1. Slides for public – no confidential information
Chair’s presentation Alectinib for untreated anaplastic lymphoma kinase-positive advanced non-small cell lung cancer – STA
2nd Appraisal Committee meeting
Committee D
Lead team: Dr Nabeel Alsindi, Susan Dutton, Malcolm Oswald
ERG: BMJ-TAG
NICE technical team: Lucy Beggs, Christian Griffiths
Company: Roche Products Ltd.
15th May 2018

2. Current treatment for advanced NSCLC
CONFIDENTIAL
Current treatment for advanced NSCLC
Ceritinib (TA395)
ALK-positive
ALK status unknown
Pemetrexed with cisplatin (TA181)
ALK-positive status confirmed
Crizotinib (TA406)
Crizotinib (TA422)
Alectinib?
Chemotherapy
Best supportive care
Ceritinib (TA500)
NB: not in scope for appraisal
Alectinib marketing authorisation: ‘…as a monotherapy is indicated for the first line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC)’
National Institute for Health and Care Excellence Pre-meeting briefing – insert title in notes master view
Issue date: [Month year]

3. Key clinical evidence: ALEX trial
ALEX open-label RCT: alectinib vs crizotinib
Overall survival data immature (median OS not reached in either arm)
Key outcomes
Hazard ratio (95% CI)
Investigator assessed PFS
0.47 (0.34, 0.65)
IRC assessed PFS using RECIST
0.50 (0.36, 0.70)
Overall survival
0.76 (0.48, 1.20)
To demonstrate alectinib’s role in the CNS, company split analyses…
Progression-free survival = survival without any progression events
CNS-progression-free survival = survival without a CNS progression event
Company’s PFS analyses used IRC CNS-RECIST and RECIST
ERG & committee preferred IRC RECIST only
Both show benefit of alectinib in delaying progression in the CNS

4. Cost-effectiveness modelling
Partitioned survival model with 4 states: progression-free survival, CNS progressed disease, non-CNS progressed disease and death
Overall survival extrapolation:
Company used exponential extrapolation
ERG & committee preferred Kaplan-Meier + exponential tail
Progression-free survival extrapolation:
Company used Kaplan-Meier + exponential tail (committee accepted)
CNS-PFS extrapolation:
Company used gamma distribution
ERG: lognormal or log-logistic better, but negligible impact on ICER
Utilities:
Progression-free state = 0.814
Non-CNS progressed disease state = 0.725
CNS-progressed disease state = 0.520

5. Management of progression
Subsequent treatments:
Subsequent therapy data only available for 41% patients in ALEX
Clinical experts at meeting estimated subsequent treatment distribution…
50%
Crizotinib
Alectinib
Chemotherapy
Best supportive care
Ceritinib
70-80%
40-50%
20-30%
50-60%
1st line
% receive 2L
% receive 3L
Key:
Management of CNS metastases:
Clinical experts expected majority of patients to receive steroids
Clinical experts at meeting estimated ~20-25% of patients would have stereotactic radiosurgery and 25% would have whole-brain radiotherapy
Surgical resection may also be an option

6. Committee’s considerations in ACD (1)
Issue
Committee’s consideration
Measurement of PFS and CNS-PFS
Preferred independent over investigator assessment
Preferred assessment using RECIST criteria (compared with RECIST & CNS-RECIST)
Clinical efficacy (compared with crizotinib)
Alectinib improves progression-free survival
Alectinib improves CNS-progression-free survival
Insufficient evidence to draw conclusion about overall survival benefit
59% missing data on subsequent treatments  potential confounding of overall survival
Extrapolation of survival curves
Non-proportional hazards
Accepted PFS extrapolation using KM data + exponential tail
Accepted CNS-PFS extrapolation using gamma distribution (although preferred log normal or log-logistic, had negligible impact on ICER)
Preferred OS extrapolation KM data + exponential tail

7. Committee’s considerations in ACD (2)
Issue
Committee’s consideration
Utility values
Accepted for progression-free health state
Accepted for CNS progressed disease state
Considered that for non-CNS progressed disease state may be too high
Wastage
‘No wastage’ assumption for alectinib & crizotinib
Subsequent treatments
Preferred clinical experts’ estimates:
Crizotinib arm:
2L ceritinib = 70-80%
3L chemotherapy = 40-50%
3L best supportive care = 50-60%
Alectinib arm:
2L chemotherapy = 50%
2L best supportive care = 50%
Oncologist visits
Preferred assumption that oncologist visits are every 4 weeks

