1. Lead team presentation
FOR PUBLIC OBSERVERS
Pembrolizumab combination for untreated non-squamous NSCLC [ID1173] – STA
Lead team presentation
1st Appraisal Committee meeting Committee D Lead team: Lindsay Smith, Robert Hodgson, Libby Mills, Malcolm Oswald ERG: Peninsula Technology Assessment Group (PenTAG), NICE technical team: Stephen Robinson, Victoria Kelly October 2019

2. Key clinical effectiveness issues
CONFIDENTIAL
Key clinical effectiveness issues
Are the comparators used by the company relevant to NHS clinical practice?
Company excluded pemetrexed maintenance therapy following chemotherapy regimens
Were the treatments received in KEYNOTE-189 relevant to current UK clinical practice?
Are the results from the company’s indirect treatment comparisons appropriate given the heterogeneity between the included studies?

3. Key cost-effectiveness issues
CONFIDENTIAL
Key cost-effectiveness issues
Is the company’s model structure appropriate?
What is the most appropriate cut off point for OS?
What is the most appropriate extrapolation to use for OS?
What is the most plausible assumption of duration of treatment effect?
Is the time to death approach used to estimate utility values appropriate?
How should subsequent therapies be modelled (company, ERG or other?)
Is the end of life criteria met?

4. CONFIDENTIAL
Disease background
In the UK, more than 45,000 people are diagnosed with lung cancer and over 35,000 people die from the condition each year
NSCLC accounts for 85-90% of lung cancer cases
Approximately 50% of people with NSCLC are diagnosed with incurable advanced local or metastatic disease (stage IV)
Estimated 5-year survival rate of approximately 10%
NSCLC: 2 major histological subtypes:
Squamous cell carcinoma (25 to 30%)
Non-squamous cell carcinoma including adenocarcinoma (30 to %), large-cell carcinoma (10 to 15%) and other cell types (5%)

5. Pembrolizumab (keytruda) + pemetrexed and platinum chemotherapy
Mechanism of action
Humanised monoclonal antibody which binds to the programmed cell death-1 (PD-1) receptor
Marketing authorisation
First-line treatment of metastatic non-squamous NSCLC in adults whose tumours have no EGFR or ALK positive mutation
Administration, dosage & duration of treatment
Intravenous infusion in outpatient setting of 200 mg every 3 weeks
Cost (list price)
£2,630 per 100 mg vial. Average cost of treatment: 77,218 (list price)
Other NICE recommendations/
appraisals
NICE TA531: Pembrolizumab for untreated PD-L1-positive metastatic non-small-cell lung cancer

6. Treatment pathway for NSCLC without EGFR or ALK mutation
CONFIDENTIAL
Treatment pathway for NSCLC without EGFR or ALK mutation
PD-L1 negative NSCLC or positive with TPS < 50%
PD-L1 positive with TPS ≥50%
Docetaxel or
Gemcitabine or
Paclitaxel or
Vinorelbine
PLUS
Carboplatin or
Cisplatin
(CG121)*
Pemetrexed + cisplatin
(TA181)
Adenocarcinoma or
Large-cell carcinoma
Pembrolizumab (TA531)
Pembrolizumab + pemetrexed + platinum chemotherapy
(TODAY)
* If platinum cannot be tolerated:
Docetaxel or
Gemcitabine or
Paclitaxel or
Vinorelbine
Pemetrexed maintenance
(TA190/TA402)
TPS = Tumour proportion score

7. Patients and carers perspective
CONFIDENTIAL
Patients and carers perspective
No new submissions from patient organisations - Previous submission from the Roy Castle Lung Cancer Foundation (TA531)
‘Targeted therapies (EGFR and ALK) have made a real difference in first line therapy to those specific patient groups. For remainder of patients, platinum-based chemotherapy is currently the first line therapy option’
‘Improving quality of life and even small extensions in duration of life are of considerable significance’
‘Outcomes remain relatively poor from traditional first line chemotherapy, with many patients experiencing significant side effects.’
‘… ‘end of life’ considerations are very important to this patient group…it is not appropriate, for example, to give the same weighting to the final six months of life as to all other six months of life’
‘Patients with metastatic NSCLC are often debilitated with multiple and distressing symptoms. Symptoms such as breathlessness are very difficult to manage clinically. Therapies with anti-tumour activity often provide the best option for symptom relief’

