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Single Technology Appraisal

Ibrutinib with venetoclax for untreated chronic lymphocytic leukaemia [ID3860] Committee Papers

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NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

SINGLE TECHNOLOGY APPRAISAL

Ibrutinib with venetoclax for untreated chronic lymphocytic leukaemia [ID3860]

Contents:

The following documents are made available to consultees and commentators:

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

Pre-technical engagement documents

1. Company submission from Janssen

• 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. Leukaemia Care-Lymphoma Action-CLL Support Association

• b. UK CLL Forum-British Society for Haematology

4. External Assessment Report prepared by Aberdeen HTA Group

5. External Assessment Report – factual accuracy check

Post-technical engagement documents

6. Technical engagement response from company

7. Technical engagement responses and statements from experts:

• a. Professor Nagesh Kalakonda – clinical expert, nominated by JanssenCilag Ltd

• b. Dr Nicolas Martinez-Calle – clinical expert, nominated by UK CLL Forum-British Society for Haematology

• c. Stephen Abrahams – patient expert, nominated by the CLL Support Association

8. Technical engagement responses from stakeholders:

• a. Leukaemia Care

9. External Assessment Report critique of company response to technical engagement prepared by Aberdeen HTA Group

Any information supplied to NICE which has been marked as confidential, has been

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redacted. All personal information has also been redacted.

NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

Single technology appraisal

Ibrutinib with venetoclax for untreated chronic lymphocytic leukaemia or small lymphocytic lymphoma [ID3860]

Document B

Company evidence submission

June 2022

Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

© Janssen-Cilag Limited (2022). All rights reserved

Contents

Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

© Janssen-Cilag Limited (2022). All rights reserved

Tables and figures

Table 1 The decision problem .................................................................................. 12 Table 2 Technology being evaluated........................................................................ 15 Table 3 CLL incidence rates in England and Wales (2016-2018) ............................ 19 Table 4 5-year survival rates for patients with CLL in the UK, by age range (20062010) ........................................................................................................................ 20 Table 5 Treatments recommended by NICE for previously untreated CLL .............. 25 Table 6 Treatment guidelines for previously untreated CLL ..................................... 29 Table 7 Summary of first-line treatment options for CLL .......................................... 31 Table 8 Clinical effectiveness evidence .................................................................... 39 Table 9 Summary of trial methodology ..................................................................... 41 Table 10 Characteristics of participants in the FD cohort (CAPTIVATE; all treated population) ............................................................................................................... 48 Table 11 Characteristics of participants in the studies across treatment groups (GLOW; ITT) ............................................................................................................ 54 Table 12 Summary of statistical analyses (CAPTIVATE) ......................................... 57 Table 13 Summary of statistical analyses (GLOW) .................................................. 59 Table 14 Quality assessment results........................................................................ 60 Table 15 Summary of clinical effectiveness at a median follow-up of 38.7 months (CAPTIVATE FD cohort; extended follow-up analysis) ............................................ 61 Table 16 Summary of clinical effectiveness at a median follow-up of 34.1 months (GLOW; ITT extended follow-up analysis) ................................................................ 70 Table 17 I+V vs. FCR PFS results summary ............................................................ 83 Table 18 Summary of TEAEs at a median follow-up of 27.9 months (CAPTIVATE; FD cohort safety population primary analysis) ......................................................... 89 Table 19 Summary of TEAEs at a median follow-up of 27.7 months (GLOW; safety population primary analysis) ..................................................................................... 92 Table 20 Key characteristics of the economic analyses ......................................... 107 Table 21 Populations considered in the submission............................................... 113 Table 22 Treatments and dosing for FCR-suitable population ............................... 115 Table 23 Treatments and dosing for FCR-unsuitable population ........................... 115 Table 24 Treatments and dosing for high-risk population....................................... 116 Table 25 Summary of data sources informing the clinical parameters ................... 121 Table 26 Summary of transition probabilities between health states for the FCRsuitable population ................................................................................................. 126 Table 27 Goodness-of-fit statistics (AIC/BIC) for the parametric models fitted to INV PFS KM data for FCR in E1912 ............................................................................. 129 Table 28 Landmark PFS estimates for the FCR INV PFS data from E1912 when capped by GPM ..................................................................................................... 130 Table 29 PFS HR of I+V vs. FCR for the ATC, ATO and ATT analyses based on the adjusted populations in the CAPTIVATE FD cohort (no del17p) and E1912 .......... 131 Table 30 Landmark PFS estimates for I+V PFS from CAPTIVATE derived from the FCR reference curve .............................................................................................. 133 Table 31 Annual mortality rate in PFS derived from CAPTIVATE FD cohort (no del17p) and E1912 ................................................................................................. 134 Table 32 Statistical goodness-of-fit indicators (AIC/BIC) values for the independent parametric models fitted to INV PFS data for ibrutinib (1-2 prior line subgroup) from the RESONATE trial final (65m) data cut ............................................................... 135 Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

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Table 33 Landmark PFS estimates for the I+V INV PFS data for ibrutinib (1-2 prior line subgroup) from the RESONATE trial final (65m) data cut ............................... 136 Table 34 Annual mortality rate in PF 2L derived from RESONATE Ibrutinib arm (1-2 prior line subgroup) ................................................................................................ 138 Table 35 Annual mortality rate in 2L PFS derived from RESONATE Ibrutinib arm (1-2 prior line subgroup) ................................................................................................ 139 Table 36 Summary of transition probabilities between health states for the FCRunsuitable population ............................................................................................. 140 Table 37 Goodness-of-fit statistics (AIC/BIC) for the independent parametric models fitted to INV-assessed PFS data for I+V ................................................................. 142 Table 38 Landmark estimates for the I+V INV PFS data from GLOW when capped by the UK GPM hazard .......................................................................................... 143 Table 39 Statistical goodness-of-fit indicators (AIC/BIC) values for the independent parametric models fitted to INV PFS data for O-Clb ............................................... 147 Table 40 Landmark estimates for the O-Clb INV PFS data from GLOW when capped by the UK GPM hazard .......................................................................................... 149 Table 41 Anchored MAIC of I+V vs. VenO and acalabrutinib PFS ......................... 150 Table 42 Landmark INV PFS estimates for model comparators when capped by the UK GPM hazard ..................................................................................................... 151 Table 43 Annual mortality rate in PFS derived from GLOW ................................... 152 Table 44 Summary of clinical parameters for the post progression transitions ...... 154 Table 45 Summary of clinical parameters for the high-risk population ................... 155 Table 46 Pre- and post-progression utility derived from the GLOW trial using the RMME model ......................................................................................................... 159 Table 47 Pre-progression utility from GLOW vs. age-adjusted general population utility ....................................................................................................................... 160 Table 48 Incidence of grade ≥3 AEs considered in the FCR-suitable population ... 164 Table 49 Incidence of grade ≥3 AEs considered in the FCR-unsuitable population164 Table 50 Incidence of grade ≥3 AEs considered in the high-risk population .......... 165 Table 51 Disutility and duration estimates for AEs ................................................. 166 Table 52 Summary of utility values for cost-effectiveness analysis, FCR-suitable population ............................................................................................................... 167 Table 53 Summary of utility values for cost-effectiveness analysis, FCR-unsuitable population ............................................................................................................... 168 Table 54 Summary of key cost input categories and data sources ........................ 169 Table 55 Unit cost of therapies ............................................................................... 170 Table 56 Patient characteristics used in the economic analysis ............................. 171 Table 57 Dosing intensity estimates ....................................................................... 171 Table 58 Drug acquisition cost per cycle ................................................................ 172 Table 59 Summary of drug related administration costs ........................................ 173 Table 60 Subsequent treatment regimens by first-line treatment option ................ 175 Table 61 Dosing regimens of subsequent treatment used in the economic analysis ............................................................................................................................... 176 Table 62 Dosing intensity estimates for subsequent treatment .............................. 176 Table 63 Drug acquisition cost for subsequent treatment, per cycle ...................... 177 Table 64 Drug administration cost for subsequent treatment, per cycle ................. 177 Table 65 Unit costs for AE management ................................................................ 178 Table 66 TLS management costs .......................................................................... 180

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Table 67 PF health state costs and resource use .................................................. 181 Table 68 PD health state costs and resource use .................................................. 181 Table 69 Growth factor dosing and unit costs ........................................................ 182 Table 70 Summary features of QALY shortfall analysis ......................................... 183 Table 71 Summary of health state benefits and utility values for QALY shortfall analysis .................................................................................................................. 183 Table 72 Summary of QALY shortfall analysis ....................................................... 184 Table 73 Summary of base case analysis inputs for the FCR-suitable population . 185 Table 74 Summary of base case analysis inputs for the FCR-unsuitable population ............................................................................................................................... 187 Table 75 Summary of base case analysis inputs for the high-risk population, where different from FCR-unsuitable population ............................................................... 190 Table 76 Summary of key model assumptions for the FCR-suitable population .... 193 Table 77 Summary of key model assumptions for the FCR-unsuitable population, where different from FCR-suitable population ........................................................ 194 Table 78 Summary of key model assumptions for the high-risk population, where different from FCR-unsuitable ................................................................................ 195 Table 79 Deterministic Results: FCR-suitable population ...................................... 196 Table 80 Average results based on the PSA: FCR-suitable population ................. 197 Table 81 Deterministic Results: FCR-unsuitable population .................................. 200 Table 82 Average results based on the PSA: FCR-unsuitable population ............. 202 Table 83 Deterministic Results: High-risk population ............................................. 207 Table 84 Average results based on the PSA: High-risk population ........................ 209 Table 85 List of scenario analysis conducted ......................................................... 213 Table 86 Scenario analysis: FCR-suitable population ............................................ 214 Table 87 Scenario analysis: FCR-unsuitable population ........................................ 216 Table 88 Scenario analysis: High-risk population ................................................... 219 Figure 1 NICE-recommended clinical pathway for previously untreated CLL ........... 24 Figure 2 Clinical pathway of care for previously untreated CLL, with proposed position of I+V in red ................................................................................................ 35 Figure 3 Trial design (CAPTIVATE FD cohort) ......................................................... 44 Figure 4 Trial design (GLOW) .................................................................................. 50 Figure 5 KM plot of INV-assessed PFS (CAPTIVATE; all treated population primary analysis) ................................................................................................................... 63 Figure 6 KM plot of INV-assessed PFS (CAPTIVATE; all treated population extended follow-up) .................................................................................................................. 64 Figure 7 KM plot of INV-assessed PFS (CAPTIVATE; all treated and no-del17p populations extended follow-up) ............................................................................... 65 Figure 8 KM plot of OS (CAPTIVATE; all treated population primary analysis) ........ 66 Figure 9 KM plot of OS (CAPTIVATE; all treated population extended follow-up) ... 67 Figure 10 KM plot of OS (CAPTIVATE; all treated and no-del17p populations extended follow-up) .................................................................................................. 68 Figure 11 KM plot of IRC-assessed PFS (GLOW; ITT primary analysis) ................. 73 Figure 12 KM plot of IRC-assessed PFS (GLOW; ITT extended follow-up analysis) 74 Figure 13 KM plot of OS (GLOW; ITT primary analysis) .......................................... 75 Figure 14 KM plot of OS (GLOW; ITT extended follow-up analysis) ........................ 76

Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

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Figure 15 Forest plot of INV-assessed CR/CRi by pre-specified subgroups (CAPTIVATE; all treated population primary analysis) ............................................. 77 At the data cut-off for the primary analysis (26 February 2021) with a median followup of 27.7 months, the improvement in IRC-assessed PFS with I+V treatment vs. O- Clb treatment was observed across pre-specified subgroups (Figure 16), XX XXX XX XXX XX XXX (Appendix E.2).(67, 70) XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX Figure 16 Forest plot of IRC-assessed PFS by prespecified subgroups (GLOW; ITT primary analysis) ................................................. 78 Figure 17 PFS INV anchored MAIC results comparing I+V (34.1 month follow-up) and VenO (28.1 month follow-up) ............................................................................ 85 Figure 18 PFS INV anchored MAIC results comparing I+V (34.1 month follow-up) and acalabrutinib (28.3 month follow-up) ................................................................. 88 Figure 19 Model structure ...................................................................................... 117 Figure 20 Naïve comparison of FCR PFS KM from E1912 (70m median), CLL8 (71m), and CLL10 (58.2m) ..................................................................................... 128 Figure 21 Parametric models overlaying the observed INV PFS KM data for FCR from E1912 ............................................................................................................. 130 Figure 22 I+V PFS capped by GPM derived from the HR vs. FCR reference curve (ATC analyses) ...................................................................................................... 132 Figure 23 PFS extrapolations of ibrutinib (1-2 prior lines) from RESONATE trial final (65m) data cut ........................................................................................................ 136 Figure 24 Observed INV PFS data extended follow-up (34.1m) of the GLOW trial 141 Figure 25 Parametric models overlaying the observed INV-assessed PFS KM data for I+V .................................................................................................................... 143 Figure 26 PFS extrapolation of I+V capped by GPM (observed KM data + exponential model) ................................................................................................. 145 Figure 27 PFS extrapolations of O-Clb capped by GPM ........................................ 148 Figure 28 Comparison of PFS extrapolations for model comparators (using exponential extrapolation for I+V) capped by GPM ................................................ 150 Figure 29 Pre-progression mortality observed in the GLOW trial vs. GPM ............ 153 Figure 30 EQ-5D-3L Utility Score Over Scheduled Visits in GLOW ....................... 159 Figure 31 EQ-5D-3L by age and gender in the UK, HSE 2014 .............................. 162 Figure 32 Cost-effectiveness plane: FCR-suitable population ................................ 197 Figure 33 Cost-effectiveness acceptability curve: FCR-suitable population ........... 198 Figure 34 DSA results of INMB per QALY of FCR vs. I+V ..................................... 199 Figure 35 Cost-effectiveness plane: FCR-unsuitable population ............................ 203 Figure 36 Cost-effectiveness acceptability curve: FCR-unsuitable population ....... 204 Figure 37 DSA results of INMB per QALY of O-Clb vs. I+V ................................... 205 Figure 38 DSA results of INMB per QALY of VenO vs. I+V ................................... 205 Figure 39 DSA results of INMB per QALY of acalabrutinib vs. I+V ........................ 206 Figure 40 Cost-effectiveness plane: High-risk population ...................................... 210 Figure 41 Cost-effectiveness acceptability curve: High-risk population .................. 211 Figure 42 DSA results of INMB per QALY of ibrutinib vs. I+V ................................ 212 Figure 43 Extrapolation of I+V CAPTIVATE FD cohort OS, uncapped and capped by GPM hazards ......................................................................................................... 225 Figure 44 Extrapolation of I+V GLOW OS .............................................................. 226

Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

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Figure 45 OS projections of technologies evaluated in the FCR-suitable population ............................................................................................................................... 227 Figure 46 OS projections of technologies evaluated in the FCR-unsuitable population ............................................................................................................................... 227

Abbreviations

Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

© Janssen-Cilag Limited (2022). All rights reserved

Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

© Janssen-Cilag Limited (2022). All rights reserved

Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

© Janssen-Cilag Limited (2022). All rights reserved

Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

© Janssen-Cilag Limited (2022). All rights reserved

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

B.1.1 Decision problem

This single technology appraisal evaluates the clinical- and cost-effectiveness of fixed duration (FD) treatment with ibrutinib in combination with venetoclax (I+V) for patients with previously untreated chronic lymphocytic leukaemia (CLL). The anticipated marketing authorisation wording is: Ibrutinib in combination with venetoclax is indicated for the treatment of adult patients with previously untreated CLL.

This submission considers three populations, defined by either mutation status or suitability for intensive chemo-immunotherapy (CIT; fludarabine + cyclophosphamide + rituximab [FCR]) based on patient fitness, in line with the classification used in recent appraisals TA689 and TA663.(1, 2) There are no standard criteria for determining fitness level in CLL, but in routine clinical practice, the assessment of fitness includes factors such as age, presence and severity of comorbidities and performance status (PS).

The economic analysis follows the National Institute for Health and Care Excellence (NICE) reference case and therefore ensures alignment with the NICE decision problem.

The decision problem for this submission is summarised in Table 1.

Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

© Janssen-Cilag Limited (2022). All rights reserved

Table 1 The decision problem

Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

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Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

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BR = bendamustine + rituximab; BSH = British Society of Haematology; CDF = Cancer Drugs Fund; CIT = chemo-immunotherapy; CLL = chronic lymphocytic leukaemia; CR = complete response; del17p = 17p deletion; FCR = Fludarabine + cyclophosphamide + rituximab; HRQoL = health-related quality of life; I+V = ibrutinib + venetoclax; IGHV = Immunoglobulin heavy chain variable region; MRD = minimal residual disease; NA = not applicable; NHS = National Health Service; NICE = National Institute for Health and Care Excellence; O-Clb = obinutuzumab + chlorambucil; OS = overall survival; PFS = progression-free survival; PSS = Personal Social Services; QALY = quality-adjusted life year; TA = technology appraisal; TP53 = tumour protein 53; UK = United Kingdom; VenO = venetoclax + obinutuzumab

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B.1.2 Description of the technology being evaluated

A link to the latest European public assessment report (EPAR) for ibrutinib is provided in Appendix C. The summary of product characteristics (SmPC) for I+V is not yet available.

Table 2 Technology being evaluated

Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

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BCL-2 = B-cell lymphoma-2; BCR = B-cell receptor; BM = bone marrow; BR = bendamustine + rituximab; BTK = Bruton’s tyrosine kinase; CHMP = Committee for Medicinal Products for Human Use; CLL = chronic lymphocytic leukaemia; EMA = European Medicines Agency; FD = fixed duration; I+V = ibrutinib + venetoclax; MHRA = Medicines and Healthcare products Regulatory Agency; NHS = National Health Service; PAS = patient access scheme; SmPC = summary of product characteristics; UK = United Kingdom

Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

© Janssen-Cilag Limited (2022). All rights reserved

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

Disease overview and burden

• CLL is a type of blood cancer, which is relatively rare (around 1% of new cancers are CLL) and is typically diagnosed in older people (median age at diagnosis of 72 years in the United Kingdom [UK]).(14, 15)

• The clinical manifestations of CLL can have a substantial negative impact on patients’ quality of life (QoL) as a result of disease-related symptoms (such as fatigue, recurrent infections and anaemia); treatment-related adverse events (AEs); and the psychological, socioeconomic and functional effects of living with the disease.(16, 17)

• Patients with CLL have been shown to have significantly lower emotional well-being than the general population and patients with other types of cancer.(16) CLL also imposes a considerable economic burden on patients, their families, the healthcare system and society.(17-19)

Clinical pathway of care

• Treatment decisions are influenced by age, fitness and mutation status.(3, 20, 21) The BSH guidelines recommend screening for TP53 disruption (i.e., del17p and/or TP53 mutation) before initiating treatment since patients with these genetic mutations are considered a high-risk group.(3) o In patients with del17p/TP53 mutations (high-risk patients), the options include idelalisib + rituximab (idelalisib is oral but treat to progression and rituximab is FD, given via intravenous [IV] infusion), venetoclax + obinutuzumab (VenO; FD but includes IV obinutuzumab infusions), acalabrutinib (oral but treat-to-progression) or ibrutinib (oral but treat to progression).

  • In patients without del17p/TP53 mutations for whom FCR/ bendamustine + rituximab (BR) is suitable, the only treatment options have been CIT (FCR/BR) for decades, with the recent addition of VenO (only through the Cancer Drugs Fund [CDF]).

  • In patients without del17p/TP53 mutations for whom FCR/BR is unsuitable, the options include obinutuzumab + chlorambucil (O-Clb; a CIT), VenO (FD but includes IV obinutuzumab infusions) or acalabrutinib (oral but treat to progression).

Unmet need

• Despite the addition of new therapies and subsequent updates to treatment guidelines for CLL management over the last decade,(3, 22) currently, patients with previously untreated CLL lack a convenient all-oral once daily FD, chemotherapy-free regimen that can be taken at home (without the need for infusion-based hospital treatments).

• This unmet need includes patients’ desire for more effective disease management, including treatments with fewer side effects and which do not contribute to the ‘medicalisation’ of patients’ lives (process by which patients become increasingly defined by their disease [and its treatment]). I+V would address these unmet needs.