8. Committee’s considerations in ACD (3)
Issue
Committee’s consideration
Management of CNS progressed disease
Preferred clinical experts’ estimates:
Majority receive steroids
Stereotactic radiotherapy = 20-25%
Whole-brain radiotherapy = 25%
End of life criteria & innovation
End of life criteria not met; life expectancy with standard care > 2 years & uncertainty about extension to life
Alectinib may be innovative but no additional evidence of benefits that had not been captured through QALYs and resulting ICERs
Cancer Drugs Fund
More mature data could resolve clinical uncertainty about benefits of alectinib
However, concluded does not show plausible potential to be cost-effective ∴ not recommended for CDF
ICER
Most plausible ICER was above £30,000 per QALY gained

9. ACD Preliminary Recommendation
Alectinib is not recommended, within its marketing authorisation, for untreated ALK-positive advanced non-small-cell lung cancer (NSCLC) in adults

10. ACD consultation responses
CONFIDENTIAL
ACD consultation responses
Consultee comments from:
Roche
Commentator comments from:
Pfizer
Web comments from:
1 GP (also a patient)
5 patients/carer
National Institute for Health and Care Excellence Pre-meeting briefing – insert title in notes master view
Issue date: [Month year]

11. Consultation topic in order of discussion
Consultation comments:
Comments on model inputs & data
Summary of web comments
Additional evidence from company:
Summary of committee preferences and company’s revised analysis
Use of RECIST only data
Subsequent treatment distributions
Management of CNS metastases
Updated data-cut
Company’s new base-case
Updated scenario analysis

12. Comments on model inputs & data
Consultation comments from Pfizer (crizotinib):
Input variable
Current input
Suggested input
Likely impact on ICER*
Crizotinib dose
500mg once daily
250mg twice daily
No impact
Administration cost
£9.20
£14.40
Minimal ↑
ALK testing
£2380 (£75 p/test)
£2380 (£75 p/test + £120 confirmation)
Data
Current
Suggested
Likely impact on ICER*
PROFILE1014 OS outcomes used in TA406
Median = 21.7 months, mean = 29 months
Median = 24.6 months, mean = 33.9 months
PROFILE1014 = supplementary info, only for validation
*calculated by NICE technical team

13. Summary of web comments
Themes from the consultation:
Profile of ALK-positive patients: ‘young, fit and ‘healthy’’
Many people diagnosed are younger than 50  treatment enables a relatively normal life and continued contribution to society
Because ALK-positive patients can be younger & non-smokers, may be misdiagnosed/diagnosed later  disadvantaged
Importance of CNS protection & avoiding risk of leptomeningeal disease
1L crizotinib has poor CNS penetration
Alectinib has fewer side effects than crizotinib
Treatment with alectinib  ‘Although I am not curable, I am currently living well with my cancer.’
‘Life saving drug which will surely make a huge difference to many patients & families’

14. Committee preferences and company’s revised analysis
CONFIDENTIAL
Committee preferences and company’s revised analysis
Committee preference:
Did company revise?
Assessment of progression by IRC using RECIST criteria ✓
OS extrapolation using KM data + exponential tail
‘No wastage’ assumption
Subsequent treatment distribution in line with clinical practice ?
Slide 18
Oncologist visit every 4 weeks
CNS metastases managed in line with clinical practice
Lower utility value for non-CNS progressed disease state
(Scenario)
Company also submitted a revised Patient Access Scheme discount
National Institute for Health and Care Excellence Pre-meeting briefing – insert title in notes master view
Issue date: [Month year]

15. Use of RECIST only data In ACM1: Consultation:
Company captured CNS & non-CNS progression events using RECIST + CNS-RECIST criteria
Committee preferred RECIST only as concluded CNS-RECIST not used in clinical practice
Consultation:
Company updated base-case to use data captured by RECIST only
However, highlighted that:
Using RECIST only could potentially underestimate number of patients with CNS-progression because ALEX clinicians were not required to capture progression location  events without further information classed as ‘non-CNS’
Events captured only by CNS-RECIST + RECIST are likely to eventually be picked up by RECIST  CNS-RECIST + RECIST just captures the same events earlier

16. Subsequent treatment distributions
In ACM1:
Committee preferred distribution reflecting clinical practice, estimated as:
Post-alectinib (2L)
Post-crizotinib (2L)
Chemo.
BSC
Ceritinib
50%
70-80% 0%
20-30%
Post-ceritinib (3L)
Chemo.
BSC
40-50%
50-60%
Consultation:
Company modelled 2 scenarios based on estimate ranges:
Scenario
Post-alectinib (2L)
Post-crizotinib (2L)
Chemo.
BSC
Ceritinib
Option 1
50%
75%
25%
Option 2
70%
30%
= company base-case

