHL Natural History Study and MK-6482-004 trial populations before matching – VHL CNS hemangioblastoma cohort (patients with VHL-associated RCC and CNS hemangioblastoma) ............................................. 102 Table 32 Baseline characteristics of the VHL Natural History Study and MK-6482-004 trial populations before matching – VHL pNET cohort (patients with VHL-associated RCC and pNET) ..................................................................................................... 103 Table 33 Baseline characteristics of the VHL Natural History Study and MK-6482-004 trial populations before and after reweighting – VHL RCC cohort .......................... 105 Table 34 Baseline characteristics of the VHL Natural History Study and MK-6482-004 trial populations before and after reweighting – VHL CNS hemangioblastoma cohort ............................................................................................................................... 106 Table 35 Baseline characteristics of the VHL Natural History Study and MK-6482-004 trial populations before and after reweighting – VHL pNET cohort ......................... 106 Table 36 Selected model parameters estimated in the reweighted VHL Natural History Study RCC cohort and the MK-6482-004 trial population....................................... 107 Table 37 Patient demographics .............................................................................. 111 Table 38 Disease status by current treatment status ............................................. 112 Table 39 EQ-5D by metastatic status ..................................................................... 113 Table 40 EQ-5D by disease status in patients with metastatic disease ................. 113 Table 41 EQ-5D by disease status, among patients without metastatic disease ... 114 Table 42 MK-6482-004 study summary of adverse events .................................... 116 Table 43 Features of the economic analysis .......................................................... 129 Table 44 Summary of clinical parameters sourced from the VHL Natural History Study and the pre-treatment period data from the MK-6482-004 trial. ............................. 137 Table 45 Cause-specific hazards and data sources for transitions from the pre-surgery state, by model cohort and treatment arm .............................................................. 141 Table 46 Cause-specific hazards and data sources for transitions from the event-free after surgery state, by model cohort and treatment arm ......................................... 142 Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

© Merck Sharp & Dohme (UK) Limited (2023). All rights reserved

Table 47 Parameters used to estimate the proportion of pre-surgery → death transitions that are attributable to CNS Hb progression in each model cohort ....... 148 Table 48 Summary of transition probability estimation approaches from pre-surgery and event-free after surgery health states .............................................................. 154 Table 49 Incidence rates of surgeries (events/person-year) for non-primary VHLrelated tumours, by cohort and treatment arm ....................................................... 158 Table 50 Distribution of surgeries for non-primary VHL-related tumours, by cohort158 Table 51 Perioperative mortality risk by VHL cohort............................................... 160 Table 52 Risks of short-term surgical complications per surgery for VHL-RCC ..... 161 Table 53 Risks of short-term surgical complications per surgery for VHL-CNS Hb 161 Table 54 Risks of short-term surgical complications per surgery for VHL-pNET .... 162 Table 55 Risks of short-term surgical complications per surgery for non-primary VHLassociated tumours ................................................................................................ 162 Table 56 Risks of long-term complications following surgery for VHL-RCC ........... 163 Table 57 Risks of long-term surgical complications per surgery for VHL-CNS Hb . 164 Table 58 Risks of long-term surgical complications per surgery for VHL-pNET ..... 164 Table 59 Risks of long-term surgical complications per surgery for non-primary VHLassociated tumours ................................................................................................ 164 Table 60 Adjustment factors applied to the hazard rates of surgery and metastatic disease between the Optum database and VHL Natural History Study (to account for real-world SOC) ..................................................................................................... 166 Table 61 Metastases by origin tumour ................................................................... 167 Table 62 Market shares of first-line regimens for metastatic disease by treatment arm with RCC as the origin tumour ............................................................................... 167 Table 63 Market shares of first-line regimens for metastatic disease by treatment arm with pNET as the origin tumour .............................................................................. 168 Table 64 Exponential models of OS and PFS with sunitinib in advanced RCC ...... 169 Table 65 HRs of OS and PFS failure with other treatments vs. sunitinib in advanced RCC ....................................................................................................................... 169 Table 66 Exponential models of OS and PFS with streptozocin/5-fluorouracil and no active treatment in the advanced pNET setting ...................................................... 171 Table 67 HRs of OS and PFS failure with other treatment regimens vs. no active treatment in the advanced pNET setting ................................................................ 171 Table 68 Hazards of death from metastatic disease by target population and treatment arm ......................................................................................................................... 173 Table 69 Landmark estimates: time to first surgery, metastases, or death ............ 176 Table 70 Landmark estimates: OS by cohort ......................................................... 180 Table 71 Risks and durations of modelled AEs ...................................................... 181 Table 72 Statistical fit for parametric models fitted to belzutifan ToT ..................... 182 Table 73 Base-case assumptions for treatment effect waning time period ............ 188 Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

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Table 74 Health state utilities in the base case by response / progression status .. 195 Table 75 Distribution of objective response level by VHL cohort and treatment arm used to calculate utility values in the pre-surgery, surgery, and event-free after surgery states ...................................................................................................................... 196 Table 76 Response-adjusted overall utility in non-metastatic health states (presurgery, surgery, and event-free after surgery) ...................................................... 196 Table 77 Long-term surgical complication disutility values in the base case .......... 199 Table 78 Short-term surgical complication disutility values in the base case ......... 200 Table 79 Summary of adverse event disutility values in the base case ................. 202 Table 80 Regression coefficients used for the estimation of age-related disutility . 202 Table 81 Summary of caregiver disutility values in the base case ......................... 203 Table 82 Belzutifan treatment acquisition and administration costs per 28-day cycle ............................................................................................................................... 204 Table 83 Unit drug costs for first- and second-line therapies for advanced RCC and pNET ...................................................................................................................... 206 Table 84 Dosing schedules and RDI for first- and second-line therapies for advanced RCC ....................................................................................................................... 207 Table 85 Dosing schedules for first- and second- line therapies for advanced pNET ............................................................................................................................... 209 Table 86 Unit costs of drug administration in the advanced RCC setting ............... 212 Table 87 ToT for second-line treatment regimens in the advanced RCC setting ... 213 Table 88 Metastatic treatment market shares and costs ........................................ 214 Table 89 Health state costs applied in the base case ............................................ 216 Table 90 Unit costs per surgical procedure ............................................................ 218 Table 91 Costs of short-term surgical complications .............................................. 219 Table 92 Annual costs of long-term surgical complications .................................... 221 Table 93 List of adverse reactions and summary of costs in the economic model . 223 Table 94 Social care costs included in this appraisal ............................................. 224 Table 95 Summary features of QALY shortfall analysis ......................................... 226 Table 96 Summary of QALY shortfall analysis ....................................................... 226 Table 97 Summary of overall model assumptions .................................................. 229 Table 98 VHL-RCC results – List price ................................................................... 232 Table 99 VHL-CNS Hb results – List price ............................................................. 232 Table 100 VHL-pNET results – List price ............................................................... 233 Table 101 Total costs, QALYs and ICERs from the PSA (list price) ....................... 234 Table 102 Scenario analysis results of the most sensitive parameters for VHL-RCC cohort ..................................................................................................................... 245 Table 103 Scenario analysis results of the most sensitive parameters for VHL-CNS Hb cohort ................................................................................................................ 246

Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

© Merck Sharp & Dohme (UK) Limited (2023). All rights reserved

Table 104 Scenario analysis results of the most sensitive parameters for VHL-pNET cohort ..................................................................................................................... 246 Table 105 Embase Search Strategy, Database(s): Embase 1974 to 2022 June 14, Searched on June 15, 2022 ................................................................................... 273 Table 106 MEDLINE Search Strategy, Database(s): Ovid MEDLINE and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions) 1946 June 14, 2022, Searched on June 15, 2022 ................................................................... 275 Table 107 Cochrane Central Register of Controlled Trials Search Strategy, Database(s): EBM Reviews - Cochrane Central Register of Controlled Trials May 2022, Searched on June 15, 2022 ......................................................................... 276 Table 108 PICOTS criteria for study inclusion ........................................................ 278 Table 109 List of citations initially included at full-text screening phase ................. 281 Table 110 List of citations initially excluded at full-text screening phase ................ 282 Table 111 MK-6482-004 summary of patient disposition (safety analysis set) ....... 298 Table 112 MK-6482-004 summary of follow-up duration (safety analysis set) ....... 299 Table 113 Cochrane risk of bias assessment for the study included from the systematic literature review ...................................................................................................... 300 Table 114 MK-6482-004 patients with adverse events by decreasing incidence (incidence ≥10%) (safety analysis set) ................................................................... 302 Table 115 MK-6482-004 patients with drug-related grade 3-5 by decreasing incidence (incidence ≥0%) (safety analysis set) ..................................................................... 303 Table 116 MK-6482-004 patients with grade 3-5 by decreasing incidence (incidence ≥0%) (safety analysis set) ...................................................................................... 304 Table 117 MK-6482-004 patients with serious adverse events by decreasing incidence (incidence >0%) (safety analysis set) ..................................................................... 305 Table 118 MK-6482-004 patients with drug-related serious adverse events by decreasing incidence (incidence >0%) (safety analysis set) .................................. 306 Table 119 MK-6482-004 adverse events leading to study drug discontinuation .... 306 Table 120 MK-6482-004 patients with adverse events resulting in treatment interruption by decreasing incidence (incidence >0%) (safety analysis set) ........... 307 Table 121 MK-6482-004 patients with drug-related adverse events resulting in treatment interruption by decreasing incidence (incidence >0%) (safety analysis set) ............................................................................................................................... 308 Table 122: Databases Searched for the Literature Review and the Search Platform ............................................................................................................................... 310 Table 123: Economic Review: Embase® search strategy (searched through Embase.com) ......................................................................................................... 312 Table 124: Economic Review: MEDLINE®In-Process searched via PubMed® ..... 312 Table 125: Economic Review: CRD York platform ................................................. 313 Table 126: Summary of search hits retrieved from Embase® and MEDLINE® (From July 1, 2020 to July 26, 2022; Embase.com) .......................................................... 314

Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

© Merck Sharp & Dohme (UK) Limited (2023). All rights reserved

Table 127: Eligibility Criteria (Search Date: July 2020) .......................................... 316 Table 128: Eligibility Criteria (Search Date: July 2022) .......................................... 317 Table 129: Summary of search hits retrieved from MEDLINE® Inprocess (From July 1, 2020 to July 26, 2022; Pubmed) ........................................................................ 319 Table 130: Summary of search hits retrieved from NHS EED, DARE and HTA (From July 1, 2020 to July 26, 2022; York CRD) ............................................................. 320 Table 131: Summary of Study Characteristics ....................................................... 323 Table 132: Summary of Population Characteristics ............................................... 324 Table 133: Cost Associated with Genetic Analysis of VHL Gene ........................... 329 Table 134: Overall Cost Burden Reported Across Six Studies ............................... 329 Table 135: Overall Cost Burden of Different Techniques Used for VHL Mutation Detection ................................................................................................................ 330 Table 136: Summary of HRU Results .................................................................... 332 Table 137: Summary of healthcare cost results ..................................................... 332 Table 138: Databases Searched for the Literature Review and the Search Platform ............................................................................................................................... 338 Table 139 Embase® search strategy for PRO’s and quality of life review ............. 340 Table 140 Search strategy for Cochrane database ................................................ 341 Table 141 Search strategy for MEDLINE®In-Process searched via PubMed® platform ............................................................................................................................... 342 Table 142 Search strategy for clinicaltrials.gov ...................................................... 342 Table 143 Embase® and MEDLINE® search strategy for PRO’s and quality of life review ..................................................................................................................... 342 Table 144 Search strategy for MEDLINE®In-Process searched via PubMed® platform ............................................................................................................................... 343 Table 145 Search strategy for Cochrane database ................................................ 345 Table 146: Eligibility Criteria (Search Date: July 2020) .......................................... 347 Table 147: Eligibility Criteria (Search Date: July 2022) .......................................... 348 Table 148: Study Characteristics ........................................................................... 351 Table 149: Patient Characteristics ......................................................................... 353 Table 150: Changes in Psychological Profile in Patients Who Attended Visit 3 ..... 358 Table 151: VHL Related Worries ............................................................................ 364 Table 152: Variables Associated with VHL Related Worries (CWS) and Distress (IES) ............................................................................................................................... 365 Table 153: Linear Regression Analysis VHL Related worries ................................ 367 Table 154: Psychosocial Impact of LFS-and VHL Among Partners and Their High-risk Spouses ................................................................................................................. 370 Table 155 Summary of variables applied in the economic model .......................... 377 Table 156 Base-case disaggregated costs and effectiveness ............................... 384 Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

© Merck Sharp & Dohme (UK) Limited (2023). All rights reserved

Table 157 Summary of QALY gain by health state – VHL-RCC cohort .................. 386 Table 158 Summary of QALY gain by health state – VHL-CNS Hb cohort ............ 386 Table 159 Summary of QALY gain by health state – VHL-pNET cohort ................ 386 Table 160 Summary of costs by health state – VHL-RCC cohort ........................... 387 Table 161 Summary of costs by health state – VHL-CNS Hb cohort ..................... 387 Table 162 Summary of costs by health state – VHL-pNET cohort ......................... 387 Table 163 Summary of predicted resource use by category of cost – VHL-RCC cohort ............................................................................................................................... 388 Table 164 Summary of predicted resource use by category of cost – VHL-CNS Hb cohort ..................................................................................................................... 388 Table 165 Summary of predicted resource use by category of cost – VHL-pNET cohort ............................................................................................................................... 389 Table 166 Tabular DSA and scenario analysis results for VHL-RCC cohort .......... 391 Table 167 Tabular DSA and scenario analysis results for VHL-CNS Hb cohort ..... 393 Table 168 Tabular DSA and scenario analysis results for VHL-pNET cohort ......... 395 Table 169 Censoring rules for PFS ........................................................................ 404 Table 170 Censoring rules for DOR ....................................................................... 405 Table 171 Time point response: patients with target (+/– non-target) disease. ...... 409 Table 172 Time point response: patients with non-target disease only. ................. 410 Table 173 Best overall response when confirmation of CR and PR required. ........ 410 Table 174 MK-6482-004 study demographic and baseline characteristics (safety analysis set) - all patients - number of key target lesions ....................................... 417 Table 175 MK-6482-004 study demographic and baseline characteristics (safety analysis set) – subgroup of patients with CNS hemangioblastoma ........................ 417 Table 176 MK-6482-004 study demographic and baseline characteristics (safety analysis set) - subgroup of patients with CNS hemangioblastoma - number of key target lesions .......................................................................................................... 419 Table 177 MK-6482-004 study demographic and baseline characteristics (safety analysis set) – subgroup of patients with pNET ..................................................... 419 Table 178 MK-6482-004 study demographic and baseline characteristics (safety analysis set) – subgroup of patients with pNET - number of key target lesions ..... 420 Table 179 Locations of the CNS hemangioblastomas, in participants with CNS hemangioblastoma (RECIST 1.1) by IRC at baseline with complete response, efficacy analysis set ............................................................................................................ 421 Table 180 Locations of the CNS hemangioblastomas, in participants with CNS hemangioblastoma (RECIST 1.1) by IRC at baseline with partial response, efficacy analysis set ............................................................................................................ 421 Table 181 Locations of the CNS hemangioblastomas, in participants with CNS hemangioblastoma (RECIST 1.1) by IRC at baseline with stable disease, efficacy analysis set ............................................................................................................ 422

Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

© Merck Sharp & Dohme (UK) Limited (2023). All rights reserved

Table 182 Locations of the CNS hemangioblastomas, in participants with CNS hemangioblastoma (RECIST 1.1) by IRC at baseline with progressive disease, efficacy analysis set ............................................................................................... 422 Table 183 Locations of the CNS hemangioblastomas, in participants with CNS hemangioblastoma (RECIST 1.1) by IRC at baseline with response not evaluable, efficacy analysis set ............................................................................................... 422 Figure 1 Molecular basis of VHL disease ................................................................. 26 Figure 2 Tumours that arise from VHL disease ........................................................ 27 Figure 3 Waterfall plot - percentage change in total sum of RCC target lesions diameters from baseline to post-baseline maximum % reduction (RECIST 1.1) – independent review committee (efficacy analysis set) ............................................. 63 Figure 4 Waterfall plot - percentage change in total sum of target lesions diameters for RCC, CNS hemangioblastoma, and pancreatic neuroendocrine tumours, from baseline to post-baseline maximum % reduction (RECIST 1.1) – independent review committee (efficacy analysis set) ............................................................................. 64 Figure 5 Spider plot - percentage change in total sum of RCC target lesion diameters from date of partial response (RECIST 1.1) – independent review committee (efficacy analysis set) ............................................................................................................. 65 Figure 6 MK-6482-004 Kaplan-Meier plot of duration of response for RCC tumours (RECIST 1.1) – independent review committee (efficacy analysis set) .................... 68 Figure 7 Kaplan-Meier plot of progression-free survival for RCC tumours (RECIST 1.1) – independent review committee (efficacy analysis set)........................................... 71 Figure 8 Distribution of all surgeries pre- and post-treatment initiation over time for individual patients - safety analysis set .................................................................... 73 Figure 9 Summary of subgroups in the MK-6482-004 study (not to scale)............... 76 Figure 10 Waterfall plot - percentage change in total sum of CNS hemangioblastoma target lesions diameters from baseline to post-baseline maximum % reduction (RECIST 1.1) – independent review committee (efficacy analysis set) .................... 79 Figure 11 Spider plot - Percentage change in total sum of CNS hemangioblastoma target lesion diameters from date of partial response (RECIST 1.1) – independent review committee (efficacy analysis set) .................................................................. 80 Figure 12 MK-6482-004 Kaplan-Meier plot of duration of response for CNS hemangioblastomas (RECIST 1.1) – independent review committee (efficacy analysis set) ........................................................................................................................... 82 Figure 13 Kaplan-Meier plot of progression free survival for CNS hemangioblastomas (RECIST 1.1) – independent review committee (efficacy analysis set) .................... 85 Figure 14 Distribution of all surgeries pre- and post-treatment initiation over time for individual patients for individual patients with baseline CNS hemangioblastomas per independent review committee - safety analysis set ................................................ 87

Figure 15 Waterfall plot - percentage change in total sum of target lesions diameters for pancreatic neuroendocrine tumours from baseline to post-baseline maximum % reduction (RECIST 1.1) – independent review committee (efficacy analysis set) .... 90

Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

© Merck Sharp & Dohme (UK) Limited (2023). All rights reserved

Figure 16 Spider plot - Percentage change in total sum of target lesion diameters for pNETs from date of partial response (RECIST 1.1) – independent review committee (efficacy analysis set) ............................................................................................... 91 Figure 17 MK-6482-004 Kaplan-Meier plot of duration of response for pancreatic neuroendocrine tumours (RECIST 1.1) – independent review committee (efficacy analysis set) ............................................................................................................. 93 Figure 18 Model schematic for the economic evaluation of belzutifan in VHL associated RCC, pNET, or CNS Hb ....................................................................... 127 Figure 19 Exponential models of OS and PFS compared with Kaplan-Meier curve extractions for sunitinib in the advanced RCC setting ............................................ 170 Figure 20 Internal validations of time to surgery, metastases, or death against original data sources in each model arm and cohort .......................................................... 174 Figure 21 Validation of OS in the SOC arm against the observed OS from the VHL Natural History Study ............................................................................................. 179 Figure 22 Modelled vs. observed ToT for belzutifan in MK-6482-004 trial under different parametric distributions during the MK-6482-004 trial .............................. 183 Figure 23 Modelled vs. observed ToT for belzutifan in MK-6482-004 trial under different parametric distributions over long-term extrapolation ............................... 183 Figure 24 Belzutifan ToT modelled using a Gompertz distribution ......................... 184 Figure 25 Scatterplots of incremental costs and effectiveness for belzutifan vs. SOC in the VHL-RCC population across 1,000 iterations of the PSA (list price) ............. 235 Figure 26 Scatterplots of incremental costs and effectiveness for belzutifan vs. SOC in the VHL-CNS Hb population across 1,000 iterations of the PSA (list price) ....... 236 Figure 27 Scatterplots of incremental costs and effectiveness for belzutifan vs. SOC in the VHL-pNET population across 1,000 iterations of the PSA (list price) ........... 236 Figure 28 Cost-effectiveness acceptability curves for belzutifan vs. SOC in the VHLRCC population (list price) ..................................................................................... 237 Figure 29 Cost-effectiveness acceptability curves for belzutifan vs. SOC in the VHLCNS Hb population (list price) ................................................................................ 238 Figure 30 Cost-effectiveness acceptability curves for belzutifan vs. SOC in the VHLpNET population (list price) .................................................................................... 238 Figure 31 DSA results – tornado diagram for belzutifan vs. SOC in the VHL-RCC population (list price) .............................................................................................. 242 Figure 32 DSA results – tornado diagram for belzutifan vs. SOC in the VHL-CNS Hb population (list price) .............................................................................................. 243 Figure 33 DSA results – tornado diagram for belzutifan vs. SOC in the VHL-pNET population (list price) .............................................................................................. 244 Figure 34 PRISMA flow diagram of study selection ............................................... 280 Figure 35: PRISMA flow diagram (Search date: July 2020) ................................... 320 Figure 36: PRISMA flow diagram (July 2022) ........................................................ 321 Figure 37: Cost analysis of the two algorithms, systematic genetic analysis, and clinically guided genetic analysis ............................................................................ 327 Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

© Merck Sharp & Dohme (UK) Limited (2023). All rights reserved

Figure 38: PRISMA Flow and Study Selection (Search Date: July 2020)............... 349 Figure 39: PRISMA Flow and Study Selection (Search Date: July 2022)............... 350 Figure 40: Quality of Life Scores of the Study Population, and of French Age-Sex Crossed Norms ...................................................................................................... 357 Figure 41 Waterfall plot - percentage change in total sum of RCC target lesions diameters from baseline to post-baseline maximum % reduction (RECIST 1.1) – independent review committee (efficacy analysis set): 01-JUN-2020 .................... 412 Figure 42 Waterfall plot - percentage change in total sum of RCC target lesions diameters from baseline to post-baseline maximum % reduction (RECIST 1.1) – independent review committee (efficacy analysis set): 01-DEC-2020 .................... 413 Figure 43 Waterfall plot - percentage change in total sum of RCC target lesions diameters from baseline to post-baseline maximum % reduction (RECIST 1.1) – independent review committee (efficacy analysis set); 15-JUL-2022 ..................... 414 Figure 44 Waterfall plot - percentage change in total sum of RCC target lesions diameters from baseline to post-baseline maximum % reduction (RECIST 1.1) – independent review committee (efficacy analysis set); 01-APR-2022 .................... 415

Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

© Merck Sharp & Dohme (UK) Limited (2023). All rights reserved

Abbreviations

Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

© Merck Sharp & Dohme (UK) Limited (2023). All rights reserved

Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

© Merck Sharp & Dohme (UK) Limited (2023). All rights reserved

Definitions and descriptions of key terms used in the

submission

The definitions of key terms in the indication wording of the Summary of Product Characteristics and decision problem addressed in the company submission are shown in Table 1. The GB marketing authorisation for belzutifan (Welireg) is: Welireg is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for VHL associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumours (pNET), and for whom localised procedures are unsuitable or undesirable.

Table 1 Definition of key terms in the indication for the product detailed in the submission

Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

© Merck Sharp & Dohme (UK) Limited (2023). All rights reserved

The GB marketing authorisation and the MK-6482-004 study in belzutifan that forms the clinical evidence base for this submission (described later in this document), namely are slightly different:

• The marketing authorisation is for patients with VHL associated “renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or

Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

© Merck Sharp & Dohme (UK) Limited (2023). All rights reserved

pancreatic neuroendocrine tumours (pNET)” i.e. could have any one of these tumours, whereas all patients in the MK-6482-004 study had RCC, and the subgroups of patients with CNS hemangioblastoma and pNET for which study results are available necessarily also had RCC.

• The marketing authorisation is for patients "who require therapy" for the VHLassociated tumours, whereas the MK-6482-004 study's participant eligibility criteria specified that patients who had an immediate need for surgical intervention for tumour treatment were excluded.

• The marketing authorisation is for patients "for whom localised procedures are unsuitable or undesirable" whereas this was not part of the participant eligibility criteria for the MK-6482-004 study.

The Medicines and Healthcare products Regulatory Agency (MHRA) granted this marketing authorisation in this indication based on the MK-6482-004 study and its results, i.e. based on which patients would benefit from treatment with belzutifan was demonstrated by the evidence from this very study. Such misalignments between marketing authorisation wording and supporting clinical trial patient population characteristics are not unusual for rare and highly specialised indications such as this one.

Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

© Merck Sharp & Dohme (UK) Limited (2023). All rights reserved

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

Summary of the decision problem, technology, and clinical care pathway

• This submission covers belzutifan’s (Welireg) full marketing authorisation: Welireg is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for VHL associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumours (pNET), and for whom localised procedures are unsuitable or undesirable.

• Belzutifan is an orally administered medicine that selectively targets a protein called hypoxia inducible factor (HIF) - 2α. HIF-2α levels are raised in people with VHL, which can lead to the growth of both benign and malignant tumours. By blocking the activity of HIF-2α, belzutifan slows down worsening of VHL and improves symptoms.

• Von Hippel-Lindau disease is a long-term debilitating and life-limiting genetic disease caused by a mutation (fault) in the VHL gene. It is a disease characterised by growth of tumours in many organs of the body. VHL disease is different in every patient, even within the same family. The trajectory of VHL disease in patients is variable and unpredictable. Some patients may only develop a few or a single tumour in a single organ while other patients may develop multiple tumours across multiple organs throughout their life. In the worst affected patients tumours may arise repeatedly in the same organ resulting in organ function impairment. Tumours may arise in locations where surgical resection of the tumour would lead to organ function impairment or loss. In the case of RCC this can result in loss of kidney function leading to the requirement for lifelong dialysis, in pNETs this can result in Whipple’s procedures or pancreatectomy leading to lifelong pancreatogenic diabetes, in CNS hemangioblastomas this can results in neurological deficits, blindness, or problematic brain injury leading to severe disability requiring 24-hour care.

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• Currently there are no systemic therapeutic interventions authorised or funded in the UK for the treatment of VHL-associated cancer. In patients with pNETs, a somatostatin analogue is used as 1st line therapy to treat these tumours when it reaches 1 cm in diameter, however this is the case regardless of whether the pNET is associated with VHL disease (3, 4)

• The objective of care in patients with VHL-associated tumours is to prevent tumours from metastasising while maintaining functioning of the affected organs. At the same time clinicians attempt to minimise symptom burden and maintain patients’ quality of life. A delicate balancing act, with decisions unique to individual patients on whether they would prefer to face the deeply undesirably sequelae following surgeries that cause loss of organ function (such as dialysis, pancreatogenic diabetes, or severe neurological disability, for the rest of their life), or the risk of letting tumours grow.

• The indication wording for belzutifan has a degree of ambiguity worth highlighting from the beginning [bold emphasis added by MSD]: Welireg is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for VHL associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumours (pNET), and for whom localised procedures are unsuitable or undesirable. This results in a subgroup of patients with VHLassociated tumours that must meet criteria: o First, they require therapy . In the absence of any approved medical treatments for VHL we interpret this to mean a surgical or related procedure for tumours >3cm in diameter for RCC, or pNETs >2cm in diameter, or CNS tumours causing symptoms that require an intervention.

  • Second, localised procedures are unsuitable or undesirable . It is important to note that the medical definition of localised procedures (described in Table 1) includes for example minor, partial nephrectomies and full nephrectomies resulting in organ loss and the

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significant associated consequences. In extensive consultation with clinicians there is a clear medical understanding of undesirable and unsuitable (see below for further explanation). It does not mean a patient would rather not have a minor surgery. It is easiest to consider this criterion by its opposite: if they can have successful localised procedures they should have localised procedures.

• The current alternative to belzutifan in routine clinical practice in the UK at this stage for these patients is a complex mix of interventions.

• The current clinical standard of care (SoC) for patients with VHL RCC or pNETs for whom localised procedures are unsuitable or undesirable are still localised procedures. However, in these patients these localised procedures would result in loss of organ function with sequelae that would not allow patients to live a healthy life. In current UK clinical practice, patients undergo these procedures because they are preferable to the dire consequence of letting the tumour continue to grow.

• No equity or equality considerations are anticipated, although the inherited nature of the disease means some families are disproportionately impacted over multiple generations. There are inequities in the type of service available to VHL patients depending on which centre leads their care

B.1.1 Decision problem

The submission covers the technology’s full marketing authorisation for this indication.

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Table 2 The decision problem

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Patients had to have sufficient organ function (as described in the MK-6482-004 study participant eligibility criteria described in section B.2.3 later in this document) to receive belzutifan.

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B.1.2 Description of the technology being evaluated

Table 3 Technology being evaluated

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

This section describes VHL disease, the burden of the disease, its aetiology and epidemiology, followed by a description of the current UK treatment pathway for this disease, and where treatment with belzutifan would fit into it.

Health condition

Von Hippel-Lindau disease

Von Hippel-Lindau (VHL) disease is a genetic disorder characterised by the growth of tumours in many organs of the body, including in the kidneys, pancreas, adrenal glands and inner ear, as well as abnormal growth of blood vessels in the eye, brain and spinal cord. It is a long-term, debilitating and life-threatening disease due to the complications caused by the tumours that has wide-ranging effects on the body (6). The types and locations of tumours that can arise from VHL disease are illustrated in Figure 2.

The disease is caused by a defect in the VHL gene which is responsible for the production of a protein that regulates cell growth. pVHL is a protein encoded by the VHL gene that is critical for the regulation of hypoxia-inducible factors (HIF, Figure 1). Normally, this gene helps to keep cell growth and proliferation in check. The loss of pVHL function results in oncogenic stimulation that leads to angiogenesis, cell proliferation, cell survival, erythropoiesis and, ultimately, the growth of cysts and benign and malignant tumours (7-10). Consequently, in patients with VHL disease, cells in as many as 10 parts of the body do not die as they normally would to be replaced by healthy cells. Instead, there is a proliferation of cells that results in the formation of cysts, benign tumours and malignant tumours.

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Figure 1 Molecular basis of VHL disease

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HIF-2α: hypoxia-inducible factor alpha; VHL: Von Hippel-Lindau Source: Mechanism of action of belzutifan (11)

Unlike in cancer, where a proliferation of cells is likely to be spontaneous and initially restricted to a single anatomical location, a person with VHL may experience cell proliferation and tumour growth on repeated occasions in multiple organs at different times or at the same time. Most VHL tumours begin as benign tumours. Benign tumours are those that stay in their primary location without invading other sites of the body. They do not spread to local structures or to distant parts of the body. Benign tumours tend to grow slowly and have distinct borders (12).

Benign tumours in this patient population are not problem-free and have serious negative consequences for the patient as they grow. These tumours cause an increased pressure on the structure around them creating symptoms including severe pain and/or disability.

While tumours may be multi-system, i.e., in multiple locations at the same time, patients often have a “primary tumour” that drives treatment decisions (unlike other oncology therapy areas, the primary tumour we refer to in VHL for this submission is not necessarily the first tumour). This is reflected in belzutifan’s marketing authorisation that identifies RCC, pNET and CNS hemangioblastoma “primary tumours”. Some unlucky patients have multiple significant tumours and the treatment plan needs to optimise the least worst approach.

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Whilst VHL is a rare genetic disease the phenotypes are highly heterogenous and patients’ experiences are very different. All diagnosed patients are kept under surveillance at regional genetic centres (13). Some patients require few, if any, surgeries in their lifetime, though being a carrier of a genetic mutation impacts life decisions such as whether to have children. At the other end of the spectrum people have a torrid experience. The most severely affected undergo many surgeries in their lifetime including surgery where organ function will be significantly impaired or completely cease, where there will be significant risk to neurological function due to CNS lesions, that require them to require medication and/or dialysis for the rest of their lives. There are patients on the spectrum between these two extremes. It is our understanding based on the regulatory process that the intent of the MHRA indication are patients that cannot be well managed by surgery.

Figure 2 Tumours that arise from VHL disease

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Image source: Figure 1, Schunemann et al. 2016 (14), adapted from Lonser et al. 2003 (15).

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Burden of VHL disease

VHL disease significantly shortens life and severely impairs quality of life. Data from the North West Regional Genetic Register Service and North West Regional Cancer Intelligence Service in England shows that VHL disease reduces median life expectancy by nearly 19 years in men and by nearly 34 years in women, with 73% of people with VHL disease having death recorded as having a VHL-disease related cause (16).

VHL severely impairs patients’ quality of life, it often requires multiple surgeries or other local procedure such as radiotherapy, thermo-ablation, or cryotherapy over a patient’s lifetime, contributing to medical anxiety and fatigue (17). RCC and pNET tumours can and do metastasize. The objective of treatment for patients with these tumours is to balance preventing tumours metastasising (through surgical removal) and maintenance of organ function. It is not uncommon for those diagnosed with RCC to have multiple surgeries leading to reduced kidney function or organ loss equivalent to end stage renal disease leading to kidney dialysis. As is well documented, patients on dialysis are at increased risk of serious cardiovascular events. The relative risk in patients on dialysis compared to the general population is >5 fold for myocardial infarction, ~6 fold for ischaemic stroke, and ~2.2 fold for venous thromboembolism, resulting in an 10x higher age-adjusted cardiovascular mortality (18-21). Approximately 60% of patients with end-stage kidney disease on haemodialysis will experience cardiovascular death, and >50% of older patients will die within the first year of starting dialysis (22, 23). Kidney dialysis patients have a reduced life expectancy. VHL patients on dialysis with no remaining kidney function may develop tumours in other organs or blood vessels.

The presence of pNETs also creates an undesirable set of circumstances. Patients who undergo a Whipple surgery, and have only part of their pancreas removed, become reliant on life-long medication for diabetes and/or pancreatic insufficiency. Whipple surgery patients may develop insulin-dependent diabetes. pNET patients may also have a full pancreatectomy leading to pancreatogenic or Type 3c diabetes, while similar to Type 1 diabetes mellitus, pancreatogenic diabetes is unique in that the individual is deprived of both the exocrine and the endocrine functions of the

pancreas: insulin and glucagon, as well as other pancreatic hormones (24). Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

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Pancreatogenic diabetes exposes people who have undergone such surgery to lifethreatening complications that arise from the wide, fast, unpredictable and inexplicable swings in blood glucose concentration this causes, often resulting in ketoacidosis or hypoglycaemic coma (24). Pancreatogenic diabetes is still treated primarily with insulin therapy (25, 26). Treatment of type 3c diabetes also should include treatment of pancreatic exocrine insufficiency with pancreatic enzyme replacement to improve absorption of fats and fat-soluble vitamins and prevent malabsorption of nutrients (26).

A Whipple surgery involves removal of the head of the pancreas, a part of the duodenum, some of the bile duct and the gall bladder. The stomach, bile duct and remainder of the pancreas will then be rejoined to the small bowel. The operation usually takes 4-6 hours. Long-term effects of this procedure include diabetes, pancreatic insufficiency, and change in bowel habit (27).

The fear of disability or death from surgery weighs heavily on minds of patients. Particularly where their tumours are asymptomatic but require intervention. i.e. asymptomatic pancreatic tumours but they have progressed necessitating the Whipple procedure which then leaves patients feeling worse than before the surgery. Patients talked about "scanxiety" ahead of every appointment where they prepare to be told that they need surgery.

While CNS hemangioblastomas do not metastasise, they can be some of the most difficult to manage. A patient that has had multiple CNS surgeries or has tumours in a location where surgery would carry too great a risk of serious complications are not suitable for surgery. There have been cases where patients have been left paralysed due to VHL tumours or their surgical treatment; with significant nerve injury or on a permanent tracheostomy, who now require 24/7 social care and increased

surveillance. Patients who have had CNS manifestations need extensive support in day to day living (3). Surgery can be associated with considerable morbidity, including facial palsy, neurological damage, paresis, blindness, meningitis, and death (3).

The above describes each primary tumour site: RCC, pNET, and CNS

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sites e.g. patients may have both RCC tumours and CNS hemangioblastomas at the same time, requiring clinical management of several tumours at the same time. Due to the nature of VHL disease, new tumours can appear in the same organ (as well as in other locations) after a tumour has been removed.