Proposed positioning of I+V

• It is anticipated that I+V will be used as first-line treatment in patients considered suitable for FCR (in line with the phase II CAPTIVATE study population) and unsuitable for FCR (in line with the phase III GLOW study population), as well as in high-risk patients.

Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

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B.1.3.1 Disease overview

CLL is the most common type of leukaemia(23) and is a lymphoproliferative B-cell malignancy characterised by the progressive expansion of monoclonal B lymphocytes in the blood, bone marrow (BM), lymph nodes or other lymphoid tissue.(24, 25) CLL is generally an incurable disease and is life-threatening due to the development of immune cytopenias and impaired production of normal immunoglobulin.(20, 26, 27)

Small lymphocytic lymphoma (SLL) is a leukaemic lymphocytic lymphoma that is considered to be the same entity as CLL by the World Health Organisation and will be referred to as CLL from here on.(25, 28)

Clinical presentation, staging and diagnosis

Guidelines from the 2018 International Workshop on CLL (iwCLL) specify that a diagnosis of CLL requires the presence of ≥5 x 10[9] /L B lymphocytes in the peripheral blood (PB) for at least 3 months.(25) These diagnostic criteria are similar to criteria published in 2012 by the British Society of Haematology (BSH), in 2021 by the European Society for Medical Oncology (ESMO) and in 2022 by the US National Comprehensive Cancer Network (NCCN).(20, 21, 29)

The majority of patients with CLL (74%) have no symptoms at the time of diagnosis and are only diagnosed when a routine blood count uncovers an absolute lymphocytosis.(24, 29-31) In patients who are symptomatic at diagnosis, there are a wide range of presenting features and physical and laboratory abnormalities.(24, 29) Common clinical signs may include enlarged lymph nodes, liver, spleen or bruising and patients may display typical cancer related symptoms such as fever, chills, night sweats and weight loss. Once a patient is diagnosed, clinical staging of CLL is established based on a physical examination and complete blood counts.

Clinical staging systems used in CLL include the Binet system, which is mostly used in the UK and Europe, and the Rai classification system, which is mostly used in North America.(32, 33) The Binet System classifies patients in three stages as A, B or C, based on the number of red blood cells and platelets and the number of areas of the lymphatic system that are enlarged.(33) The Rai system classifies patients in five Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

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stages as 0, I, II, III or IV, based on the number of lymphocytes, red blood cells and platelets and whether the lymph nodes, spleen or liver are enlarged.(32) The Binet C and Rai III/IV represent patients with advanced disease and at high risk, respectively.(20)

The prognosis of patients with CLL is dependent on a variety of patient-related (age, gender, comorbidities and PS), disease-related (disease stage, cytogenetics, marrow failure, immunodeficiency, lymphomatous transformation and biomarkers) and treatment-related (type of treatment, response, toxicity and minimal residual disease [MRD] status) factors.(29) In particular, TP53 aberration (del17p and/or TP53 mutation) is an established prognostic marker in CLL, providing the strongest prognostic and predictive relevance among the relevant cytogenetic factors in CLL; del17p and/or TP53 mutation predict an aggressive disease course and are associated with a poor prognosis and a negative impact on treatment outcomes.(20)

Epidemiology

CLL accounts for 1% of total cancer cases in the UK with around 3,800 new cases in the UK every year, corresponding to 10 cases each day (based on 2016-2018 data from Cancer Research UK).(14) There were 3,157 new cases of CLL in England in 2017 based on data from the Office for National Statistics.(34) CLL meets the UK Medicines and Healthcare products Regulatory Agency (MHRA) criteria for a rare disease (prevalence of <5 per 10,000),(35, 36) with a prevalence of ~3 per 10,000 people,(14) based on a population of 62.8 million in 2010.(37) Table 3 presents the agestandardised incidence rates.

Table 3 CLL incidence rates in England and Wales (2016-2018)

CLL = chronic lymphocytic leukaemia Source: Cancer Research UK, 2021(14)

CLL is typically diagnosed between the ages of 65 and 74 years, with a median age at diagnosis of 72 years reported in England; 27% of patients with CLL are diagnosed

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below 65 years.(15) CLL is a chronic disease with patients experiencing episodes of relapse and remission, although the natural course of CLL is highly variable.(22) In the UK, the age-standardised mortality rate is 1.5 per 100,000; since the early 1970s, mortality rates for CLL have decreased in most age groups, excluding in ≥80 year olds (28% increase).(38) Survival decreases with advancing age (Table 4).

Table 4 5-year survival rates for patients with CLL in the UK, by age range (2006-

2010)

CLL = chronic lymphocytic leukaemia; UK = United Kingdom Source: Pulte, 2015(15)

B.1.3.2 Disease burden

CLL is a chronic disease which impacts patients’ QoL negatively through the symptoms experienced, treatment-related AEs, impact on work and family life. Additionally, there is an economic burden associated with CLL.

Symptom burden

CLL develops slowly and most patients are asymptomatic at the time of diagnosis. Nonspecific symptoms of CLL include weight loss, fatigue, night sweats and fever.(24, 29, 39) Symptoms of CLL can include swollen lymph nodes, having frequent infections, severe sweating at night, weight loss, breathlessness and tiredness due to anaemia.

CLL patients have an increased risk of other secondary cancers and infections, because CLL is a cancer of B-lymphocytes and consequently causes impairment to the immune system through impact of the disease on the lymphatic system, spleen and other organs.(40, 41) During an advisory board with patients, they identified risk of infection, along with fatigue, as a key factor that limited their social activities, which further impacts their QoL.(42)

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Fatigue is one of the most common symptoms of CLL, and the severity of fatigue is higher in patients with CLL compared to the general population and increases in line with disease stage.(16, 43, 44) CLL trustees/patients who participated in an advisory board in 2022 said “I hadn’t experienced fatigue like this” and another person with CLL said “the fatigue meant I wasn’t pleasant to be around, so I felt frustrated and guilty”.(18)

In addition to the symptom burden of CLL, AEs associated with treatment add to the clinical burden of CLL.(45) The most commonly reported AEs among patients receiving FCR were anaemia, neutropenia (leading to infections) and leukocytosis (resulting in fever, bruising, fatigue).(18)

Impact on quality of life

In the UK, many patients with CLL are on ‘Watch and Wait’, which is a process whereby patients with CLL are regularly monitored to track disease progression, with treatment only initiated once intervention criteria are met and treatment required.(20) This ‘Watch and Wait’ strategy is supported by studies that failed to demonstrate a survival advantage with early intervention with chemotherapy.(20) It has been estimated that the proportion of symptomatic (eligible to receive treatment at initial diagnosis) and asymptomatic (‘Watch and Wait’) patients ranges from 26% to 34% and 66% to 74%, respectively.(30) During the ‘Watch and Wait’ period, patients are frequently monitored and face constant uncertainty and emotional strain.

CLL trustees/patients who participated in an advisory board in 2022 described ‘Watch and Wait’ as “lonely and worrying” and “found the thought of waiting to be ill very anxiety-inducing”. They also mentioned that “the diagnosis can come as a shock, especially for those who are younger” given that patients are mostly asymptomatic.

They said that ‘Watch and Wait’ made them “apprehensive about the future and worried about potential impacts of the disease and treatment, not knowing when it will come”.(18)

The clinical manifestations of CLL can have a substantial negative impact on patients’ QoL as a result of disease-related symptoms (such as fatigue, recurrent infections and Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860] © Janssen-Cilag Limited (2022). All rights reserved Page 21 of 239

anaemia); treatment-related AEs; and the psychological, socioeconomic and functional effects of living with the disease.(16, 17)

The emotional well-being of patients with CLL has been shown to be significantly lower than that of the general population (p=0.001), as well as that of patients with other types of cancer (p=0.001).(16) In addition, compared with the general population, patients with CLL experience worse depression, fatigue, anxiety, sleep disturbance and detriment in physical functioning, social functioning and pain interference.(17)

The effect of CLL treatment on QoL was evaluated in a UK study which recruited 100 individuals from the general population to rate nine different health states within the typical disease and treatment course of CLL.(42) The CLL health state of “progressionfree survival (PFS) without therapy” was considered the least burdensome, followed by “PFS without second-line therapy” and “PFS on initial therapy oral treatment” (mean utility scores: 0.82, 0.71 and 0.71, respectively).(42) This study highlights the importance of convenient therapies and long-lasting PFS when considering QoL in patients with CLL.(42) Currently in the first-line setting, patients with CLL lack a convenient all-oral once daily FD treatment which can be taken at home.

Economic burden

CLL also imposes a considerable economic burden on patients and their families, as well as on the healthcare system and society. Hospitalisation is a primary cost driver for patients with CLL in the UK, with outpatient and hospice care adding to overall healthcare costs incurred by patients initiating first-line treatment.(19) The economic burden of CLL increases further when patients relapse (especially when disease progression occurs early), with increased healthcare resource use (including inpatient admissions and outpatient visits) driving cost increases.(17, 46-48)

Additional burden on patients stems from the impact of CLL on their ability of work. Once diagnosed with CLL, patients may need sick leave and/or a reduction in work hours, and maybe even stopping work eventually. A CLL trustee/patient who participated in an advisory board in 2022 said “I felt so tired all the time – all my energy

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was going into work. I had to have some energy for my family, so I stopped working”. This leads to an impact on their personal finances, causing an emotional burden.(18)

B.1.3.3 Clinical pathway of care

Certain patients with CLL may be considered for allogeneic stem cell transplantation (patients refractory to CIT with TP53 mutation or del17p, but fully responsive to novel inhibitor therapy; patients refractory to CIT and to novel inhibitor therapy; patients with Richter’s transformation in remission after therapy and clonally related to CLL).(20) Otherwise, CLL remains an incurable disease for symptomatic patients who require treatment but are ineligible for haematopoietic stem cell transplantation.(20) The clinical burden of CLL is high, particularly as it is a chronic relapsing and remitting disease.(49) Historically, the choice of therapy was a trade-off between efficacy and tolerability, especially for CIT, and often depended on the patient’s ability to tolerate treatment.(49) However, the role of CIT in first-line treatment has diminished following the approval of targeted pathway inhibitors in recent years.(3)

Treatment decisions are influenced by age, fitness and mutation status.(3, 20, 21) Agreement on a definition for fitness status has not been reached, but the following thresholds are commonly cited:(21, 50)

• More fit: CIRS ≤6, CrCl ≥70 mL/min and ECOG PS <2

• Less fit: CIRS >6 and CrCl <70 mL/min

The BSH guidelines recommend screening for TP53 disruption (i.e., del17p and/or TP53 mutation) before initiating treatment since patients with these genetic mutations are considered a high-risk group.(3) The presence of del17p/TP53 mutation remains a statistically significant negative prognostic factor regardless of patient’s fitness when treated with CIT, such as O-Clb and FCR, as well as other CLL treatments, such as VenO.(20, 51-53)

Despite the addition of new therapies and subsequent updates to treatment guidelines for CLL management over the last decade,(3, 22) currently, patients with previously

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untreated CLL lack a convenient all-oral once daily FD, chemotherapy-free regimen that can be taken at home (without the need for infusion-based hospital treatments).

The current UK clinical pathway for first-line treatment of CLL is directed by NICE guidance, summarised in Figure 1. Current treatments which are recommended by NICE for previously untreated CLL are summarised in Table 5.

Figure 1 NICE-recommended clinical pathway for previously untreated CLL

==> picture [468 x 267] intentionally omitted <==

BR = bendamustine + rituximab; CLL = chronic lymphocytic leukaemia; del17p = 17p deletion; FCR = fludarabine + cyclophosphamide + rituximab; TP53 = tumour protein 53

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Table 5 Treatments recommended by NICE for previously untreated CLL

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BR = bendamustine + rituximab; BSH = British Society for Haematology; CDF = Cancer Drugs Fund; CIT = chemo-immunotherapy; CLL = chronic lymphocytic leukaemia; CYP3A = cytochrome P450; del17p = 17p deletion; FCR = fludarabine + cyclophosphamide + rituximab; FD = fixed duration; IV = intravenous; NICE = National Institute for Health and Care Excellence; O-Clb = obinutuzumab + chlorambucil; SmPC = summary of product characteristics; TLS = tumour lysis syndrome; TP53 = tumour protein 53; VenO = venetoclax + obinutuzumab

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Recommendations from the BSH and recognised international and national authorities (ESMO and NCCN) also guide the UK clinical pathway. BSH, ESMO and NCCN treatment recommendations for previously untreated CLL, stratified by fitness and mutation status, are summarised in Table 6.

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Table 6 Treatment guidelines for previously untreated CLL

BCR = B-cell receptor; BR = bendamustine + rituximab; BSH = British Society for Haematology; CD20 = cluster of differentiation 20; CDF = Cancer Drugs Fund; CIT = chemo-immunotherapy; CLL = chronic lymphocytic leukaemia; CrCl = creatinine clearance; del17p = 17p deletion; ESMO = European Society for Medical Oncology; FCR = fludarabine + cyclophosphamide + rituximab; IGHV = immunoglobulin heavy chain variable region; IV = intravenous; NCCN = National Comprehensive Cancer Network; O-Clb = obinutuzumab + chlorambucil; TP53 = tumour protein 53; VenO = venetoclax + obinutuzumab a The BSH guidelines include all licensed treatments; however, note that the following are not reimbursed in the UK in the first-line setting: ibrutinib monotherapy for patients without del17p/TP53 mutation and acalabrutinib + obinutuzumab

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b Use of BR can be considered for patients aged >65 years

c Fit patients were defined as those aged <65 years and without significant comorbidities; unfit patients were defined as those aged ≥65 years or younger patients with significant comorbidities (CrCl <70 mL/min)

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B.1.3.4 Unmet need

Based on the information presented above, the current treatment options used in UK clinical practice (and the relevant comparators for the three populations considered in this submission) are summarised in Table 7.

Table 7 Summary of first-line treatment options for CLL

BR = bendamustine + rituximab; CLL = chronic lymphocytic leukaemia; del17p = 17p deletion; FCR = fludarabine + cyclophosphamide + rituximab; IV = intravenous; O-Clb = obinutuzumab + chlorambucil; TP53 = tumour protein 53; VenO = venetoclax + obinutuzumab

Unmet need from a patient perspective

Treatment choice is informed by physicians recommending the most appropriate treatment, based on fitness and mutation status, and patient choice. There is a strong patient preference for less toxic therapies, without loss of efficacy, which can reduce the burden of hospital appointments.

Oral treatments

CLL trustees/patients who participated in an advisory board in 2022 highlighted the following:(18)

• “An oral therapy has got to win hands down compared to a combination or infusion therapy. The disruption, logistics, the discomfort - all of that”

• “An oral thing would be great, really handy. Be in contact less often with doctors is a good thing”

• “If you physically don’t have to go to the hospital, it’s just easier”

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• “I don’t know who would choose an infusion if you could take a pill”

• “There is a lot more freedom if you are just taking the pills. You could go on vacation”

• “So much better for the quality of life to take pills at home”

Fixed duration treatments

CLL trustees/patients who participated in an advisory board in 2022 highlighted the following:(18)

• “The fixed thing is fantastic. You only have to have it for a certain time and then you're done. The fixed is good for me.”

• “I will have a time when I don't have to take any drugs. And that has to be a good thing”

• “You can live normally and plan things”

• “I think I would like the short duration. Done and dusted.”

Currently, patients with previously untreated CLL lack a convenient all-oral once daily, FD, chemotherapy-free treatment regimen that can be taken at home (without the need for infusion-based hospital treatments) and that can be administered regardless of patient fitness and mutation status. An oral therapy would give patients the convenience, freedom and independence associated with treatment administered at home.

Treatment with an all-oral regimen would also reduce the number of hospital visits needed. Hospital visits can increase anxiety levels in anticipation of the appointments. A positive recommendation for I+V would reduce the need for: elderly or frail patients with mobility issues to rely on others for transport to a hospital; young and fit patients in the workforce to repeatedly request time off work; and parents with young children to organise childcare during hospital appointments. CLL trustees/patients who participated in an advisory board in 2022 highlighted “it’s inconvenient to go to hospital, to drive there and pay for parking”, described hospital appointments as “disruptive,

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uncomfortable and having to organise logistics” and mentioned “not having those trips to the hospital is just easier on the mind. People start to get anxious the week before they go into hospital and then really nervous on the day, and they're just sweating by the time they get in there, even if it's just a check-up”.(18)

A FD regimen would reduce the duration of patient exposure to treatment compared to treat to progression comparators, decrease the duration of AEs and allow patients to have a ‘treatment holiday’ between finishing first-line treatment and initiating second-line treatment after disease progression.

CLL trustees/patients who participated in an advisory board in 2022 highlighted wanting to regain “some sort of control” and live “as normal a life as possible” as key aspects of the impact of CLL treatment on daily life and emotional well-being.(18)

Additionally, clinicians would value the option to administer a combination of effective agents upfront to reduce the resource burden associated with relapse.(17, 46-48) This would have positive resource implications for the National Health Service (NHS), which is currently recovering from a global pandemic, by helping to alleviate the backlog of patients waiting to be treated.

I+V will address these unmet needs, and help patients avoid a life of medicalisation (process by which patients become increasingly defined by their disease [and its treatment]) by reducing hospital appointments and offering patients a ‘treatment-free holiday’.

FCR-suitable patients

FCR-suitable patients with previously untreated CLL in the UK only had FCR as a treatment option for decades, with VenO becoming available in 2020 only through the CDF); no fully oral regimens are available to these patients.(3)

Toxicity and risks of secondary malignancy remain areas of concern with FCR.(3, 20) Patients being considered for FCR are typically younger people whose daily lives can be particularly impacted by the burden of hospital appointments for IV treatment

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administration. These patients would thus greatly benefit from an all-oral treatment regimen conveniently administered at home, with reduced burden in terms of travel time to the hospital, time off work and childcare planning. A CLL trustee/patient who participated in an advisory board in 2022 mentioned she was told she would receive FCR because she was young and “could hit the disease hard” but she was “dreading FCR” because of the side effects.

FCR-unsuitable patients

FCR-unsuitable patients with CLL require convenient, all oral, FD treatment options that reduce burden on patients and carers. NICE-recommended treatment options for these patients are limited to FD regimens involving IV administration and the need for premedication (O-Clb and VenO) or an oral regimen that is administered continuously until disease progression (acalabrutinib). There remains an unmet need in this population for a treatment regimen that could be taken from home (leading to fewer hospital appointments), avoid the need for IV administration (especially beneficial in elderly and frail patients) and allow for a ‘treatment holiday’ after completion of the FD regimen.

High-risk patients

High-risk patients with previously untreated CLL face a poor prognosis, with del17p shown to have the worst prognosis among genetic mutations identified as important independent predictors of disease progression and survival in CLL.(65) An additional efficacious treatment option providing deep and durable responses would be valuable for these patients with high-risk disease. Furthermore, high-risk patients would benefit from an all oral, FD alternative to the currently available NICE-recommended therapies (acalabrutinib monotherapy, VenO and ibrutinib monotherapy).

B.1.3.5 Proposed positioning of I+V

The proposed positioning of I+V (an oral, once daily FD regimen) in the treatment pathway for previously untreated CLL is depicted in Figure 2. It is anticipated that I+V will be used as first-line treatment in patients considered suitable for FCR (in line with

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the phase II CAPTIVATE study population) and unsuitable for FCR (in line with the phase III GLOW study population), as well as in high-risk patients.

Figure 2 Clinical pathway of care for previously untreated CLL, with proposed position of I+V in red

==> picture [452 x 294] intentionally omitted <==

BR = bendamustine + rituximab; CLL = chronic lymphocytic leukaemia; del17p = 17p deletion; FCR = fludarabine + cyclophosphamide + rituximab; TP53 = tumour protein 53

B.1.4 Equality considerations

There is an urgent need for access to novel treatments for younger, fitter patients with CLL, as currently only FCR or VenO via CDF are available to them, both of which require IV infusions. I+V will address this inequality.

In addition to the clinical benefits, there is a social value judgement relating to reducing medicalisation which I+V is well positioned to address. Specifically, I+V helps patients avoid a life of medicalisation by reducing hospital appointments and offering patients a ‘treatment-free holiday’.