8. Clinical expert comments
CONFIDENTIAL
Clinical expert comments
Longer progression free survival (PFS) with combination compared with monotherapy
Toxicity is no greater than when chemotherapy and pembrolizumab given separately
Experience of managing patients on combination should not be significantly different
No greater capacity required, will actually reduce chemo suite chair numbers as both given together rather than sequentially
Outcomes superior to standard of care
No increased adverse event rates
KEYNOTE-189 suggests the PD-L1 marker is irrelevant in this setting of combination therapy which would simplify patient selection

9. NHS England comments CONFIDENTIAL
platinum plus pemetrexed +/- maintenance pemetrexed is the most commonly used standard treatment
the median duration of follow-up in the KEYNOTE trial is short (median months) and at the most recent data cut, there are very few patients in the survival analysis who are at risk after 15 months
link between degree of benefit and PD-L1 status is seen → hazard ratios for overall survival for the PD-L1 groups show a greater benefit as TPS increases
concerned that the serious, longer term toxicities of pembrolizumab (colitis, pneumonitis, hepatitis etc) may not have been fully captured in the economic model → 39 deaths due to an adverse event were observed in the pembrolizumab arm whereas the corresponding figure was 12 deaths in the placebo arm
company’s long term projection of overall survival is pessimistic for the comparator arm
The company and ERG have used the wrong chemotherapy delivery tariffs although NHS England does not regard this as making a substantial difference to the ICERs

10. Decision problem & company’s submission
Scope
Company
Population
Adults with untreated metastatic non-squamous NSCLC ✓
Intervention
Pembrolizumab combination
Comparators
Pemetrexed + carboplatin or cisplatin
Chemotherapy + carboplatin or cisplatin
(both with or without pemetrexed maintenance)
Pembrolizumab monotherapy X
Outcomes
overall survival (OS)
progression-free survival (PFS)
response rates (RRs)
adverse effects (AEs) of treatment
health-related quality of life (HRQoL)
Duration of response (DOR)
Time on treatment (ToT)
ERG comment: Pemetrexed maintenance was excluded from the pair-wise comparisons with platinum plus vinorelbine, gemcitabine, docetaxel, and paclitaxel. No reason given by company but most trials included in the ITC pre-dated it’s availability for this indication.
Company excluded pemetrexed maintenance with chemotherapy
What is standard of care for this population and is pemetrexed maintenance therapy used with chemotherapy?

11. Clinical effectiveness

12. Clinical effectiveness
CONFIDENTIAL
CONFIDENTIAL
Clinical effectiveness
Clinical evidence for pembrolizumab in combination with chemotherapy: KEYNOTE-189
Data from the final analysis of KEYNOTE-189 is currently anticipated in 77,218
Trial design
Randomised, double blind, Phase III : ONGOING
Population
adults with advanced or metastatic non-squamous NSCLC
No EGFR or ALK
ECOG performance score of 0 or 1
Intervention*
(n=410)
Pembrolizumab 200 mg + pemetrexed 500 mg/m2 + platinum cisplatin [75 mg/m2] or carboplatin [AUC 5 mg/mL/min] every 3 weeks for 4 cycles, followed by pembrolizumab + pemetrexed
Comparator*
(n=206)
Placebo + pemetrexed + platinum cisplatin or carboplatin, followed by placebo + pemetrexed
Outcomes
Primary: Overall survival, progression free survival
Secondary: objective response rates (ORRs), adverse effects (AEs) of treatment, health-related quality of life (HRQoL), Duration of response (DOR)
*Treatment with pembrolizumab or placebo continued until 35 study treatments had been administered or one of the discontinuation criteria occurred