Patients at all stages of VHL disease have to plan their lives to revolve around constant scans, surgeries, recovery, and the long-term consequences of reduced function resulting from their surgeries. Many experience frustration arising from misrepresentation or misunderstanding of the disease due its complexity and different forms of manifestation making it difficult for many to fully understand. All of this has a severely negative effect on patients’ quality of life. While quantitative data are scarce in the scientific literature on the impact of VHL disease and specifically VHL-associated cancer on patients’ quality of life (28), feedback from patients consistently demonstrates a considerable negative impact on the quality of life and levels of distress of patients as well as their family members (29). Additionally, there is the impact of VHL-related appointments on patients education and careers (including not easily being able to relocate to progress their career, or having to delay surgery because they’ve had too many sick days to be eligible for sick pay that year), the impact of lifestyle changes they have to make around the need for monitoring appointments and surgeries (including having to pay for hotel accomodation to go to appointments with specialists), the impact on family reproductive rights, impact of multiple individuals within one family being affected, and the enormous mental health impact of living with an aggressive manifestation of VHL disease.

Statements from patients with VHL disease are provided below that illustrate the psychological, emotional, and quality life impact of VHL disease and dealing with the tumours that arise from it. These are sourced from the VHL UK/Ireland charity website (https://vhl-uk-ireland.org/stories/) and the 2022 patient/carer survey (17, 30).

Not every patient has such severe presentation, these patients are not eligible for chronic systemic treatment with belzutifan according to the GB marketing authorisation.

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Since being diagnosed with VHL 13 years ago I have had 3 cerebellar haemangioblastomas (brain tumours) removed, a full Whipples procedure & my latest operation (of which I am currently at home recovering) a Laparoscopic Adrenalectomy – the removal of my left adrenal gland and its attached tumour.

It’s only in the last 2 years, since going through 3 operations within the space of 20 months, also the fact that I’m ‘growing up’ (not sure that I ever really will!), that I’ve started to understand the full impact VHL has not only on yourself but your family and friends too. The pain you see in their eyes when you get the results of various MRI scans, blood tests almost hurts more than the physical results themselves.

…

My biggest operation, both physically and mentally, was the Whipple’s Procedure that I underwent January 2017. I was not prepared for just how poorly I would feel afterwards, it was an extremely tough time. I don’t remember too much but I do remember the pain I was in straight after the operation and my family telling me all about how they couldn’t believe how many lines and drains I had, which stayed in for at least a couple of weeks. Since then I’ve lost a total of 2 and a half stone, this was due to it taking months for me to get my food intake back on track. I used to eat one mouthful and be full, I couldn’t see the discomfort and pain getting any better but it does. Even now, over a year down the line, I don’t feel as good as I felt before that operation.

• VHL UK/Ireland website - Sep 8, 2019

With me, the cancer was close to the major blood vessels in the kidney. […] I spent hours every day for a week after my surgery praying to God to stop the pain. I cried. I’m not ashamed to say it. I’m a teenage boy and I cried in front of my Aunt and Uncle, in front of nurses, and even in front of one of the most beautiful doctors I have ever seen in my life. […] I spent hours praying, but there was nothing. I even pleaded to God to “take me away”. Being in so much pain that you are literally praying for death is not a place I ever want to be in again.[…]

There’s something about pain. It’s a strange thing. It can make you want to throw your whole life away just for relief. […] That was the worst pain I had ever felt. That’s what I thought, until December 4th 2015. That was the day my incredible Mam, the woman who raised me and my two big brothers by herself while fighting this awful disease, passed away.

• VHL UK/Ireland website - Sep 8, 2019

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Epidemiology and aetiology

Von Hippel-Lindau disease (VHL) is caused by a mutation (fault) in the VHL gene. ≈ Based on UK clinical expert feedback, 80% of patients with VHL disease will have inherited disease and be known to genetics services and so will be identified ≈ reasonably early. Feedback from clinical experts suggest 20% of patients will present with a de novo VHL mutation (i.e. no family history and so not already known to genetics services) (3, 13).

VHL is rare with a prevalence lower than 1:50,000 in England. A national audit of VHL disease in the UK published in 2022 found 842 individuals had a clinical and/or molecular diagnosis of the disease in the 22 UK regional genetics centres surveyed over the 2012-2017 audit period, and estimated that the prevalence of VHL disease in the UK is likely to be between 1 in 91,111 to 1 in 68,493 with approximately 842 patients in the UK (13, 31). Taking into account the specific group of patients with VHL disease that belzutifan is indicated for (as described in Table 2), approximately 69 people in England and Wales are eligible for treatment with belzutifan (details provided in the company budget impact analysis submission document).

VHL disease affects males and females and all ethnic groups equally (32). In patients with VHL disease in the UK, the mean age at detection of detection of relevant tumour types is 39.4 years (SD ± 12.7) for RCC and 37.04 years (9-66 years) for CNS hemangioblastomas, the earliest recorded age at diagnosis for a pNET was 18 years (13).

Treatment pathway

Current clinical practice

Patients are diagnosed with VHL disease in two ways, either they are identified through genetic counselling due to having family member already diagnosed with VHL disease (this is the case in 80% of patients), or de novo when they are tested

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for VHL disease upon presentation of a tumour (this is the case in 20% of patients) (13).

Since it is impossible to predict exactly how and when the disease will present for each person, it is necessary to check regularly for possible VHL manifestations throughout a person’s lifetime. All diagnosed patients receive active surveillance usually led by the clinical genetics service, though sometime by the endocrinology service (13). Most of the surveillance clinics led by a clinical genetics service include other specialties such as ophthalmology, endocrinology, urology paediatrics, neurology, nephrology, and radiology (13). The surveillance recommendation for RCC and pNETs is usually “magnetic resonance imaging (MRI) or ultrasound examinations of the abdomen every 12 months, beginning from the age of 16 years” (13). The surveillance recommendation for CNS hemangioblastomas is usually “MRI scans of the head for every 12–36 months, beginning in adolescence”. The first CNS MRI scan is generally performed at 14 to 16 years of age and for those centres that performed regular MRI scans the most common interval was 36 months for both brain and spine (13).

Care of VHL patients is fragmented and inconsistent across the UK. VHL is not listed in the Highly Specialised Commissioning Policy therefore centres do not receive funding for VHL clinics. Most patients are managed by via a genetic service and received regular and frequent scans as part of “active surveillance”. We are aware of some MDTs managed VHL experts with a more joined up set of monitoring and appointments, but in other centres, once multiple manifestations in different parts of the body occur there can be a lack of coordination (e.g. a patient may have a MRI on their abdomen and then require three separate appointment with consultants to discuss tumours on the kidney, pancreas, and spleen individually).

Surveillance of diagnosed patients will identify the point at which VHL-associated tumours need treatment; following scans patients will either remain under active surveillance if their tumour(s) have not reached the threshold at which treatment is required or receive treatment if the threshold is reached (the relevant thresholds for these are described in Table 1).

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Treatment of VHL in the UK is variable. The objective of care in patients with VHL disease-associated tumours in the UK is to prevent tumour growth within an organ to prevent permanent damage and prevent tumours from metastasising while maintaining function of affected organs, minimising symptom burden, and preserving patients’ quality of life, a delicate balancing act. Clinicians treat patients as well as they can, this might include high-risk procedures that are not desirable and/or that are known to have very serious sequelae.

In patients with pNETs, a somatstatin analogue is used as 1st line therapy to treat these tumours when it reaches 1 cm in diameter, surgery is considered when these tumours grow to 2 cm in diameter and are progressing or likely to metastasise, this is the case regardless of whether the pNET is associated with VHL disease (3, 4). In patients for whom surgery is appropriate, these may sometimes be delayed in patients with VHL-associated tumours in more than one location, e.g. surgery for one tumour may be delayed to prioritise or recover from surgery on a more urgent tumour elsewhere.

Once a patient has undergone localised therapy to resect a tumour that had reached the threshold for treatment, the cycle of active surveillance resumes until the treatment decision point relevant to this appraisal whereby an intervention is needed (i.e. “require therapy” as stated in the GB marketing authorisation wording) but localised procedures are unsuitable or undesirable. In patients for whom surgery is not suitable or desirable the standard of care (SoC) at this point is a highly varied sequence of interventions and not a single treatment strategy (for either the entire VHL disease population or for any tumour site-defined subgroup considered separately) that can appropriately be described as the “best alternative care”. The treatment aim of all modalities of current management is to preserve organ function and prevent tumours becoming advanced or metastatic, while maintaining patient quality of life.

In patients for whom surgery is not suitable or desirable the standard of care (SoC) at this point is a highly varied sequence of interventions and not a single treatment strategy (for either the entire VHL disease population or for any tumour site-defined subgroup considered separately) that can appropriately be described as the “best

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alternative care”. The treatment aim of all modalities of current management is to preserve organ function and prevent tumours becoming advanced or metastatic, while maintaining patient quality of life.

In some patients whose VHL disease-associated RCC, CNS hemangioblastoma, or pNET have grown to an extent where localised procedures would otherwise be used in current SoC, available localised procedures may no longer be suitable nor desirable due to an elevated risk of loss of organ function or adverse effects of the procedure. The circumstances that would make localised procedures unsuitable or undesirable for the tumour(s) in question, or the patient as a whole, are manifold and include (but are not limited to):

• In VHL-associated RCC, when the localised procedure would render the patient renal replacement therapy-dependent.

• In VHL-associated pNET, when the localised procedure would lead to loss of pancreatic function leading to lifelong pancreatogenic diabetes and being immune-compromised such that the patient will require lifelong insulin therapy, antibiotic therapy and/or pancreatic enzyme insufficiency impacting digestion.

• In VHL-associated CNS hemangioblastoma, when the localised procedure could lead to severe neurological or neuromuscular deficits equating to severe permanent disability. This most often arises with tumours located in the brainstem where they are difficult to access or operate on without damaging important nearby tissues, potentially leading to significant morbidity and death.

Patients with VHL RCC or pNETs for whom localised procedures are unsuitable or undesirable may still have a localised procedure. However, the localised procedure would not preserve organ function and result in significantly burdensome sequelae. In current UK clinical practice, patients undergo surgery where organ function will be significantly impaired or completely cease, or where there will be significant risk to neurological function for CNS lesions, as they are the only treatment option available to keep patients alive, or prevent symptomatic disease progressing to the point where the severe sequelae of such procedures are on-balance preferable, or prevent

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the patient developing advanced or metastatic disease. Such procedures in no way constitute satisfactory treatment options.

• For RCC tumours, the localised procedures that are no longer capable of preserving organ function are radical (i.e. full) bilateral nephrectomies.

• For pNETs, such localised procedures that are no longer capable of preserving organ function are Whipple procedures/ pancreatectomies and splenectomies (A Whipple surgery involves removal of the head of the pancreas, a part of the duodenum, some of the bile duct and the gall bladder. The stomach, bile duct and remainder of the pancreas will then be rejoined to the small bowel. The operation usually takes 4-6 hours. Long-term effects of this procedure include but are not limited to diabetes, pancreatic insufficiency, and change in bowel habit).

• For CNS hemangioblastomas, where surgery would result in significant neurofunctional loss and/or high risk of mortality, including those close to the brain stem and in the spinal cord.

There are patients in whom tumour resection surgeries are contraindicated. This may be due to characteristics of the patient such as frailty, comorbidities or characteristics of the tumour such as CNS hemangioblastoma located at a physically inaccessible site. Currently these patients can receive symptom management, until their tumours/disease have progressed to the point where first-line systemic anticancer therapies (SACT) for unresectable or advanced cancer are used, or palliation.

This stage of disease is downstream of the position of belzutifan in the treatment pathway as specified in its GB marketing authorisation i.e., where patients can end up if treatment with belzutifan or current management fails, and so such SACT are not relevant comparators to belzutifan. The SACT which are not relevant

comparators to belzutifan in this indication include monotherapy or combination therapy with immunotherapies or kinase inhibitors for RCC, and monotherapy with lutetium (177Lu) oxodotreotide or combination therapy with everolimus and sunitinib for pNETs.

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The place of belzutifan

There are currently no satisfactory existing treatment options for the patients in the position described above. Patients who are suitable for surgery should have surgery instead of belzutifan. Surgery is an effective option for such patients and belzutifan should not be considered as a treatment option for them.

The place of belzutifan in the clinical pathway is therefore to give patients for whom localised organ-sparing procedures are unsuitable or undesirable (as described previously) an alternative to surgeries where organ function will be significantly impaired or lost, or where there will be significant risk to neurological function for CNS lesions. Patients must have sufficient organ function (as described in the MK6482-004 study participant eligibility criteria described in section B.2.3 later in this document) to be eligible to receive belzutifan. The objective of the treatment to prevent or reverse symptomatic disease progression thereby offering significant additional benefit over existing treatment options.

MSD were disappointed and surprised that the NICE Topic Selection Oversight Panel (TSOP) made the decision not to route this indication into the Highly Specialised Technologies (HST) programme. We disagree with the decision. However, in order to facilitate access for patients with VHL we are moving ahead the STA process.

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B.1.4 Equality considerations

No equality considerations are anticipated. It should be noted that the onset of RCC, pNETs, and/or CNS hemangioblastomas can affect patients with VHL disease when they are very young. VHL disease is an inheritable genetic disease and so some families are disproportionately affected. There are inequities in the type of service available to VHL patients depending on which centre leads their care.

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B.2 Clinical effectiveness

Summary of key clinical effectiveness information

Clinical trial:

• MK-6482-004 is a Phase 2, open-label, single-arm trial, that investigated the efficacy and safety of orally administered belzutifan, in patients with RCC associated with VHL disease. The primary end point was objective response (complete or partial response) in RCC tumours. Objective response to belzutifan in patients with non–renal cell carcinoma neoplasms was also assessed.

• Belzutifan provided a clinically meaningful overall response rate (ORR) in patients with VHL disease-associated RCC of 63.9% (95% CI: 50.6%, 75.8%).

• Among the subgroup of 50 participants with both RCC and CNS hemangioblastoma, belzutifan provided a clinically meaningful confirmed ORR of 44.0% (95% CI: 30.0%, 58.7%) in the CNS hemangioblastomas.

• Among the subgroup of 22 participants with both RCC and pNETs, belzutifan provided a clinically meaningful confirmed ORR of 90.9% (95% CI: 70.8%, 98.9%) in pNETs.

• Belzutifan provided a disease control rate (DCR, i.e. CR + PR + SD) in patients with VHL disease-associated RCC of 98.4% (95% CI: 91.2%, 100%).

• Among the subgroup of 50 participants with CNS hemangioblastoma, belzutifan provided a DCR of 90.0% (95% CI: 78.2%, 96.7%) in these tumours.

• Among the subgroup of 22 participants with pNETs, belzutifan provided a DCR of 100% (95% CI: 84.6%, 100%) in these tumours.

• Responses to belzutifan treatment were long and durable as shown by a median duration of response (DOR) not reached after a median follow-up of 37.7 months (range: 4.2 to 46.1 months). The median time-to-response (TTR)

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was 11.1 months (range 2.7 to 30.5 months) among 39 patients with a confirmed best overall response of complete response (CR) or partial response (PR).

• Later data cuts for RCC tumour response indicate patients response improves over time. The number and proportion of patients with a best overall response of complete response (CR) or partial response (PR), increases in later data cuts. ORR increasing from 36.1% (95% CI: 24.2%, 49.4%) at the 01-JUN-2020 data cut-off date to 63.9% (95% CI: 50.6%, 75.8%) at 01-APR-2022 data cutoff date.

Clinical safety

• Belzutifan was generally well tolerated. Adverse events (AEs) leading to treatment discontinuations were reported in 4 (6.6%) participants.

• Belzutifan had a manageable safety profile. Most AEs were Grade 1 to 2.

Relative treatment effect – real world study:

• Relative effectiveness information versus UK standard of care was derived from a retrospective, non-interventional study (VHL Natural History Study). The Optum study (34) is used to align effectiveness data with real world UK SoC for the purposes of the cost-effectiveness analysis.

Health-related quality of life

• Health-related quality of life data were from a VHL patient survey, a noninterventional international, cross-sectional patient survey that collected European Quality of Life – 5 Dimension Survey (EQ-5D-5L) data.

B.2.1 Identification and selection of relevant studies

To identify and select relevant studies, a systematic literature review (SLR) search was carried out in accordance with NICE guidance, according to a previously

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any relevant comparator treatments for this the indication of interest for this appraisal. Please refer to Appendix D for full details of the process and methods undertaken.

B.2.2 List of relevant clinical effectiveness evidence

A SLR was performed to identify all relevant published and unpublished randomised controlled trials (RCTs) and non-randomised clinical trials (non-RCTs) relating to belzutifan as per the final scope.

A single trial was identified from the SLR that provided clinical effectiveness information on belzutifan in the patient population of relevance to this submission. At the time of the SLR search, evidence from the MK-6482-004 study was available from a peer-reviewed journal publication (35), an European Society for Medical Oncology (ESMO) presentation (36), as well as from internal MSD data (37).

Table 4 Clinical effectiveness evidence

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Study

An Open-Label Phase 2 Study to Evaluate PT2977 for the Treatment of Von Hippel Lindau Disease-Associated Renal Cell Carcinoma (MK-6482-004) • 01-APR-2022 (36, 37), the key set of results presented in this submission

B.2.3 Summary of methodology of the relevant clinical effectiveness evidence

Summary of the methodology of the MK-6482-004 study

The methodology of the MK-6482-004 study is summarised in Table 5 and described in detail in the following subsections.

The MK-6482-004 study enrolled patients with VHL-associated RCC. While some patients in the study also had VHL-associated CNS hemangioblastomas and/or VHLassociated pNETs, all patients had VHL-associated RCC. This therefore means that the population of the MK-6482-004 study does not align with (i.e. is narrower than, in this respect) the marketing authorisation for belzutifan as described previously in section B.1), the population under consideration in this assessment.

The MHRA marketing authorisation decision and wording were based on the evidence from the MK-6482-004 study, which despite it being limited to patients with VHL disease who must have at least one RCC tumour, the MHRA found that the effect of treatment with belzutifan on the other VHL disease-associated tumours (in particular CNS hemangioblastomas and pNETs) that the patients with VHLassociated RCC achieved were sufficiently impressive, and the unmet need in patients with VHL disease sufficiently high, to warrant the marketing authorisation extending to patients with CNS hemangioblastomas and/or pNETs without RCC.

There is also misalignment between the GB marketing authorisation and the MK6482-004 study in terms of:

• The marketing authorisation is for patients "who require therapy" for the VHLassociated tumours, whereas the MK-6482-004 study's participant eligibility criteria specified that patients who had an immediate need for surgical intervention for tumour treatment were excluded.

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• The marketing authorisation is for patients "for whom localised procedures are unsuitable or undesirable" whereas this was not part of the participant eligibility criteria for the MK-6482-004 study.