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A CLL trustee/patient who participated in an advisory board in 2022 highlighted the ‘medicalised’ feeling patients live with “You hear things like cancer is not going to define me, it does control you there's no doubt about it, you might think you have a certain control, but you do whatever the disease demands of you, so in that sense you are not in control.”(18)

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B.2 Clinical effectiveness

A systematic literature review (SLR) identified two high-quality clinical trials for I+V in the relevant patient population as defined by the NICE scope (CAPTIVATE FD cohort and GLOW).

• CAPTIVATE was a non-comparative phase II trial designed to evaluate I+V in the FCR-suitable population in two cohorts (the FD cohort and the MRD cohort); the open-label, one-group FD cohort is in line with how I+V will be administered in clinical practice and is therefore of interest to this submission. The FD cohort was designed to evaluate the depth of response per complete response (CR)/CR with incomplete BM recovery (CRi; primary endpoint) following FD I+V.(66)

• • GLOW was a randomised, open-label, multi-centre phase III trial designed to evaluate FD I+V vs. O- Clb among patients in the FCR-unsuitable population. The primary endpoint of GLOW was Independent Review Committee (IRC)-assessed PFS.(67)

• • The extended follow-up analysis of both trials (median follow-up of 38.7 months in CAPTIVATE(68, 69) and 34.1 months in GLOW(67, 70)) informed the indirect treatment comparisons (ITCs) and economic analysis.

GLOW and CAPTIVATE demonstrated the efficacy of FD I+V in previously untreated CLL.

• In FCR-suitable patients in the CAPTIVATE FD cohort, INV-assessed CR/CRi rate (primary endpoint) was 55.9% (95% confidence interval [CI]: 47.5, 64.2) for patients without del17p at the primary analysis (median 27.9 months follow-up).(66) CR/CRi rates increased slightly to 58.1% (95% CI: 49.8, 66.4) with approximately 9 months of further follow-up.(68)

• Secondary endpoint analyses from CAPTIVATE FD cohort supported the favourable CR rates, with the majority of CRs being durable for at least 12 months.(66, 68)

• In FCR-unsuitable patients in GLOW, primary analysis (median follow-up of 27.7 months) concluded that patients treated with I+V had a significantly reduced risk of disease progression or death of 78% per IRC assessment (hazard ratio [HR] 0.22; 95% CI: 0.13, 0.36; nominal p<0.0001) compared to patients treated with O-Clb.(67) INV-assessed PFS was consistent with IRC-assessed PFS. PFS benefit with I+V vs. O-Clb was maintained long-term with approximately 6 months of further followup.(67, 70)

• Secondary endpoint analyses from GLOW indicated that the I+V group also had a significantly higher overall MRD negative rate in BM by NGS and significantly higher IRC-assessed CR/CRi compared to the O-Clb group at the primary analysis; the XXXX and MRD negative rates with I+V remained high and the benefit vs. O-Clb was sustained throughout the first year after treatment completion.(70, 71) XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX(70)

The safety profile of I+V is consistent with data about safety of use of ibrutinib and venetoclax in CLL.

• Together, results of CAPTIVATE and GLOW demonstrated an acceptable safety profile in patients with previously untreated CLL.(66, 67)

• With a 3-cycle lead-in, ibrutinib allowed for an initial reduction in tumour burden, decreasing the number of patients at higher risk of tumour lysis syndrome (TLS).(66, 67)

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There are currently no data on direct comparisons of I+V with FCR, VenO or acalabrutinib, so ITCs were needed to derive comparative efficacy.

• In a patient-level data (PLD) ITC of I+V and FCR in the FCR-suitable population, I+V demonstrated statistically significant PFS advantage over FCR in patients without del17p with no missing covariate values. After adjustment using average treatment effect in the treated population (ATT) in the same population, a trend for better PFS with I+V over FCR was observed.

• Results of an anchored matching-adjusted indirect comparison (MAIC) show that the HRs for PFS and OS were in favour of I+V vs. VenO, before and after adjusting for baseline characteristics. HRs for PFS and OS from another anchored MAIC were in favour of acalabrutinib before adjusting, but not statistically significant. After adjusting for baseline characteristics, PFS and OS outcomes were similar between I+V and acalabrutinib.

I+V is an effective regimen which prolongs PFS, offers deep and durable responses and addresses the unmet need in CLL by being the first all-oral, once daily, chemotherapy-free, FD regimen that patients can take at home, without the need for infusion-based hospital treatments.

B.2.1 Identification and selection of relevant studies

An SLR was conducted to identify relevant clinical evidence on efficacy and safety of treatments for untreated CLL, published between 2011 and 2022.

A broad SLR was conducted, capturing 92 publications. Seventeen randomised controlled trials (RCTs) reported across the 92 publications were relevant to decisionmaking in the UK (i.e., they reported evidence for either I+V or a relevant comparator in the first-line treatment setting, as defined in the PICOS table presented in Appendix D.1.2). Five of the trials were available only in conference proceedings and the remaining 12 were available in full-text publications. Most of the included RCTs were phase III, multicentre trials and were open-label in design. PFS was the most commonly assessed primary outcome, being evaluated in 10 RCTs, followed by CR. Very few studies reported complete information on the safety outcomes.

Five trials were identified which carried out analysis for patients with del17p/TP53 mutation. These RCTs reported either survival and/or response estimates for the highrisk population. All five RCTs were available in full-text publications and were phase III, multicentre trials. O-Clb was the most evaluated comparator, having been investigated in three of the five trials. PFS was the primary outcome assessed in all of the RCTs.

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None of the identified publications reported on the safety profile for the treatments in the high-risk subgroup.

Only the studies including I+V or comparators of interest in the first-line setting underwent data extraction. Full details of the SLR search strategy, methodology and results are presented in Appendix D.1.1 through D.1.7.

B.2.2 List of relevant clinical effectiveness evidence

The SLR identified two clinical trials which provided comprehensive efficacy and safety data for I+V in first-line CLL, summarised in Table 8:

• CAPTIVATE (NCT02910583), a non-comparative phase II trial of I+V in the FCR-suitable population

• GLOW (NCT03462719), a randomised phase III trial of I+V vs. O-Clb in the FCR-unsuitable population

Table 8 Clinical effectiveness evidence

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AE = adverse event; CIRS = Cumulative Illness Rating Scale; CLL = chronic lymphocytic leukaemia; CNS = central nervous system; CR = complete response; CrCl = creatinine clearance; CRi = complete response with incomplete bone marrow recovery; CT = computerised tomography; del17p = 17p deletion; DOR = duration of response; ECOG = Eastern Cooperative Oncology Group; FACIT-Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue; FD = fixed duration; FISH = fluorescent in situ hybridisation; O-Clb = obinutuzumab + chlorambucil; iwCLL = International Workshop on Chronic Lymphocytic Leukaemia; MRD = minimal residual disease; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PS = performance status; SLL = small lymphocytic lymphoma; TLS = tumour lysis syndrome; TP53 = tumour protein 53 a Only the FD cohort is used in the economic model.

b Outcomes that are incorporated into the model are bolded. Note that OS is not directly used in the model, but is used for validation.

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

The methodology of the phase II CAPTIVATE study (FD cohort) and the phase III GLOW study is summarised in Table 9.

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Table 9 Summary of trial methodology

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AE = adverse event; CIRS = Cumulative Illness Rating Scale; CLL = chronic lymphocytic leukaemia; CNS = central nervous system; CR = complete response; CrCl = creatinine clearance; CRi = complete response with incomplete bone marrow recovery; CT = computerised tomography; del11q = 11q deletion; del17p = 17p deletion; ECOG = Eastern Cooperative Oncology Group; FD = fixed duration; HRQoL = health-related quality of life; I+V = ibrutinib + venetoclax; IGHV = immunoglobulin heavy chain variable region; IRC = Independent Review Committee; IV = intravenous; iwCLL = International Workshop on Chronic Lymphocytic Leukaemia; LDH = lactic acid dehydrogenase; MRD = minimal residual disease; O-Clb = obinutuzumab + chlorambucil; OS = overall survival; PFS = progressionfree survival; PS = performance status; SLL = small lymphocytic lymphoma

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B.2.3.1 CAPTIVATE

Trial design

CAPTIVATE was a multi-centre, phase II trial in two cohorts of patients with previously untreated CLL/SLL:(73)

• The FD cohort was an open-label, one-group cohort designed to evaluate the depth of response per CR/CRi following I+V combination therapy for a fixed duration.

• The MRD cohort included three phases (a pre-randomisation phase with I+V, an MRD-guided randomisation phase with therapy reintroduction, and a post disease progression follow-up phase) designed to evaluate the effect on 1-year disease-free survival of discontinuing ibrutinib therapy in patients who achieved MRD negativity.

The focus of this submission is the FD cohort because it is in line with how I+V

will be administered in clinical practice. An overview of the CAPTIVATE trial design is depicted in Figure 3.

Figure 3 Trial design (CAPTIVATE FD cohort)

==> picture [451 x 122] intentionally omitted <==

----- Start of picture text -----
Primary endpoint: Ibrutinib lead-in
• CR/CRi Ibrutinib 420 mg/day for 3
Secondary endpoints: cyclesa
FD I+V cohort
• ORR Followed by I+V
• DOR Add venetoclax ramp-up to 400
• MRD negative rate in bone mg/day for 12 cycles
marrow or peripheral blood Enrolment = 159 patients
• PFS • Patients without del17p = 136
• OS • Patients with del17p = 20
• TLS risk • Patients with unknown del17p/TP53 mutation status = 3
----- End of picture text -----

CR = complete response; CRi = complete response with incomplete bone marrow recovery; del17p = 17p deletion; DOR = duration of response; FD = fixed duration; I+V = ibrutinib + venetoclax; MRD = minimal residual disease; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; TLS = tumour lysis syndrome a One cycle = 28 days Source: Pharmacyclics [Data on File], 2019(73)

Patient eligibility

Eligible patients enrolled into the FD cohort of the CAPTIVATE study were adults aged ≤70 years who had previously untreated CLL/SLL that met iwCLL criteria for active disease requiring treatment.(73) Patients in the FD cohort were enrolled

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sequentially after the MRD cohort and included a total of 159 patients of which 136 patients without del17p.(66) The full eligibility criteria are summarised in Appendix M.1.1.

Settings and locations of data collection

The CAPTIVATE study FD cohort was conducted in XXX centres across XXX countries in Europe XXX XXX, North America (US) and Asia-Pacific XXX XXX.(68)

Trial drugs

Participants in the FD cohort of the CAPTIVATE study received ibrutinib monotherapy (420 mg/day orally) as a lead-in treatment for three cycles. A dose ramp-up for venetoclax was initiated (from 20 mg/day to 400 mg/day orally over 5 weeks) from Cycle 4. Treatment with venetoclax was continued (400 mg/day orally) in combination with ibrutinib (420 mg/day orally) for 12 cycles, until Cycle 15 unless discontinued early for toxicity. Venetoclax and ibrutinib were administered at the same time (or within 60 minutes) each day with a meal and water. After administration of the first dose of ibrutinib and after completion of the 5-week venetoclax dose ramp-up, each drug was typically administered on an outpatient basis.(73)

Participants who had disease progression per iwCLL criteria after completion of the FD I+V regimen could be retreated with continuous ibrutinib monotherapy until disease progression or unacceptable toxicity. Those with durable efficacy after I+V could be retreated with the I+V FD treatment regimen per investigator (INV) clinical discretion and Medical Monitor’s approval.(73) No patients in the FD cohort had been retreated with I+V as of April 2022.(69) Safety results for patients retreated with ibrutinib monotherapy are presented in B.2.10.1 Subsequent therapy.

Dose modification of ibrutinib was recommended following development of liver impairment and was mandated in response to the following(73):

• Haematological events (absolute neutrophil count [ANC] <500 cells/µL for >7 days, platelets <50,000 cells/µL in the presence of clinically significant bleeding or platelets <25,000 cells/µL)

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• Gastrointestinal events (grade 3 nausea, grade 3/4 vomiting or grade 3/4 diarrhoea if persistent despite optimal anti-emetic or anti-diarrhoeal therapy)

• Any other grade 4 or unmanageable grade 3 toxicity.

Dose modification of venetoclax was recommended in response to blood chemistry changes or symptoms suggestive of TLS, grade 3 or 4 non-haematologic toxicities and haematologic toxicities (ANC <1,000 cells/µL with infection or fever, ANC <500 cells/µL, platelets <25,000 cells/µL and haemoglobin levels <8 g/dL).(73)

The risks and benefits of ibrutinib treatment were to be considered in case of grade 3 or 4 atrial fibrillation or any grade persistent atrial fibrillation. Ibrutinib could be temporarily held in case of leukocytosis/leukostasis.(73)

Study outcomes

The primary endpoint for the FD cohort in the CAPTIVATE study was the depth of response per CR/CRi following treatment with the FD I+V combination regimen. The primary analysis was conducted when a clinically meaningful evaluation of durable CR rate (≥12 months) was possible for the study cohort.(73)

Secondary endpoints for the FD cohort in the CAPTIVATE study included the following:(73)

• Overall response rate (ORR) defined as the proportion of participants who achieve a response (CR, CRi, nodular partial response [PR], PR or PR with lymphocytosis per iwCLL 2008 criteria)

• Duration of response (DOR) defined as the interval between achievement of response (CR, CRi, nodular PR or PR per iwCLL response criteria, including PR with lymphocytosis) and disease progression or death from any cause

• MRD negative rate (<1 CLL cell per 10,000 leukocytes) by flow cytometry in BM or PB

• PFS from the date of first study treatment dose until disease progression (per iwCLL 2008 criteria) or death from any cause

• Overall survival (OS) from the date of first study treatment dose to death from any cause

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• Reduction of TLS risk from baseline to after the ibrutinib lead-in dosing, based on tumour burden, with TLS risk/burden categories defined based on lymph node size and absolute lymphocyte count (ALC):

  • Low: all lymph nodes <5 cm and ALC <25 x 10[9] /L

  • Medium: any lymph node 5 to <10 cm or ALC ≥25 x 10[9] /L

  • High: any lymph node ≥10 cm, or ALC ≥25 x 10[9] /L and any lymph node ≥5 cm

• Safety and tolerability

Exploratory endpoints for the FD cohort were as follows:(73)

• Rate of sustained haemoglobin improvement (haemoglobin levels XXX XXX

  • XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX

• Rate of sustained platelet improvement (platelet counts XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX

• Response to ibrutinib reintroduction following disease progression

Baseline patient and disease characteristics

A total of 159 participants were included in the FD cohort, of which 147 completed planned ibrutinib treatment and 149 completed planned venetoclax treatment.(66) Additional information on patient disposition in the FD cohort of the CAPTIVATE study can be found in Appendix D.2.1.

The all treated population (n=159) included 129 patients without del17p or TP53 mutation, 27 patients with del17p or TP53 mutation (including 20 with del17p) and 3 patients with unknown del17p or TP53 mutation status.(66) The population of patients in the FD cohort without del17p (n=136; excluding 20 patients with del17p and 3 patients with unknown del17p or TP53 mutation status) is used for most analyses in this submission.

The populations including and excluding del17p were generally similar in terms of baseline characteristics (Table 10). The median age of the patients without del17p was XXX years (range XXX to XXX years); XXX XXX XXX participants were ≥65 Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

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years old XXX.(68) XXX XXX XXX XXX the participants were male XXX, and

XXXXXX were white XXX.(68)

XXX of patients without del17p in the FD cohort had an initial diagnosis of CLL and all patients had ECOG PS 0 XXX or 1 XXX. Among patients without del17p, the proportions of patients with TP53 mutation, chromosome 11q deletion (del11q) and immunoglobulin heavy chain variable region (IGHV) mutation were XXX XXX XXX XXX, respectively.(68)

Table 10 Characteristics of participants in the FD cohort (CAPTIVATE; all

treated population)

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CLL = chronic lymphocytic leukaemia; del11q = 11q deletion; del17p = 17p deletion; ECOG = Eastern Cooperative Oncology Group; IGHV = immunoglobulin heavy chain variable region; INV = investigator; SLL = small lymphocytic lymphoma; TP53 = tumour protein p53

a Baseline is defined as the last measurement taken on or prior to first dose date of study treatment. b Bulky disease is based on the largest longest diameter of target lymph node at screening per INV assessmentSource: Pharmacyclics [Data on File], 2021(68); Wierda, 2022(69)

B.2.3.2 GLOW

Trial design

GLOW is a randomised, open-label, multi-centre, phase III trial in patients with previously untreated CLL/SLL who met iwCLL treatment criteria and were suitable for treatment with O-Clb but not a more intense fludarabine-containing regimen.(67, 70) The primary objective of the study was to evaluate IRC-assessed PFS for patients randomised 1:1 to combination therapy with I+V vs. O-Clb.(67)

An overview of the GLOW trial design is depicted in Figure 4.

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Figure 4 Trial design (GLOW)

Enrolment = 211 patients

• Patients randomised to Ibr+Ven = 106

• Patients randomised to O-Clb = 105

Stratification:

• IGHV status (mutated vs. unmutated vs. not available)

• • Del11q (yes vs. no)

BM = bone marrow; C = cycle; Clb+Ob = chlorambucil + obinutuzumab; CR = complete response; D = day; del11q = 11q deletion; DOR = duration of response; Ibr+Ven = ibrutinib + venetoclax; IGHV = immunoglobulin heavy chain variable region; MRD = minimal residual disease; O-Clb = obinutuzumab + chlorambucil; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PRO = patient-reported outcome; TLS = tumour lysis syndrome; TTNT = time to next treatment a One cycle = 28 days Source: Janssen Research & Development LLC [Data on File], 2021(70)

Patient eligibility

Eligible patients in GLOW were aged ≥65 years, or 18 to 64 years with CIRS score >6 and/or estimated CrCl <70 mL/min.(67) Included patients had previously untreated CLL/SLL that met iwCLL criteria for active disease requiring treatment.(67) The full eligibility criteria are summarised in Appendix M.2.1.

Settings and locations of data collection

The GLOW study was conducted in 67 centres across 14 countries in Europe and North America, including eight centres in the UK.(67)

Trial drugs

Participants in the GLOW study were randomised 1:1 to receive either FD I+V or O- Clb, with randomisation stratified by IGHV status and del11q.(67)

In the I+V group, participants received ibrutinib monotherapy (420 mg/day orally) as a lead-in treatment for three cycles.(67) A dose ramp-up for venetoclax was initiated (from 20 mg/day to 400 mg/day orally over 5 weeks) from Cycle 4, following a risk

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assessment for TLS.(67, 70) Treatment with venetoclax was continued (400 mg/day orally) in combination with ibrutinib (420 mg/day orally) for 12 cycles, until Cycle 15, in the absence of progressive disease or treatment-limiting toxicity.(67, 70) During cycles with combination dosing, ibrutinib and venetoclax were to be taken at the same time with a glass of water and a meal.(70) After the 5-week ramp-up, the I+V regimen was typically administered on an outpatient basis.(72)

Similar dose modifications of ibrutinib and venetoclax were permitted in GLOW as in CAPTIVATE (described in the Trial Drugs section above).

In the O-Clb group, participants received six cycles of obinutuzumab (1,000 mg IV on Days 1, 8 and 15 of Cycle 1 and 1,000 mg IV on Day 1 of Cycles 2 to 6) in combination with chlorambucil (0.5 mg/kg orally on Days 1 and 15 of Cycles 1 to 6).(70) The first 1,000 mg dose of obinutuzumab could be split over 2 days if patients did not tolerate the first 100 mg given IV on Day 1, in which case the remaining 900 mg was administered IV on Day 2. The O-Clb regimen was generally administered in the healthcare clinic; on days in which chlorambucil was administered alone (i.e., Day 15 of Cycles 2 to 6 only), chlorambucil could either have been given in the clinic or issued to the patient for administration at home.(72)

In the O-Clb group, premedication for infusion-related reactions and TLS was recommended, and dose delays of obinutuzumab were allowed in response to any toxicity meriting a dose delay in the opinion of the INV, including active infection, severe or life-threatening cytopenia or grade ≥2 non-haematologic toxicity. Dose reductions of obinutuzumab were not permitted. Dose modifications of chlorambucil were allowed in response to cytopenia (defined as one of the following: ANC <500 cells/µL for ≥7 days, platelets <50,000 cells/µL in the presence of bleeding, platelets <25,000 cells/µL or haemoglobin levels <8 g/dL) and grade 3 or 4 unmanageable non-haematologic toxicity.(72)

If a medicine was discontinued due to toxicity, the other medicine in the combination regimen could be continued.(72)

In the subsequent therapy phase (after completion of FD treatment regimens with I+V or O-Clb), participants in either treatment group who developed IRC-confirmed progressive disease following first-line treatment and had active disease requiring Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

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treatment may have been eligible to receive ibrutinib monotherapy until progressive disease or unacceptable toxicity per INV assessment.(70, 72) Safety results for patients retreated with ibrutinib monotherapy are presented in B.2.10.2 Subsequent therapy.

