TA904 · STA
Pembrolizumab plus lenvatinib is recommended only if the companies provide them according to the commercial arrangements
Source documents
Interventions
Conditions
Comparators
| Name | Type | Established | Committee preferred |
|---|---|---|---|
| paclitaxel | active drug | Yes | — |
| doxorubicin | active drug | Yes | — |
| paclitaxel or doxorubicin monotherapy | active drug | Yes | — |
Clinical trials
| Trial | Design | Phase | Pivotal |
|---|---|---|---|
| KEYNOTE-775 | RCT | phase III | Yes |
| KEYNOTE-146 | single_arm | 1b/2 | — |
| ECHO | observational | — | — |
| Heffernan (2022) | observational | — | — |
Economic model
ICER
Methodological decisions (10)
Adjustment for treatment switching - proportion of control arm patients receiving pembrolizumab plus lenvatinib or other PD-1/PD-L1 or VEGF/VEGFR inhibitors after paclitaxel or doxorubicin monotherapy
Company: Applied two-stage estimation (TSE) method without recensoring; TSE method considered least biased
ERG: Noted TSE method assumes same treatment effect for all treatments after switching, which may not be appropriate given variety of treatments; true effect likely lies between adjusted and unadjusted values
Committee: Used EAG scenario of all patients waning at 5-7 years; noted adjusted result is less biased than unadjusted but the unadjusted is more conservative; true result likely between adjusted and unadjusted
ICER impact: decreases
Treatment switching adjustment in comparison between EAG scenarios
ERG: Provided scenarios both adjusted and unadjusted for treatment switching
Committee: Most plausible ICERs between EAG's scenario adjusted for treatment switching and unadjusted for treatment switching
ICER impact: uncertain_direction
Partitioned survival model with 3 health states and 24-month pembrolizumab stopping rule
Company: Proposed model with 24-month stopping rule matching KEYNOTE-775
ERG: Considered the model structure reasonable
Committee: Model structure generally appropriate
ICER impact: negligible
Average age of population modelled
Company: Used age from KEYNOTE-775 trial
ERG: Clinical experts felt average age in KEYNOTE-775 was slightly lower than likely in UK clinical practice
Committee: Mean age of 67 years, between trial estimate and EAG estimate, consistent with real-world studies ECHO
ICER impact: negligible
Choice of parametric curve for extrapolating overall and progression-free survival beyond trial follow-up
Company: Originally used standard parametric and 2-piece parametric curves; later revised to one-knot spline model using odds scale
ERG: Recommended more sophisticated flexible models (cubic splines) rather than standard parametric curves with arbitrary breakpoints
Committee: One-knot spline model was an appropriate choice for extrapolation of both overall and progression-free survival in both arms, given that EAG scenarios testing alternatives had minimal impact on ICER
ICER impact: uncertain_direction
Whether treatment effect continues indefinitely or wanes over time after pembrolizumab stops at 2 years
Company: No treatment effect waning for the duration of the 40-year model time horizon; cites evidence from KEYNOTE-775 showing sustained benefit and long-term data from melanoma and other immunotherapy trials
ERG: Some evidence to support some duration of effect after stopping pembrolizumab but not sufficient to conclude no waning; preferred EAG scenario of waning from years 3-5
Committee: Waning from years 5-7 after starting treatment applied to all patients, based on evidence that treatment effect is likely durable but must assume some waning; committee concluded true result likely between adjusted and unadjusted values
ICER impact: increases
Application of waning from years 5 to 7 after starting treatment (3 to 5 years after treatment with pembrolizumab stops)
Company: Did not incorporate waning in base case
Committee: Apply waning from years 5 to 7 after starting treatment
ICER impact: increases
Adjustment for treatment switching: proportion of comparator arm receiving subsequent PD-1/PD-L1 or VEGF/VEGFR inhibitor therapies not available in NHS practice
Company: Applied two-stage estimation (TSE) method to adjust for treatment switching and incorporated adjusted data in base case
ERG: Noted that committee did not request treatment switching adjustment in preferred base case; company had independently chosen to include it
Committee: Not explicitly stated; committee noted the adjustment gives most optimistic estimate of treatment benefits
ICER impact: increases
Approach to deriving health-state utilities - time-to-death versus progression status
Company: Time-to-death approach with 6 TTD categories allows finer gradations and captures utilities across full spectrum of disease; more comprehensive for immunotherapy trials with limited post-progression utility assessments
ERG: Progression status approach is more consistent with model structure; company approach divorces health-related quality of life from disease status
Committee: EAG approach of deriving utilities using progression status is more appropriate; committee noted increased granularity from company's 6 TTD categories increases uncertainty; maintained that progression status approach is more appropriate
ICER impact: uncertain_direction
Using progression status to derive utilities
Company: Did not incorporate this approach in base case
Committee: Using progression status to derive utilities
ICER impact: uncertain_direction
Evidence gaps
Commercial arrangement
Special considerations
Cross-references