Public observer slides Chair’s presentation Venetoclax for treating chronic lymphocytic leukaemia [ID944] 3rd Appraisal Committee meeting Committee C ERG: Warwick Evidence NICE technical team: Ross Dent, Nicola Hay Company: AbbVie 14 June 2017

Venetoclax marketing authorisation Indicated for treatment of CLL: ‘in the presence of 17p deletion or TP53 mutation in adults unsuitable for or who have failed a B-cell receptor pathway inhibitor’ ‘in the absence of 17p deletion/TP53 mutation in adults who have failed both chemo-immunotherapy and a B-cell receptor pathway inhibitor’ Conditional on submitting additional data when M14-032 trial completes (March 2018) Before marketing authorisation was granted, available through the early access to medicines scheme and had promising innovative medicine designation

Current management of CLL People with CLL 17p deletion or TP53 mutation chemo-immuno unsuitable B-cell receptor inhibitor Population 3 BSC Venetoclax? Chemo-immunotherapy BCRi unsuitable Population 2 No 17p deletion or TP53 mutation Untreated Chemo-immunotherapy BCRi unsuitable Population 1 Alemtuzumab BSC Venetoclax? B-cell receptor inhibitor Chemo-immunotherapy B-cell receptor inhibitor Relapsed/Refractory Population 4 BSC Venetoclax?

Clinical effectiveness evidence Venetoclax 2 phase II and 1 phase I trial – all single-arm Results difficult to interpret as trials included mixed populations with and without 17p deletion Comparison with BSC Company: Rituximab arm of 116 trial (idelalisib vs. rituximab for CLL) rationale: rituximab is used as BSC in clinical practice ERG: Post-progression survival after idelalisib from 116 trial Scenario analysis for population with 17p deletion or TP53 mutation using post-progression survival after ibrutinib from RESONATE trial rationale: these patients have disease progression after a BCRi which reflects the venetoclax marketing authorisation

116 trial survival outcomes Source: Furman et al. (2014), NEJM

BSC survival extrapolations Idelalisib appraisal, company extrapolated progression-free and overall survival for idelalisib arm of 116 trial, using a Weibull distribution. Reproduced by ERG below: del(17p)/TP53 non-del(17p)/TP53 ERG takes difference between OS and PFS curves to get mean post-progression survival after a BCRi and uses this as the basis of a BSC overall survival curve

Estimates of OS, PFS and PPS 17p deletion/TP53 mutation OS PFS PPS Venetoclax (ERG corrected company HRs) 4.95 2.71 2.24 BSC: Rituximab arm of 116 trial – company choice 0.95 0.44 0.51 BSC: Rituximab arm of 116 trial (ERG corrected company HRs) 0.99 0.54 BSC: Idelalisib arm of 116 trial – ERG choice 3.61 1.76 1.86 BSC: Ibrutinib arm of RESONATE – ERG scenario 6.11 3.99 2.12 No 17p deletion/TP53 mutation 8.10 4.35 3.76 1.80 0.74 1.06 1.61 0.61 1.00 5.64 1.62 4.02

Committee conclusions Clinical effectiveness results Results difficult to interpret as trials included mixed populations with and without 17p deletion Trials single-arm, few patients, potentially subject to bias - large degree of uncertainty in clinical evidence Noted clinical expert comments that venetoclax appears to be effective for people with few alternative treatments Generalisability of trials Patients in venetoclax trials likely to have a lower burden of disease than people for whom venetoclax would be an option in England - treatment benefit for these people uncertain Comparison with best supportive care Company’s approach flawed - rituximab arm eligible for BCRi Venetoclax and 116 trial populations not matched for baseline characteristics (including Rai disease stage) Preferred ERG approach: post-progression survival from idelalisib arm of 116. All had disease progression after BCRi. PFS utility value Company originally used a value of 0.853 from trials, but this is higher than age-matched general population Committee preferred 0.748 from idelalisib appraisal Adverse events Preferred to use more recent cost data and include disutility

Cost effectiveness analyses presented at 1st committee meeting – with PAS 17p deletion or TP53 mutation Incremental ICER Costs QALYs Company original submission: rituximab arm of 116 for BSC XXXXXX 2.40 ERG’s base case: PPS after idelalisib for BSC 1.66 No 17p deletion or TP53 mutation Incremental ICER Costs QALYs Company original submission: rituximab arm of 116 for BSC XXXXXX 3.53 ERG’s base case : PPS after idelalisib for BSC 1.74 XXXXXxxxxxxxxxxxxxxxxX *initial proposed complex PAS