The Medicines and Healthcare products Regulatory Agency (MHRA) granted this marketing authorisation in this indication based on the MK-6482-004 study and its results, based on which patients would benefit from treatment with belzutifan based on what was demonstrated in this very study. Such misalignments are not unusual for rare and highly specialised indications such as this one.

Table 5 Summary of trial methodology

Trial design

The MK-6482-004 open-label, multicentre, single-arm, non-randomised, interventional, Phase 2 study evaluated the efficacy and safety of belzutifan as treatment for participants with VHL disease who had at least 1 measurable RCC tumour. Participants may have also had VHL disease-associated tumours in other organ systems at screening which could have been measurable and/or nonmeasurable lesions. Patients were enrolled at 11 centres in the United States,

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Denmark, France, and the United Kingdom between May 31, 2018, and March 29, 2019. Patients received belzutifan administered orally at a dose of 120 mg once daily (in three 40-mg tablets) unless unacceptable adverse events or disease progression occurred.

The primary end point was objective response to treatment with belzutifan (complete response or partial response), as defined according to RECIST, version 1.1 (described in Appendix N), in patients with VHL-disease–associated renal cell carcinoma. Participants were evaluated with imaging every 12 weeks.

Measurements of VHL-associated RCC target lesions at 2 timepoints prior to the screening imaging were collected to determine the tumour growth rate before treatment with belzutifan. All images obtained were submitted to an independent review committee (IRC) to assess objective response and progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Radiographic response assessments were made separately for each VHLassociated organ system using RECIST 1.1 (e.g. RCC, pancreas lesions, and CNS hemangioblastomas). Retinal angiomas were assessed by an independent central committee of ophthalmologists, reviewing fundoscopic images.

Assignment, randomisation, and blinding

The MK-6482-004 study was an open-label single-group trial and so had no assignment, randomisation, or blinding.

Eligibility criteria

Patient inclusion criteria

Male and female participants of at least 18 years of age were eligible for enrolment in this study. Key inclusion criteria were as follows:

• Had a diagnosis of VHL disease based on a germline VHL alteration.

• Had at least 1 measurable solid RCC tumour and no RCC tumour greater than 3.0 cm that requires immediate surgical intervention. The diagnosis of RCC could be radiologic (histologic diagnosis not required). Participants could have VHL disease-associated tumours in other organ systems.

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• Had an ECOG performance status of 0 to 1.

• Had adequate organ function as defined below:

  • Absolute neutrophil count ≥1,000/μL, haemoglobin level ≥10 g/dL and platelet count ≥100,000/μL without transfusion or growth factor support within 2 weeks prior to obtaining the haematology values at screening.

  • Serum creatinine level ≤2.0 x upper limit of normal (ULN).

  • AST and ALT <2.5 x ULN, total bilirubin <1.5 x ULN (<3 x ULN in patients with Gilbert’s disease), and alkaline phosphatase ≤2.5 x ULN.

Patient exclusion criteria

Participants were excluded from the study if they met any of the following criteria:

• Had any systemic anticancer therapy (included anti-VEGF therapy or a systemic investigational anticancer agent).

• Had a surgical procedure for VHL disease or any major surgical procedure completed within 4 weeks prior to study enrolment.

• Had received prior treatment with PT2977 or another HIF-2α inhibitor.

• Had radiotherapy within 4 weeks prior to study enrolment.

• Had an immediate need for surgical intervention for tumour treatment.

• Had evidence of metastatic disease on screening imaging.

• Had malabsorption due to prior GI surgery or GI disease.

• Had any major cardiovascular event within 6 months prior to study drug administration including but not limited to myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic event, pulmonary embolism, clinically significant ventricular arrhythmias (e.g., sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes) or New York Heart Association Class III or IV heart failure.

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Settings and locations where the data were collected

Patients were enrolled at 11 centres in the United States, Denmark, France, and the United Kingdom. One patient received treatment in the UK.

Trial drugs and concomitant medications

Trial treatment

Use of belzutifan as specified in MK-6482-004 is presented in Table 6.

Table 6 MK-6482-004 study intervention

QD: once daily

Concomitant medications

The protocol specified that patients may not receive any approved or any additional investigational anti-neoplastic agent during the course of this study.

Pre-treatment administration of prophylactic anti-emetics was not allowed, but may be given if needed during study treatment. There will be no constraint on the use of growth factors, including erythropoietin, during treatment; however, prophylactic use is discouraged and adherence to the American Society of Clinical Oncology (ASCO) or European Society for Medical Oncology (ESMO) guidelines is recommended.

Patients should receive all necessary supportive care, including blood products, transfusions, antibiotics, pain medications, bisphosphonates, and replacement hormonal therapies (insulin, thyroid hormones, oestrogen/progesterone).

Belzutifan has been shown to induce the enzymes CYP3A4 at concentrations about 2-times the expected plasma concentration of PT2977 at the clinical dose of 120 mg/day. Belzutifan may decrease the exposure of medications metabolized by CYP3A4. If co-administration with drugs of a narrow therapeutic index that are metabolized by CYP3A4 cannot be avoided, additional monitoring of drug effect is recommended i.e. if a patient absolutely must receive a concomitant medication that

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is metabolised by the CYP3A4 enzyme, such a patient a patient would be monitored more frequently to check if the drug is working.

All concomitant medication(s) used during the study and within 28 days before the start of study drug administration were reported.

Outcomes assessed

A summary of the objectives and associated endpoints/outcomes assessed in the MK-6482-004 study is shown in Table 7.

Table 7 Objectives and associated endpoints of the MK-6482-004 study

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*Subgroup data on tumours other than VHL-associated RCC, CNS hemangioblastomas, or pNETs are presented in detail in this document as they are not included in the GB marketing authorisation for belzutifan in this indication or the scope of this appraisal.

Pre-planned subgroups

Summaries of the response endpoints were planned to be provided for subgroups of the Efficacy Analysis Set defined based on site of primary tumours other than RCC at screening. The analyses of ORR, DOR, TTR, PFS, and TTS were planned to be performed in each of these subgroups

Analysis populations

The data sets analysed as part of the study are described in Table 8.

Table 8 Analysis populations

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Baseline characteristics of trial participants

The baseline characteristics of the participants of the MK-6482-004 study are shown in Table 9 to Table 176. All patients included in the study had at least one concurrent non-RCC tumour at baseline. Median time from original diagnosis of VHL-associated RCC to initiation of treatment with belzutifan was 77.60 months (6.5 years). Participants had a mean (SD) of 5.5. (3.34) prior surgeries. Based on investigators assessment, the common concurrent non-RCC tumour types were CNS hemangioblastoma (n=51, 83.6%), pancreatic lesions (n=32, 52.5%), and retinal hemangioblastomas (n=17, 27.9%). The median time from last surgery to initiation of belzutifan was 23.49 months (1.96 years).

The baseline characteristics of this study have been shown to UK clinical experts who treat patients with VHL disease, who broadly agreed that these were representative of/applicable to the patients in the UK who would be treated with belzutifan in accordance with the marketing authorisation.

All participants

Table 9 MK-6482-004 study demographic and baseline characteristics (safety analysis set) - all patients

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Table 10 MK-6482-004 study demographic and baseline characteristics (safety analysis set) - all patients – additional data

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[1] (First Dose Date-Date of first positive biopsy+1)/30.4375

[2] (Date of VHL associated RCC diagnosis-Birthdate+1)/365.25

[3] The number patients with CNS hemangioblastomas shown in this table is according to investigator assessment, study results are reported later on in this document in terms of the number of patients with CNS hemangioblastoma according to independent review committee determination where this was found to be n=50.

*T1a means that the tumour is less than 4cm across, and is completely inside the kidney. Date of Data Cut-off: 01APR2022

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B.2.4 Statistical analysis and definition of study groups in the relevant clinical effectiveness evidence

Statistical analysis and definition of study groups in the MK-6482-004 study

Key information on the statistical analysis and definition of study groups in the MK6482-004 study are summarised in Table 11 with details presented in Appendix M.

Table 11 Summary of MK-6482-004 study statistical methods

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B.2.5 Critical appraisal of the relevant clinical effectiveness evidence

The quality assessment of the MK-6482-004 study is provided in Appendix D section D1.3. The main limitation of the MK-6482-004 study is that a single-arm trial does not directly compare the effects of belzutifan to that of UK clinical practice in this disease. Consequently, the relative effectiveness of belzutifan to current UK clinical practice is assessed via a control arm from a US VHL registry, methods described in section B.2.9 and section B.3.

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B.2.6 Clinical effectiveness results of the relevant studies

Clinical effectiveness data from the ongoing MK-6482-004 study at the 01-APR-2022 database cut-off date are presented in this section.

Patient disposition and follow-up duration

A total of 61 participants were allocated and received at least 1 dose of belzutifan. As of the 01-APR-2022 database cut-off date, 38 participants (62.3%) were receiving belzutifan, 23 participants (37.7%) had discontinued belzutifan and 6 participants 9.8%) had discontinued from the study (Table 12). The median duration of follow-up among the 61 participants with RCC in the safety analysis set was 37.7 months (range: 4.2 to 46.1 months) (Table 13).

Table 12 MK-6482-004 summary of patient disposition (safety analysis set)

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[1] Patients are still on study treatment or in long term follow-up as of the cutoff date. Date of Data Cut-off: 01APR2022

*The two deaths (suicide attempt and toxicity to various agents) were assessed a not drugrelated by the investigator.

Table 13 MK-6482-004 summary of follow-up duration (safety analysis set)

Follow-up duration is defined as the time from first dose to the date of death or the database cut-off date if the subject is still alive.

Extent of exposure

Duration of exposure is summarised in Table 14. The median duration of exposure to belzutifan was --------------------------- at the 01-APR-2022 database cut-off date.

Table 14 MK-6482-004 study drug exposure (safety analysis set)

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Summary of MK-6482-004 study efficacy results

The efficacy results of the MK-6482-004 study at the 01-APR-2022 data cutoff date are summarised in Table 15 and are presented in greater detail in the subsections of this section.

Table 15 Summary of MK-6482-004 study efficacy results (01-APR-2022 data cutoff)

Date of Data Cut-off: 01APR2022

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VHL RCC

Summary of key RCT clinical effectiveness results

In patients with VHL disease-associated RCC:

• MK-6482-004 study results from the latest available 01-APR-2022 cut-off date (not yet published) are presented in this section. The median duration of followup among the 61 participants with RCC in the APaT population was 37.7 months (range: 4.2 to 46.1 months). The median duration of exposure to belzutifan was ---------------------------------------.

• Belzutifan provides a clinically meaningful confirmed ORR among the 61 participants with RCC in the Efficacy Analysis Set (APaT population) of 63.9% (95% CI: 50.6%, 75.8%).

• Belzutifan provided a disease control rate (DCR, i.e. CR + PR + SD) in patients with VHL disease-associated RCC of 98.4% (95% CI: 91.2%, 100%).

• Responses to belzutifan treatment were long and durable as shown by a median DOR that was not reached as of the 01-APR-2022 database cut-off date. The range of DOR was 5.4+ to 35.8+ months.

• The median TTR was 11.1 months (range: 2.7 to 30.5 month) among 39 participants with a confirmed best observed response (BOR) of CR or PR.

• The median (95% CI) PFS was --------------------------------------- months. The PFS rate at Month 36 was ----- and at Month 42 was -----.

• At the 01-APR-2022 database cut-off date, 7 patients (11.5%) had undergone surgery. Consequently, the median time to surgery is not evaluable.

Overall response rate

The confirmed ORR among the 61 participants with RCC in the Efficacy Analysis Set was 63.9% (95% CI: 50.6, 75.8), with a rate and associated lower 95% CI >50% (i.e. even at the lowest estimate of efficacy at least half of patients experience CR or PR), Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

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this is demonstrative of the efficacy of belzutifan in treating these tumours, as such tumours do not shrink/respond spontaneously in the absence of effective treatment. Detailed response results are shown in Table 16 and Figure 3. Note that that best overall response according to RECIST 1.1 criteria (described in more detail in Appendix N) is determined by more than only the change in tumour size between baseline and last measurement (38). Therefore it is possible for, e.g. the best overall response [BOR] of a tumour to be SD even though it may have a greater percentage reduction in diameter than a different tumour with a BOR of PR, as shown in certain patients in the figure.

Tumour response results from several data cut-off dates are shown in Table 16, it can be seen that the number and proportion of patients with complete response (CR), and with partial response (PR), increases with later data cut-off dates, indicating that more patients experienced a better response as time went on. These are further illustrated in Appendix N.

Of the four patients who experienced a complete response in their target RCC tumour by the 01-APR-2022 data cut-off date, their target RCC tumour -------------------- from the timepoint complete response (as per RECIST 1.1) was first recorded to the 01-APR-2022 data cut-off date, showing that complete responses that arise during treatment with belzutifan persist. For the 35 patients who had experienced a partial response by the 01-APR-2022 data cut-off date, the change in their target RCC tumour size from the timepoint partial response (as per RECIST 1.1) was first recorded to the 01-APR-2022 data cut-off date are shown in Figure 5. -------------------

No patients had a best overall response of PD (shown in Table 16) despite there being 6 patients who discontinued treatment due to disease progression per RECIST 1.1 for VHL disease-associated RCC tumours (shown in Table 12), and 9 patients are shown to have disease progression in the analysis of PFS (discussed later in this document and shown in Table 19). This because best overall response is the best response status recorded in the target tumour in the patient at any point during their

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follow-up period i.e. if a patient had an overall tumour response state of PR or SD at any point prior to disease progression their best overall response would be PR or SD (whichever was the better one had). The only way a patient could have a best overall response of PD is if they were recorded to have PD at their first post-baseline followup scan and then discontinued the trial or never subsequently experienced a CR, PR, or SD.

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Table 16 MK-6482-004 summary of best overall tumour response for RCC tumours (RECIST 1.1) – independent review committee (efficacy analysis set)

Note: 95% and 90% confidence intervals are constructed using 2-sided Clopper-Pearson method. Best overall response of RCC CR and PR should be confirmed by a second assessment at least 4 weeks after the initial response.

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Figure 3 Waterfall plot - percentage change in total sum of RCC target lesions diameters from baseline to post-baseline maximum % reduction (RECIST 1.1) – independent review committee (efficacy analysis set)

==> picture [676 x 280] intentionally omitted <==

----- Start of picture text -----
100 Best Overall Response (N=61)
PD SD
PR CR
50
0
-50
-100
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61
Subject
Percent Change from Baseline
----- End of picture text -----

Subjects without either post-baseline evaluable lesion measurements or target lesions or with all post-baseline non-evaluable time-point responses appear as blank on the right of the figure.

Note that best overall response according to RECIST 1.1 criteria is determined by more than only the change in tumour size between baseline and last measurement (see Appendix N for a description of best overall response according to RECIST 1.1).

Number (%) of patients with maximum % reduction in sum of diameters of target lesions <0 = 56 (91.8), i.e. 98.1% of patients had their tumour reduce in size at some point during follow-up in their RCC target lesions. Date of Data Cut-off: 01APR2022

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Figure 4 Waterfall plot - percentage change in total sum of target lesions diameters for RCC, CNS hemangioblastoma, and pancreatic neuroendocrine tumours, from baseline to post-baseline maximum % reduction (RECIST 1.1) – independent review committee (efficacy analysis set)

==> picture [428 x 230] intentionally omitted <==

Date of Data Cut-off: 01APR2022.

Note: Only data from 60 of the 61 participants in the efficacy analysis set are shown as one participant was without either post-baseline evaluable lesion measurements or target lesions or with all post-baseline non-evaluable time-point responses for RCC and CNS tumours, and therefore the percentage change could not be calculated.

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Figure 5 Spider plot - percentage change in total sum of RCC target lesion diameters from date of partial response (RECIST 1.1) – independent review committee (efficacy analysis set)

==> picture [428 x 230] intentionally omitted <==

Date of Data Cut-off: 01APR2022

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Duration of response

In the 39 patients for whom CR or PR was recorded (also shown in Table 16), the median DOR was not reached as of the 01-APR-2022 database cut-off date (50% of the patients who had CR or PR need to have subsequently had disease progression or death in order for median DOR to be calculated, but only 5 such patients [12.8%] had progressed or died by the 01-APR-2022 data cutoff date). Bearing in mind that at the 01-APR-2022 data cut-off date the median length of follow-up is 37.7 months and the median time-to-response is 11.1 months (detailed in a later subsection), the fact that only 12.8% of patients who had CR or PR have subsequently had disease progression or death at this data cut-off date is indicative of a durable response. The range of DOR was 5.4+ to 25.8+ months (Table 17 and Figure 6).

Table 17 MK-6482-004 summary of duration of response for RCC tumours (RECIST 1.1) – independent review committee (efficacy analysis set)

NE: Not Estimable.

Duration of Response is analysed using the Kaplan-Meier estimator. Median, first and third quartiles of Duration of

Response is reported along with 95% Brookmeyer-Crowley confidence intervals. [1] Arithmetic mean.

[2] % is calculated by Kaplan-Meier method. For the patients without extended response duration at each duration threshold, they either experienced disease progression or death or their response duration had not reached that duration threshold yet.

• indicates there was no progressive disease by the time of last disease assessment. Date of Data Cut-off: 01APR2022

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Figure 6 MK-6482-004 Kaplan-Meier plot of duration of response for RCC tumours (RECIST 1.1) – independent review committee (efficacy analysis set)

==> picture [428 x 229] intentionally omitted <==

This figure shows the proportion of patients (1.0 = 100%) still with response (have not had tumour progression or have died) at timepoints measured from the first recording of confirmed response (at Time (Months) = 0). Note that the number at risk changes with time which affects the denominator and data point relative to the y-axis in this figure.

Duration of Response is analysed using the Kaplan-Meier estimator and their 95% confidence intervals are estimated with the generalised Brookmeyer-Crowley method.

NE = Not estimable.

Date of Data Cut-off: 01APR2022

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Time to response

The median TTR was 11.1 months (range: 2.7 to 30.5 months) among 39

participants with a confirmed best overall response (BOR) of CR or PR (Table 18).

Table 18 MK-6482-004 summary of time to response for RCC tumours (RECIST 1.1) – independent review committee (efficacy analysis set)

Date of Data Cut-off: 01APR2022

Progression-free survival

The median (95% CI) PFS was ----------------------- months. The PFS rate at Month 36 was ----- (Table 17 and Figure 7).