13. Pembrolizumab combination
CONFIDENTIAL
CONFIDENTIAL
Clinical effectiveness results
KEYNOTE-189 cut-off date for the analysis 8 November 2017
Median duration of follow-up of 10.5 months (range 0.2 to 20.4 months)
Outcome
Pembrolizumab combination
(n=410)
Control
(n=206)
Primary outcomes
Overall Survival
Median, months (95% CI)
Not reached
11.3 (8.7 to 15.1)
HR (95% CI)
HR 0.49 (0.38 to 0.64) p <
OS rate at 6 months %
77,218
OS rate at 12 months %
69.2%
49.4%
Progression free survival
8.8 (7.6 to 9.2)
4.9 (4.7 to 5.5)
HR 0.52 (0.43 to 0.64) p <
PFS rate at 6 months
PFS rate at 12 months
34.1%
17.3%
KEY ISSUE: In KEYNOTE-189 patients with a TPS ≥50% received standard of care. In current UK clinical practice these patients would receive pembrolizumab monotherapy as first line.
Were the treatments received relevant to current UK clinical practice?

14. Company’s indirect treatment comparisons
CONFIDENTIAL
Company’s indirect treatment comparisons
Company did 2 indirect treatment comparisons (ITC) to compare pembrolizumab with other drugs
ITC 1 compared pembrolizumab combination vs:
Platinum + pemetrexed
Platinum + gemcitabine
Platinum + vinorelbine
Platinum + docetaxel
Platinum + bevacizumab + paclitaxel
Platinum + paclitaxel
ITC 2 compared pembrolizumab combinations vs pembrolizumab monotherapy
ERG comments: Agree with decision (and broadly the methodology used) to carry out an ITC of combination vs monotherapy as a separate analysis

15. Company’s ITC 1 results CONFIDENTIAL Overall Survival
Pembrolizumab combination statistically significantly improved overall survival vs all other comparators
Biggest benefit observed vs platinum + paclitaxel (HR 0.40, 95% CrI 0.25 to 0.63)
Progression free Survival
Pembrolizumab combination statistically significant improved progression free survival vs all other comparator
Biggest benefit observed vs platinum + paclitaxel (HR 0.28, 95% CrI 0.13 to 0.55)
ERG comments: ERG noted a large treatment benefit with combination therapy but that 95% Credible confidence intervals were wide, which may be due to the limited number of studies included and indicates significant heterogeneity between studies – ERG queries the size of the effect of pembrolizumab combination vs chemotherapy regimens
Are the results of the company’s NMA appropriate given the heterogeneity between included studies?

16. Company’s ITC2: Pembrolizumab combination vs pembrolizumab monotherapy
In this ITC, studies KEYNOTE-189 and KEYNOTE-024 (pembrolizumab monotherapy vs pemetrexed plus carboplatin/cisplatin) were used
Only those patients with a tumour proportion score (TPS) ≥50%)were selected from both studies. As the control arm in KEYNOTE-189 is carboplatin/cisplatin plus pemetrexed chemotherapy, patients with the corresponding investigators’ choice of SOC were selected from the KEYNOTE-024 dataset.
Numerical benefit in overall survival for pembrolizumab combination vs pembrolizumab monotherapy
Difference was not statistically significant HR 77,218
Numerical benefit in progression free survival for pembrolizumab combination vs pembrolizumab monotherapy
Difference was not statistically significant (HR 77,218

17. Key clinical effectiveness issues
CONFIDENTIAL
Key clinical effectiveness issues
Are the comparators used by the company relevant to NHS clinical practice?
Company excluded pemetrexed maintenance therapy following chemotherapy regimens
Were the treatments received in KEYNOTE-189 relevant to current UK clinical practice?
Are the results from the company’s indirect treatment comparisons appropriate given the heterogeneity between the included studies?

18. Cost effectiveness

19. Company’s model structure
CONFIDENTIAL
Company’s model structure
Model structure as reported in company submission:
Model design
Three-state partitioned survival
Time horizon
20 years
Cycle length
1 week
Half cycle correction
Yes
Treatment waning effect No
Discount rate
3.5%
Perspective
NHS (PSS)
Stopping rule
2-years
Treatment effect
Lifetime

20. ERG’s comments on model structure
Structure is not a 3 health state partitioned survival model:
uses 4 states to estimate utility, based on the OS outcome, using a time-to-death approach
costs are based on intent of treatment
progression status does not drive model
Subsequent therapy is modelled only as far as 2nd line
Same structure used in TA447/531 pembrolizumab monotherapy 1st line
ERG interpretation of the company base case model - cost evaluation
ERG interpretation of the company base case model - utility evaluation
<30 days to death
Death
≥ 360 days to death
30 to 180 days to death
180 to 360 days to death
Death
Alive – on treatment
Alive – not on treatment
Is the company’s model structure appropriate?