17. Management of CNS metastases
In ACM1:
Committee preferred distribution reflecting clinical practice, estimated as:
Scenario
SRS
WBRT
Surgical resection
Steroids
Clinical expert estimates
20-25%
25%
Sometimes used
Most people
Consultation:
Company modelled 2 scenarios based on estimate ranges:
Scenario
SRS
WBRT
Surgical resection
Steroids
Option 1
22.5%
25% 5%
100%
Option 2
20% 0%
= company base-case

18. Company’s new base case
Updated assumptions:
RECIST only data
No wastage
Oncologist visits every 4 weeks
OS extrapolation = KM data for 18 months + exponential tail
Subsequent treatment distribution = Option 2
CNS metastases management = Option 2
Updated base case results (list price):
Total costs
Total LYG
Total QALYs
Inc costs
Inc
LYG
Inc QALYs
ICER £/QALY
Crizotinib
£143,986
4.32
2.84
Alectinib
£209,668
5.14
3.79
£65,681
0.83
0.95
£69,310

19. Updated data-cut Updated ALEX data cut *******
Only available for investigator-assessed outcomes as both IRCs were disbanded after primary analysis
Outcome
Alectinib median
Crizotinib median
HR (95% CI)
PFS
*********
****************
DOR OS
Alectinib ********PFS in subgroups with CNS metastases at baseline **************** and without ****************
Because committee preferred IRC assessed PFS, updated PFS data not included in base-case economic analysis
Updated OS results included as scenario analysis

20. Company scenario analysis
Scenarios:
Subsequent treatment = Option 1, CNS management = Option 1
Subsequent treatment = Option 2, CNS management = Option 2, Updated OS data cut
Subsequent treatment = Option 1, CNS management = Option 1, Updated OS data cut
Subsequent treatment distribution = Option 2, CNS management = Option 2, Roughley et al. utility value used for non-CNS progressed disease health state (0.65 instead of 0.725)
Scenario analysis results (list price):
Inc costs
Inc LYG
Inc QALYs
ICER £/QALY
Scenario 1
£63,380
0.83
0.95
£66,881
Scenario 2
£67,234
1.05
1.10
£61,070
Scenario 3
£64,949
£58,994
Scenario 4
£65,681
0.88
£74,563

21. ERG comment on revised analysis Subsequent treatments & utilities
Accept company’s modelling of cost of subsequent treatments
Agree that limiting analysis to 2L tx helps ‘contain’ uncertainty
However, concerned that impact on quality of life not captured
In company’s model, progression utilities associated with subsequent treatment (regardless of progression site)
ERG preferred to model utility based on site of tumour progression (e.g. CNS vs non-CNS)
Utilities weighted to reflect distributions of subsequent tx in each arm
Applied Roughley et al. decrement to CNS-PD utility  0.52 to 0.58
ERG revised utilities:
2L TKI
2L chemo
BSC
PFS
Non-CNS
CNS
Alectinib
0.81
Do not receive TKI
0.57
0.58
0.47
Crizotinib
0.65
Do not receive chemo

22. ERG’s preferred base-case
Accept modelling of IRC RECIST only, frequency of oncologist visits, no wastage assumption & management of CNS metastases
Prefer original IRC PFS and updated OS analysis (BUT caveat that updated OS is still immature & confounded by missing subsequent tx data)
Preferred assumptions:
Progressed disease utility values related to progression-site
Utilities weighted to reflect subsequent treatment distributions in each treatment arm
Roughley et al. decrement applied to CNS progressed disease utility  increased from 0.52 to 0.58
Using OS data from updated data-cut
ERG base case results (list price):
Total costs
Total QALYs
Inc costs
Inc QALYs
ICER £/QALY
Crizotinib
£144,255
2.53 –
Alectinib
£211,490
3.39
£67,234
0.86
£78,555

23. Key Issues
Does the updated modelling of subsequent treatment distribution reflect clinical practice?
Should the post-progression utilities be modelled as:
One utility applied to all patients post-progression, regardless of progression site? (company)
Related to progression site, dependent on treatment (ERG)
Should the Roughley et al. decrement be applied to CNS-PD utility (0.58 or 0.52)?
Does the new data-cut provide information about whether alectinib prolongs survival compared with crizotinib?
Should the most plausible ICER used for decision making be based on an OS extrapolation (KM + exponential) using Kaplan- Meier data from the old or new data cut?