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Table 19 MK-6482-004 summary of progression-free survival for RCC tumours (RECIST 1.1) – independent review committee (efficacy analysis set)

NE: Not Estimable.

[1] Progression-Free Survival are analysed using the Kaplan-Meier estimator. Median, first and third quartiles of PFS are reported along with 95% Brookmeyer-Crowley confidence intervals.

Date of Data Cut-off: 01APR2022

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Figure 7 Kaplan-Meier plot of progression-free survival for RCC tumours (RECIST 1.1) – independent review committee (efficacy analysis set)

==> picture [428 x 229] intentionally omitted <==

Progression-Free Survival is analysed using the Kaplan-Meier estimator and their 95% confidence intervals are estimated with the generalized Brookmeyer-Crowley method. Note that the number at risk changes with time which affects the denominator and data point relative to the y- axis in this figure.

NE = Not estimable. Date of Data Cut-off: 01APR2022

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Time to surgery

At the 01-APR-2022 database cut-off date, 7 patients (11.5%) had undergone surgery, the median time to surgery is not evaluable.

Table 20 Summary of time to surgery for RCC tumours (efficacy analysis set)

The Q1, median, Q3, and 95% CI are obtained from Kaplan-Meier estimates. Surgery includes any procedure, excluding radiation, which leads to reduction of RCC tumor size.

NE: Not Estimable.

Date of Data Cut-off: 01APR2022

Rate of surgeries

A comparison of the VHL disease-associated tumour-related surgeries patients underwent before and after initiation of treatment with belzutifan is shown in Figure 8 (note that only pre-treatment surgeries less than 10 years prior to treatment initiation are presented). From this it can be seen that that the frequency of VHL diseaseassociated surgeries in the time period after initiation of treatment with belzutifan is lower than observed in the time period before, which is indicative of a potentially practice-changing favourable effect of belzutifan treatment on subsequent rate of VHL disease-associated surgeries.

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Figure 8 Distribution of all surgeries pre- and post-treatment initiation over time for individual patients - safety analysis set

==> picture [697 x 319] intentionally omitted <==

Horizontal bars represent each patient.

Only pre-treatment surgeries less than 10 years prior to treatment initiation are presented. Length of the bars on the right side of the y-axis represents duration of treatment at time of data cut-off. Surgery is defined as a tumour reduction procedure excluding radiation. Date of Data Cut-off: 01-APR-2022.

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B.2.7 Subgroup analysis

Summary of key subgroup analyses results:

Patients with VHL-associated RCC and CNS hemangioblastomas:

• Belzutifan provides a clinically meaningful confirmed ORR among the 50 participants with CNS hemangioblastoma at baseline per IRC assessment of 44.0% (95% CI: 30.0, 58.7). Four patients (8.0%) achieved a BOR of CR and 18 participants (36.0%) achieved a BOR of PR.

• Belzutifan provided a DCR of 90.0% (95% CI: 78.2%, 96.7%) in CNS hemangioblastomas.

• • Responses to belzutifan treatment were long and durable as shown by a median DOR that was not reached as of the 01-APR-2022 database cut-off date. The range of DOR was 3.7+ to 38.7+ months, 12 patients achieved a DOR ≥30 months.

• • The median TTR was ---------------------------------------------------- participants with a confirmed BOR of CR or PR.

• • The median PFS for patients with CNS hemangioblastoma --------------- at the 01-APR-2022 database cut-off date, ---------------- had a PFS event (9 had disease progression and 2 died).

• • At the 01-APR-2022 database cut-off date, only one patient with CNS hemangioblastoma had undergone surgery.

• In patients with VHL disease-associated RCC and pancreatic neuroendocrine tumours:

• Belzutifan provides a clinically meaningful confirmed ORR among 22 participants with pancreatic neuroendocrine tumours at baseline per IRC assessment of 90.9% (95% CI: 70.8, 98.9). As of the 01-APR-2022 database

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cut-off date, 7 participants (31.8%) achieved a BOR of CR and 13 participants (59.1%) achieved a BOR of PR. • Among the subgroup of 22 participants with pNETs, belzutifan provided a DCR of 100% (95% CI: 84.6%, 100%) in these tumours. • Responses to belzutifan treatment were long and durable as shown by a median DOR that was not reached as of the 01-APR-2022 database cut-off date. The range of DOR was 11.0+ to 37.3+ months, 15 participants achieved a DOR ≥24 months. • The median TTR was ----------------------------------------------- participants with a confirmed BOR of CR or PR. • The median PFS for patients with pancreatic neuroendocrine tumours -------------- at the 01-APR-2022 database cut-off date, -------------- had a PFS event. • At the 01-APR-2022 database cut-off date, no patient with pancreatic neuroendocrine tumour had undergone surgery.

Results are presented in this subsection for the subgroups of patients with VHL RCC who also had central nervous system (CNS) hemangioblastomas or pancreatic neuroendocrine tumours (pNETs). In terms of numbers of patients in the MK-6482004 study (also summarised in Figure 9):

• Of the total 61 patients with RCC (results for this population reported in section B.2.6):

  • 50 of the 61 patients with RCC also had CNS hemangioblastomas (results for this population reported later in this section B.2.7. Please note that 50 of the 61 patients with RCC also had CNS hemangioblastomas according to IRC, this number differs slightly to the number of patients with RCC also had CNS hemangioblastomas reported in the baseline characteristics table in Table 10 as being 51 as the 51 is the number according to only investigator assessment and not IRC).

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• 17 of the 50 patients with RCC and CNS hemangioblastomas also had pNETs (results for this population not reported separately)

• 33 of the 50 patients with RCC and CNS hemangioblastomas did not also have pNETs (results for this population not reported separately)

• 22 of the 61 patients with RCC also had pNETs (results for this population reported later in this section B.2.7)

  • 17 of the 22 patients with RCC and pNETs also had CNS hemangioblastomas (results for this population not reported separately)

  • 5 of the 22 patients with RCC and pNETs did not also have CNS hemangioblastomas (results for this population not reported separately)

Figure 9 Summary of subgroups in the MK-6482-004 study (not to scale)

==> picture [268 x 256] intentionally omitted <==

----- Start of picture text -----
With RCC
(N=61)
With RCC & CNS
hemangioblastoma
(N=50)
With RCC & CNS
hemangioblastoma &
pNET
(N=17)
With RCC & pNET
(N=22)
----- End of picture text -----

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Central nervous system hemangioblastomas

Overall response rate

The confirmed ORR among the 50 participants with CNS hemangioblastoma at baseline per IRC assessment was 44.0% (95% CI: 30.0, 58.7). Four patients (8.0%) achieved a BOR of CR and 18 participants (36.0%) achieved a BOR of PR (Table 21 and Figure 10). The specific locations in the CNS of the tumours with each category of vest overall response are shown in Appendix P, due to the very low sample sizes, no conclusive patterns/trends can be observed with regard to precise locations of tumours in the CNS.

Of the four patients in whom a complete response was reported in their target CNS hemangioblastoma by the 01-APR-2022 data cut-off date, their target tumour -------------------- from the timepoint complete response (as per RECIST 1.1) was first recorded to the 01-APR-2022 data cut-off date, showing that complete responses that arise during treatment with belzutifan persist. For the 18 patients in whom a partial response was reported by the 01-APR-20223 data cut-off date, the change in their target CNS hemangioblastoma size from the timepoint partial response (as per RECIST 1.1) was first recorded to the 01-APR-2022 data cut-off date are shown in

Figure 11. It can be seen that ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

No patients had a best overall response of PD (shown in Table 21) despite there being 9 patients shown to have disease progression in the analysis of PFS (discussed later in this document and shown in Table 24). This because best overall response is the best response status recorded in the patient at any point during their follow-up period i.e. if a patient had an overall tumour response state of PR or SD at any point prior to disease progression in their target tumour their best overall response would be PR or SD (whichever was the better one had). The only way a patient could have a best overall response of PD is if they were recorded to have PD at their first post-baseline follow-up scan and then discontinued the trial or never subsequently experienced a CR, PR, or SD.

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Table 21 MK-6482-004 summary of best overall tumour response for CNS hemangioblastomas (RECIST 1.1) – independent review committee (efficacy analysis set)

Note: 95% and 90% confidence intervals are constructed using 2-sided Clopper-Pearson method.

Best overall response of RCC CR and PR should be confirmed by a second assessment at least 4 weeks after the initial response. Patients evaluable at baseline per IRC are included.

• There were changes in assessments of imaging data that resulted in an overall decrease in the number of participants with responses for CNS hemangioblastoma (from 16 to 15 participants with confirmed response) and an overall decrease in the number of PFS events for pancreatic neoplasms (1 less PFS event) and CNS hemangioblastomas (1 less PFS event) since submission of initial application, at the 01-DEC-2020 data cut-off date.

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Figure 10 Waterfall plot - percentage change in total sum of CNS hemangioblastoma target lesions diameters from baseline to post-baseline maximum % reduction (RECIST 1.1) – independent review committee (efficacy analysis set)

==> picture [675 x 280] intentionally omitted <==

----- Start of picture text -----
100 Best Overall Response (N=50)
PD SD
PR CR
50
0
-50
-100
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 50
Subject
Percent Change from Baseline
----- End of picture text -----

Subjects without either post-baseline evaluable lesion measurements or target lesions or with all post-baseline non-evaluable time-point responses appear as blank on the right of the figure.

Note that best overall response according to RECIST 1.1 criteria is determined by more than only the change in tumour size between baseline and last measurement (see Appendix N for a description of best overall response according to RECIST 1.1).

Number (%) of patients with maximum % reduction in sum of diameters of target lesions < 0 = 27 (54.0), i.e. 54.0% of patients had their tumour reduce in size at some point during follow-up in their CNS hemangioblastoma target lesions. Date of Data Cut-off: 01APR2022

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Figure 11 Spider plot - Percentage change in total sum of CNS hemangioblastoma target lesion diameters from date of partial response (RECIST 1.1) – independent review committee (efficacy analysis set)

==> picture [428 x 230] intentionally omitted <==

Database cut-off date: 01APR2022

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Duration of response

The median DOR was not reached as of the 01-APR-2022 database cut-off date.

The range of DOR was 3.7+ to 38.7+ months, 12 patients achieved a DOR ≥30 months (Table 22 and Figure 12).

Table 22 MK-6482-004 summary of duration of response for CNS hemangioblastomas (RECIST 1.1) – independent review committee (efficacy analysis set)

NE: Not Estimable.

Duration of Response is analyzed using the Kaplan-Meier estimator. Median, first and third quartiles of Duration of Response are reported along with 95% Brookmeyer-Crowley confidence intervals.

[1] Arithmetic mean.

[2] % is calculated by Kaplan-Meier method. For the patients without extended response duration at each duration threshold, they either experienced disease progression or death or their response duration had not reached that duration threshold yet.

• indicates there was no progressive disease by the time of last disease assessment. Date of Data Cut-off: 01APR2022

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Figure 12 MK-6482-004 Kaplan-Meier plot of duration of response for CNS hemangioblastomas (RECIST 1.1) – independent review committee (efficacy analysis set)

==> picture [428 x 229] intentionally omitted <==

This figure shows the proportion of patients (1.0 = 100%) still with response (have not had tumour progression or have died) at timepoints measured from the first recording of confirmed response (at Time (Months) = 0). Note that the number at risk changes with time which affects the denominator and data point relative to the y-axis in this figure.

Duration of Response is analysed using the Kaplan-Meier estimator and their 95% confidence intervals are estimated with the generalised Brookmeyer-Crowley method.

NE = Not estimable.

Date of Data Cut-off: 01APR2022

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Time to response

The median TTR was ---------------------------------------------------- participants with a

confirmed BOR of CR or PR (Table 23).

Table 23 MK-6482-004 summary of time to response for CNS hemangioblastomas (RECIST 1.1) – independent review committee (efficacy analysis set)

Date of Data Cut-off: 01APR2022

Progression-free survival

The median PFS for patients with CNS hemangioblastoma --------------- at the 01-

APR-2022 database cut-off date, ------- patients had a PFS event (Table 24 and Figure 13).

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Table 24 MK-6482-004 summary of progression-free survival for CNS hemangioblastomas (RECIST 1.1) – independent review committee (efficacy analysis set)

NE: Not Estimable.

[1] Progression-Free Survival are analysed using the Kaplan-Meier estimator. Median, first and third quartiles of PFS are reported along with 95% Brookmeyer-Crowley confidence intervals.

Date of Data Cut-off: 01APR2022

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Figure 13 Kaplan-Meier plot of progression free survival for CNS hemangioblastomas (RECIST 1.1) – independent review committee (efficacy analysis set)

==> picture [428 x 229] intentionally omitted <==

Progression-Free Survival is analysed using the Kaplan-Meier estimator and their 95% confidence intervals are estimated with the generalised Brookmeyer-Crowley method. Note that the number at risk changes with time which affects the denominator and data point relative to the y- axis in this figure.

NE = Not estimable. Date of Data Cut-off: 01APR2022

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Time to surgery

At the 01-APR-2022 database cut-off date, only one patient with CNS

hemangioblastoma had undergone surgery. Consequently, the median time to surgery is not evaluable for this subgroup.

Rate of surgeries

A comparison of the VHL disease-associated tumour-related surgeries these patients underwent before and after initiation of treatment with belzutifan is shown in Figure 14 (note that only the blue bars indicate patients with CNS hemangioblastomas at baseline per IRC).

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Figure 14 Distribution of all surgeries pre- and post-treatment initiation over time for individual patients for individual patients with baseline CNS hemangioblastomas per independent review committee - safety analysis set

==> picture [428 x 230] intentionally omitted <==

Horizontal bars represent each patient.

Blue bars indicate patients with CNS Hemangioblastomas at baseline per IRC. Only pre-treatment surgeries less than 10 years prior to treatment initiation are presented. Length of the bars on the right side of the y-axis represents duration of treatment at time of data cut-off. Surgery is defined as a tumour reduction procedure excluding radiation. Date of Data Cut-off: 01-APR-2022.

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Pancreatic neuroendocrine tumours

Overall response rate

The confirmed ORR among 22 participants with pancreatic neuroendocrine tumours at baseline per IRC assessment was 90.9% (95% CI: 70.8, 98.9). As of the 01-APR2022 database cut-off date, 7 participants (31.8%) achieved a BOR of CR and 13 participants (59.1%) achieved a BOR of PR (Table 25 and Figure 15).

Of the seven patients who experienced a complete response in their target pNET by the 01-APR-2022 data cut-off date, their target tumour --------------------- from the timepoint complete response (as per RECIST 1.1) was first recorded to the 01-APR2022 data cut-off date, showing that complete responses that arise during treatment with belzutifan persist. For the 13 patients who experienced a partial response by the 01-APR-20223 data cut-off date, the change in their target pNET size from the timepoint partial response (as per RECIST 1.1) was first recorded to the 01-APR2022 data cut-off date are shown in Figure 16. It can be seen that -------------------------

----------------------.

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Table 25 MK-6482-004 summary of best overall tumour response for pancreatic neuroendocrine tumours (RECIST 1.1) – independent review committee (efficacy analysis set)

Note: 95% and 90% confidence intervals are constructed using 2-sided Clopper-Pearson method.

Best overall response of RCC CR and PR should be confirmed by a second assessment at least 4 weeks after the initial response.

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Figure 15 Waterfall plot - percentage change in total sum of target lesions diameters for pancreatic neuroendocrine tumours from baseline to post-baseline maximum % reduction (RECIST 1.1) – independent review committee (efficacy analysis set)

==> picture [675 x 280] intentionally omitted <==

----- Start of picture text -----
100 Best Overall Response (N=22)
PD SD
PR CR
50
0
-50
-100
1 4 7 10 13 16 19 22
Subject
Percent Change from Baseline
----- End of picture text -----

Subjects without either post-baseline evaluable lesion measurements or target lesions or with all post-baseline non-evaluable time-point responses appear as blank on the right of the figure.

Note that best overall response according to RECIST 1.1 criteria is determined by more than only the change in tumour size between baseline and last measurement (see Appendix N for a description of best overall response according to RECIST 1.1).

Number (%) of patients with maximum % reduction in sum of diameters of target lesions < 0 = 22 (100.0), i.e. 100% of patients had their tumour reduce in size at some point during follow-up in their pNET target lesions. Date of Data Cut-off: 01APR2022

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Figure 16 Spider plot - Percentage change in total sum of target lesion diameters for pNETs from date of partial response (RECIST 1.1) – independent review committee (efficacy analysis set)

==> picture [428 x 229] intentionally omitted <==

Database cut-off date: 01APR2022

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Duration of response

The median DOR was not reached as of the 01-APR-2022 database cut-off date, no patients in this subgroup had progression or died by the 01-APR-2022 data cutoff date. The range of DOR was 11.0+ to 37.3+ months, 15 participants achieved a DOR ≥24 months (Table 26 and Figure 17).

Table 26 MK-6482-004 summary of duration of response for pancreatic neuroendocrine tumours (RECIST 1.1) – independent review committee (efficacy analysis set)

NE: Not Estimable.

Duration of Response is analysed using the Kaplan-Meier estimator. Median, first and third quartiles of Duration of Response are reported along with 95% Brookmeyer-Crowley confidence intervals.

[1] Arithmetic mean.

[2] % is calculated by Kaplan-Meier method. For the patients without extended response duration at each duration threshold, they either experienced disease progression or death or their response duration had not reached that duration threshold yet.

• indicates there was no progressive disease by the time of last disease assessment. Date of Data Cut-off: 01APR2022

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Figure 17 MK-6482-004 Kaplan-Meier plot of duration of response for pancreatic neuroendocrine tumours (RECIST 1.1) – independent review committee (efficacy analysis set)

==> picture [428 x 229] intentionally omitted <==

This figure shows the proportion of patients (1.0 = 100%) still with response (have not had tumour progression or have died) at timepoints measured from the first recording of confirmed response (at Time (Months) = 0). Note that the number at risk changes with time which affects the denominator and data point relative to the y-axis in this figure.

Duration of Response is analysed using the Kaplan-Meier estimator and their 95% confidence intervals are estimated with the generalised Brookmeyer-Crowley method.

NE = Not estimable.

Date of Data Cut-off: 01APR2022

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Time to response

The median TTR was ----------------------------------------------- participants with a

confirmed BOR of CR or PR (Table 27).