21. Company’s overall survival extrapolations (1)
2-phase piecewise model chosen (because proportional hazards did not hold)
For both arms, a piecewise model was fitted using the Kaplan-Meir data up to week 28 followed by an exponential distribution (see next slide)
2 additional cut offs explored in sensitivity analyses (at week 18 and week 38)
KEYNOTE-189 cut-off date for the analysis 8 November 2017
Median duration of follow-up of 10.5 months (range 0.2 to months)

22. Company’s overall survival extrapolations (2)
77,218
Company preferred extrapolation : Exponential

23. Company’s overall survival estimates
Company’s overall survival estimates from KEYNOTE-189
Pembrolizumab combination
(n=410)
Control
(n=206)
Overall Survival
Median, months (95% CI)
Not reached
11.3 (8.7 to 15.1)
HR (95% CI)
HR 0.49 (0.38 to 0.64) p <
OS rate at 6 months %
77,218
OS rate at 12 months %
69.2%
49.4%
Company’s overall survival estimates for 3 data cut-offs
Week 28
Week 38
Week 18
Pembro+
SoC
5yr
10yr
Exponential
77,21 8
77,2 18
Log Logistic

24. ERG comments on company’s approach to estimate overall survival
KEYNOTE-189’s median survival is only reached in SoC arm  considerable uncertainty in extrapolations
Exponential distribution provides the worst statistical fit for SoC
Clinically implausible overall survival estimates at 5 & 10 years
Proportional hazards assumption did not hold  exponential distribution inappropriate
According to DSU guidance the company incorrectly:
Used only one cut-point of the 3  “…exponential distributions with different rate parameters should be fitted to each of the time periods identified as having different (constant) hazard rates.”[DSU TSU14]
Other distribution choices do not require use of cut-offs in this way  “Models other than the exponential also allow for non-constant hazards over time”
Use of the naïve KM curve up to week 28: this is trial data so sample data.
should be used to inform the trend of whole population  should be a smooth trend
ERG in its base case followed DSU guidance and separately fitted the log-logistic curve from Week 0 to both arms. Based on:
consistently good statistical fit of the curve to the observed data (AIB and BIC),
external face validity of SoC 5 and 10 year OS estimates (8% and 2.88%).

25. Overall survival extrapolations – comparison of approaches
Issue
Company
ERG
Proportional Hazards does not hold ✓
Hazard Ratios change over time
Modelling approach
2-phase piecewise model with a single cut-off point at week 28
Full KM data fit from week 0
Distribution choice for 2nd phase
Exponential
Log-logistic

26. ERG comments: comparison of overall survival estimates
In TA447/531 committee accepted 8-11% as a reasonable overall survival for standard of care at 5 years
Source/Population
5-year OS
10-year OS
Company approach: Standard of Care arm using KM up to 28 weeks + exponential curve after 28 weeks
77,218
ERG approach: Standard of care arm using Log- logistic from week 0
NICE TA447/531 (ERG): Standard of care untreated PD-L1-positive mNSCLC estimate
9.60%
1.50%
What is the most appropriate cut off point for OS?
What is the most appropriate extrapolation to use for OS?