Study outcomes

The primary endpoint for the GLOW study was IRC-assessed PFS (defined as the time between randomisation and the first instance of either progressive disease or death due to any cause) for I+V vs. O-Clb.(67) PFS was also evaluated based on progressive disease (PD) assessed by INV.(67)

Secondary objectives in the GLOW study included efficacy, safety and pharmacokinetic outcomes.(67) The following key secondary efficacy endpoints were tested hierarchically in the following order:(67, 70)

• MRD negative rate (<1 CLL cell per 10,000 leukocytes) by next generation sequencing (NGS) in BM (primary MRD analysis for hierarchical testing) and PB (supportive analysis)

• CR (with or without incomplete marrow recovery) prior to initiation of subsequent anti-leukaemic therapy, including ibrutinib monotherapy, per IRC assessment

• ORR (defined as the proportion of participants who achieved a best overall response of either CR, CRi, nodular PR, or PR per iwCLL criteria) on or prior to initiation of subsequent anti-leukaemic therapy, including ibrutinib monotherapy, per IRC assessment

• OS from the date of randomisation to death from any cause

• Rate of sustained platelet improvement (platelet counts increased ≥50% over baseline for ≥56 days without blood transfusion or growth factors)

• Rate of sustained haemoglobin improvement (haemoglobin levels increased ≥2 g/dL from baseline for ≥56 days without blood transfusion or growth factors)

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• Time to first meaningful improvement in Functional Assessment of Chronic Illness Therapy-Fatigue scale (FACIT-Fatigue) score

Other secondary endpoints for the GLOW study were:(67, 70, 72)

• DOR defined as the interval between achievement of response (CR, CRi, nodular PR or PR per iwCLL response criteria, including PR with lymphocytosis) and disease progression or death from any cause

• Time to next anti-leukaemic therapy subsequent to study treatment from randomisation (TTNT)

• Reduction of TLS risk from baseline to after the ibrutinib lead-in dosing, based on tumour burden, with TLS risk/burden categories defined based on lymph node size and ALC:

  • Low: all lymph nodes <5 cm and ALC <25 x 10[9] /L

  • Medium: any lymph node 5 to <10 cm or ALC ≥25 x 10[9] /L

  • High: any lymph node ≥10 cm, or ALC ≥25 x 10[9] /L and any lymph node ≥5 cm; any lymph node size and ALC and CrCl ≤50 mL/min

• Time to first meaningful deterioration in functional status per the EuroQoL-5 Dimension-5 Levels (EQ-5D-5L) questionnaire and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)

Safety parameters included AEs and laboratory tests.(70, 72)

Baseline patient and disease characteristics

A total of 211 participants were randomised and included in the intent-to-treat (ITT) population of GLOW (I+V: n=106; O-Clb: n=105).(67) Additional information on patient disposition in the GLOW study can be found in Appendix D.2.2.

Demographic characteristics were well balanced between the treatment groups and reflected the target population of elderly and unfit patients with previously untreated CLL who were suitable for treatment with O-Clb but not a more intense fludarabinecontaining regimen (Table 11).(70) The median age of the patient population was 71 years (range 47 to 93 years); approximately one third of participants were ≥75 years Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

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old (34.1%). Over half of the participants were male (57.8%) and the majority were white (95.7%).(67, 70, 75)

Baseline disease characteristics were generally balanced between the treatment groups, except for CIRS score >6 and lactic acid dehydrogenase (LDH) elevation, both of which had a >10% difference between the groups (Table 11). The majority of participants had an initial diagnosis of CLL (93.4%) and over half had high-risk disease (58.3%; defined as those with TP53 mutation, del11q or unmutated IGHV).(67, 70)

Note that while patients with known TP53 mutation were excluded from GLOW, the inclusion criteria did not require testing, meaning that patients with unknown TP53 mutation status could still enrol in the trial. After randomisation, central testing identified 9 (4.3%) patients with a TP53 mutation (including 7 in the I+V group and 2 in the O-Clb group).(67) Although TP53 mutation is a strong negative prognostic factor for O-Clb, the impact on results of 2 patients having the mutation should be minimal.

Table 11 Characteristics of participants in the studies across treatment groups (GLOW; ITT)

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CIRS = Cumulative Illness Rating Scale; CLL = chronic lymphocytic leukaemia; del11q = 11q deletion; ECOG = Eastern Cooperative Oncology Group; O-Clb = obinutuzumab + chlorambucil; IGHV = immunoglobulin heavy chain variable region; ITT = intent-to-treat; I+V = ibrutinib + venetoclax; LDH = lactic acid dehydrogenase; PS = performance status; SD = standard deviation; SLL = small lymphocytic lymphoma; TP53 = tumour protein 53; ULN = upper limit of normal a Unless otherwise indicated, the number of participants evaluated was 106 for I+V group and 105 for the O-Clb group. b Cytopenia was defined as one of the following: haemoglobin ≤110 g/dL, platelet counts ≤100 x 109/L or ANC ≤1.5 x 10[9] /L. c High-risk population was defined as the presence of any one of the following: TP53 mutation, del11q or unmutated IGHV. Sources: Janssen Research & Development LLC [Data on File], 2021(70); Kater, 2022(67); Clinicaltrials.gov, 2022(75)

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

B.2.4.1 CAPTIVATE (FD cohort)

In CAPTIVATE, 159 participants were included in the FD cohort, as depicted in the CONSORT diagram in Appendix D.2.1.(66) This included 129 patients without del17p or TP53 mutation, 27 patients with del17p or TP53 mutation (including 20 with del17p) and 3 patients with unknown del17p or TP53 mutation status.(66) All 159 participants who received at least one dose of study treatment were analysed as part of the all treated population, which was used for efficacy and safety analyses.(66) Efficacy analyses of the 136 patients without del17p were also conducted.(66)

Primary analysis of CAPTIVATE was conducted based on a data cut-off date of 12 November 2020 (median 27.9 months follow-up).(66, 68) Analysis of extended follow-up data based on a data cut-off date of 4 August 2021 was also conducted to supplement the primary analysis with approximately 9 months of further follow-up (total 38.7 months follow-up).(68, 69) The extended follow-up data for the 136 patients without del17p informed the ITCs (B.2.9 Indirect and mixed treatment comparisons) and economic analysis (B.3 Cost effectiveness).

Statistical analyses undertaken in the phase II CAPTIVATE study are summarised in Table 12.

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Table 12 Summary of statistical analyses (CAPTIVATE)

BR = bendamustine +rituximab; CI = confidence interval; CLL = chronic lymphocytic leukaemia; CR = complete response; CRi = complete response with incomplete bone marrow recovery; del17p = 17p deletion; FCR = fludarabine + cyclophosphamide + rituximab; FD = fixed duration; I+V = ibrutinib + venetoclax; KM = KaplanMeier; SLL = small lymphocytic lymphoma Source: Pharmacyclics [Data on File], 2019(73); Tam, 2022(66)

B.2.4.2 GLOW

In the GLOW study, 211 participants were randomised 1:1 to the two treatment groups (106 in the I+V group and 105 in the O-Clb group), as depicted in the CONSORT diagram in Appendix D.2.2.(67, 70) All 211 randomised participants were Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

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included in both the ITT population (used for all primary and secondary efficacy endpoints) and the safety population (defined as all randomised participants who received at least one dose of study drug).(67)

Primary analysis of GLOW was conducted based on a data cut-off date of 26 February 2021 (median 27.7 months follow-up). Analysis of extended follow-up data based on a data cut-off date of XXX XXX XXX was also conducted to supplement the primary analysis with approximately 6 months of further follow-up (total median 34.1 months follow-up).(67, 70) The extended follow-up data informed the ITCs

(B.2.9 Indirect and mixed treatment comparisons) and economic analysis (B.3 Cost effectiveness).

Statistical analyses undertaken in the phase III GLOW study are summarised in Table 13.

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Table 13 Summary of statistical analyses (GLOW)

CLL = chronic lymphocytic leukaemia; CR = complete response; FACIT-Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue; HR = hazard ratio; I+V = ibrutinib + venetoclax; IRC = Independent Review Committee; KM = Kaplan-Meier; MRD = minimal residual disease; NGS = next generation sequencing; O-Clb = obinutuzumab + chlorambucil; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; SLL = small lymphocytic lymphoma

Sources: Janssen Research & Development LLC [Data on File], 2021(70); Janssen Research & Development LLC [Data on File], 2019(72)

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B.2.5 Critical appraisal of the relevant clinical effectiveness evidence

The quality assessment of CAPTIVATE (FD cohort) and GLOW, which are highquality studies and are pertinent to the decision problem, is provided in Table 14 below. A detailed quality assessment of the CAPTIVATE and GLOW trials is provided in Appendix D.2.3.

Table 14 Quality assessment results

Adapted from Systematic reviews: CRD’s guidance for undertaking reviews in health care (University of York Centre for Reviews and Dissemination)

B.2.6 Clinical effectiveness results of the relevant studies

B.2.6.1 CAPTIVATE (FD cohort)

Outcomes for the extended follow-up analysis (median 38.7 months follow-up) of the primary and secondary efficacy endpoints tested in the CAPTIVATE study FD cohort are summarised in Table 15. Appendix M.1.2 includes a similar summary of clinical effectiveness based on the primary analysis (median 27.9 months follow-up).

Primary and certain secondary endpoint (PFS, OS, reduction of TLS risk) results from both analyses of CAPTIVATE (all treated and non-del17p populations) are discussed in more detail in subsequent sections. Discussion of the other secondary endpoints and exploratory endpoints results is presented in Appendix M.1.4 and M.1.5, respectively.

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Table 15 Summary of clinical effectiveness at a median follow-up of 38.7 months (CAPTIVATE FD cohort; extended followup analysis)

BM = bone marrow; CI = confidence interval; CR = complete response; CRi = complete response with incomplete bone marrow recovery; DOR = duration of response; I+V = ibrutinib + venetoclax; INV = investigator; IRC = Independent Review Committee; MRD = minimal residual disease; NE = not estimable; ORR = overall response rate; OS = overall survival; PB = peripheral blood; PFS = progression-free survival; TLS = tumour lysis syndrome XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX

b After three cycles of ibrutinib monotherapy

c Results are presented based on the primary analysis; no analysis on reduction of TLS risk was conducted during extended follow-up Source: Pharmacyclics [Data on File], 2021(68)

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All treated patients and patients without del17p

Primary endpoint: depth of response per CR/CRi

As of the data cut-off for the primary analysis with a median follow-up of 27.9 months, the INV-assessed CR/CRi rate was 55.3% (95% CI: 47.6, 63.1) for all patients in the FD cohort and 55.9% (95% CI: 47.5, 64.2) for patients without del17p.(66) The CR/CRi rate for patients without del 17p was significantly higher than the study-assumed minimum rate of 37% (p<0.0001) as well as the 40% rate achieved in this population with FCR in the CLL10 study.(66, 76) Similar CR/CRi rates were observed for all patients and those without del17p with extended followup (median 38.7 months) (57.2% [95% CI: 49.5, 64.9] and 58.1% [95% CI: 49.8, 66.4], respectively).(68, 69) The majority (>86%) of CR/CRis were durable (defined as duration of CR/CRi for 12 months) based on INV assessment at the primary analysis and extended follow-up.(68)

XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX IRC-assessed CR/CRi was 59.7% (95% CI: 52.1, 67.4) for all patients in the FD cohort and 61.0% (95% CI: 52.8, 69.2) for patients without del17p at the primary analysis.(66) XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX

Results from the primary and extended follow-up analyses of CR/CRi and durable CR/CRi per INV and IRC assessments are presented in Appendix M.1.3. Subgroup analyses of CR/CRi rate are presented in B.2.7 Subgroup analysis.

Secondary endpoint: PFS

As of the data cut-off for the primary analysis with a median follow-up of 27.9 months, median INV-assessed PFS was not reached for all patients in the FD cohort(74) or for patients without del17p (Figure 5).(66) In the all treated population,

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24-month PFS rates were high (97%-100%) regardless of clinical response (CR/CRi or PR/nPR) and MRD status in BM (undetectable or detectable) at 3 months after end of treatment.(66)

Figure 5 KM plot of INV-assessed PFS (CAPTIVATE; all treated population primary analysis)

==> picture [452 x 349] intentionally omitted <==

CI = confidence interval; del17p = 17p deletion; INV = investigator; KM = Kaplan-Meier; PFS = progression-free survival

Note: Due to rapid enrolment in the study, the number of patients at risk drops substantially. The KM curve has therefore been truncated at 28 months due to instability of the curves. Source: Tam, 2022(66)

At extended follow-up (median 38.7 months), median INV-assessed PFS was still

not reached for all patients in the FD cohort (Figure 6) XX XXX XX XXX XX XXX

(Figure 7).(68) The Kaplan-Meier (KM) point estimates for INV-assessed PFS at 36

months were 88.1% (95% CI: 81.7, 92.3) for all patients, XX XXX XX XXX XX XXX

XX XXX XX XXX XX XXX and 80% (95% CI: 58%, 91%) for high-risk patients.(68,

69)

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Figure 6 KM plot of INV-assessed PFS (CAPTIVATE; all treated population extended follow-up)

==> picture [426 x 485] intentionally omitted <==

CI = confidence interval; del17p = 17p deletion; IGHV = immunoglobulin heavy chain variable region; INV = investigator; KM = Kaplan-Meier; PFS = progression-free survival; TP53 = tumour protein p53 Note: Due to rapid enrolment in the study, the number of patients at risk drops substantially between 36 and 39 months. The KM curves have therefore been truncated at 38 months due to instability of the curves. Source: Wierda, 2022(69)

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Figure 7 KM plot of INV-assessed PFS (CAPTIVATE; all treated and no-del17p populations extended follow-up)

==> picture [448 x 265] intentionally omitted <==

del17p = 17p deletion; FD = fixed duration; INV = investigator; KM = Kaplan-Meier; PFS = progression-free survival

Source: CAPTIVATE IPD

The median IRC-assessed PFS was also not reached in either population at the

primary analysis XX XXX XX XXX XX XXX XX The XXX XX XXX XX XXX XX XXX XX XXX XXwere XXX XX XXX XX XXX XX Xfor all patients and X XXX XX XXX Xfor patients without del17p X XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XX and were thereforeX XX XXX XX

X The KM plots of IRC-assessed PFS as of the primary analysis and at extended follow-up are shown in Appendix M.1.4.4.

Secondary endpoint: OS

As of the data cut-off for the primary analysis with a median follow-up of 27.9 months, median OS was not reached for all patients in the FD cohort(74) or for

patients without del17p (Figure 8).(66, 68) A total of XX XXX XXwere reported XXX

XX due to XXX XX XXXand XX Xdue to XX XX XXX XX XXX all of which occurred in XX XXX XX XXX XX XXX XX XXX.(68)

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Figure 8 KM plot of OS (CAPTIVATE; all treated population primary analysis)

==> picture [441 x 341] intentionally omitted <==

CI = confidence interval; del17p = 17p deletion; KM = Kaplan-Meier; OS = overall survival Note: Due to rapid enrolment in the study, the number of patients at risk drops substantially. The KM curve has therefore been truncated at 28 months due to instability of the curves. Source: Tam, 2022(66)

At extended follow-up (median 38.7 months), median OS was still not reached for all patients in the FD cohort (Figure 9) XX XXX XX XXX XX XXX XX XXX (Figure 10), and no additional deaths occurred.(68) The KM point estimates at 36 months were 98.1% (95% CI: 94.2, 99.4) for all patients, XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX and 96% (95% CI: 76%, 99%) for high-risk patients.(68, 69)

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Figure 9 KM plot of OS (CAPTIVATE; all treated population extended follow-up)

==> picture [385 x 453] intentionally omitted <==

CI = confidence interval; del17p = 17p deletion; FD = fixed duration; IGHV = immunoglobulin heavy chain variable region; KM = Kaplan-Meier; OS = overall survival; TP53 = tumour protein p53 Note: Due to rapid enrolment in the study, the number of patients at risk drops substantially between 36 and 39 months. The KM curves have therefore been truncated at 38 months due to instability of the curves. Source: Wierda, 2022(69)

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Figure 10 KM plot of OS (CAPTIVATE; all treated and no-del17p populations extended follow-up)

==> picture [448 x 265] intentionally omitted <==

CI = confidence interval; del17p = 17p deletion; FD = fixed duration; KM = Kaplan-Meier; OS = overall survival Source: CAPTIVATE IPD

Secondary endpoint: reduction of TLS risk

The risk of TLS was reduced in patients who received lead-in treatment with ibrutinib monotherapy, based on high tumour burden.(66) Tumour burden was reduced in patients with high risk of TLS at baseline (n=34; 21.4%), with 94.1% of these patients being reclassified as having medium or low risk of TLS after three cycles of ibrutinib monotherapy. Furthermore, fewer patients had an indication for hospitalisation after three cycles of ibrutinib monotherapy (17.6%) than at baseline (39.6%).(66) XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX

High-risk patients

Efficacy results from CAPTIVATE for the subgroup of patients with del17p and/or TP53 (n=27) are comparable to patients without del17p mutations, indicating I+V is likely to be effective in this patient population with a poor prognosis.

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Primary endpoint: Depth of response per CR/CRi

The INV-assessed CR/CRi rate at primary analysis was 55.6% (95% CI: 36.8, 74.3) for high-risk patients, similar to patients without del17p.(66) A similar CR/CRi rate was observed for high-risk patients with extended follow-up (median 38.7 months) (55.6% XX XXX XX XXX).(68, 69)

Secondary endpoint: PFS

The KM point estimate for INV-assessed PFS at 36 months was 80% (95% CI: 58%, 91%) for high-risk patients, similar to patients without del17p.(69)

Secondary endpoint: OS

The KM point estimate at 36 months was 96% (95% CI: 76%, 99%) for high-risk patients, similar to patients without del17p.(69)

B.2.6.2 GLOW (ITT)

Outcomes for the extended follow-up analysis (median 34.1 months follow-up) of the primary and secondary efficacy endpoints tested in the GLOW study are summarised in Table 16. Appendix M.2.2 includes a similar summary of clinical effectiveness based on the primary analysis (median 27.7 months follow-up).

Primary and key secondary endpoint (OS) results from both the primary and extended follow-up analyses of GLOW ITT are discussed in more detail in subsequent sections. Discussion of the other key secondary endpoints and additional secondary endpoints results is presented in Appendix M.2.4 and M.2.5, respectively.