Table 27 MK-6482-004 summary of time to response for pancreatic neuroendocrine tumours (RECIST 1.1) – independent review committee (efficacy analysis set)

Progression-free survival

The median PFS for patients with pancreatic neuroendocrine tumours --------------- at

the 01-APR-2022 database cut-off date, ---------- had a PFS event (Table 28).

Table 28 MK-6482-004 summary of progression-free survival for pancreatic neuroendocrine tumours (RECIST 1.1) – independent review committee (efficacy analysis set)

NE: Not Estimable.

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[1] Progression-Free Survival are analysed using the Kaplan-Meier estimator. Median, first and third quartiles of PFS are reported along with 95% Brookmeyer-Crowley confidence intervals.

Date of Data Cut-off: 01APR2022

Time to surgery

At the 01-APR-2022 database cut-off date, no patient with pancreatic neuroendocrine tumour had undergone surgery. Consequently, the time to surgery is not evaluable for this subgroup. Data sources used to estimate time to surgery in this population for the cost-effectiveness analyses are described in section B.3.

Other tumours

The MK-6482-004 study collected data on several other tumour types in addition to the tumour types covered in the MHRA marketing authorisation and the scope of this current appraisal. Key results for these tumours are summarised in the following subsections. The results indicate treatment with belzutifan were associated with valuable positive effects in these tumours.

Pancreatic lesions

Results from the MK-6482-004 study were collected for the pancreatic lesions subgroup, which included both pNET and non-pNET lesions, pNET lesions were defined as solid parenchymal lesions that do not communicate with the pancreatic duct, while non-pNET lesions were defined as all pancreatic lesions that were not pNET lesions.

Treatment with belzutifan showed --------------------- ORR in participants with

pancreatic lesions; the ORR by IRC was ------------------------------------------------------------------. The DCR for pancreatic lesions was ----------------------------------------------.

The median DOR for participants with pancreatic lesions was -----------, and based on Kaplan-Meier estimation, ----- of responders had an ongoing response at 30 months.

The median TTR was -------------------------------. Median PFS and TTS were -----------. - -------------- underwent surgery for pancreatic lesions as of the 01-APR-2022 data cutoff date.

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Retinal hemangioblastoma

Twelve of 17 participants in the MK-6482-004 study with baseline retinal hemangioblastomas were evaluable for response with follow-up evaluations. Of 12 participants with retinal hemangioblastoma, evaluable retinal hemangioblastomas were determined in 16 eyes at baseline per IRC assessment.

Treatment response in retinal hemangioblastoma, per IRC, was assessed using multiple parameters such as number/size/location, degree of feeder/drainer engorgement (mild/prominent), presence of intraretinal heme, presence of preretinal heme, presence of vitreous heme, presence of lipid exudation, presence of subretinal fluid, and presence of fibrosis (37).

An improvement of retinal hemangioblastoma was observed after treatment with belzutifan. The response of ‘Improved’ was 100% (95% CI: 79.4, 100.0) in all 16 eyes and 100% (95% CI 73.5, 100.0) in all 12 participants. Median DOR was not reached. All 12 participants had an improvement for ≥12 months, and of these, 9 participants had improvement for ≥30 months. Median TTR was ---------------------------

---.

Visual acuity of participants with retinal hemangioblastoma underwent ophthalmologic evaluation (by investigator assessment). Visual acuity in most participants -----------------------------.

Adrenal lesions and endolymphatic sac tumours

As of the 01-APR-2022, per investigator assessment, ---------------- with adrenal lesions (n=3) and endolymphatic sac tumours (n=1) had a BOR of --; median TTR ----------------------. Median PFS was -----------.

Epididymal cystadenomas

Sixteen participants had epididymal cystadenomas at baseline and were followed up by ultrasound examination. Per investigator assessment, at Week 49, -------------- had improvement in lesions compared with baseline, - had stable lesions, and -------------- had progressed.

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B.2.8 Meta-analysis

The MK-6482-004 study is the only study that reports clinical effectiveness data on the treatment effect of belzutifan in the relevant indication, therefore no metaanalysis possible. Information on the effectiveness of the comparator (standard of care in UK clinical practice) was derived from data collected in a retrospective noninterventional study conducted in the United States (the VHL Natural History Study) described in section B.2.9.

B.2.9 Indirect and mixed treatment comparisons

• A matching adjusted indirect comparison (MAIC) using data from the MK-6482004 study and a retrospective non-intervention VHL Natural History Study was conducted to compare the outcomes of treatment with belzutifan with the outcomes observed in the standard of care for this patient population, in order to inform the cost-effectiveness analyses. The inclusion criteria for the realworld study reflected the inclusion criteria for the MK-6482-004 study, which is different to the final MHRA indication wording as described earlier. Therefore, there are some generalisability considerations required as the patients in these two studies are not quite the same as those covered by the MHRA label.

• The MAIC found that treatment with belzutifan, compared to standard of care, was associated with a lower exponential rate parameter for the cause-specific hazards of pre-surgery to first surgery (0.03692 events/person-year compared to 0.25324 events/person-year) and a lower incidence of non-RCC VHLrelated surgeries with therapeutic intent (0.02119 events/person-year compared to 0.178984 events/person-year).

• Additionally, the Optum study was used to align effectiveness data sourced from the VHL Natural History Study with real world UK SoC for the purposes of the cost-effectiveness analysis (34). Details of this are provided in section B.3.3.

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Propensity score weighting-based matching-adjusted indirect comparison versus standard of care

Objective and rationale

For the purposes of the cost-effectiveness analyses described in section B.3, it is necessary to compare the outcomes of treatment with belzutifan with the outcomes observed in the standard of care for this patient population. This required data to inform the comparator arm of patients (i.e. patients managed via standard of care) that are comparable to the population of the MK-6482-004 study. This was done by generating a comparator population from the population assessed in the VHL Natural History Study from which a matching-adjusted indirect comparison can be performed.

The VHL Natural History Study was commissioned prior to GB marketing authorisation was finalised. While it provides useful data it does not describe well the standard of care population specific to current indication under assessment.

Data source for the comparator arm

The VHL Natural History study was a retrospective non-interventional study of existing medical records, with supplemental electronic medical record (EMR) data abstraction and central imaging review of abdominal imaging scans obtained during routine clinical care. Patients with VHL disease who had ≥1 measurable renal solid tumour measured during the study period and met the other patient eligibility criteria of the VHL Natural History Study were identified and followed until the end of the assessment window (July 31, 2004 to June 30, 2020).

The study used data collected by the United States National Cancer Institute’s (NCI) Urologic Oncology Branch (UOB) of patients with VHL disease managed and treated at the United States National Institutes of Health (NIH) Clinical Center in Bethesda, Maryland, a global leader in comprehensive care for VHL disease patients. Data collected on VHL patient characteristics, treatment, and follow-up information is available in medical records for all patients treated at the NCI’s UOB since approximately 1987 (though the assessment window for the current analyses was July 31, 2004 to June 30, 2020). For the current analyses, the data source included

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data registered by the NCI using a hybrid of existing structured data fields in the UOB Hereditary Database, linked to other structured NCI and external database (e.g., NCI laboratory and prescription database, and US National Death Index [NDI]), supplemented with available serial tumour measurements and additional medical record abstraction of unstructured data fields. The study leveraged existing serial tumour measurements that the NCI registered in the Hereditary Database to assess growth rates of renal solid tumours. Additional details on the methodology of the VHL Natural History Study are provided in Appendix O.

MAIC methods

Sample selection criteria

In order to benchmark against the results of the MK-6482-004 phase 2 trial of belzutifan and generate key parameters for elements of the standard of care arm of the cost-effectiveness model, a sub-population of patients was identified from the VHL Natural History Study who met inclusion and exclusion criteria that closely matched that of the trial. Patients were followed from the patient-level index date, defined as the earliest date that a measurable renal solid tumour was detected during the study period (July 31, 2004 to June 30, 2020). The available follow-up time for each patient spanned from their patient-level index date until the first of: mortality date; or last clinical encounter date during the study period.

The following study inclusion and exclusion criteria were applied to identify the patient population used to generate cost-effectiveness model inputs for the VHLRCC indication:

Inclusion criteria:

• Patients treated at the NCI with VHL syndrome who are residents of the US or Canada

• Patients with ≥1 renal solid tumour identified and measured during the study period (July 31, 2004 to June 30, 2020)

• Patients with a diagnosis of VHL disease based on germline VHL alteration

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Exclusion criteria:

• Patients with any renal procedure in the 30 days on or prior to patient-level index date

• Patients whose last follow-up date was on or prior to patient-level index date

• If the largest renal solid tumor at patient-level index date is ≥30 millimetres (mm), patients with a renal surgical procedure with therapeutic intent performed within 60 days on or after patient-level index date

• Patients who received treatment with belzutifan or another hypoxia inducible factor 2 alpha (HIF-2α) inhibitor any time prior to patient-level index date

• Patients who received systemic oncologic or investigational therapy any time prior to patient-level index date

• Patients with evidence of VHL disease-associated metastatic disease prior to patient-level index date

In order to generate cost-effectiveness model parameters for the VHL-CNS hemangioblastoma and VHL-pNET indications, patients who met the above inclusion/exclusion criteria were further restricted to those with a recorded history of CNS hemangioblastoma and pNET, respectively. As a limitation, it was not feasible using the available Natural History Study data to identify whether patients in these subsets had CNS hemangioblastoma and pNET at the patient-level index date (i.e., it was only feasible to identify patients with a recorded history of CNS hemangioblastoma or pNET at some point prior to the patient-level index date). In contrast, patients in the corresponding CNS hemangioblastoma and pNET subpopulations of the MK-6482-004 trial were confirmed to have CNS

hemangioblastoma and pNET tumours at the baseline visit (the MK-6482-004 study baseline visit is equivalent to the VHL Natural History Study patient-level index date for the purposes of designating the time point from which follow-up should begin for these analyses). Due to this imbalance, certain parameter inputs that were estimated using VHL Natural History Study data for the VHL-RCC model cohort were obtained

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from other data sources for the VHL-CNS hemangioblastomas and VHL-pNET model cohorts (these are detailed later in section B.3).

The resulting sample selection process is presented in Table 29 below.

Table 29 Sample selection process: Trial Population Subgroup

CNS Hb, central nervous system hemangioblastoma; HIF-2α: hypoxia inducible factor 2 alpha; mm, millimeters; pNET, pancreatic neuroendocrine tumor; RCC, renal cell carcinoma; US, United States; VHL, Von Hippel-Lindau

Baseline risk adjustment through propensity score reweighting

After applying inclusion/exclusion criteria similar to those used in the MK-6482-004,

the key population characteristics of the selected samples for the relevant cohorts

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(all [RCC] patients, the CNS hemangioblastoma subgroup, and the pNETs

subgroup) are those summarised in in Table 30 to Table 32.

Table 30 Baseline characteristics of the VHL Natural History Study and MK6482-004 trial populations before – VHL RCC cohort

1 Effective sample size is computed as the square of the summed weights divided by the sum of the squared weights.

2 This “Number of renal surgeries with therapeutic intent prior to patient-level index date” variable and its definition/criteria is not the same as (it is more restrictive than) that of the "Number of Prior Surgeries per Subject" variable shown in Table 10.

Table 31 Baseline characteristics of the VHL Natural History Study and MK6482-004 trial populations before matching – VHL CNS hemangioblastoma cohort (patients with VHL-associated RCC and CNS hemangioblastoma)

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1 Effective sample size is computed as the square of the summed weights divided by the sum of the squared weights.

Table 32 Baseline characteristics of the VHL Natural History Study and MK6482-004 trial populations before matching – VHL pNET cohort (patients with VHL-associated RCC and pNET)

1 Effective sample size is computed as the square of the summed weights divided by the sum of the squared weights.

The patients in these selected samples were then reweighted to further match the distribution of key baseline covariates among patients in the MK-6482-004 trial. Population-level baseline characteristics for patients in the MK-6482-004 trial were used for this analysis. The Natural History Study cohorts were reweighted to match the corresponding patient samples from MK-6482-004 using the matching-adjusted indirect comparison (MAIC) method, an inverse propensity weighting method which allows the logistic regression for propensity score to be estimated without individual patient data in one of the populations. Given that an anchor-based comparison of belzutifan vs. SOC was not feasible, the use of the MAIC method was considered a priori to be important for mitigating potential confounding due to baseline differences between the MK-6482-004 and VHL Natural History Study populations.

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The baseline variables used for weighting adjustment are listed below for each patient cohort. These variables were selected after eliciting input from clinical experts on patient baseline characteristics that are prognostic of transition probabilities starting from the pre-surgery state, or that may modify the effect of belzutifan on these transition probabilities:

• Baseline covariates adjusted in the VHL-RCC cohort:

  • Age at patient-level index date (patient-level index date as defined earlier in the sample selection criteria subsection)

  • Gender

  • Number of renal surgeries with therapeutic intent prior to patient-level index date

  • Tumour size of the largest renal solid tumour at the patient-level index date

• Baseline covariates adjusted in the VHL-CNS Hb cohort:

  • Age at patient-level index date

  • Gender

  • Number of CNS surgeries with therapeutic intent prior to patient-level index date

• Baseline covariates adjusted in the VHL-pNET cohort:

  • Age at patient-level index date

o Gender

• Number of pancreatic surgeries with therapeutic intent prior to patientlevel index date

The following additional covariates were noted as potentially relevant by the

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limitations: VHL type and VHL gene alteration type (excluded due to a high proportion of missing values in the Natural History Study); number of concomitant measured tumours (unavailable at the time of analysis); and size of the largest CNS tumour at the patient-level index date in the VHL-CNS Hb cohort or size of the largest pancreatic tumour in the VHL-pNET cohort (the presence/absence of CNS Hb and pNET at the patient-level index date could not be identified using the available data).

For each cohort, the distribution of baseline characteristics before and after reweighting are displayed in the following tables. After reweighting, the effective sample size from the Natural History Study decreased by 65% (from 260 to 92.2) in the VHL-RCC cohort and by 83% (from 228 to 37.9) in the VHL-CNS

hemangioblastoma cohort, as patients in these cohorts had fewer prior surgeries on average than their corresponding MK-6482-004 trial samples prior to matching. The effective sample size decreased by 36% (from 94 to 60.4) after reweighing the VHLpNET Natural History Study cohort, as the number of prior pancreatic surgeries in this cohort was relatively well-balanced with the corresponding MK-6482-004 trial subgroup before matching.

For each cohort, the distribution of baseline characteristics after reweighting are displayed below in Table 29 to Table 31.

Table 33 Baseline characteristics of the VHL Natural History Study and MK6482-004 trial populations before and after reweighting – VHL RCC cohort

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1 Effective sample size is computed as the square of the summed weights divided by the sum of the squared weights.

2 This “Number of renal surgeries with therapeutic intent prior to patient-level index date” variable and its definition/criteria is not the same as (it is more restrictive than) that of the "Number of Prior Surgeries per Subject" variable shown in Table 10.

Table 34 Baseline characteristics of the VHL Natural History Study and MK6482-004 trial populations before and after reweighting – VHL CNS hemangioblastoma cohort

1 Effective sample size is computed as the square of the summed weights divided by the sum of the squared weights.

Table 35 Baseline characteristics of the VHL Natural History Study and MK6482-004 trial populations before and after reweighting – VHL pNET cohort

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1 Effective sample size is computed as the square of the summed weights divided by the sum of the squared weights.

MAIC results

Table 36 summarises key parameter inputs that were estimated from the reweighted VHL Natural History Study RCC cohort, alongside input values that were estimated analogously in the MK-6482-004 population. As shown, the weekly exponential rate of pre-surgery → 1st surgery transition was 0.00487 (0.25324 events/person-year) in the matched Natural History Study sample versus 0.00071 (0.03692 events/personyear) in the MK-6482-004, implying an 85% reduction in the cause-specific hazards of renal surgery with belzutifan. The incidence of non-RCC VHL-related surgeries in the two populations was 0.03692 events/person-year in the matched VHL Natural History Study sample versus 0.02119 events/person-year in the MK-6482-004 trial, a percentage reduction of 88%.

Table 36 Selected model parameters estimated in the reweighted VHL Natural History Study RCC cohort and the MK-6482-004 trial population

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Uncertainties in the indirect and mixed treatment comparisons

The MAIC used the data from the MK-6482-004 study (N=61) and a relatively small post-selection and post-matching sample of the VHL Natural History Study (effective N=92.2) and so was based on a relatively small underlying data set. The number of relevant events (non-RCC VHL-related surgeries with therapeutic intent) observed in the MK-6482-004 study for belzutifan was also very small (only four events), which also limits the robustness of the MAIC results.

The inclusion criteria for the real-world study reflected the inclusion criteria for the MK-6482-004 study, which is different to the final MHRA indication wording as described earlier. Therefore, there are some generalisability considerations required as the patients in these two studies are not quite the same as those covered by the MHRA label.

Health-related quality-of-life data used in the cost-effectiveness analysis – VHL

patient survey

• As the MK-6482-004 study did not collect HRQoL data, such data to inform the cost-effectiveness analyses were sourced from a non-interventional crosssectional VHL patient survey that collected EQ-5D-5L that was converted to UK-specific EQ-5D-3L values using the standard crosswalk method.

• This is the first study of its kind in patients with VHL disease - through this study we have filled a gap in the current understanding of the HRQoL impact of VHL disease on patients.

Health-related quality of life data used in the cost-effectiveness analyses were obtained from a VHL patient survey, a non-interventional international, crosssectional patient survey spanning the US, Canada, the UK, France, and Germany.

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Over 200 patients were asked to complete one structured survey, designed to be completed in one sitting. Participation in the survey was voluntary, data collection took place between December 2021 and June 2022.

Objective

The objective of the survey was to understand the patient experience and burden of disease with current management practices in the treatment of VHL disease and the treatment preferences of patients with RCC, CNS hemangioblastoma, or pNET manifestations, including:

• To assess the patients’ health-related quality of life.

• To assess the patients’ work productivity loss and activity impairment.

Research methods

The data collected in this survey included patient perceptions of the burden of VHL and their experiences of undergoing surgery. The survey also included patientreported outcome tools to help describe the burden (direct and indirect) of the condition. Data collection was conducted by a contract research organisation through a patient advocacy group, the VHL Alliance who operates in the US, and screened online. Prior to the start of data collection, all participating patients were provided with the relevant survey materials and instructions and provided informed consent prior to commencing the survey. The survey took approximately 30 minutes to complete and was only completed once by each participant. The survey materials were developed in English and translated then validated as applicable for each country. The survey was administered online and delivered to participants via email for completion on tablet or laptop.