27. Company modelling assumptions: quality of life
Company modelled EQ-5D data from KEYNOTE-189 & pooled the values for both arms
Difference between pre and post-progression utilities is small, indicating that utility values were only collected for a few weeks after progression  time to death (TTD) approach used by company
Correlation between utility and time to death
2 company scenarios:
Using progression-based utilities as an alternative approach to estimate quality adjusted life years (QALYs) based on KEYNOTE-189
Using utilities per treatment arm instead of pooled utilities from KEYNOTE-189:
With the time to death approach
With the progression-based approach
Time to death
Mean utility
≥ 360 days
77,218
between 180 and 360 days
between 30 and 180 days
< 30 days
Progression status
Mean utility
Progression free
77,218
Progressive disease

28. ERG comments on company's approach on quality of life
In TA447 (updated in TA531), utilities based on time to death alone, with 4 health states considered  same approach used here
Method supported by clinical opinion gathered by the ERG: quality of life correlates better using this approach than occurrence of first progression
ERG in its scenarios analyses explored utility values based on:
progression status
Time to death with a quality of life decrement associated with progressive disease applied for progressed patients
progression status with a quality of life decrement associated with time to death of less than 360 days applied for patients with less than 360 days to live
Is the time to death approach used to estimate utility values appropriate?

29. Subsequent 2nd line therapies
Company assumed 43% of patients who discontinue 1st line therapy in the pembrolizumab combination arm, and 56% in the SoC arm, receive second line (2L) pembrolizumab as per KEYNOTE-189
Company adjusted the proportions to exclude the 7% patients who had pembrolizumab monotherapy after it had been discontinued first line (1L) in the combination arm of KEYNOTE-189 as this was not clinically plausible
ERG comments:
Third and subsequent lines of therapy not included in company base case
ERG not able to establish the adjustment methods used by the company in their calculation of the up-take and the distribution of therapies at second-line
ERG in its scenario analyses explored unadjusted estimates from KEYNOTE-189 of the proportion of patients taking-up 2L treatment after 1L discontinuation
30.5% for pembrolizumab arm, 46.6% for SoC - unadjusted estimates from KEYNOTE-189 (Ghandi Supp.)
How should subsequent therapies be modelled (company, ERG or other?)

30. CONFIDENTIAL
Assumptions from previous lung cancer appraisal: TA531 Pembrolizumab monotherapy
Conclusion from TA447/531
Company base case
ERG base case
2-year treatment stopping rule ✓
Duration of treatment effect: scenarios of 3 & 5 years explored
Lifetime
5 years (3 years in scenario analyses)
Cost of PD-L1 testing
Included for patients receiving pembrolizumab 2L
Removed cost from both arms as PD-L1 testing is routine
Time to death approach for HRQoL
✓ (method based on progression in scenario analyses
✓ (various methods explored in scenario analyses)
End of life criteria met

31. Company’s deterministic base case results
CONFIDENTIAL
Company’s deterministic base case results
Including confidential discount for pembrolizumab, but not including confidential discount for pemetrexed maintenance (available in part 2)
Pembrolizumab combinations vs
Incremental costs (£)
Incremental QALYs
ICER per QALY gained
Standard of care
£41,344
0.89
£46,568
Platinum + Paclitaxel
£58,956 
1.08
£54,654
Platinum + Docetaxel
£56,932 
0.73
£78,242
Platinum + Gemcitabine
£57,752
1.01
£57,064
Platinum + Vinorelbine
 £56,661
0.90
£63,262
Platinum + Pemetrexed
 £42,077
 £46,504

32. ICER (£) versus baseline (QALYs)
Company base case result of sub-population comparison for PD-L1 positive with TPS ≥50%
Including confidential discount for pembrolizumab, but not including confidential discount for pemetrexed maintenance (available in part 2)
Technologies
Total costs (£)
Total LYG
Total QALYs
Incremental costs (£)
Incremental QALYs
ICER (£) versus baseline (QALYs)
Pembrolizumab monotherapy
£72,319
2.17
1.57 -
Pembrolizumab combination
£102,480
3.20
2.35
£30,161
0.78
£38,699
TPS= Tumour proportion score

33. ERG’s changes and base case
ERG preferred changes:
Coding correction (% patients utilising 2nd line therapy; half-cycle correction)
Log-logistic parametric distributions for overall survival extrapolation from week 0
Adjustment for background mortality (due to the relatively short length of the trial compared to the model time horizon)
Treatment effect discontinued at 5 years (effect unlikely to remain over 20 year time- horizon)
Excluding cost of PD-L1 testing (now routine in the NHS)
Other ERG scenarios included:
Estimation of long term OS
Estimation of utilities
Estimation of high cost drug consumption
Exponential from week 0, 18, 28 and 38
TTD (Chang 2017)
Dose intensity (actual vs expected)
Log-Normal and Log-Logistic from week 0
ToT as proxy for PS
Proportion taking up 2nd line treatment after 1st line discontinuation
Generalised Gamma/Weibull/Gompertz
Combined TTD and classic progression
Less pembrolizumab at 2nd line in SoC strategy