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Table 16 Summary of clinical effectiveness at a median follow-up of 34.1 months (GLOW; ITT extended follow-up analysis)

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BM = bone marrow; CI = confidence interval; CR = complete response; CRi = complete response with incomplete bone marrow recovery; del11q = 11q deletion; DOR = duration of response; EORTC QLQ C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; EQ-5D-5L = EuroQoL-5 Dimension-5 Levels; FACIT-Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue; O-Clb = obinutuzumab + chlorambucil; HR = hazard ratio; I+V = ibrutinib + venetoclax; IGHV = immunoglobulin heavy chain variable region; INV = investigator; IRC = Independent Review Committee; MRD = minimal residual disease; NE = not estimable; NGS = next generation sequencing; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; PRO = patient reported outcome; TLS = tumour lysis syndrome; TTNT = time to next treatment; VAS = visual analogue scale

a p-value is from a log-rank test stratified by IGHV mutational status and presence of del11q

b Results are presented based on the primary analysis; no additional assessment of MRD status by NGS was performed after the primary analysis c p-value is from a Cochran-Mantel-Haenszel chi-square test stratified by IGHV mutational status and presence of del11q d Results are presented based on the primary analysis; no additional assessment of PRO measures was performed after the primary analysis e After three cycles of ibrutinib monotherapy f Results are presented based on the primary analysis; no analysis on reduction of TLS risk was conducted during extended follow-up Source: Janssen Research & Development LLC [Data on File], 2021(70); Kater, 2022(67); Clinicaltrials.gov, 2022(75); Janssen Research & Development LLC [Data on File], 2021(77)

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Primary endpoint: IRC-assessed PFS

PFS in GLOW was assessed by IRC (primary endpoint) and by the INV at both the primary analysis and the extended follow-up analysis.(67, 70) The primary endpoint was met. IRC- and INV-assessed PFS were consistent at both the primary and extended follow-up analyses.(70) Note that the economic analysis uses INV-assessed PFS based on the extended follow-up.

At the data cut-off for the primary analysis (26 February 2021) with a median follow-up of 27.7 months, patients treated with I+V had a significantly reduced risk of disease progression or death of 78% per IRC assessment compared to the O-Clb group (HR 0.22; 95% CI: 0.13, 0.36; nominal p<0.0001).(67, 70) At 24 months, the IRC-assessed PFS rate was 84.4% for the I+V group and 44.1% for the O-Clb group.(67) The KM plot from the primary analysis of IRC-assessed PFS is shown in Figure 11. The marked drop in the KM plot of PFS for O-Clb at approximately 15 months can be attributed to the protocol-specified mandatory imaging at fixed timepoints after randomisation and a period of 6 months without imaging prior to the evaluations at 15 months. Subgroup analyses of IRC-assessed PFS are presented in B.2.7 Subgroup analysis.

As of the primary analysis, IRC-assessed PFS was consistent with INV-assessed PFS and all conducted sensitivity analyses.(67, 70) The KM plot of INV-assessed PFS as of the primary analysis is shown in Appendix M.2.3.

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Figure 11 KM plot of IRC-assessed PFS (GLOW; ITT primary analysis)

==> picture [468 x 288] intentionally omitted <==

CI = confidence interval; IRC = Independent Review Committee; ITT = intent-to-treat; KM = Kaplan-Meier; PFS = progression-free survival Source: Kater, 2022(67)

Extended follow-up (median 34.1 months) demonstrated that the difference in IRCassessed PFS between the treatment groups was maintained long-term, with a significantly reduced risk of disease progression or death of 79% for the I+V group vs. the O-Clb group (HR 0.21; 95% CI: 0.13, 0.35; nominal p<0.0001; Figure 12).(67) Median IRC-assessed PFS was not reached for the I+V group and XX XXX XX XXX XX XXX XX XXX.(70) At 30 months, the IRC-assessed PFS rate was 80.5% for the I+V group and 35.8% for the O-Clb group.(67)

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Figure 12 KM plot of IRC-assessed PFS (GLOW; ITT extended follow-up analysis)

==> picture [468 x 253] intentionally omitted <==

CI = confidence interval; HR = hazard ratio; IRC = Independent Review Committee; ITT = intent-to-treat; KM = Kaplan-Meier; PFS = progression-free survival Source: Kater, 2022(67)

XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX

XX XXX The KM plot of INV-assessed PFS at extended follow-up (used in the economic analysis) is shown in Appendix M.2.3.

Key secondary endpoint: OS

At the primary analysis with a median follow-up of 27.7 months, there was no statistically significant difference in OS between the treatment groups (HR 1.05; 95% CI: 0.45, 2.42; nominal p=0.9121), with 11 deaths reported for the I+V group and 12 deaths reported for the O-Clb group. In the I+V group, four deaths occurred during ibrutinib lead Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

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in, three during I+V treatment and four during follow-up. In the O-Clb group, two deaths occurred during treatment and the remaining 10 deaths occurred during follow-up.(67) The KM plot from the primary analysis of OS is shown in Figure 13.

Figure 13 KM plot of OS (GLOW; ITT primary analysis)

==> picture [468 x 282] intentionally omitted <==

CI = confidence interval; HR = hazard ratio; ITT = intent-to-treat; KM = Kaplan-Meier; OS = overall survival Source: Kater, 2022(67)

At extended follow-up (median 34.1 months), four additional deaths occurred in the O- Clb group and the HR for OS in the I+V vs. O-Clb groups decreased to 0.76 (95% CI:

0.35, 1.64 XX XXX).(67, 70) Median OS was not reached in either treatment group.(70) XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX (Figure 14).(70) XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX X.(70)X XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX.(70)

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Figure 14 KM plot of OS (GLOW; ITT extended follow-up analysis)

==> picture [468 x 243] intentionally omitted <==

CI = confidence interval; HR = hazard ratio; ITT = intent-to-treat; KM = Kaplan-Meier; OS = overall survival Source: Kater, 2022(67)

B.2.7 Subgroup analysis

B.2.7.1 CAPTIVATE (FD cohort)

As of the data cut-off for the primary analysis with a median follow-up of 27.9 months, the improvement in INV-assessed CR/CRi observed for all patients in the FD cohort was consistent across most pre-specified subgroups; a higher CR rate was observed in patients with unmutated vs. mutated IGHV (62% vs. 47%, respectively) and patients with bulky disease ≥5 cm vs. <5 cm (66% vs. 31%, respectively).(66) XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX

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Figure 15 Forest plot of INV-assessed CR/CRi by pre-specified subgroups

(CAPTIVATE; all treated population primary analysis)

==> picture [468 x 439] intentionally omitted <==

CI = confidence interval; CR = complete response; CRi = complete response with incomplete bone marrow recovery; del11q = 11q deletion; del17p = 17p deletion; ECOG = Eastern Cooperative Oncology Group; FISH = fluorescence in situ hybridisation; IGHV = immunoglobulin heavy chain variable; INV = investigator; TP53 = tumour protein p53 Source: Tam, 2022(66)

XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX (forest plot shown in Appendix E.1).(68) XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX

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XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX

XXX XX XXX

B.2.7.2 GLOW

At the data cut-off for the primary analysis (26 February 2021) with a median follow-up of 27.7 months, the improvement in IRC-assessed PFS with I+V treatment vs. O-Clb treatment was observed across pre-specified subgroups (XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX

Figure 16), XX XXX XX XXX XX XXX (Appendix E.2).(67, 70) XX XXX XX XXX XX XXX

XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX

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Figure 16 Forest plot of IRC-assessed PFS by pre-specified subgroups (GLOW; ITT primary analysis)

==> picture [468 x 465] intentionally omitted <==

CI = confidence interval; CIRS = Cumulative Illness Rating Scale; del11q = 11q deletion; ECOG = Eastern Cooperative Oncology Group; IGHV = immunoglobulin heavy chain variable region; IRC = Independent Review Committee; ITT = intent-to-treat; LDH = lactic acid dehydrogenase; PFS = progression-free survival; PS = performance status Source: Kater, 2022(67)

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B.2.8 Meta-analysis

B.2.8.1 FCR-suitable population

Given the single-arm nature of the non-comparative FD cohort from the phase II clinical trial CAPTIVATE, it could not be considered for inclusion in a Bucher analysis or network meta-analysis (NMA) to generate comparative efficacy estimates vs. FCR, the key comparator. The NMA feasibility assessment in the FCR-suitable population is described in more detail in Appendix D.1.8.1.

B.2.8.2 FCR-unsuitable population

The feasibility of an NMA was assessed in the FCR-unsuitable population; however, the evidence suggested that an NMA would provide biased results. Therefore, it was concluded that pairwise comparisons using MAIC would be more appropriate to generate comparative efficacy estimates vs. VenO and acalabrutinib. The NMA feasibility assessment in the FCR-unsuitable population is described in more detail in Appendix D.1.8.1.

B.2.9 Indirect and mixed treatment comparisons

Relevant comparators for I+V include FCR in the FCR-suitable population, and O-Clb, VenO and acalabrutinib in the FCR-unsuitable population. In the high-risk population, the relevant comparators are VenO, acalabrutinib and ibrutinib.

GLOW provides head-to-head data for I+V vs. O-Clb, and ibrutinib efficacy is assumed equivalent to acalabrutinib in the high-risk population, based on the assumption made and accepted in TA689.

There are currently no data on direct comparisons of I+V with FCR, VenO or acalabrutinib, so ITCs are needed to derive comparative efficacy. The results for the ITC in the FCR-suitable population and the MAICs in the FCR-unsuitable population are described below. Appendix D.1.8.5 presents the strengths and limitations of these analyses.

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B.2.9.1 ITC: I+V vs. FCR

Methods

The SLR identified several randomised trials of adult patients with previously untreated CLL eligible for fludarabine-based therapy and with FCR arms (namely, the CLL8, CLL10 and E1912 studies).

The CLL8 trial, an older FCR trial than the other identified trials, was ruled out because the FCR population differed in several ways from the CAPTIVATE I+V population (described in Appendix D.1.8.2). CLL10 was a newer FCR trial than CLL8 with a population that was more aligned with that of CAPTIVATE than CLL8. The E1912 (NCT02048813) trial studied FCR and ibrutinib + rituximab (I+R) treatment efficacy in adults with previously untreated CLL who were eligible for FCR.(78, 79) This trial was preferred to CLL8 and CLL10, since Janssen had access to individual patient data (IPD) from the E1912 48m median follow-up and was thus able to better align the CAPTIVATE and E1912 trial populations for the ITC analyses. Also, enrolled patients in E1912 and CAPTIVATE FD cohort were comparable:

• Diagnosed with CLL

• Treatment-naïve and required treatment per iwCLL 2008 criteria

• Aged between 18 and 70 years (both inclusive)

• Have an ECOG PS 0-2

A key difference in inclusion/exclusion criteria was that E1912 excluded patients with del17p while these patients were allowed in the CAPTIVATE study FD cohort. Therefore, only patients with no del17p in the CAPTIVATE FD cohort were included in the ITC analysis, and the analysis population was defined as adults with previously untreated CLL who would be eligible for fludarabine-based therapy, with no del17p, and who received at least one dose of study treatment. Based on data from CAPTIVATE and E1912, all treated patients without del17p consisted of 136 patients treated with I+V and 158 patients treated with FCR.

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• Inverse probability for treatment weighting (IPTW) with ATT weighting was used as the primary approach. The average treatment effect in the control population (ATC; i.e., adjusting to the FCR arm of E1912) and average treatment effect in the combined/overall population (ATO) were used as scenario analyses to explore robustness of the results in matching to different target populations.

The efficacy of I+V vs. FCR was analysed based on the following efficacy endpoints: PFS, OS, ORR and CR rate. For PFS, a weighted Cox proportional hazards model was used to derive a HR and its respective 95% CI. KM curves using IPTW were plotted. A weighted log-rank test was used to test the treatment effect between I+V and the comparator group. For binary outcomes (e.g., ORR, CR rate), a weighted logistic regression was used to derive an odds ratio (OR) with its respective 95% CI.

Results

After IPTW adjustment for all treated patients without del17p, applying ATT, ATC and ATO weighting, balance between the patient populations was generally achieved in all three approaches, except for some variables where missing values were key drivers of imbalances. Analyses excluding patients with missing covariate values achieved good model balance and were preferred for economic model analysis (see Appendix D.1.8.2).

Before adjustment, I+V demonstrated statistically significant PFS advantage over FCR for all treated patients without del17p, with XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX, when excluding and including patients with missing covariate data, respectively. After adjustment using ATT for all treated patients without del17p excluding any patients with missing covariate data, the HR increased slightly for I+V vs FCR XX XXX XX XXX XX XXX In an analysis in which I+V was adjusted to the FCR arm of the E1912 trial (ATC approach), the I+V demonstrated statistically significant PFS advantage over FCR XX XXX XX XXX XX XXX XX XXX XX XXX

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(see Appendix D.1.8.2). Sensitivity analyses excluding patients with known TP53 mutation was also carried out and are presented in Appendix D.1.8.2 along with other outcome results.

Table 17 I+V vs. FCR PFS results summary

• ATC is used in the economic modelling, see B.3.3 Clinical parameters and variables ATC = average treatment effect in the control population; ATT = average treatment effect in the treated population; CI = confidence interval; del17p = 17p deletion; HR = hazard ratio

B.2.9.2 Anchored MAIC: I+V vs. VenO

Methods

The SLR identified two randomised phase III studies of I+V or VenO in patients who would not be eligible for fludarabine-based therapies: the GLOW and CLL14 trials.

Given both trials had O-Clb as a comparator arm, anchored forms of ITC (Bucher and anchored MAIC) were considered. Although both studies used O-Clb as comparator treatment, there were notable differences in the inclusion/exclusion criteria as well as in patient baseline characteristics which were considered treatment-effect modifiers (TEMs) (see Appendix D.1.8.3). Given the differences in distribution of TEMs, anchored MAIC analyses were preferred over Bucher analyses since they aim to adjust for imbalances in TEMs and thus provide an unbiased estimate of treatment effect.

The longest follow-up for GLOW with 34.1-month median follow-up was selected for the MAIC to leverage the most mature data available for I+V. The 28.1-month follow-up from CLL14 was selected to closely align with the follow-up from GLOW. PFS was seen to be the most relevant endpoint given the maturity of data.

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As a first step, the MAIC analysis excluded patients from the GLOW population who would not have been eligible for the CLL14 study based on the inclusion criteria differences identified, namely those without either CIRS score >6 or CrCl>70 mL/min. The remaining patients in the GLOW dataset were then weighted such that the mean values for relevant baseline parameters reflected the means, medians or proportions reported in CLL14.

Four characteristics (Age, ECOG PS, CIRS score, TP53 mutation status) were matched in the comparison of I+V vs. VenO. This approach was considered to offer an acceptable trade-off between matching characteristics and retaining effective sample size (Neff), according to insights from an advisory board held with clinical and health economic experts from the UK in March 2022.(4)

There was evidence suggesting that the proportional hazards (PH) assumption was violated in GLOW and CLL14 for PFS. However, based on clinical expert feedback sought in May 2022, the use of a single HR approach (rather than the time-varying HR) was preferred as the base case analysis.(5) Nevertheless, scenario analyses were conducted by applying time-varying HR to investigate the impact on the results.

Results

Baseline characteristics of patients in GLOW before and after matching to CLL14 are presented in Appendix D.1.8.3. The exclusion step removed patients who did not have a CIRS >6 or did not have CrCl >70mL/min, in line with CLL14 inclusion criteria.

The results of the analyses for PFS (based on matching of the four top-ranked characteristics) are presented in Figure 17. Without adjusting for differences in baseline patient characteristics between the GLOW and CLL14 studies, the HR for PFS was XX XXX XX XXX XX XXX. After applying CLL14 exclusion criteria and matching of the four top-ranked characteristics, the HR for PFS was XX XXX XX XXX XX XXX.

Scenario analyses were conducted and are presented in Appendix D.1.8.3.

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Figure 17 PFS INV anchored MAIC results comparing I+V (34.1 month follow-up) and VenO (28.1 month follow-up)

==> picture [646 x 224] intentionally omitted <==

CI = confidence interval; CLL = chronic lymphocytic leukaemia; ECOG = Eastern Cooperative Oncology Group; HR = hazard ratio; TP53 = tumour protein 53

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B.2.9.3 Anchored MAIC: I+V vs. acalabrutinib

Methods

The SLR identified two randomised phase III studies of I+V or acalabrutinib in patients who would not be eligible for fludarabine-based therapies: the GLOW and ELEVATE-TN trials.

The GLOW and ELEVATE-TN studies both used O-Clb as comparator therapy. Therefore, an ITC using a common comparator was considered. Anchored MAIC analyses were preferred for similar reasons to those described above in B.2.9.2 Anchored MAIC: I+V vs. VenO.

The 34.1-month median follow-up from GLOW was used, and the 28.3-month follow-up from ELEVATE-TN was selected to closely align with the follow-up from GLOW. Four characteristics (Age, ECOG PS, CIRS score, TP53 mutation status) were matched in the comparison of I+V vs. acalabrutinib.

There was evidence suggesting that the PH assumption was violated in GLOW and CLL14 for PFS. However, based on clinical expert feedback sought in May 2022, the use of a single HR approach (rather than the time-varying HR) was preferred as the base case analysis.(5) Nevertheless, scenario analyses were conducted by applying time-varying HR to investigate the impact on the results.

Results

Baseline characteristics of patients in the GLOW trial before and after matching to the ELEVATE-TN study are presented in Appendix D.1.8.4. The exclusion step did not remove any patients as inclusion and exclusion criteria were generally aligned between the two studies; the only difference in exclusion criteria between the trials was that patients with del17p were excluded from GLOW, whereas these patients could be included in ELEVATE-TN. This difference could not be addressed owing to the unavailability of data specifically for those patients in the ELEVATE-TN study who did not have del17p (i.e., patients with del17p could not be removed from the dataset).

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The results of the analyses for PFS (based on matching to the four characteristics listed above) are presented in Figure 18. Without adjusting for baseline patient characteristics between the GLOW and ELEVATE-TN studies, the HR for PFS was XX XXX XX XXX XX XXX. After applying the ELEVATE-TN exclusion criteria and matching of four characteristics, the HR for PFS was XX XXX XX XXX XX XXX XX XXX.

Scenario analyses were conducted and are presented in Appendix D.1.8.4.

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Figure 18 PFS INV anchored MAIC results comparing I+V (34.1 month follow-up) and acalabrutinib (28.3 month

follow-up)

==> picture [646 x 207] intentionally omitted <==

CI = confidence interval; CIRS-G = Cumulative Illness Rating Scale-Geriatric; ECOG = Eastern Cooperative Oncology Group; HR = hazard ratio; TP53 = tumour protein 53

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B.2.10 Adverse reactions

B.2.10.1 CAPTIVATE (FD cohort)

Overview

At the data cut-off for the primary analysis of the FD cohort with a median follow-up of 27.9 months, the median treatment duration was 13.8 months(66) and the median dose intensity was XXX for all study drugs. (XX)

An overview of treatment-emergent AEs (TEAEs) reported in the FD cohort of the CAPTIVATE study is presented in Table 18. Overall, most patients (99.4%) experienced a TEAE, with grade ≥3 TEAEs and serious TEAEs occurring in 62.3% and 22.6% of patients, respectively.(74) TEAEs leading to treatment discontinuation were reported in 5.0% of patients (3.1% discontinued ibrutinib only; 0.63% discontinued venetoclax only; 1.3% discontinued I+V).(66) Dose reductions due to TEAEs occurred in 20.8% of patients (5.7% reduced ibrutinib only; 11.3% reduced venetoclax only; 3.8% reduced both).(66)

One fatal AE (sudden death) occurred in the FD cohort (during ibrutinib lead-in).(66) The event was determined to be possibly related to XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX

XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX

Table 18 Summary of TEAEs at a median follow-up of 27.9 months (CAPTIVATE; FD cohort safety population primary analysis)

I+V = ibrutinib + venetoclax; TEAE = treatment-emergent adverse event a Of any study drug Source: ClinicalTrials.gov, 2022(74) Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

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TEAEs by preferred term

An overview of common TEAEs (incidence ≥10% for any grade event or ≥2% for grade ≥3 events) reported in the FD cohort of the CAPTIVATE study is presented in Appendix F.1.1.

The most common TEAEs occurring in ≥20% of patients were diarrhoea (62.3%), nausea (42.8%), neutropenia (41.5%), arthralgia (33.3%), muscle spasms (29.6%), headache (25.2%), fatigue (24.5%), upper respiratory tract infection (23.3%), increased tendency to bruise (22.0%) and vomiting (22.0%).(68, 74)

The most common grade ≥3 TEAEs occurring in ≥5% of patients were neutropenia (32.7%), hypertension (5.7%) and neutrophil count decreased (5.0%).(66) The most common serious TEAEs occurring in ≥2% of patients were cellulitis (2.5%).(66)

Among TEAEs assessed by the INV to be related to treatment, TEAEs related to ibrutinib were reported in 92.5% of patients and TEAEs related to venetoclax were reported in 84.3% of patients.(74) The most common TEAEs related to ibrutinib occurring in ≥20% of patients included XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX

XXX The most common TEAEs related to venetoclax occurring in ≥20% of patients included XX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX

AEs of clinical interest

In the CAPTIVATE study, major haemorrhage, including serious or grade ≥3 haemorrhagic AEs and any grade central nervous system (CNS) haemorrhage, was categorised as an adverse event of special interest (AESI).(73)

Treatment-emergent major haemorrhage events occurred in three (1.9%) patients and included cerebral haemorrhage, haemorrhagic cerebral infarction and retinal haemorrhage, of which none were fatal.(66) Treatment-emergent AESIs and select

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events of potential clinical relevance to ibrutinib treatment are summarised in Appendix F.1.2.