Inclusion Criteria

Patients needed to meet all of the following inclusion criteria to be eligible for inclusion in the study:

• Adult, aged ≥18 years

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• Have a diagnosis of VHL with manifestations in at least one of the following areas:

  • Kidney or

  • Brain or spinal cord or

  • Pancreas

Exclusion Criteria

Patients who met the following exclusion criteria were not eligible for inclusion in the study:

• Aged <18 years

• Do not have a diagnosis of VHL

Patient reported outcome measures

Patient reported outcome measures collected as part of the survey were the European Quality of Life – 5 Dimension Survey (EQ-5D-5L) and the Work Productivity and Activity Impairment: Specific Health Problem (WPAI:SHP). However, only the EQ-5D data are of relevance to this appraisal and were incorporated into the cost-effectiveness analyses (as described in section B.3.)

The EQ-5D was derived in two ways, namely the direct EQ-5D-5L scoring, and the crosswalk method which maps the EQ-5D-3L value sets to the 5-level questions, resulting in crosswalk value sets. The following methods were used for each of the domains: UK (crosswalk and direct) (39), Canada (direct), US (direct), France (direct and crosswalk), Italy (crosswalk) and Spain (direct).

Results

Patient demographics

Patient demographics are described in Table 37. Mean patient age was 42.5 years, 68.2% of patients were female and the majority of patients were white (88.6%). Time since diagnosis was 210.4 months (overall mean). Of the overall sample, 66.4% of

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86.4% of patients had CNS-Hb manifestations. Their disease status and whether they were prescribed medication for their VHL-related cancer is shown in Table 38.

Table 37 Patient demographics

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Table 38 Disease status by current treatment status

Overall, 61 patients were currently prescribed treatment for their VHL-related cancer, and 159 patients were not. Of patients currently prescribed treatment, 42.6% (n=26) had stable disease, 34.4% (n=21) had progressive disease, and 6.6% (n=4) had partial response. For patients not currently prescribed treatment, 54.7% (n=87) had stable disease, 23.3% (n=37) had progressive disease, 0.6% (n=1) patients had a complete response, and 2.5% (n=4) patients had a partial response.

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EQ-5D results

All patients

Overall, patients with VHL-related tumours had a mean EQ-5D score of 0.699, using the UK crosswalk. Patients with metastatic disease (n=16) had a mean EQ-5D score of 0.550 and patients without metastatic disease (n=195) had a mean EQ-5D score of 0.714 (Table 39).

Table 39 EQ-5D by metastatic status

Patients with metastatic disease

Sixteen of the 220 patients had metastatic disease. Among these, patients who classified themselves as having progressive disease (n=6) had a mean EQ-5D score of 0.412 and patients who classified themselves as having stable disease (n=4) had a mean EQ-5D score of 0.525. Full data presented in Table 40.

Table 40 EQ-5D by disease status in patients with metastatic disease

Patients without metastatic disease

Mean EQ-5D by disease status, surgery history, number of tumours among patients without metastatic disease are presented in Table 41. Among patients without metastatic disease (n=195), patients who classified themselves as having

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progressive disease (n=49) had a mean EQ-5D of 0.665, patients who classified themselves as having stable disease or complete or partial response (n=116) had a mean EQ-5D of 0.754. Mean EQ-5D scores of 0.665 and 0.754 are indicative of poor HRQoL as they are 33.5% and 24.6% lower, respectively, than the score of 1 which represents perfect health (these values would be age and gender corrected to the relevant populations they are sourced from and applied to, in the case of the costeffectiveness analyses of this appraisal, these are performed in the costeffectiveness model itself, described in section B.3.

Patients who had their most recent surgery within the last 6 months had a mean EQ5D of 0.666 and patients who had their most recent surgery over 6 months ago had a mean EQ-5D of 0.705. Patients with more than one tumour type had a mean EQ5D of 0.708 and patients with only one tumour type had a mean EQ-5D of 0.757.

Table 41 EQ-5D by disease status, among patients without metastatic disease

CR: complete response; PR: partial response

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B.2.10 Adverse reactions

Summary of adverse events information

• The MK-6482-004 study showed that belzutifan had a manageable safety profile in participants with VHL disease-associated RCC.

• All participants experienced at least 1 AE, and all experienced an AE that was assessed as related to study intervention by the investigator.

• Belzutifan was generally well tolerated. The proportion of participants who discontinued study intervention due to an AE was low (4 [6.6%] participants).

• Two deaths have occurred during the study, one due to suicide and one due to an AE (acute fentanyl toxicity) that was reported as not related to study drug by the investigator.

The adverse events reported in the MK-6482-004 study are summarised in Table 42, these are presented in more detail in Appendix F. As would be expected with the passage of time, the number of patients with adverse events increased with later data cut-off dates, and the proportion of patients reporting a higher grade of severity for adverse events (and treatment-related adverse events) as their highest severity adverse event experienced thus far also increased with later data cut-off dates.

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Table 42 MK-6482-004 study summary of adverse events

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B.2.11 Ongoing studies

There is currently an ongoing phase 2 single-arm study to evaluate the efficacy and safety of belzutifan monotherapy in participants with advanced

pheochromocytoma/paraganglioma, pNET or VHL disease-associated tumours (the MK-6482-015 study) (40), the primary objective of the study is to evaluate the ORR associated with treatment with belzutifan, the estimated primary completion date for this study is 12-AUG-2026.

Additionally, a condition of the MHRA marketing authorisation for belzutifan in this indication is for MSD to set up and report on results from a prospective patient registry with the objective to further characterise efficacy and understand long term safety of belzutifan, particularly in VHL-associated RCC and CNS

hemangioblastomas. The protocol for this prospective patient registry is currently being assessed by the MHRA.

B.2.12 Interpretation of clinical effectiveness and safety evidence

There are currently no active systemic interventions that are used (or recommended by NICE or funded on the NHS) for the treatment of adult patients with VHL disease who require therapy for VHL associated RCC, CNS hemangioblastomas, or pNETs, and for whom localised procedures are unsuitable or undesirable. Whilst the

marketing authorisation states surgery is undesirable or unsuitable in these patients, it may be the only option. The relevant comparator in this indication in current clinical practice is therefore established clinical management without belzutifan.

Given the substantial unmet need for effective treatment for patients with VHLtumours and the burden this disease places on patients and their families and carers, the outcomes from the MK-6482-004 study represent a step change in the treatment of this disease. The benefit the regulators perceived in this treatment is clear from the expansion of the primary tumours eligible for treatment, from that expected in RCC only to including also CNS hemangioblastomas and pNETs. Response rates and disease control rates across the ITT population represent a clinically profound treatment effect.

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As demonstrated in the MK-6482-004 study, after a median follow-up of 37.7 months (range: 4.2 months to 46.1 months), the percentage of patients with RCC who had an objective response was 63.9% (95% confidence interval: 50.6% to 75.8%). Responses were also observed in patients with pancreatic neuroendocrine lesions (20 of 22 patients [90.9%]) and central nervous system hemangioblastomas (22 of 50 patients [44.0%]). The results show that belzutifan is able to offer significant additional benefit compared to current standard of care (i.e. no systemic therapy or surgical options) by effectively slowing the growth of tumours, thereby significantly delaying the time at which surgical resections become necessary or avoiding it completely in patients who have a durable complete response, and consequently decreasing the frequency of necessary surgical resections. Doing so is expected to greatly improve patients’ quality of life in the long term.

Belzutifan also shows a tolerable and manageable safety profile in these patients. Treatment-related adverse events were mostly grades 1 and 2 and consisted of anaemia, fatigue, headache, and dizziness. The rate of discontinuations is low with 62.3% of patients in the MK-6482-004 study still continuing with a daily-administered treatment after a >3 year (median 37.7 months) follow-up period. Adherence to treatment is particularly important in the context of a chronic disease like VHL disease, in which patients may need lifelong, regular medical intervention from a young age.

The immediate effect of treatment with belzutifan on the course of disease in terms of surgical interventions patients undergo is especially notable, the number of VHLdisease associated surgical procedures patients underwent decreased from >300 in the group included in the study in the 10 year period prior to treatment initiation to <10 in the >3 year (median 37.7 months) follow-up period after initiation of treatment with belzutifan (by the 01-APR-2022 data cut-off date, as shown in Figure 8). The results observed in the MK-6482-004 study therefore indicate that the use of belzutifan may spare patients with VHL disease multiple surgeries, decrease their risk of loss of organ function (such as renal and/or pancreatic failure), and reduce their risk of death from metastatic RCC, metastatic pNET, or CNS hemangioblastomas.

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The MK-6482-004 study included patients with VHL disease-associated RCC, and subgroup data are reported for those patients with RCC who also had CNS hemangioblastomas and patients with RCC who also had pNETS. Strictly speaking this differs from the marketing authorisation for belzutifan and its scope in this appraisal which does not specify that patients with CNS hemangioblastomas or pNETs need to also have RCC. However, the patients with CNS hemangioblastoma and pNETS in the MK-6482-004 trial with RCC are likely to be representative of patients with CNS hemangioblastoma and pNETS in general as patients with VHL disease have a tendency to develop tumours in multiple sites and organ systems with RCC being the most common form of tumours (13), and so it is likely that many patients with VHL disease-associated CNS hemangioblastoma and pNETS will also develop or have RCC. Indeed, the MK-6482-004 study found that, in the population of VHL RCC patients recruited, 82% had CNS hemangioblastomas and 33% had pNETs.

The number of patients with CNS hemangioblastoma and pNETs in the MK-6482004 trial and included in the analyses were low at 50 and 22 patients, respectively. However, the results in terms of ORR in these groups of patients are still impressive, with responses to belzutifan treatment being long and durable to the extent that median DOR that was not reached (i.e. less than half the patients with response had lost response) as of the 01-APR-2022 database cut-off date for either of these subgroups. We do not have composite data for the 17 patients who had all three tumours, therefore the potential for such patients to benefit due to response in tumours in multiple organs is not known.

It is also worthwhile to note that the MK-6482-004 trial showed positive effects of treatment with belzutifan on VHL disease-associated retinal hemangioblastomas, adrenal lesions, endolymphatic sac tumours, epididymal cystadenomas and pancreatic lesions (not just limited to pNETs). While these tumours do not fall within the marketing authorisation for belzutifan, the fact that patients with VHL disease associated RCC, CNS hemangioblastomas, and pNETs are likely to also have some or all of these tumours due to the nature of VHL disease, and belzutifan appears to

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have a positive effect on these also, is an additional benefit of treatment with belzutifan that should not be overlooked when considering its true value.

There is also misalignment between the GB marketing authorisation and the MK6482-004 study in terms of the fact that the marketing authorisation is for patients "who require therapy" for the VHL-associated tumours, whereas the MK-6482-004 study's participant eligibility criteria specified that patients who had an immediate need for surgical intervention for tumour treatment were excluded. Also, the marketing authorisation is for patients "for whom localised procedures are unsuitable or undesirable" whereas this was not part of the participant eligibility criteria for the MK-6482-004 study. The MHRA granted this marketing authorisation in this indication based on the MK-6482-004 study and its results, i.e. based on which patients would benefit from treatment with belzutifan was demonstrated by the evidence from this very study. Such misalignments between marketing authorisation wording and supporting clinical trial patient population characteristics are not unusual for rare and highly specialised indications such as this one.

The MK-6482-004 study was single-arm trial that did not compare the treatment effect of belzutifan to UK SOC directly. While the comparison to UK-relevant SOC was made via a MAIC, the results from such techniques are inevitable associated with a lower degree of certainty than direct head-to-head results from a randomised clinical trial.

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B. 3 Cost effectiveness

Summary of key cost effectiveness information

Objective:

• The purpose of this cost-effectiveness analysis is to assess the costeffectiveness of belzutifan for patients with VHL-associated RCC, CNS Hb or pNET tumours who require treatment and for whom surgery is unsuitable or undesirable against the current SOC in the UK.

Model overview:

• A de novo cost-effectiveness model has been developed using a Markov cohort structure to estimate health outcomes and costs for belzutifan compared to the UK SOC from a National Health Service (NHS) and Personal Social Services (PSS) perspective.

• The MHRA conditional marketing authorisation is in patients who require therapy for VHL associated RCC, CNS Hb and pNET, and for whom localised procedures are unsuitable or undesirable. This population misalignment is a source of uncertainty in the economic analysis; however, the MK-6482-004 trial is the most appropriate source of data for this appraisal.

Base-case results and sensitivity analyses:

• Belzutifan is cost-effective across each of the cohorts when compared to the current SOC with an ICER of £42,997 per QALY in the VHL-RCC cohort, £33,490 per QALY in the VHL-CNS Hb cohort and £45,676 in the VHL-pNET cohort with the severity weighting incorporated into the ICER calculation.

• Probabilistic sensitivity analyses produce a 0.3%, 7.8% and 0.2% likelihood of cost-effectiveness for the VHL-RCC, VHL-CNS Hb and VHL-pNET cohorts respectively at a willingness-to-pay threshold of £30,000 per QALY gained when parameters are varied simultaneously.

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Scenario analyses:

• The ICERs across the three cohorts remained largely stable to the parameters and assumptions tested in extensive scenario analyses with the exception of time horizon and treatment effect waning.

Cost effectiveness conclusions:

• Considering the complexities of modelling VHL, the rarity of the disease and paucity of published data, the cost-effectiveness analysis presented in this appraisal robustly demonstrates that belzutifan delivers clinically meaningful QALY and LY gains compared with SOC in patients with VHL-associated RCC, pNET, and CNS Hb. The full value of belzutifan is not captured in the economic model and therefore produces results that are marginally above the decisionmaking threshold. The economic evaluation highlights that belzutifan is a stepchange in the management of VHL, a rare disease with high unmet need.

B.3.1 Published cost-effectiveness studies

There are no published economic models evaluating the cost-effectiveness or budget impact of belzutifan

An SLR was conducted to identify published cost-effectiveness studies for belzutifan or other VHL therapies. Searches were performed in July 2020 and were

subsequently updated in July 2022 to cover the period of July 2020 to July 2022. The cost-effectiveness SLR was designed and executed in line with NICE guidance and was run as part of a broader SLR designed to identify (i) RCTs and non-RCTs, (ii) utility data, and (iii) cost and resource use data. Further information on the SLR methodology, search strategy, and results is provided in the following section: Appendix G: Published cost-effectiveness studies .

Given the rarity of disease and absence of approved therapies with the exception of belzutifan, the SLR did not identify any economic models evaluating the costeffectiveness or budget impact of any treatments for VHL, including belzutifan.

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B.3.2 Economic analysis

In the absence of published economic analyses, a de novo cost-effectiveness analysis was developed for this appraisal. The economic model uses a Markov cohort structure to estimate health outcomes and costs for belzutifan compared to the UK standard of care (SOC) in patients with VHL who require therapy for VHL RCC, CNS Hb, or pNET, and for whom localised procedures are unsuitable or undesirable.

Patient population

The model population is aligned to the marketing authorisation for belzutifan

The economic analysis considers adult patients (aged 18 years or older) with VHL disease who require treatment for: (i) VHL-associated RCC, (ii) VHL-associated CNS Hb, or (iii) VHL associated pNET. In line with the characteristics of patients in the key trial informing the economic analysis (see B.2 Clinical effectiveness ), patients enter the model at an age of 41.0 years, with a mean (SD) weight of 79.7 kg (23.4 kg) and a mean (SD) body surface area of 1.9 m[2] (0.3 m[2] ), and with 47.5% female patients.

The population assessed in the economic analysis is aligned to the population as specified in the marketing authorisation for belzutifan, with clinical evidence informed by the MK-6482-004 trial (37) and real-world data for SOC. Based on data from the MK-6482-004 trial in support of the license application for belzutifan, the MHRA decided to specify eligibility to adult patients with VHL “who require therapy” for VHL associated RCC, CNS Hb, or pNET, “and for whom localised procedures are unsuitable or undesirable”. This contrasts with the inclusion criteria of the MK-6482004 trial, which did not specifically require participants to be considered unsuitable or undesirable for localised procedures.

Treatment decision point

The patient population stipulated by the MHRA label identifies a specific VHL patient group “who require therapy” and “for whom localised procedures are unsuitable or undesirable”. This patient population have exhausted alternative options to control VHL tumour manifestations and are at the “end of the road”, they must have

sufficient organ function as per the inclusion criteria for the trial.

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In routine clinical practice, the decision point for a patient meeting the criteria of belzutifan eligibility would have three options: 1) surgery that is unsuitable or undesirable because it results in loss of organ function, 2) active surveillance to monitor a tumour that is above 3cm (RCC) or 2cm (pNETs) and therefore there is an increased risk of metastatic disease and/or other symptoms of tumour burden (particularly in CNS Hb tumours), or 3) belzutifan. At this point on the disease/treatment pathway occurs, patients and their disease progression will have been carefully monitored over many years. Any treatment decision would be made very carefully between a patient and their treating clinician and for some, this decision may not be immediate. A simplifying assumption was taken to initiate the model at the point this treatment decision is ‘enacted’, i.e. when the patient is faced with a choice between receiving surgery, routine surveillance, or belzutifan.

Model structure

A de novo Markov cohort model was developed to estimate the costeffectiveness of belzutifan versus UK SOC in patients with VHL who require therapy for VHL associated RCC, CNS Hb, or pNET, and for whom localised procedures are unsuitable or undesirable

A de novo cost-effectiveness model was developed using a Markov cohort structure to estimate health outcomes and costs for belzutifan compared to the UK SOC in patients with VHL who require therapy for VHL RCC, CNS Hb, or pNET, and for whom localised procedures are unsuitable or undesirable. Markov models feature an explicit structural linkage between intermediate health states and death and are therefore commonly used in economic analyses for chronic diseases with critical outcomes of relevance other than mortality.

The Markov model was initially built when the expectation for the marketing authorisation was for VHL-associated RCC only. Following the granting of the market authorisation, featuring both an expansion and restriction compared to the population assessed in the belzutifan pivotal trial, the model was adapted to reflect the updated eligible patient population. The model captures the most relevant clinical events in VHL disease i.e., surgery resulting in loss of organ function, development of

metastatic disease, and death.

Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

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The model structure consists of five mutually exclusive health states aligned with important outcomes in the disease progression of VHL-associated RCC, CNS Hb, and pNET.