34. ERG deterministic base case results
CONFIDENTIAL
ERG deterministic base case results
Including confidential discount for pembrolizumab, but not including confidential discount for pemetrexed maintenance (available in part 2)
Strategy
Incremental costs (£)
Incremental QALYs
ICER (£/QALY)
SoC -
Pembrolizumab combination
£42,454
1.13
£37,622
Platinum + Gemcitabine
£59,571
1.43
£41,710
Platinum + Vinorelbine
£57,946
1.00
£57,939
Platinum + Docetaxel
£58,201
1.26
£46,337
Platinum + Paclitaxel
£60,926
1.52
£40,096

35. ERG base case result of sub-population comparison for patients with TPS ≥ 50%
PC versus pembrolizumab monotherapy (deterministic)
Strategy
Total Costs (£)
Total LYG
Total QALYs
Incremental costs (£)
Incremental LYG
Incremental QALYs
ICER (£/QALY) PC
£106,292
4.19
3.11
Pembrolizumab
monotherapy
£76,503
3.21
2.37
£29,788
0.98
0.74
£40,225

36. End of life considerations for ITT population
Confidential
End of life considerations for ITT population
Strategy 
Source (time in months)
Standard of care (SoC)
Pembrolizumab combination (PC)
Increment
(life extension)
Mean OS: company base case
16.61
32.17
15.56
Mean OS: ERG base case
22.73
43.68
20.96
Median OS in KEYNOTE- 189
11.3
(95%CI, )
Not reached NA
SoC = Standard of Care
National Institute for Health and Care Excellence Pre-meeting briefing – insert title in notes master view
Issue date: [Month year]

37. Increment life extension
Confidential
End of life considerations by TPS ≥ 50%: standard of care vs pembrolizumab combination
Source (time in months)
Strategy 
SoC PC
Increment life extension
Company base case mean OS
17.11
42.24
25.12
ERG base case mean OS
23.89
58.33
34.44
ERG: With background mortality; 5 year DoT effect; No test costs*
16.88
35.22
18.34
Median in KEYNOTE-189
Not reported
Not reached NA
*Differs from the ERG base case for whole population analysis in one assumption only: the method of OS extrapolation follows that of the company (2-phase piecewise exponential independent, both KM plot arms, fitted from week 28)
National Institute for Health and Care Excellence Pre-meeting briefing – insert title in notes master view
Issue date: [Month year]

38. Increment life extension
Confidential
End of life considerations by TPS ≥ 50%: pembrolizumab monotherapy vs pembrolizumab combination
Source (time in months)
Strategy PM PC
Increment life extension
Company base case mean OS
27.59
42.24
14.65
ERG base case mean OS
44.44
58.33
13.89
ERG: With background mortality; 5 year DoT effect; No test costs*
26.92
35.22
8.3
Median in KEYNOTE-189
Not reported
Not reached NA
SoC = Standard of Care
*Differs from the ERG base case for whole population analysis in one assumption only: the method of OS extrapolation follows that of the company (2-phase piecewise exponential independent, both KM plot arms, fitted from week 28)
National Institute for Health and Care Excellence Pre-meeting briefing – insert title in notes master view
Issue date: [Month year]

39. End of life consideration: ERG comments
CONFIDENTIAL
End of life consideration: ERG comments
Considerable uncertainty around extrapolation of overall survival beyond study follow-up
Median overall survival was not reached in the pembrolizumab combination arm of KEYNOTE-189
Evidence from KEYNOTE-189, company and ERG economic models suggest that the average overall survival on standard of care treatment is <24 months; and life extension >3 months
Pembrolizumab combination in the ITT setting probably fulfils the criteria for end-of-life status
Whilst estimates of the extension to life are not robust the various point estimates are far in excess of the requirement
Is the end of life criteria met?