Subsequent therapy

At the extended follow-up analysis, nine patients in the FD cohort had been retreated with single-agent ibrutinib therapy following disease progression, of which seven patients had a best response of PR and the remaining two patients were pending

response evaluation.(66) XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX

B.2.10.2 GLOW

Safety data presented in this section are from the data cut-off for the primary analysis unless otherwise noted.

Overview

At the data cut-off for the primary analysis with a median follow-up of 27.7 months, all participants (N=211) in the GLOW study were off study treatment, of whom 77% had completed the I+V treatment course and 95% had completed the O-Clb treatment course. The median treatment duration (and AE reporting period) was substantially longer (2.7-fold difference) for the patients in the I+V group (13.8 months) vs. those in the O-Clb group (5.1 months).(67, 70) XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX.(70)

An overview of TEAEs reported in the GLOW study is presented in Table 19. The overall incidence of TEAEs and grade ≥3 TEAEs was similar (<10% difference) between the groups during the treatment period (13.8 months for I+V and 5.1 months for O- Clb).(67, 70) The proportion of participants with serious TEAEs during the treatment period was higher in the I+V group vs. the O-Clb group.(67) XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX

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XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX

XX XXX XX XXX XX XXX XX XXX.(70)

XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX

XX XXX XX XXX XX XXX.(70) Treatment discontinuation of all study treatment due to AE occurred in 10.4% of I+V and 1.9% of O-Clb patients.(66, 67)

Nine participants died due to TEAEs, seven in the I+V group (including four during ibrutinib lead-in) and two in the O-Clb group. All four patients in the I+V group who died to due cardiac or sudden death had a CIRS score of ≥10 or an ECOG score of 2 and a medical history of diabetes, cardiovascular disease and/or hypertension. One death in each group (cardiac failure and pneumonia in the I+V group and pneumonia in the O- Clb group) considered by the INV to be related to study treatment.(67)

XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX.(70)

Table 19 Summary of TEAEs at a median follow-up of 27.7 months (GLOW; safety population primary analysis)

I+V = ibrutinib + venetoclax; O-Clb = obinutuzumab + chlorambucil; TEAE = treatment-emergent adverse event a Of any study drug

Source: Janssen Research & Development LLC [Data on File], 2021(70); Kater, 2022(67)

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TEAEs by preferred term

An overview of common TEAEs (incidence ≥10% for any grade event or ≥2% grade ≥3 events) reported in the GLOW study is presented in Appendix F.2.1.

The most common TEAEs occurring in ≥20% of patients in the I+V group were diarrhoea (50.9%), neutropenia (including ‘neutropenia’ and ‘neutrophil count decreased’; 41.5%) and nausea (26.4%) and in the O-Clb group were neutropenia (including ‘neutropenia’ and ‘neutrophil count decreased’; 58.1%), infusion-related reaction (29.5%), thrombocytopenia (26.7%) and nausea (25.7%).(67) TEAEs that were more frequently reported in the I+V group vs. the O-Clb group (≥10% difference) were diarrhoea, rash, urinary tract infection, oedema peripheral, atrial fibrillation and hyperphosphatemia.(67) Conversely, TEAEs that were more frequently reported in the O-Clb group vs. the I+V group were neutropenia, thrombocytopenia, infusion-related reaction and pyrexia.(67, 70)

The most common grade ≥3 TEAEs occurring in ≥5% of participants in the I+V group were neutropenia (34.9%), diarrhoea (10.4%) hypertension (7.5%), atrial fibrillation (6.6%), pneumonia (6.6%), hyponatraemia (5.7%) and thrombocytopenia (5.7%) and in the O-Clb group were neutropenia (49.5%), thrombocytopenia (20.0%), pneumonia (5.7%) and TLS (5.7%).(67, 70) Grade ≥3 TEAEs that were more frequently reported in the I+V group vs. the O-Clb group (≥5% difference) were diarrhoea, hypertension, atrial fibrillation and hyponatraemia.(67) Conversely, grade ≥3 TEAEs that were more frequently reported in the O-Clb group vs. the I+V group vs. were neutropenia, thrombocytopenia and TLS.(67)

The most common serious TEAEs occurring in ≥2% of participants in the I+V group were atrial fibrillation (6.6%), pneumonia (5.7%), anaemia (2.8%), cardiac failure (2.8%) and diarrhoea (2.8%) and in the O-Clb group were pneumonia (5.7%), febrile neutropenia (2.9%) and infusion-related reaction (2.9%).(67) Serious TEAEs that were more frequently reported in the I+V group vs. the O-Clb group (≥2% difference) were atrial fibrillation (6.6% vs. 0%, respectively) and cardiac failure (2.8% vs. 0%).(67)

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Conversely, serious TEAEs that were more frequently reported in the O-Clb group vs. the I+V group were infusion-related reaction and TLS (2.9% vs. 0% for both events).(67)

Overall and within the first 6 months of study treatment, the proportion of patients with TEAEs that were considered by the INV to be XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX

XXX XX XXX XX XXX XX XXX XX XXX Drug-related TEAEs that were more frequently reported in the I+V group vs. the O-Clb group (≥10% difference) were XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX(70)

AEs of clinical interest

XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX.(70)

Treatment-emergent AESIs and select events of potential clinical relevance to ibrutinib treatment are summarised in Appendix F.2.2. XX XXX XX XXX XX XXX XX XXX XX

XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX.(70)

Subsequent therapy

Four patients in the I+V group required subsequent treatment due to CLL progression (n=2) or Richter’s transformation (n=2). In the O-Clb group, 25 patients required subsequent treatment due to CLL progression and two patients required subsequent Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

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treatment for Richter’s transformation, of which 21 patients received single-agent ibrutinib and one patient received acalabrutinib.(67)

B.2.10.3 Safety summary

The safety observations from CAPTIVATE and GLOW demonstrated that the safety profile of FD I+V is consistent with the safety profiles of ibrutinib and venetoclax when administered as single agents. Together, results of CAPTIVATE and GLOW demonstrated an acceptable safety profile in patients with previously untreated CLL.(66, 67)

In the CAPTIVATE study, no new safety signals were identified for either study treatment.(66) TEAEs of any grade were reported in 99.4% of patients and grade ≥3 TEAEs were reported in 62.3% of patients.(74) Notable observations included a higher rate of diarrhoea and neutropenia compared to ibrutinib alone.(66) Most diarrhoea events were grade 1-2 in severity (62.3% any grade; 3.1% grade ≥3).(66) Rates of discontinuation due to AEs were <10% for both ibrutinib and venetoclax.(66)

In the GLOW study, the median treatment duration in the I+V group was 2.7-fold longer than the O-Clb group (13.8 vs. 5.1 months, respectively), which is important when comparing the incidence of TEAEs between groups. TEAEs of any grade and grade ≥3 TEAEs were reported in a similar proportion of patients in the I+V group (99.1% any grade; 75.5% grade ≥3) and the O-Clb group (94.3% any grade; 69.5% grade ≥3). A higher proportion of patients in the I+V group reported serious TEAEs compared to patients in the O-Clb group (46.2% vs. 27.6%, respectively). The incidence of TEAEs leading to discontinuation of any study drug was XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX

XXX XX XXX XX XXX.(70) Treatment discontinuation of all study treatment due to AE occurred in 10.4% of I+V and 1.9% of O-Clb patients.(66, 67)

The safety observations for the extended follow-up were XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX

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XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX

B.2.11 Ongoing studies

The CAPTIVATE and GLOW studies are both ongoing. XXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX

• XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXXXXXXX

• XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXXXXXXX

B.2.12 Interpretation of clinical effectiveness and safety evidence

B.2.12.1 Principal interim findings from the clinical evidence highlighting the clinical benefits and harms of the technology

The efficacy and safety of I+V in first-line CLL have been demonstrated in patients who are suitable for FCR (CAPTIVATE FD cohort) and in patients who are unsuitable for FCR (GLOW).(66, 70)

Efficacy

In the multi-centre, phase II CAPTIVATE study FD cohort, INV-assessed CR/CRi rate (primary endpoint) was 55.3% (95% CI: 47.6, 63.1) for all patients treated with FD I+V and 55.9% (95% CI: 47.5, 64.2) for patients without del17p at the primary analysis (median 27.9 months follow-up).(66) CR/CRi rates increased slightly to 57.2% (95% CI: 49.5, 64.9) and 58.1% (95% CI: 49.8, 66.4), respectively, with approximately 9 months of further follow-up.(68) CR/CRi rate across most pre-specified subgroups was higher than the study-assumed minimum rate of 37% and the rate observed with FCR in CLL10 (40%).(66, 76)

Secondary endpoint analyses from CAPTIVATE FD cohort supported the favourable CR rates, with the majority of CRs being durable for at least 12 months.(66, 68) INVassessed ORR was 96.2% (95% CI: 93.3, 99.2) for all patients and 95.6% (95% CI:

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92.1, 99.0) for patients without del17p at the primary analysis.(66) The overall proportion with MRD negativity in CAPTIVATE FD was ≥60% in the BM and ≥75% in the PB among all patients and patients without del17p at the primary analysis.(66) Response and MRD negative rates were maintained with extended follow-up, thereby attesting to the durability of efficacy in patients treated with FD I+V. Median XX XXX PFS or OS were not reached at the primary analysis or at extended follow-up. The KM point estimates for INV-assessed PFS and OS at 36 months were 88%, and 98%, respectively, among all patients.(69) The KM point estimates for INV-assessed PFS and OS at XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX

In a comparison of I+V and FCR in the FCR-suitable population, I+V demonstrated statistically significant PFS advantage over FCR in patients without del17p with no missing covariate values. After adjustment using ATT in the same population, a trend for better PFS with I+V over FCR was observed.

In the randomised, open-label, multi-centre, phase III GLOW study, primary analysis (median follow-up of 27.7 months) concluded that patients treated with I+V had a significantly reduced risk of disease progression or death of 78% per IRC assessment (HR 0.22; 95% CI: 0.13, 0.36; nominal p<0.0001) compared to patients treated with O- Clb.(67) Results from the primary analysis of PFS were consistent across pre-specified subgroups, including in XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX and in INV-assessed PFS (HR 0.21; 95%CI: 0.12-0.36).(67, 70) PFS benefit with I+V vs. O-Clb was maintained long-term with approximately 6 months of further follow-up XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX (67, 70)

The I+V group also had significantly higher overall MRD negative rate in BM by NGS XX XXX XX XXX XX XXX XX XXX XX XXX and significantly higher IRC-assessed CR/CRi XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX p<0.0001) compared to the O-Clb group at the primary analysis of GLOW. The XX XXX and MRD negative rates with I+V

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remained high and the benefit vs. O-Clb was sustained throughout the first year after treatment completion.(70, 71) Furthermore, PFS rates 1 year after end of treatment of I+V were similar regardless of response and MRD status and better sustained than after treatment of O-Clb.(71) Lymph node responses were similar between I+V and O-Clb in patients with undetectable BM MRD but were better sustained with I+V in patients with detectable BM MRD.(71) Median OS was not reached in either treatment group with median 34.1 months follow-up, XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX Similar improvements in health status and HRQoL were observed in the XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX

Results of an MAIC show that the HRs for PFS and OS were in favour of I+V vs. VenO, before and after adjusting for baseline characteristics. HRs for PFS and OS from another MAIC were in favour of acalabrutinib before adjusting, but not statistically significant. After adjusting for baseline characteristics, PFS and OS outcomes were similar between I+V and acalabrutinib.

Safety

I+V demonstrated an acceptable safety profile in CAPTIVATE and GLOW, consistent with the known safety profiles of ibrutinib and venetoclax in other CLL regimens.(66, 67)

In the FCR-suitable population treated with FD I+V in CAPTIVATE, the rate of any grade TEAEs and grade ≥3 TEAEs was 99.4% and 62.3%, respectively, with rates of discontinuation due to AEs being <10% for both ibrutinib and venetoclax.(66, 74)

In the FCR-unsuitable population (GLOW), any grade TEAEs and grade ≥3 TEAEs were reported in a similar proportion of patients in the I+V group (99.1% any grade; 75.5% grade ≥3) and the O-Clb group (94.3% any grade; 69.5% grade ≥3), despite the exposure time for O-Clb being shorter (2.7-fold difference); the incidence of TEAEs leading to discontinuation of any study drug was XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX and treatment discontinuation of all study Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860] © Janssen-Cilag Limited (2022). All rights reserved Page 98 of 239

treatment due to AE occurred in 10.4% of I+V and 1.9% of O-Clb patients.(67, 70) Grade ≥3 neutropenia and thrombocytopenia, common AEs associated with CIT,(80-82) were observed at higher rates with O-Clb than I+V in GLOW.(67)

No cases of TLS with I+V treatment were reported in the CAPTIVATE or GLOW studies.(66, 67)

B.2.12.2 Strengths and limitations in context to UK clinical practice

Strengths

Internal validity of CAPTIVATE and GLOW

I+V has been extensively studied in two international, multi-centre RCTs investigating its efficacy and safety in previously untreated patients with CLL considered suitable for FCR (CAPTIVATE study) and considered unsuitable for FCR (GLOW study). Both studies were considered to be of high quality.

The results were considered to be at low risk of bias because:

• Investigator-assessed outcomes were further assessed and confirmed by an IRC

  • Assessment of the primary outcome in CAPTIVATE FD cohort, CR/CRi rate,

was consistent with XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX

• The primary outcome in GLOW, IRC-assessed PFS, was consistent with INV-assessed PFS at the primary analysis XX XXX XX XXX.(70)

• All randomised patients in GLOW were included in the efficacy analysis, thus preserving randomisation.(67)

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External validity of CAPTIVATE and GLOW

Results from CAPTIVATE and GLOW can be generalised to the UK population, considering over 90% of patients were Caucasian in both studies, and GLOW included eight UK study sites.(67, 74)

• Patients included in the CAPTIVATE study FD cohort appropriately represented the population of patients with CLL considered suitable for more intense treatment with FCR, with most patients being <65 years of age and more fit with CrCl ≥60 mL/min.(66); 27% of patients with CLL are diagnosed below 65 years in England.(15)

• Patients included in the GLOW trial appropriately represented the population of CLL patients who are unsuitable for fludarabine-based CIT but are likely to tolerate less-intense treatment with O-Clb, based on age (≥65 years) or CIRS score >6 and CrCl <70 mL/min. The median patient age in GLOW was 71.0 years, which is similar to the median age of CLL diagnosis reported in England (72 years).(15, 67)

• Both studies assessed a range of efficacy outcomes considered relevant to patients and clinicians (PFS, CR/CRi, OS, MRD, ORR and DOR); GLOW also included EQ-5D-5L and EORTC QLQ-C30 assessments to evaluate HRQoL.(68, 70)

Limitations

While substantial and clinically meaningful benefits have been demonstrated with I+V in patients with previously untreated CLL in the CAPTIVATE and GLOW studies, certain potential limitations should be considered.

Immature data

In CAPTIVATE, median PFS and OS were not reached at primary analysis or at extended follow-up.(66, 69)

In GLOW, while the IRC-assessed PFS rate at 24 months was significantly higher in the I+V group than in the O-Clb group (84.4% vs. 44.1%; p<0.0001), median PFS was not Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

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reached in the I+V group.(67) Moreover, the IRC-assessed ORR was not significantly different between treatment groups (XX XXX XX XXX XX XXX XX XXX XX XXX),

though significant differences were observed in IRC-assessed CR rate and MRD negative rate at the primary analysis (both p<0.0001). Median OS was also not reached in the I+V or O-Clb group, and OS was comparable between treatment groups at the primary analysis (HR 1.05; 95% CI: 0.45, 2.42; nominal p=0.9121).(67, 70)

Further follow-up is required to capture the full PFS benefit of I+V in patients with previously untreated CLL and to reduce uncertainty about whether PFS benefit translates to OS benefit. PFS benefits with first-line treatment of CLL have translated to OS benefits with longer follow-up (>5 years) for several treatments (including O-Clb, I+R and ibrutinib monotherapy).(6, 83, 84)

Indirect comparison

While the INV-assessed CR/CRi rate in patients treated with I+V in CAPTIVATE was higher than the CR/CRi rate of patients treated with FCR in CLL10 (>55% vs. 40%), no clinical trials have directly compared the efficacy of first-line I+V with FCR.(66, 76)

There are no results currently available from any ongoing clinical trials directly comparing the efficacy of first-line I+V with VenO and acalabrutinib in the previously untreated FCR-unsuitable CLL population.

In the FCR-suitable population, a patient-level data ITC was conducted to inform efficacy of I+V vs. FCR. This approach has high internal validity, given that it uses individual patient data to match patients and make the patient populations more comparable. In the FCR-unsuitable population, anchored MAICs were conducted to inform comparative efficacy of I+V vs. VenO and acalabrutinib. Anchored comparisons are preferred over unanchored comparisons, and this approach was validated by clinical experts.

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Efficacy estimation in high-risk patients

Efficacy results from CAPTIVATE for the subgroup of patients with del17p and/or TP53 mutation indicates that I+V is likely to be effective in this patient population with a poor prognosis. However, there is a general paucity of evidence in the high-risk population considering:

• the low number of patients with these characteristics (del17p/TP53 mutation) in the CAPTIVATE and GLOW trials(66, 67)

• the low number of patients in this population contributing to efficacy data and lack of published OS data for this subgroup for other comparators such as VenO (CLL14) and acalabrutinib (ELEVATE-TN)(85, 86)

Therefore, the clinical efficacy of I+V in high-risk patients was assumed equivalent to FCR-unsuitable patients. This assumption was used and accepted in TA689,(2) where clinical experts explained that it was reasonable to assume a similar treatment effect of acalabrutinib for the populations with untreated CLL whether or not they had high-risk CLL. This assumption was further validated by clinical expert opinion in May 2022,(5) but results should still be interpreted with caution.

B.2.13 Conclusion

I+V is a combination of two targeted agents; the complementary effects of ibrutinib and venetoclax lead to more effective clearance of CLL from the blood, BM and lymph node compartments, as well as direct killing of CLL cells. This synergistic action may result in greater long-term PFS benefits compared with currently available FD treatment regimens; PFS with current follow-up was not dependent on MRD status with I+V.(66, 71)

Patients and physicians in the UK desire effective, targeted regimens that induce CRs and reduce relapses in the broadest population of patients with CLL without continuous administration and with an acceptable safety profile. Patients with previously untreated CLL lack a convenient all-oral, FD, chemotherapy-free treatment regimen that does not induce substantial treatment-related toxicities. In particular, younger patients who are

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suitable for FCR would benefit from treatment options that can be administered at home, thereby reducing disruption to daily life, e.g., in terms of work commitments and childcare.

I+V addresses the unmet need in CLL by being the first all-oral, once daily, chemotherapy-free, FD regimen that patients can take at home, without the need for infusion-based hospital treatments. The unique dual-oral posology may be preferred by some patients and has positive resource implications for the NHS, which is currently recovering from a global pandemic, by helping to alleviate the backlog of patients waiting to be treated. Furthermore, patients and the clinical community will value the opportunity to administer a combination of two effective agents upfront to reduce the resource burden associated with relapse.(17, 46-48)

I+V prolonged PFS with deep and durable response rates in previously untreated patients with CLL in CAPTIVATE and GLOW.(66, 67) The safety profile of I+V demonstrated in CAPTIVATE and GLOW was consistent with the known safety profiles of ibrutinib and venetoclax in other CLL regimens.(66, 67) With a 3-cycle lead-in, ibrutinib allowed for an initial reduction in tumour burden, decreasing the number of patients at higher risk of TLS.(66, 67)

In addition to the clinical benefits, I+V helps patients avoid a life of medicalisation by reducing hospital appointments and offering patients a ‘treatment-free holiday’ between finishing the FD treatment and beginning second line treatment upon progression.

