1. 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

2. 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 M trial completes (March 2018)
Before marketing authorisation was granted, available through the early access to medicines scheme and had promising innovative medicine designation

3. 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?

4. 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

5. 116 trial survival outcomes
Source: Furman et al. (2014), NEJM

6. 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

7. 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

8. 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 from trials, but this is higher than age-matched general population
Committee preferred from idelalisib appraisal
Adverse events
Preferred to use more recent cost data and include disutility

9. 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

10. 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 years
ERG: PPS after idelalisib from years
Company: rituximab arm of years
ERG: PPS after idelalisib from 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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)

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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?