17p deletion/TP53 mutation No 17p deletion/TP53 mutation End-of-life criteria 17p deletion/TP53 mutation No 17p deletion/TP53 mutation 1. Short life expectancy <24 months Company: rituximab arm of 116 - 0.95 years ERG: PPS after idelalisib from 116 - 1.86 years Company: rituximab arm of 116 - 1.80 years ERG: PPS after idelalisib from 116 - 4.02 years 2. Extension to life >3 months Company and ERG models: >3 months Committee conclusion Accepted the ERG’s modelling but noted: that the short life expectancy criterion was met for the population without a 17p deletion or TP53 mutation in both the idelalisib and ibrutinib appraisals venetoclax is 1 line of therapy later than these therapies Agreed that the end-of-life criteria met in both populations

1st appraisal committee meeting - ACD1 Despite meeting the end-of-life criteria, the committee’s preferred ICERs were higher than the range normally considered a cost-effective use of NHS resources for end-of-life treatments Committee’s preferred ICERs represented the lower end of the range of plausible ICERs using post-progression data after ibrutinib increased ICERs Venetoclax not recommended for either population: with a 17p deletion or TP53 mutation without a 17p deletion or TP52 mutation

2nd appraisal committee meeting - ACD2 Company presented analyses assuming BSC overall survival of 2 years for the population without a 17p deletion or TP53 mutation based on the committee’s conclusion that the end-of-life criteria were met Committee conclusion: not an acceptable modelling approach, because it is based only on assumptions and not on any epidemiological or clinical trial evidence

Cost-effectiveness analyses presented at 2nd committee meeting – with PAS Simple discount PAS agreed with Department of Health 17p deletion or TP53 mutation Incremental ICER Costs QALYs Company’s ACD1 response – survival based on end of life decision XXXXXX 2.38 £43,310 ERG’s modified base case – PPS after idelalisib for BSC 1.76 £57,476 No 17p deletion or TP53 mutation Incremental ICER Costs QALYs Company’s ACD1 response – survival based on end of life decision XXXXXX 3.00 £49,929 ERG’s modified base case – PPS after idelalisib for BSC 1.88 £77,779

2nd appraisal committee meeting - ACD2 End-of-life criteria Committee revisited end-of-life criteria for population without 17p deletion or TP53 mutation: noted that although end-of-life criteria met for idelalisib and ibrutinib, BCRis represented a step-change in treatment: it doesn’t necessarily follow that people have a short life expectancy after these treatments BCRis could have a tumour-modifying effect which continues to influence post-progression survival noted venetoclax also appears to have a tumour-modifying effect – estimated post-progression survival in this population is almost 4 years: a new treatment after venetoclax would not meet the end of life criteria EPAR acknowledges that data on outcomes post-treatment with BCRis are limited, as the BCRis are relatively new Committee conclusion: ERG’s estimate of 4 years plausible, end of life criteria not met for population without 17p deletion or TP53 mutation Venetoclax not recommended for either population

ACD2 consultation responses Consultee comments from: CLL support association Leukaemia care NHS England - Peter Clarke, NHS England chemotherapy lead Web comments from: UK CLL forum Company: AbbVie Clinical experts: George Follows, consultant haematologist

Comments on life expectancy Patient and professional groups Generally accepted that this small population of patients live less than 24 months after they stop BCRi treatment, with or without a 17p deletion or TP53 mutation unable to find any evidence that this group of patients has a life expectancy of 4 years estimate is derived from extremely limited data, limiting credibility Published data on the survival of patients following idelalisib failure are sparse but 1 study reported median overall survival of only 64 days (Barrientos, 2015) Tumour-modifying effect of BCRis is an unsubstantiated hypothesis

Comments on life expectancy Clinical expert UK CLL forum data show that patients who stopped ibrutinib treatment before venetoclax available have very short overall survival (median 33 days) UK CLL forum (2017) n=315, 30 month follow-up Stopping ibrutinib treatment n=140 Progressive disease without Richter’s transformation n=25 1st year – no venetoclax available n=10 Median overall survival: 33 days (0 – 360) All dead at 30 months After 1st year – venetoclax available 5 died 1: idelalisib + rituximab 9: venetoclax. median follow-up 107 days (9 – 498)