Reactions to the concept of an all-oral FD treatment were generally positive in an advisory board conducted with three trustees/patients from the CLL Support Association. Respondents highlighted the following as benefits associated with an alloral treatment: reduced “stress of coming into a clinical setting when your immune system is compromised”, “freedom to go on vacation, peace of mind and better QoL”. Respondents also described several advantages of FD treatment, such as being able to “live normally and plan things” and to regain “some sort of control” during treatment-free periods.(18)

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B.3 Cost effectiveness

Model Overview

• A de novo semi-Markov four health state model was created to identify the cost-effectiveness of I+V in comparison to:

  • FCR in the FCR-suitable population

  • O-Clb, VenO and acalabrutinib in the FCR-unsuitable population

  • VenO, acalabrutinib and ibrutinib in the high-risk population

• State occupancy was modelled in 28-day cycles over a lifetime horizon (up to 40-year and 30year time horizons for FCR-suitable and FCR-unsuitable/high-risk populations, respectively) using data from key clinical trials with the longest available follow-up to inform first-line PFS, second-line PFS, mortality during PFS and post second-line survival.

• In FCR-suitable patients, the E1912 trial with 70 months of follow-up data was used to inform long-term PFS in the FCR arm, and I+V comparative efficacy was based on a propensity score comparison using IPD for CAPTIVATE and E1912 (B.2.9 Indirect and mixed treatment comparisons).

• In FCR-unsuitable patients, data from GLOW was used to model I+V and O-Clb independently. Comparative efficacy data for I+V vs. VenO and acalabrutinib was generated from anchored MAICs, after adjusting for differences in trial population characteristics (GLOW, CLL14 and ELEVATE-TN).

• Due to limited evidence in the high-risk population, inputs for this group were assumed to be equivalent to the FCR-unsuitable population, based on the assumption accepted in TA689 and further clinical validation. Ibrutinib efficacy was assumed to be equivalent to acalabrutinib, based on the assumption from TA689.

• Costs incorporated in the model included drug acquisition and administration for first- and second-line treatment, AE management, disease management and terminal care. Utility was based on the GLOW trial, accounting for age adjustments, and previous NICE appraisals.

Results

• The output of the model demonstrates that I+V is cost-effective in all three subpopulations:

  • In the FCR-suitable population, the incremental cost-effectiveness ratio (ICER) is £8,277. Results are driven by comparatively longer PFS and OS with I+V vs. FCR, and subsequent offsets in costs from delaying subsequent treatments.

  • In the FCR-unsuitable population, I+V dominates VenO and O-Clb (i.e., I+V is less costly and more effective). Compared with acalabrutinib, I+V is less costly and less effective (southwest quadrant) at an ICER of £1,546,602 per quality-adjusted life year (QALY) forgone.

  • In the high-risk population, I+V dominates VenO (i.e., I+V is less costly and more effective). Compared with acalabrutinib and ibrutinib, the ICERs are £1,546,602 and £675,793per QALY forgone, respectively (falling in the southwest quadrant).

  • Note that because I+V is a ‘southwest quadrant’ technology with respect to acalabrutinib and ibrutinib, this means higher ICERs make I+V more cost-effective – ICERs in the range demonstrated above are far in excess of any threshold NICE has historically used.

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• These results were consistent in all the scenario and sensitivity analyses conducted.

• Validation of model projections involved comparisons against long-term data (70 months for E1912, 65 months for RESONATE and 88.5 months for RESONATE-2) and elicitation of clinical expert opinion

Benefits not captured in the QALY calculation

• I+V offers benefits not captured in the QALY by its potential to reduce medicalisation in all three populations compared to current standard of care. In addition to the clinical benefits, I+V helps patients avoid a life of medicalisation by reducing hospital appointments and offering patients a ‘treatment-free holiday’ between finishing the FD treatment and beginning second line treatment upon progression.

• The unique dual-oral posology of I+V has positive resource implications for the NHS, which is currently recovering from a global pandemic, by helping to alleviate the back-log of patients waiting to be treated.

Conclusions

• I+V is an effective use of NHS resources in all subpopulations. The clinical evidence and economic analysis highlight that I+V would address significant unmet need for previously untreated CLL patients.

B.3.1 Published cost-effectiveness studies

An SLR was conducted to identify studies, published between 2011 and 2022, reporting economic outcome data for patients with previously untreated CLL.

The review identified three cost and resource use studies and 38 economic evaluation publications in the FCR-suitable and -unsuitable patients. Of the 38 cost-effectiveness analyses, 19 publications reported analyses which were conducted using a UK healthcare perspective. Fifteen out of 19 publications evaluated a treatment of interest in the UK; nine were UK HTA submissions, whereas the other six were models with a UK perspective published in journal articles.

Five cost-effectiveness analyses were identified which carried out analysis for patients with del17p/TP53 mutation. All five publications were previously published HTA submissions from a UK perspective.

Studies were only extracted if they included I+V or comparators of interest (FCR, O-Clb, VenO, acalabrutinib, ibrutinib monotherapy) in the first-line setting from a UK

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perspective. Full details of the SLR search strategy, methodology and results are presented in Appendices G and I.

B.3.2 Economic analysis

A de novo economic model was developed in Microsoft Excel[©] to estimate the ICER of I+V vs. the corresponding first-line comparators in the FCR-suitable, FCR-unsuitable and high-risk populations. Features of the current economic analysis are summarised and compared to the NICE appraisals in previously untreated CLL for VenO (TA663) and acalabrutinib (TA689) in Table 20.

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Table 20 Key characteristics of the economic analyses

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1L = first line; 2L = second line; AE = adverse event; AFT = accelerated failure time; BNF = British National Formulary; BSH = British Society for Haematology; BTKi = Bruton’s tyrosine kinase inhibitor; CLL = chronic lymphocytic leukaemia; del17p = 17p deletion; ERG = Evidence Review Group; FCR = fludarabine, cyclophosphamide, rituximab; HR = hazard ratio; HTA = health technology assessment; ITC = indirect treatment comparison; ITT = intent to treat; I+V = ibrutinib + venetoclax; MAIC = matching-adjusted indirect comparison; MIMS = Monthly Index of Medical Specialties; NA = not applicable; NHS = National Health Service; NICE = National Institute for Health and Care Excellence; O-Clb = obinutuzumab + chlorambucil; OS = overall survival; PD = progressive disease; PF = progression-free; PFS = progression-free survival; PH = proportional hazards; PLD = patient-level data; PPS = post-progression survival; PRO = patient-reported outcome; PSS = Personal Social Services; QALY = quality-adjusted life year; TA = technology appraisal; TFI = treatment-free interval; TP53 = tumour protein 53; TTNT = time to next treatment; VenO = venetoclax + obinutuzumab; VenR = venetoclax + rituximab Ϯ Excludes patients with del17p mutation

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B.3.2.1 Patient population

The model considered three separate patient populations with previously untreated

CLL, as follows:

• FCR-suitable patients: patients with no del17p mutation, with CIRS ≤6, CrCl ≥70 mL/min and ECOG PS <2

• FCR-unsuitable patients: patients with no del17p mutation, with CIRS >6 and/or CrCl <70 mL/min who are ≥65 years old or 18-64 years old with comorbidity

• High-risk patients: Patients with del17p/TP53 mutation

The three populations considered in the evidence submission are defined in Table 21.

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Table 21 Populations considered in the submission

CIRS = Cumulative Illness Rating Scale; CrCl = creatinine clearance; del17p = 17p deletion; ECOG = European Cooperative Oncology Group; FCR = fludarabine + cyclophosphamide + rituximab; FD = fixed duration; ITT = intent-to-treat; I+V = ibrutinib + venetoclax; NICE = National Institute for Health and Care Excellence; O-Clb = obinutuzumab + chlorambucil; PS = performance status; TP53 = tumour protein 53

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B.3.2.2 Intervention technology and comparators

The intervention technology in the model is combination therapy with I+V. As stated in B.1.1 Decision problem, the relevant comparators in the model depend on the patient population:

• FCR-suitable patients: FCR

• FCR-unsuitable patients: O-Clb, VenO and acalabrutinib monotherapy

• -

• High risk patients: VenO, acalabrutinib monotherapy, and ibrutinib monotherapy

There is a difference in the number of cycles of Clb used in the control arm of the CLL14 trial (12 cycles) and the number of cycles in the control arm of the GLOW or ELEVATE-TN trial (6 cycles). 6 cycles of Clb are used in UK clinical practice.(60) Based on VenO’s appraisal (1), the overall dose is likely to have a larger impact on efficacy than the number of cycles – this was further confirmed during an advisory board of clinical (n=5) and health economic experts (n=3) conducted in March 2022.(4) The overall dose of Clb used across trials is comparable for a typical patient.

The treatments and dosing for the FCR-suitable population, FCR-unsuitable population, and high-risk population are summarised in Table 22, Table 23, and Table 24, respectively.

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Table 22 Treatments and dosing for FCR-suitable population

CSR = clinical study report; FCR = fludarabine + cyclophosphamide + rituximab; FD = fixed duration; mg = milligram; IV = intravenous I+V = Ibrutinib + venetoclax All cycles comprise 28 days

Table 23 Treatments and dosing for FCR-unsuitable population

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C = cycle; CSR = clinical study report; D = day; FD = fixed duration; mg = milligram; IV = intravenous; I+V = ibrutinib + venetoclax; O-Clb = obinutuzumab + chlorambucil; VenO = venetoclax + obinutuzumab. All cycles comprise 28 days

Table 24 Treatments and dosing for high-risk population

C = cycle; CSR = clinical study report; D = day; mg = milligram; IV = intravenous I+V = ibrutinib + venetoclax; VenO = venetoclax + obinutuzumab. All cycles comprise 28 days.

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B.3.2.3 Model structure

The cost-effectiveness model utilised a semi-Markov structure with four mutually exclusive health states: progression free in first-line treatment (PF 1L), progression free in second-line treatment (PF 2L), disease progression (PPS) and death (Figure 19). The model explicitly considered up to two lines of active treatment. Unlike a conventional Markov, the semi-Markov model captures and follows each cohort of patients entering the PF 2L state in each cycle using tunnel states.

Figure 19 Model structure

==> picture [368 x 278] intentionally omitted <==

1L = first-line; 2L = second-line; PFS = progression-free survival; PPS = post-progression survival; tx = treatment

State occupancy was modelled at four-week intervals (28 days) over the course of the modelled time horizon (40 years for FCR-suitable patients and 30 years for FCRunsuitable and high-risk patients). Costs were assigned to each health state, and utilities were applied according to the patients’ disease progression status. As the model progressed cycle by cycle for the duration of the time horizon, cost and utility data were summed per treatment arm, allowing for calculation of costs and comparative

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effectiveness at model completion. Total costs and QALYs per treatment were estimated by combining the proportion of patients in each health state over time.

Health states

The health states included within the model were:

• 1. PF 1L: All patients in the model began on active treatment in the PF 1L state and could either remain in this state, progress, or die during each cycle. Depending on the nature of first-line treatment (FD or treat to progression), patients could be off active treatment for a period of time in PF 1L.
  • i. Once patients progressed from 1L, they either began the next line of active therapy (PF 2L state) or received best-supportive care (BSC; PPS state).
• 2. PF 2L: Patients in the PF 2L state remained in this state until disease progression or death. Similar to PF 1L, patients could remain on active treatment for the time in PF 2L if they received a treat to progression regimen, such as a Bruton’s tyrosine kinase inhibitor (BTKi), or up to a fixed period of time (if they received a FD regimen such as venetoclax + rituximab [VenR]).
  • i. Following progression after first-line treatment, the base case assumes a delay of 14 cycles (based on TA689 ERG preferred scenario(9)) before initiating second-line treatment, to reflect what often happens in clinical practice.
• 3. PPS: Captured patients who have progressed during second-line treatment or those who progressed during first-line treatment that do not receive an active second-line treatment; patients in the PPS state received BSC but no active treatment. Patients in the PPS state remained on BSC until death.
• 4. Death: Captured patients who died in any other health state. The death state is an absorbing state, meaning patients transitioning to this health state are assumed to occupy it indefinitely.

Transitions

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• 1. Transition from PF 1L to either PF 2L or PPS: Modelled using PFS curves and assumptions around pre-progression mortality.

  • i. Although the individual PLD for the time to progression endpoint was available for within-trial comparators which could be used to model the transition from PF 1L to PF 2L or PPS, PFS was more broadly available to compare with external comparators.

  • ii. Since PFS is a composite endpoint which includes both progression and death events, the pre-progression mortality is subtracted from the PFS hazard rate to derive the transition probabilities for those who progress on their first-line treatment and remain alive to receive a subsequent treatment or post 2L progression time.

  • iii. The model has the functionality to specify the proportion of patients who are eligible to receive a second-line treatment upon progression. A subset of eligible patients transitions from PF 1L to PF 2L, while the remaining patients transition from PF 1L to the PPS state.

• 2. Transition from PF 1L to death: Informed by mortality in PFS (pre-progression mortality).
  • i. The trial-derived mortality estimates in the model are constrained by general population mortality (GPM) to ensure that the survival never exceeds that of the general population.
• 3. Transition from PF 2L to PPS: Derived from external PFS data representative of R/R CLL patients who are progression free.
  • i. As in PF 1L, the composite PFS endpoint is broken down into progression and death events by subtracting the mortality in PF 2L from the PFS hazard rate. Patients who experience progression events in PF 2L transition to PPS where they receive BSC.
• 4. Transition PF 2L to death: Derived from external data representative of R/R CLL patients who are progression free.

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• i. Using annual mortality data from the external source, a constant probability of death per cycle was computed and applied throughout the model horizon. Similar to PF 1L, the transition probabilities are capped by GPM.

• 5. PPS to death: The transition probabilities for PPS to death were handled similarly to that of PF 2L to death.

The clinical parameters and variables used to inform the analyses are described in detail in the next section.

B.3.3 Clinical parameters and variables

B.3.3.1 Input sources for clinical efficacy

As a result of using a semi-Markov model, individual survival analyses were required for each possible transition. ITCs were required to inform transitions between health states for external comparators. The data sources summarised in Table 25 informed the clinical parameters for the three populations.

The following sections describe the transition probabilities and additional details for the individual populations of interest: B.3.3.2 FCR-suitable , B.3.3.3 FCR-unsuitable population and B.3.3.4 High-risk population.

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Table 25 Summary of data sources informing the clinical parameters

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1L = first line; 2L = second line; BR = bendamustine + rituximab; BTK = Bruton’s tyrosine kinase; CIRS = Cumulative Illness Rating Scale; CLL = chronic lymphocytic leukaemia; CrCl = creatinine clearance; del17p =17p deletion; FC = fludarabine, cyclophosphamide; FCR = fludarabine, cyclophosphamide, rituximab; FD = fixed duration; HR = hazard ratio; I+R = ibrutinib + rituximab; I+V = ibrutinib + venetoclax; IPD = individual patient data; MAIC = matching-adjusted indirect comparison; NICE = National Institute for Health and Care Excellence; O-Clb = obinutuzumab + chlorambucil; OS = overall survival; PFS = progression-free survival; RCT = randomised controlled trial; R/R = relapsed/refractory

ϯ CLL8 study started in 2003 and enrolment ended in 2006; CLL10 trial primary completion in 2011; E1912 stated in February 2014; Ϯ GLOW I+V PFS’ shape parameter was informed by the shape parameter of CLL14’s VenO extrapolations (52.4m) in a Bayesian framework.

~ CAPTIVATE is an international, multi-centre, phase II, 2-cohort clinical trial, including the FD cohort (the focus of this submission for CAPTIVATE) and the MRD cohort where patients are assessed during a pre-randomization phase (ibrutinib lead-in followed by combination I+V treatment), an MRD-guided randomisation phase, and a post-PD follow-up phase

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B.3.3.1 Approaches to extrapolation

The clinical trials used to inform clinical outcomes only provided survival data up to a limited follow-up time. To apply a lifetime perspective in the cost-effectiveness analysis, extrapolations of clinical outcomes beyond the trial follow-up period were necessary. Extrapolations of PFS were done in line with methods in Decision Support Unit (DSU) Technical Support Document (TSD) 14 and TSD 21,(95, 96) using parametric survival analyses, spline analyses and Bayesian parametric survival analyses. Goodness of fit was assessed by Akaike information criterion (AIC) and Bayesian information criterion (BIC) statistics and comparing observed and predicted data. Due to immaturity of the available PFS data, selection of the approach and distribution for extrapolation was mainly driven by clinical plausibility of long-term predictions.

Appendix O.1 provides details of the various methodologies explored to extrapolate clinical efficacy data beyond the trial follow-up period. The choice of the reference curves and the methodology of indirect comparisons are described in B.2.9

Indirect and mixed treatment comparisons.

B.3.3.2 FCR-suitable population

There are five relevant clinical transitions in the FCR-suitable population (summarised in Table 26):

• the transition from PF 1L to PF 2L or PPS

• the transition from PF 2L to PPS

• the transitions from the three alive states (PF 1L, PF 2L, PPS) to the death state

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Table 26 Summary of transition probabilities between health states for the FCRsuitable population

1L = first line; 2L = second line; FCR = fludarabine, cyclophosphamide, rituximab; FD = fixed duration; I+V = ibrutinib + venetoclax; PF = progression free; PFS = progression-free survival; PPS = post-progression survival

PF 1L to PF 2L or PPS

Base case: FCR PFS - E1912 trial, Weibull distribution; I+V – PFS HR applied to E1912

curve (Table 26)

PFS reference curve

As outlined in Table 25, several sources of data were explored for informing the model PFS reference curve and other clinical inputs:

• CAPTIVATE trial FD cohort

• FCR arm from E1912

• FCR arms from CLL8 and CLL10 trials

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The use of INV-assessed PFS from the CAPTIVATE trial FD cohort (no del17p subgroup) was not used to inform I+V PFS long-term extrapolation due to immature data.

• In the extended follow up of 38.7m, XX XXX XX XXX XX XXX XX XXX XX XXX XX

  • XXX XX XXX XX XXX (Figure 7). At XX XXX months, the I+V PFS rate in the FD cohort (no del17p subgroup) was XX XXX

• From visual inspection of the observed data (Figure 7), it is clear that the PFS data from CAPTIVATE for the FD cohort excluding del17p patients is immature. XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX

XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX

XX XXX This pattern is different from the pattern observed in the GLOW trial

(B.3.3.3 FCR-unsuitable population), in which PFS events occurred early and then the PFS plateaued.

CAPTIVATE FD was also a non-comparative (single-arm) cohort, thus, external data were required to provide the comparative efficacy against FCR, which was the most relevant comparator. External data sources that were available for FCR and details about these are summarised in Table 25.

Given the highly immature PFS data from CAPTIVATE, alternative sources of data were assessed to inform the PFS reference curve in the model. Instead, the E1912 trial was chosen to inform FCR PFS, due to IPD being available (facilitates ITC vs. I+V) and provides long-term follow up for extrapolation. The E1912 trial provided the INVassessed PFS data for the previously untreated FCR-suitable population.

• This trial was preferred to other sources of FCR data, since Janssen had access to IPD from the 36.6m and 48m median follow-up and were able match the populations of CAPTIVATE and E1912 trials for ITC analyses using the IPTW approach (B.2.9 Indirect and mixed treatment comparisons) and also estimate transition for death during PFS.

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• In addition, long-term follow up data (70m median follow up) from E1912 were published. These data were digitised and converted to virtual patient-level data (VPLD) using Guyot method and used for long-term extrapolation of FCR arm in the model.

CLL8 (90) and CLL10(91), which also evaluate the clinical efficacy of FCR in an FCRsuitable population, were not used to inform FCR PFS in the model because IPD are not available and the CLL8 trial differed in several ways from CAPTIVATE (Table 25 and Appendix D.1.8.2). From comparison of the PFS KM data, the CLL10 and E1912 appear very similar and have equivalent follow-up (Figure 20), but as noted, E1912 was preferred due to the availability of IPD for earlier data cuts(89) which enabled the propensity score based analyses between the I+V arm from the CAPTIVATE trial vs. the FCR arm from E1912 (ITC described in B.2.9 Indirect and mixed treatment comparisons).