• i. Pre-surgery (model entry)

• ii. Surgery tunnel state, patients remain in this state for one week and receive surgery that results in loss of organ function (for RCC and pNET primary tumours) or results in brain injury (for CNS Hb primary tumours) as a ‘last resort’ intervention.

• iii. Event-free after surgery state, which represents patients who have undergone one surgery, have not developed metastatic disease, and are still alive:

• iv. Metastatic disease

• v. Death

Each primary tumour site i.e. the VHL-RCC, VHL-CNS Hb, or VHL-pNET tumour with the greatest burden on the patient is modelled as a separate cohort using the same model structure. Reflective of the natural history of VHL disease, patients in each primary tumour site cohort may also have one, two or all three tumour types simultaneously. Although the incidence of non-primary tumours, and therefore related surgeries, is captured in the model, the additional burden on costs and quality of life of having multiple tumour manifestations simultaneously is not specifically captured.

Patients transition from the pre-surgery health state to either:

• Surgery then event-free after first surgery

• Metastatic disease

• Death

Patients transition from the event-free after surgery health state to either:

Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

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• Metastatic disease

• Death

The surgery health state refers specifically to surgery relating to the primary tumour type. There is no surgery-specific health state for surgeries at non-primary tumour sites (e.g. a patient in the RCC cohort who has a subsequent pNET surgery is not captured in a specific health state transition). The cost and health implications of surgeries for non-primary tumours as well as their associated complications were reflected as per-event costs and QALY decrements applied on incidence of each non-primary tumour surgery. This approach to modelling primary and non-primary tumours differently is used to reflect typical disease progression in VHL: patients may require surgeries at multiple sites but clinicians focus on the highest risk tumour site, as this is where tumours are likely to be the most progressed. Given the incidence of non-primary surgeries is not reflected by explicit state transitions within the model, the cumulative health impact of having undergone multiple non-primary surgeries is therefore not captured. This is a conservative approach as evidence from MK-6482-004 has shown that belzutifan reduces tumour size, and would therefore have metastases and mortality benefits, not only in primary tumours.

The event-free after surgery health state corresponds to time spent post-surgery during which a patient is at risk of metastases, short-term and long-term consequences of surgery.

The metastatic disease health state is included to reflect the clinical pathway of patients with VHL-associated tumours. In each tumour type cohort, transitions to the metastatic disease state are assumed to be due to either RCC or pNET as the origin tumour (CNS Hb tumours do not metastasize), consistent with findings from the VHL Natural History Study.

The model’s health states and available transitions is presented in Figure 18. Note that the pre-surgery health state describes patients who have not had surgery since belzutifan trial initiation, and for the purposes of the economic analysis, the treatment decision point. The majority of participants in the MK-6482-004 trial had multiple

surgeries prior to trial initiation (mean 5.5).

Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

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Figure 18 Model schematic for the economic evaluation of belzutifan in VHL associated RCC, pNET, or CNS Hb

==> picture [186 x 283] intentionally omitted <==

*Transitions to death are possible from all health states. Arrows to the death state are omitted from the diagram for simplicity.

Note: Analogous Markov cohort structures are used for each of the three tumour-specific populations (VHL-associated RCC, CNS Hb and pNET). In each of these populations, subsets of patients also have one or both of the other two tumour types. In the Markov model, the surgery states refer specifically to surgeries corresponding to the primary tumour type for each population. Costs and QALY decrements due other tumour types are modelled separately for each population and layered onto the costs and QALYs that are modelled accordingly to patients’ Markov state residency over time.

CNS Hb: central nervous system haemangioblastoma; pNET: pancreatic neuroendocrine tumour; RCC: renal cell carcinoma; QALY: quality adjusted life year; VHL: Von Hippel Lindau

One general limitation of Markov models is their memoryless property, by which history of patients’ movements through the model structure is not tracked over time. Transition probabilities, utilities, and costs at each model cycle therefore depend only on a patient’s current health state, the cycle number, and time-constant factors instead of reflecting patient’s past sequence of events or time spent in an

intermediate health state. To mitigate this limitation while accounting for practical data constraints, functionality was incorporated into the Markov structure to track the occurrence of certain important clinical events. Specifically, surgery and event-free

Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

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after surgery health states were used to capture perioperative mortality and surgical complications to which costs and disutilities could be applied accordingly. Separate health states were also defined to track patients’ treatment discontinuation status over time (i.e., on-treatment vs. off-treatment).

As described in B.2 Clinical effectiveness , the primary outcome assessed in the MK6482-004 trial for belzutifan was ORR in VHL-associated RCC tumours per RECIST 1.1, with best overall response categorised as CR, PR, SD, or PD. Secondary outcomes included DOR (i.e. time from the first documented evidence of CR or PR until either disease progression or death from any cause), TTR, PFS, and TTS in VHL-RCC. Secondary outcomes also included ORR, DOR, TTR, PFS, and TTS evaluated for non-RCC VHL-associated tumours (CNS Hb, pNET, retinal Hb, adrenal endolymphatic sac tumours, and epididymal cystadenomas). Responder status is understood to have implications on patients’ health-related quality of life (HRQoL), as patients with larger tumour burdens may be more likely to experience direct symptoms from their tumours (particularly in the case of CNS Hb) and may have greater anxiety about their VHL disease. Each non-metastatic health state (i.e., presurgery, surgery, and event-free after surgery) therefore allows three different categories of objective response for primary tumours (e.g., complete response [CR], partial response or stable disease [PR/SD], and progressive disease [PD]), to reflect a distinct utility value. In the model, this is implemented as an average utility value weighted by response status.

Of note, PD per RECIST 1.1 criteria does not necessarily indicate a need for surgery, nor does the occurrence of surgery necessarily imply PD. A tumour size threshold [for RCC and pNET] or the manifestation of symptoms [for CNS Hb] along with other clinical factors collectively determine the need for surgery in patients with VHL-associated tumours. Consequently, the model allowed for the possibility that some patients have a PD while residing in the pre-surgery state, and that some patients have CR, PR, or SD in the surgery and event-free after surgery states.

Table 43 summarises the features of the economic analysis.

Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

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Table 43 Features of the economic analysis

Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

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Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

© Merck Sharp & Dohme (UK) Limited (2023). All rights reserved

Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

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*No previous evaluations have been performed in VHL.

AE: adverse event; BNF: British National Formulary; HRQoL: health related quality of life; NHS: national health service; NICE: national institute for health and care excellence; PSSRU: Personal Social Services Research Unit; QALY: Quality adjusted life year; QoL: Quality of Life; RW: Real-World; SOC: standard of care; TP: transition probability; TRAE: treatment-related adverse event; VHL: Von Hippel Lindau

Intervention technology and comparators

Belzutifan is compared with SOC in patients who require therapy for VHL associated RCC, CNS Hb, or pNET, and for whom localised procedures are unsuitable or undesirable

Intervention: belzutifan

The recommended dose of belzutifan is 120 mg administered orally once daily until disease progression or unacceptable toxicity (5) (see Appendix C1.1 SmPC for more information). Dose adjustments and modifications have been reflected as per the MK-6482-004 trial data as described in the Time to treatment discontinuation section.

Comparator: SOC

There are currently no approved systemic treatments specifically for VHL other than belzutifan. The comparator in the economic analysis is therefore SOC, defined as established clinical practice without belzutifan in line with the final scope. Also per the final scope, localised procedures are unsuitable or undesirable for the patient population eligible for belzutifan. Clinical experts consulted for this appraisal described the trade-off between the risks associated with localised procedures and versus the risks of metastatic and/or symptomatic disease that arise in the absence of urgently needed surgical procedures. These experts therefore define the patient population for whom localised procedures are unsuitable or undesirable as those

Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

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patients who have exhausted all options and for whom localised procedures would be a ‘last resort’ and likely result in loss of organ function with extremely poor outcomes (3).

For patients who require therapy and for whom localised procedures are unsuitable or undesirable, SOC interventions they receive includes localised procedures; however, these will not be able to preserve organ function and so result in problematic sequalae that can have a negative impact on HRQoL (3).

• For RCC tumours, the localised procedures that are no longer capable of preserving organ function are any further partial/full bilateral nephrectomies after which patients will require renal replacement therapy. Following this procedure, no further surgeries related to RCC tumours would take place or be considered as organ function would be lost.

• For pNET, the localised procedures that are no longer capable of preserving organ function are Whipple procedures/ pancreatectomies and splenectomies. Laparoscopic surgery (e.g. distal pancreatectomy) is considered if the tumour is in the pancreas tail or peripheral pancreas. The Whipple procedure is considered if the tumour is in the pancreas head, or if the tumour is at least 2 centimetre in diameter and not amenable to distal pancreatectomy. Following this procedure, no further surgeries related to pNET would take place as organ function would be lost.

• For CNS Hb, these localised procedures are only considered where the tumour is peripherally located in the cerebellum; however, with or without the unsuitable/undesirable localised procedure the outcome is likened to symptoms of patients with motor neurone disease or following major stroke either because of the surgery risk or tumour burden (3).

In routine clinical practice in the UK, for such patients “who require therapy” these unsuitable/undesirable localised procedures would take place immediately as these patients have reached the point in which active surveillance or watchful waiting is no longer an option due to unbearable symptomatic disease or unacceptable risk of

metastases. For VHL-RCC and VHL-pNET cohorts, immediate surgery is assumed Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

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for 90% of patients. For VHL-CNS Hb, immediate surgery is assumed for 50% of patients; however, the outcomes associated with surgery is assumed for 100% of the cohort due to tumour burden creating neurological disability for the remaining 50% not operated on, which is assumed to have similar impact on HRQoL as the serious complications from CNS surgery. See Cost of surgery and complications for further details on how the costs are applied to reflect this.

Following immediate surgery, efficacy inputs for the SOC arm were informed by data from the VHL Natural History Study (see Section B.2.9 for more information on the VHL Natural History Study) (46). The VHL Natural History Study included a large patient population (n=247) and similar eligibility criteria to the MK-6482-004 trial, enabling reasonable comparability to the belzutifan eligible population. To ensure sufficient matching between the VHL Natural History Study and the MK-6482-004 trial populations, the VHL Natural History Study cohorts were reweighted to match the corresponding patient samples from MK-6482-004 trial using the MAIC method, an inverse propensity weighting method which allows the logistic regression for propensity score to be estimated without individual patient data in one of the populations, as described in greater detail in B.2.9 Indirect and mixed treatment comparisons .

• Similar to the belzutifan arm, the VHL Natural History Study population informing the SOC arm was not limited to only those patients for whom localised procedures were unsuitable or undesirable. Therefore, the rationale for using the MK-6482-004 trial to inform the belzutifan arm described in the Patient population section also applies to the use of the VHL Natural History Study in the SOC arm.

• The VHL Natural History Study collected data from US-based centres of excellence and patients in the study may therefore have received a different SOC compared to standard UK clinical practice. It is expected that patients treated at these sites had better access to surgery, and as a result, higher rates of surgery and therefore lower rates of metastasis were observed than would be expected in UK clinical practice. To account for this, the hazards of 1) surgery from the pre-surgery health state and 2) metastatic disease from the

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pre-surgery and event-free after surgery states were adjusted in the model using real-world metastatic disease rates data from an additional study (Optum Clinformatics Data Mart claims study) of VHL patients treated in a setting more reflective of real-world practice. This adjustment is described further in Aligning risk of surgery and metastatic disease to real-world SOC . Of note, the Optum study could not be used in place of the VHL Natural History study as it did not have the breadth of availability of matching variables to the MK-6482-004 trial.

B.3.3 Clinical parameters and variables

Clinical efficacy: transition probabilities

Overview of data sources

MK-6482-004 trial data and real-world evidence have been used to estimate the clinical parameters used in the economic model. A summary is provided in Table 44 below.

MK-6482-004 trial

TPs from the pre-surgery → surgery state for belzutifan are informed by TTS data for the VHL-RCC cohort from the MK-6482-004 trial (37). For the VHL-pNET cohort, the pre-treatment period from the MK-6482-004 trial is used to inform the TP from the pre-surgery → surgery state for the 10% who do not receive immediate surgery in the SOC arm (further described in Transition from the pre-surgery and event-free after surgery states below). The baseline characteristics from the MK-6482-004 trial were also used to reweight the VHL Natural History Study population to match the eligibility criteria of the trial for the SOC arm as described in section B.2.9.

VHL Natural History Study

Given the single-arm design of the MK-6482-004 trial, clinical efficacy data for SOC were primarily sourced from external data collected in the VHL Natural History Study, which informed the following transitions in the model: (46):

• For the 10% of the VHL-RCC cohort who do not receive immediate surgery in the SOC arm, TPs from pre-surgery → surgery. The corresponding TPs for the

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VHL-pNET and VHL-CNS Hb cohorts are informed by the pre-treatment period from the MK-6482-004 trial, described below

• TPs from pre-surgery → metastatic disease and event-free after surgery metastatic disease in all cohorts

• TPs from pre-surgery → death and event-free after surgery → death in all cohorts

Although the inclusion criteria limited the study sample to US and Canadian patients, the VHL Natural History Study included a large study sample (308 patients) followed up for a mean of 8.75 years (46). This study was designed to generate model inputs for the SOC arm following immediate surgery that would allow for a balanced comparison against belzutifan-treated patients with VHL-associated RCC in the MK6482-004 trial. Based on the data fields available in the VHL Natural History Study, it was feasible to apply inclusion/exclusion criteria analogous to those used in the trial to identify eligible patients with VHL-associated RCC at the patient-level index date. However, it was not feasible to identify whether patients in the VHL Natural History Study had CNS Hb or pNET tumours on the patient-level index date. The criteria for identifying the CNS Hb and pNET cohorts of the MK-6482-004 trial could not be wellreplicated within the VHL Natural History Study. Given this limitation, TTS for the proportion of SOC patients who do not receive immediate surgery was estimated using a retrospective analysis of the pre-treatment period of the MK-6482-004 trial.

Retrospective analysis of the MK-6482-004 trial pre-treatment period

History of surgery prior to trial initiation was collected retrospectively based on patient medical records collected in the MK-6482-004 trial (i.e. before patients began receiving belzutifan) (37) and this is used as a proxy for outcomes associated with the SOC arm. This “pre-treatment” data was used to inform the TP for pre-surgery → surgery in the SOC arm for the proportion who do not receive immediate surgery in the VHL-pNET cohort and following treatment effect waning in the belzutifan arm for the VHL-CNS Hb and VHL-pNET cohorts. Parametric survival models were fitted to patient-level data on time (looking backwards) to the most recent primary tumour surgery prior to belzutifan initiation in patients with VHL-CNS Hb and VHL-pNET Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

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tumours in the MK-6482-004 trial. This retrospective analysis was also used to inform the incidence rate (in the SOC arm) and distribution of non-primary-VHLrelated tumour surgeries (assumed equal in both arms) for the VHL-CNS Hb and VHL-pNET cohorts.

Whilst the MK-6482-004 pre-treatment analysis provides a robust source of data to inform the parameters described above for the VHL-CNS Hb and VHL-pNET cohorts, as per the eligibility criteria of the trial, patients were (by definition) alive and metastases-free prior to belzutifan initiation. Hence, the pre-treatment period data from MK-6482-004 could not be used to estimate the TP from pre-surgery → metastatic disease nor event-free after surgery → metastatic disease or death in these cohorts for the SOC arm. Instead, the TPs from pre-surgery and event-free after surgery → metastatic disease or death were estimated based on data collected in patients in the VHL Natural History Study who had a history of CNS Hb and pNET prior to the patient-level index date (although these tumours may have not been present on the index date).

The methods used to estimate transition probabilities described above are summarised in Table 44.

Table 44 Summary of clinical parameters sourced from the VHL Natural History Study and the pre-treatment period data from the MK-6482-004 trial.

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Company evidence submission template for belzutifan for treating tumours associated with von Hippel-Lindau disease

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*Note: Under the SOC arm in the VHL-CNS Hb cohort, all patients are assumed to have either immediate CNS Hb surgery or experience equivalent sequelae (i.e., the same costs and disutilities of surgical complications) to reflect the severity of inoperable CNS Hb. Patients who experience the equivalent sequalae of CNs Hb surgery are modelled as entering the surgery state, but do not incur the costs of the surgical procedure itself.

Optum Clinformatics Data Mart claims study

The Optum Clinformatics Data Mart claims database study conducted by Jonasch et al. (2022) collected real-world data from 160 patients with VHL from a wide geographic area in the US (34, 41). Patients with VHL-RCC were identified within the claims database using a customised algorithm. They were then matched to population controls without VHL disease or RCC, and comparisons were made with the matched cohort to conduct analysis on the prevalence, treatment patterns and healthcare resource use (HCRU) associated with VHL. Analysed outcomes included the rates of metastasis, surgery, and short- and long-term surgical complications for all three primary tumour sites.

In contrast to the Optum study, patients included in the VHL Natural History Study were managed by a multidisciplinary team with broad experience in detection, prevention and treatment of hereditary genitourinary malignancies in line with the intended treatment-eligible population in MK-6482-004. It is expected that patients at the NCI received an elevated SOC and thus had improved access to surgery and lower rates of metastatic disease due to improved control of tumours relative to realworld treatment patterns expected for many patients with VHL managed in the UK. To account for this difference in SOC, data from the Optum study were used to adjust surgery rates downwards and metastatic disease rates upwards to better align

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with real world practice of VHL treatment. The adjustments are described in further detail in Aligning risk of surgery and metastatic disease to real-world SOC .

Transitions from the pre-surgery and event-free after surgery states

This section describes how TPs estimated for each transition from the pre-surgery and event-free after surgery states for each of the 3 VHL cohorts (i.e. RCC, CNS Hb, pNET).

Parametric models were fitted to time-to-event data to estimate the cause-specific hazards of each transition starting from the pre-surgery state (i.e., pre-surgery → surgery, pre-surgery → metastatic disease, and pre-surgery → death) and event-free after surgery state (i.e., event-free after surgery → metastatic disease, and eventfree after surgery → death) over time within the belzutifan and SOC arms. In each weekly cycle of the model, the probability of each of these transitions (as well as the composite probability of any transition from the pre-surgery state) was calculated as a function of all three cause-specific hazards.

Cause-specific hazards for transitions from the pre-surgery health state and hazards for transitions from the event-free after surgery health states are summarised below in Table 45 and Table 46 respectively. Further details on how the derivation of each TP by tumour site and treatment arm are provided in the proceeding sections.

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Table 45 Cause-specific hazards and data sources for transitions from the presurgery state, by model cohort and treatment arm