40. Equality and Innovation
CONFIDENTIAL
Equality and Innovation
Equality
No equality or equity issues were identified by either the company or the ERG
Innovation (company view)
The clinical efficacy and safety data show that pembrolizumab, when combined with chemotherapy, offers benefit in progression free survival and overall survival for all lung cancer patients, regardless of PD-L1 expression levels, with an acceptable tolerability profile

41. Committee decision-making: CDF recommendation criteria
Proceed down if answer to each question is yes
Starting point: drug not recommended for routine use due to clinical uncertainty
1. Is the model structurally robust for decision making? (omitting the clinical uncertainty)
2. Does the drug have plausible potential to be cost-effective at the offered price, taking into account end of life criteria?
3. Could further data collection reduce uncertainty?
4. Will ongoing studies provide useful data?
5. Is CDF data collection via SACT relevant and feasible?
and
Consider recommending entry into CDF
(invite company to submit CDF proposal)
Define the nature and level of clinical uncertainty. Indicate the research question, analyses required , and number of patients in NHS in England needed to collect data.

42. Key cost-effectiveness issues
CONFIDENTIAL
Key cost-effectiveness issues
Is the company’s model structure appropriate?
What is the most appropriate cut off point for OS?
What is the most appropriate extrapolation to use for OS?
What is the most plausible assumption of duration of treatment effect?
Is the time to death approach used to estimate utility values appropriate?
How should subsequent therapies be modelled (company, ERG or other?)
Is the end of life criteria met?

43. Additional slides

44. ERG overall survival extrapolations scenarios
Distribution choice for 2nd phase
Cut-off (weeks)
Treatment benefit discontinuation (yrs)
5 year OC SoC
ICER (£/QALY)
Exponential 3
2.95%
£61,480 18
1.82%
£60,087 28
2.22%
£63,980 38
5.70%
£70,070 5
£50,569
£48,724
£53,208
£62,111
Log-logistic
8.05%
£43,418
13.38%
£49,147
17.53%
£54,870
18.15%
£56,711
£37,622
£50,549
£64,671
£65,192
ERG preferred

45. ERG HRQoL and resource use scenarios
Estimation of utilities
Scenario
PC vs SoC
Inc. costs
Inc. QALYs
ICER
Utilities driven by progression status - ToT as proxy for PS (follows company SA)
£42,454
0.99
£43,092
Combined TTD and classic Progression status approach
1.03
£41,352
Estimation of high cost drug consumption
Scenario
PC vs SoC
Inc. costs
Inc. QALYs
ICER
‘Dose intensity’ (actual vs. expected treatment cycles) of pembrolizumab combination: 95.6% reduced by 20% (76.5%)
£33,207
1.13
£29,428
Proportion of patients taking-up 2L treatment after 1L discontinuation: unadjusted estimates from KEYNOTE-189: 30.5% PC, 46.6% SoC
£44,960
£39,843
Less pembrolizumab at 2L in SoC strategy: from 72% in PC to 50% (and Docetaxel from 14% to 35%)
£45,857
£40,534

46. ERG scenarios (combined)
Description 11
Utilities based on progression status
12.a
Combined approach for utilities – main utility values based on TTD, with a utility decrement associated with progressive disease applied for progressed patients.
12.b
Combined approach for utilities – main utility values based on progression status, with a utility decrement associated with TTD of less than 360 days applied for patients with less than 360 days to live 14
Unadjusted estimates from KEYNOTE-189 of the proportion of patients taking-up 2L treatment after 1L discontinuation (30.5% for PC, 46.6% for SoC) 16
Treatment benefit discontinuation at 3 years
Scenarios
Incremental costs (£)
Incremental QALYS
ICER (£/QALY)
ERG base case
£42,454
1.13
£37,622 11
0.99
£43,092
12.a
1.03
£41,352
12.b
0.98
£43,491 14
£44,960
£39,843 16
£41,395
0.95
£43,418
14, 16
£43,810
£45,950
11, 14, 16
0.84
£52,091
12.a, 14, 16
0.87
£50,138
12.b, 14, 16
0.83
£52,755