Comments on life expectancy Company Literature does not support life expectancy of 4 years for people with no 17p deletion (next slide) Venetoclax will be used after idelalisib and ibrutinib, which both met the short life expectancy criterion Clinical expert input from over 10 clinicians and 2 internal key opinion leaders a patient having best supportive a care following BCRi failure would not live longer than 2 years, whether they present with a 17p deletion or TP53 mutation or not tumour-modifying effect of BCRis following disease progression lacks clinical plausibility

BCRi discontinuation studies Jain (2015), n=127 30-month follow-up Maddocks (2015), n=308 med. follow-up 20 months Jain (2017), n=320 median follow-up 38 months Stopping ibrutinib treatment n=33 Progressive disease (without Richter’s transformation) n=7 No 17p deletion, n=3 Overall survival: 1.9*, 2.1 and 2.8 months *still alive at follow-up Stopping ibrutinib treatment n=76 Progressive disease (without Richter’s transformation) n=13 No 17p deletion, n=6 Median overall survival: 17.6 months* *with and without 17p deletion, subsequent therapies permitted but not recorded Stopping ibrutinib treatment n=90 Progressive disease (without Richter’s transformation) n=19 No 17p deletion, n=4 Overall survival: 0, 3.7 months (no subsequent therapy) 15.8, 16.6 months (idelalisib, venetoclax) ERG comment: 67%, 76% and 45% of people in above studies had Rai disease stage 3 or 4 at study entry vs. 28% (at diagnosis) in venetoclax trials The venetoclax trial populations do not match the populations in these studies

Other patient and professional group comments There is a significant unmet need for treatments for CLL patients with or without 17p deletion or TP53 mutation, after a BCRi Venetoclax is a highly effective and innovative therapy Venetoclax can offer a return to ‘normal life’ for people with CLL and alleviate significant symptom burden the high progression-free survival utility value in the trial should not be used as evidence that the trial population does not reflect the UK population for whom venetoclax would be an option

Comments from NHS England chemotherapy lead BCRis are generally used late in the natural history of the disease Prognosis of patients in England after ibrutinib or idelalisib is poor and less than 2 years regardless of whether they have a 17p deletion or TP53 mutation Long survival in venetoclax trials suggests that in clinical practice in England: people are more heavily pre-treated than those recruited to venetoclax trials idelalisib and ibrutinib are used in a different place in the CLL treatment pathway therefore the benefit of venetoclax may be less in NHS clinical practice than in trials Feedback from NHS clinicians is that venetoclax appears to be effective when used in England in people late in the disease and with a short life expectancy

Cost effectiveness analyses – with PAS In ACD2 response, company reverts to original model using rituximab arm of 116 as source of BSC data updates original analysis to reflect committees other preferred assumptions (PFS utility value of 0.748, updated adverse event costs and disutility) 17p deletion or TP53 mutation Incremental ICER Costs QALYs Company ACD2 response: 116 rituximab arm, committee’s pref. utility and cost assumptions XXXXXX 2.19 £39,940 ERG’s modified base case – PPS after idelalisib for BSC 1.76 £57,476 No 17p deletion or TP53 mutation Incremental ICER Costs QALYs Company ACD2 response: 116 rituximab arm, committee’s pref. utility and cost assumptions XXXXXX 2.81 £47,370 ERG’s modified base case – PPS after idelalisib for BSC 1.88 £77,779

End-of-life Short life expectancy 17p deletion or TP53 mutation No 17p deletion or TP53 mutation OS: rituximab arm of 116 –Company model 0.95 years 1.8 years PPS: idelalisib arm of 116 – ERG model 1.86 years 4.02 years PPS: ibrutinib arm of RESONATE – ERG model 2.12 years Not available Idelalisib and ibrutinib met end-of-life criteria, but these represented a step-change in treatment: it doesn’t necessarily follow that people have a short life expectancy after these treatments BCRis could have a tumour-modifying effect which continues to influence post-progression survival Venetoclax also appears to have a tumour-modifying effect – estimated post-progression survival is >2 years for both populations: a new treatment positioned after venetoclax would not meet the end of life criteria

Key issues Is the ERG’s estimate of 4 years survival after a BCRi for the no 17p deletion or TP53 mutation group plausible? Do the venetoclax trial populations match the population who would be offered venetoclax in clinical practice in England? Are the end-of-life criteria met? Which source of best supportive care data is appropriate for decision-making? What are the most plausible ICERs?