Figure 20 Naïve comparison of FCR PFS KM from E1912 (70m median), CLL8 (71m), and CLL10 (58.2m)

==> picture [448 x 205] intentionally omitted <==

CLL = chronic lymphocytic leukaemia; FCR = fludarabine + cyclophosphamide + rituximab; KM = Kaplan-Meier; PFS = progression-free survival

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PFS parametric fits

FCR

Survival data from the E1912 trial (Figure 20) was used to inform PFS for FCR (70 months [5.8 years] median follow-up).(83) The PFS data were mature with a 5 year PFS rate of 51% reported for the FCR arm (i.e., nearly a 5 year median). The published data for PFS were digitised and then converted to VPLD using the methodology described in Guyot et al.(97) The accuracy of the VPLD data was checked by comparing observed vs. estimated using VPLD medians and number at risk over time. Parametric survival analyses were then conducted using VPLD.

A summary of the goodness-of-fit statistics for the INV-assessed PFS for FCR in E1912 (70m data cut) is presented in Table 27.

Table 27 Goodness-of-fit statistics (AIC/BIC) for the parametric models fitted to INV PFS KM data for FCR in E1912

AIC = Akaike information criteria; BIC = Bayesian information criteria; PFS = progression-free survival

Figure 21 shows the parametric extrapolations with and without capping by GPM hazard overlaying the PFS INV KM data for FCR from E1912.

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Figure 21 Parametric models overlaying the observed INV PFS KM data for FCR from E1912

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FCR = fludarabine + cyclophosphamide + rituximab; GPM = general population mortality; KM = Kaplan-Meier; PFS = progression-free survival

Table 28 shows the landmark PFS estimates for the standard parametric functions fitted to the observed I+V INV PFS data from E1912 which helped assess clinical plausibility of extrapolations.

Table 28 Landmark PFS estimates for the FCR INV PFS data from E1912 when capped by GPM

==> picture [458 x 93] intentionally omitted <==

----- Start of picture text -----
Distribution 1-year 2-year 5-year 10-year 15-year 20-year 30-year
Exponential XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XX
Weibull XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XX
Log-logistic XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XX
Log-normal XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XX
Gamma XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XX
Gompertz XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XX
----- End of picture text -----

FCR = fludarabine + cyclophosphamide + rituximab; GPM = general population mortality; INV = investigator; PFS = progression-free survival

Based on visual inspection of standard parametric functions fitted to the E1912 PFS curves (Figure 21) and the AIC/BIC values, all distributions provide similar fits to the observed data. Weibull and exponential are the best fitting distributions in terms of the AIC/BIC values. However, long-term extrapolations differ across the fitted distributions.

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The Weibull projection was chosen as the base case extrapolation based on the clinical plausibility of long-term extrapolations (Weibull yield a 5-year PFS estimate of XX XXX and E1912 estimates XX XXX PF patients at ~5 years).(4)

I+V

The I+V PFS was estimated by applying a HR derived from the propensity score matching (described in B.2.9 Indirect and mixed treatment comparisons and Appendix D.1.8.2) to the FCR reference curve. Table 29 shows the PFS HR of I+V vs. FCR using the weighting for the E1912 trial (ATC approach) as well as weighting based on the I+V PFS from CAPTIVATE FD (ATT approach), and an average treatment effect in the combined/overall populations of the two trials (ATO approach). The ATC analysis in which the CAPTIVATE FD cohort is matched to E1912 FCR group for all treated patients was considered as the base case, given that the E1912 FCR PFS is used as the reference curve. The analysis excluding patients with missing covariate values was selected as this analysis showed better balance between covariates for the populations (see Appendix D.1.8.2). The ATO, which reflects an overlapped population, and ATT, which reflects a population matched to the CAPTIVATE FD cohort were explored in scenario analyses. The HRs in these analyses were relatively consistent across analyses (see B.2.9 Indirect and mixed treatment comparisons) and are also consistent with the HR seen for I+R vs. FCR in the E1912 trial, where the PFS HR from over 70 months of follow-up was 0.37 (p<0.001).(83)

Table 29 PFS HR of I+V vs. FCR for the ATC, ATO and ATT analyses based on the adjusted populations in the CAPTIVATE FD cohort (no del17p) and E1912

ATC = average treatment effect in the control population; ATO = average treatment effect in the combined/overall population; ATT = average treatment effect in the treated population; CI = confidence interval; del17p = 17p deletion; HR = hazard ratio

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Figure 22 shows the parametric extrapolations of the I+V PFS from the CAPTIVATE FD cohort (no del17p) based on the derived HR vs. the FCR arm from E1912. It is clear from visual inspection that standard parametric functions cannot capture the steep drop observed in the PFS curve (the second drop in the PFS curve is artificial due to the low number of patients at risk). This shape is a result of short recruitment time in CAPTIVATE FD which leaves very few patients at risk at the last months of follow-up time due to censoring which amplifies the impact of any events observed during this period on KM curve. The shape is expected to change with further follow-up.

Figure 22 I+V PFS capped by GPM derived from the HR vs. FCR reference curve (ATC analyses)

==> picture [448 x 206] intentionally omitted <==

del17p = 17p deletion; FD = fixed duration; GPM = general population mortality; I+V = ibrutinib + venetoclax; KM = Kaplan-Meier; PFS = progression-free survival I+V applied to the Weibull distribution from FCR PFS extrapolation

Table 30 shows the landmark PFS estimates for the I+V PFS arm from CAPTIVATE derived from the FCR reference curve which helped analyse the clinical plausibility of the extrapolations.

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Table 30 Landmark PFS estimates for I+V PFS from CAPTIVATE derived from the

FCR reference curve

FCR = fludarabine + cyclophosphamide + rituximab; I+R = ibrutinib + rituximab

Since an independent fit to the I+V arm was ruled out due to data immaturity, the current base case approach of applying a HR derived from the ATC analysis vs. the exponential FCR curve is reasonable. The estimated PFS at 5 years is XX XXX for I+V vs. XX XXX for the I+R arm of the ECO1912 trial. The resulting estimate for I+V FD is slightly lower when compared with long-term data from the I+R arm of the E1912 trial.

Scenario analyses based on the FCR extrapolations (exponential, gompertz and gamma) and the HR of I+V PFS vs. FCR (ATT, ATO methods in all treated population) were conducted to understand the impact on the results.

PF 1L to Death

Base case: Pre-progression mortality derived from FCR arm of E1912 and applied to FCR and I+V arms (Table 26)

To estimate the deaths from the composite endpoint of PFS, an annualised mortality rate was applied to PFS. Pre-progression deaths observed in the CAPTIVATE FD cohort (no del17p) and E1912 FCR arm (36.6m data cut) from PLD were used to assess mortality rate during PFS for the model. The annualised mortality rate derived from the FCR arm of the E1912 trial CAPTIVATE FD cohort (no del17p) was converted to a transition probability from PF to death and was assumed to be a constant probability per cycle throughout the model horizon.

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2020 for England (qx: death probability between age x and x+1) published by the Office for National Statistic. This ensured that the probability of dying in pre-progression is never lower than the probability of dying due to GPM.

Table 31 shows the annual mortality rate in PFS for the I+V and FCR arms based on total follow-up days and the number of death events occurring during PFS in CAPTIVATE FD cohort (no del17p) and E1912 respectively.

Table 31 Annual mortality rate in PFS derived from CAPTIVATE FD cohort (no del17p) and E1912

FCR = fludarabine + cyclophosphamide + rituximab; I+V = ibrutinib + venetoclax; PFS = progression-free survival

The hazard of pre-progression mortality for FCR derived from E1912 (36.6m data cut) coincides with that of the general population at approximately 5 years as shown in the hazard plots (Appendix O.3) where a change in the curve from a straight line coincides with the stepwise increase in mortality risk. The pre-progression mortality hazard for I+V converged with that of the GPM from the first cycle, meaning the pre-progression mortality of I+V patients with previously untreated CLL is the same as that of the UK general population. This may be unrealistic in the longer term, so the model assumes a pre-progression mortality derived from E1912 (36.6m data cut) capped by GPM for both the I+V and the FCR arms. The pre-progression mortality of the I+V and FCR arms compared with GPM is shown in Appendix O.3.

PF 2L to PPS

Base case: All subsequent treatments - PFS from ibrutinib arm of RESONATE (1-2 prior lines subgroup). Exponential distribution (Table 26)

Reference curve

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and acalabrutinib, the duration of treatment aligns with PFS since these are given as treat to progression. In the case of VenR, the duration of treatment is only up to 24 cycles per the indication.

IPD for patients who received ibrutinib in 2-3 line (i.e., 1-2 prior lines) in the RESONATE trial with a median follow-up of 65 months (final analysis; shown in Figure 23 and Appendix P.2), was analysed to inform the reference curve for second line PFS. This subgroup did not include heavily pre-treated patients that would bias the efficacy outcome and was therefore assumed to represent the prognosis of the FCR-suitable CLL patients upon progression in the current treatment landscape. RESONATE trial was preferred over E1912 to estimate post-progression survival for several reasons:

• 1. data from the ibrutinib arm of RESONATE reflects the disease prognosis of patients receiving a targeted agent (BTKi) in the R/R CLL setting(2),
• 2. long-term data are available, and
• 3. access to IPD was not available to estimate post-progression transitions.

To derive the reference curve for second line treatment PFS during and beyond the observed period of data in the RESONATE trial, parametric survival analyses (see the approach described in Appendix O.1) of the subgroup of patients with 1-2 prior lines of treatment in the ibrutinib arm was conducted.

A summary of the goodness-of-fit statistics for the 2L PFS endpoint, estimated from the ibrutinib arm of the RESONATE trial final (65m) data cut (1-2 prior line subgroup), is presented in Table 32.

Table 32 Statistical goodness-of-fit indicators (AIC/BIC) values for the

independent parametric models fitted to INV PFS data for ibrutinib (1-2 prior line subgroup) from the RESONATE trial final (65m) data cut

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AIC = Akaike information criteria; BIC = Bayesian information criteria; GPM = general population mortality; PFS = progression-free survival

Figure 23 shows the parametric extrapolations overlaying the PFS INV KM data for ibrutinib (1-2 prior line subgroup) from the RESONATE trial final (65m) data cut.

Figure 23 PFS extrapolations of ibrutinib (1-2 prior lines) from RESONATE trial final (65m) data cut

==> picture [448 x 206] intentionally omitted <==

PFS = progression-free survival

Table 33 shows the landmark PFS estimates for ibrutinib (1-2 prior line subgroup no del17p) from the RESONATE trial final (65m) data cut.

Table 33 Landmark PFS estimates for the I+V INV PFS data for ibrutinib (1-2 prior line subgroup) from the RESONATE trial final (65m) data cut

I+V = ibrutinib + venetoclax; INV = investigator; PFS = progression-free survival

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Based on the goodness of fit statistics, all distributions provided similar and good fit to the observed data. The estimated median PFS is approximately 6 years for all standard parametric functions. The exponential distribution was selected due to its constant hazard nature as the model cannot track the survival of patients stratified by the cycle of progression. It so happens that the exponential distribution provides the best fit to the observed data (i.e., AIC and BIC) and long term extrapolations are in the middle between the most optimistic scenario (i.e., log-normal) and pessimistic scenario (i.e., generalised gamma). Both the log-logistic and log-normal models were ruled out as the relatively flatter tail upon reaching median PFS seemed unrealistic.

Comparative efficacy

In the base case, the PFS associated with all second line treatments is assumed to be the same and reflect the reference curve estimated from RESONATE data (subgroup with 1-2 prior lines of treatment in the ibrutinib arm). The clinical equivalence of ibrutinib continuous use and acalabrutinib in the R/R CLL setting was accepted in the TA689 given outcomes of an ITC.(2) Assuming the same clinical equivalence across subsequent treatments was an assumption used and accepted in prior NICE appraisals (TA663 and TA689).

PF 2L to Death

Base case: All treatments use annual mortality rate during 2L PFS based on ibrutinib arm of RESONATE (1-2 prior lines subgroup) (Table 26)

Reference curve

Since the data from the CAPTIVATE FD cohort were immature to provide information on mortality during second line PFS, external data from the ibrutinib arm of the RESONATE trial final (65m) data cut (1-2 prior line subgroup) was used to calculate an annual mortality rate. The annual mortality rate was converted into a constant probability of death per cycle while patients are progression free during second line treatment. The probability of death during second line treatment is capped by the corresponding age and gender adjusted GPM to prevent logical inconsistencies.

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Table 34 shows the annual mortality rate for the ibrutinib arm (1-2 prior line subgroup) based on total follow-up days and number of death events occurring during PFS in RESONATE.

Table 34 Annual mortality rate in PF 2L derived from RESONATE Ibrutinib arm (1-

2 prior line subgroup)

PFS = progression-free survival

The annual mortality rate is converted to a constant probability of death per cycle which is capped by the corresponding age adjusted GPM. While the risk of dying in subsequent line PFS remains constant throughout the model horizon, the risk of dying due to GPM increases with age.

Relative treatment effects

In the base case, the mortality risk associated with all second line treatments is assumed to be the same and reflect the RESONATE trial ibrutinib arm data (1-2 prior line subgroup), given there is no current evidence to show otherwise.

PPS to Death

Base case: All treatments use annual mortality rate during 2L post-progression based on ibrutinib arm of RESONATE (1-2 prior lines subgroup) (Table 31)

Reference curve

PPS follows the same approach used for death in second-line PFS, with a constant annual mortality rate derived from the post-progression data from the RESONATE trial ibrutinib arm (1-2 prior line subgroup) and capped by the general population hazards.

Table 35 shows the annual mortality rate for the ibrutinib arm (1-2 prior line subgroup) based on total follow-up days and number of death events occurring during PPS in RESONATE

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Table 35 Annual mortality rate in 2L PFS derived from RESONATE Ibrutinib arm

(1-2 prior line subgroup)

PPS = post-progression survival

Comparative efficacy

Based on clinician feedback, patients may continue to receive treatments beyond progression on second-line treatment in the current treatment landscape. However, there are no clinical data on the treatment efficacy beyond progression on second line treatment in an FCR-suitable population or otherwise. Given the data uncertainty, it is assumed that treatments will not have any effect on survival. Only the annual risk of death is modelled, and it is informed by the post-progression risk of death in the ibrutinib arm subgroup with 1-2 prior lines of treatment from RESONATE trial. A constant annualised risk of death of XX XXX is applied.

B.3.3.3 FCR-unsuitable population

There are five relevant clinical transitions in the FCR-unsuitable population (summarised in Table 36):

• the transition from PF 1L to PF 2L or PPS

• the transition from PF 2L to PPS

• the transitions from the three alive states (PF 1L, PF 2L, PPS) to the death state

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Table 36 Summary of transition probabilities between health states for the FCR-unsuitable population

1L = first line; 2L = second line; CLL = chronic lymphocytic leukaemia; GPM = general population mortality; INV = investigator; MAIC = matching-adjusted indirect comparison; O-Clb = obinutuzumab + chlorambucil; PF = progression free; PFS = progression-free survival; PPS = post-progression survival; VenO = venetoclax + obinutuzumab; *Death is a self-absorbing health state. In other words, patients who transition to the death state do not leave the health state

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PF 1L to PF 2L or PPS

Base case: I+V PFS – GLOW trial, KM for 15 cycles, followed by exponential distribution; O-Clb- GLOW trial, 7-knot spline curve (Table 36)

I+V PFS

The observed INV-assessed PFS data from the GLOW trial (70) at the extended follow up of median 34.1 months (KM shown in Figure 24) was used to estimate extrapolations of PFS 1L for I+V. In the I+V arm, the PFS shows the occurrence of early events followed by a plateau with few patients experiencing events.

INV-assessed PFS was selected rather than IRC-assessed PFS (GLOW primary endpoint), since only INV-assessed PFS was available for the external comparators (VenO and acalabrutinib).

Figure 24 Observed INV PFS data extended follow-up (34.1m) of the GLOW trial

==> picture [448 x 309] intentionally omitted <==

I+V = ibrutinib + venetoclax; O-Clb = obinutuzumab + chlorambucil Source: Janssen Research & Development LLC [Data on File], 2021(70) Company evidence submission template for ibrutinib with venetoclax for CLL or SLL [ID3860]

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Visual inspection of the KM data of I+V and O-Clb suggests that the PH and accelerated failure time (AFT) assumptions are violated. This was confirmed by further examination of cumulative hazard plots, Schoenfeld residual plots, the log-survival odds and normal quantiles plots. Appendix O.1.2 describes the test for PH and AFT assumptions in detail. Thus, parametric models fitted to each arm separately (independent) were considered for extrapolating PFS for I+V and O-Clb.

The extrapolations of I+V PFS from different models were assessed based on goodness-of-fit statistics, a comparison of observed vs. predicted survival and clinical plausibility.

Table 37 presents a summary of the goodness-of-fit statistics for the INV PFS endpoint of I+V from GLOW.

Table 37 Goodness-of-fit statistics (AIC/BIC) for the independent parametric models fitted to INV-assessed PFS data for I+V

AIC = Akaike information criteria; BIC = Bayesian information criteria; GPM = general population mortality; NE = not estimable; PFS = progression-free survival

Figure 25 shows the parametric extrapolations, with (dotted curves) and without capping (solid curves) by UK GPM, overlaying the INV-assessed PFS KM data for I+V.

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Figure 25 Parametric models overlaying the observed INV-assessed PFS KM data for I+V

==> picture [448 x 206] intentionally omitted <==

GPM = general population mortality; I+V = ibrutinib + venetoclax; INV = investigator; KM = Kaplan-Meier; PFS = progression-free survival

Table 38 shows the landmark estimates for the standard parametric functions fitted to

the observed I+V INV PFS data from GLOW that were used to determine the clinical plausibility of extrapolations. These were validated by clinical expert opinion in May 2022.(5)

Table 38 Landmark estimates for the I+V INV PFS data from GLOW when capped

by the UK GPM hazard

==> picture [473 x 158] intentionally omitted <==

----- Start of picture text -----
Distribution 6 1-year 2-year 5-year 10-year 15-year 20-year 30-year
month
Exponential XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX
Weibull XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX
Log-logistic XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX
Log-normal XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX
Gamma XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX
Gompertz XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX XX XXX
External data TA689 suggested that a PFS landmark rate of 70% at 5 years with BTKi was
TA689 reasonable (2)
----- End of picture text -----

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BTKi = Bruton’s tyrosine kinase inhibitor; PFS = progression-free survival; TA = technology appraisal

Based on fit statistics, all models provided similar fit for I+V INV PFS (Table 38) over the observed follow up; however, there was a large degree of variability in the predicted PFS over the model horizon (Figure 25). The generalised gamma, Gompertz and Weibull extrapolations predict the observed KM data well, especially within the first 3 months, but provide unrealistic long-term projections: predicting XX XXX XX XXX XX XXX XX XXX XX XXX progression free at 30 years, respectively. This was deemed implausible by the advisory board of clinical and health economic experts conducted in March 2022(4) because the curves reflect a highly optimistic prognosis for FCRunsuitable CLL patients. In addition, the gamma and gompertz extrapolations never reach median PFS when not capped by GPM (which is clinically implausible) and converge to GPM within 5 years. Weibull, log-logistic and log-normal extrapolations converge with the GPM within 10 years. Although this is more reasonable than the gamma and gompertz extrapolations, the clinical plausibility of an FCR-unsuitable CLL patient becoming equivalent to a patient without the disease at any timepoint is uncertain.

The exponential extrapolation was selected in the base case analysis as this was the most conservative extrapolation in the long term and better aligned with external trial data and clinical opinion (per the advisory board of clinical and health economic experts conducted in March 2022).(4)

The RESONATE-2 trial (6) (which follows an FCR-unsuitable cohort with no del17p receiving ibrutinib monotherapy) demonstrated a PFS rate of 59% at 7 years. This external data acts as a secondary validation (Appendix P.1) for the exponential extrapolation of the I+V arm from GLOW, whose PFS at 7 years was XX XXX

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