TA865 · STA
Recommended for routine use only when pembrolizumab is unsuitable. Only for adults whose tumour cells express PD-L1 at 1% or more. PD-L1 testing for nivolumab and pembrolizumab suitability should be done concurrently.
Source documents
Intervention
Conditions
Comparators
| Name | Type | Established | Committee preferred |
|---|---|---|---|
| fluoropyrimidine-based and platinum-based chemotherapy alone | active drug | Yes | — |
| pembrolizumab plus fluoropyrimidine- and platinum-based chemotherapy | active drug | Yes | Yes |
| pembrolizumab plus chemotherapy | active drug | Yes | — |
| chemotherapy alone | standard of care | Yes | — |
Clinical trials
| Trial | Design | Phase | Pivotal |
|---|---|---|---|
| CheckMate 648 | RCT | Phase 3 | Yes |
| KEYNOTE-590 | RCT | Phase 3 | Yes |
Economic model
ICER
Methodological decisions (18)
Chemotherapy alone versus pembrolizumab plus chemotherapy as appropriate comparators depending on PD-L1 suitability.
Company: Maintained pembrolizumab was recommended too recently to be considered standard of care; chemotherapy as main comparator
Committee: Chemotherapy is comparator when only nivolumab is suitable (PD-L1 ≥1% and CPS <10); pembrolizumab plus chemotherapy is comparator when both are suitable (PD-L1 ≥1% and CPS ≥10)
ICER impact: uncertain_direction
Calculation of treatment costs adjusted for delayed or missed doses. Company weighted relative dose intensity by time on treatment; ERG excluded time on therapy from base case.
Company: Time on therapy relevant for capturing relative dose intensity weighted by time each patient spent on treatment
ERG: Time on therapy not relevant; omitted from base case
ICER impact: uncertain_direction
Treatment cost adjustment methodology relative to dose intensity
Company: Adjusted treatment costs by relative dose intensity weighted by time on treatment
ERG: Did not weight relative dose intensity by time on treatment
ICER impact: increases
In-trial switching to anti-PD-L1 therapies (including nivolumab and pembrolizumab) observed in CheckMate 648. Company assumed no switching adjustment; ERG preferred adjustment using NICE DSU technical support document 16 methods.
Company: Few people switched to anti-PD-L1 therapy in trial; switching adjustment methods place large demands on limited data creating more uncertainty; base case excludes adjustment
ERG: Switching evidence present and difference between trial and clinical practice switching proportions suggests bias; adjustment preferred to avoid ICER underestimation
ICER impact: increases
Clinical expectation of immunotherapy 'class effect' between nivolumab and pembrolizumab
Committee: Clinical experts maintained effectiveness is almost the same in other cancers and expect consistency in oesophageal squamous cell carcinoma, but noted comparing across different PD-L1 definitions was 'risky' in terms of validity
ICER impact: negligible
Nivolumab plus chemotherapy indirectly compared with pembrolizumab plus chemotherapy using data from CheckMate 648 (nivolumab subgroup) and KEYNOTE-590 (pembrolizumab). No direct trial comparison exists.
Company: Compared populations from CheckMate 648 for whom both nivolumab and pembrolizumab were suitable, generating time-varying HRs
ERG: Preferred including people from CheckMate 648 for whom pembrolizumab was suitable to maintain maximum trial comparability. Generated time-varying HRs favoring pembrolizumab across all time points.
Committee: Acknowledged complexity and that no definitive evidence of superiority of one treatment over the other had been presented. Wide credible intervals crossed 1.
ICER impact: uncertain_direction
Company and ERG used different approaches to ITC. Company included CheckMate 648 people suitable for both drugs and KEYNOTE-590 people suitable for pembrolizumab, using log-normal distribution. ERG included only CheckMate 648 people suitable for pembrolizumab, using log-logistic distribution.
Company: Log-normal extrapolation and inclusion of people from CheckMate 648 for whom both nivolumab and pembrolizumab were suitable
ERG: Log-logistic parametric extrapolation and inclusion of only people from CheckMate 648 for whom pembrolizumab was suitable to maintain maximum trial comparability
ICER impact: uncertain_direction
ITC methodology for comparing nivolumab (from CheckMate 648) with pembrolizumab (from KEYNOTE-590). Company and ERG differed on which patient populations to include and which baseline/scaling approach to use.
Company: Included outcome data from people in CheckMate 648 for whom both nivolumab and pembrolizumab were suitable, and from KEYNOTE-590 for whom pembrolizumab was suitable. Scaled survival using chemotherapy as baseline. Used log-normal distribution for OS extrapolation.
ERG: Included people from CheckMate 648 for whom only pembrolizumab was suitable. Different distribution and baseline used for scaling pembrolizumab survival.
ICER impact: uncertain_direction
Modelling of background mortality in overall survival prediction. Company and ERG disagreed on whether to include additional background mortality rate beyond predicted overall survival.
Company: Background mortality included additional to predicted overall survival, with minimal impact on results
ERG: This approach double-counts mortality; alternative methods should prevent implausibly low hazard rates
ICER impact: negligible
Including all-cause mortality additional to predicted OS mortality
Company: Included all-cause mortality additional to predicted OS mortality
ERG: Not explicitly stated as different in this section
ICER impact: uncertain_direction
Comparability of CheckMate 648 (oesophageal squamous cell carcinoma only) with KEYNOTE-590 (squamous and adenocarcinoma, oesophagus and gastro-oesophageal junction)
ERG: Agreed subgroup appeared comparable but noted conclusions limited due to restricted characteristics presented and data availability issues
Committee: Noted uncertainty about comparability of the 2 trials used in ITC
ICER impact: uncertain_direction
Disagreement on approach to model overall survival. Company used semi-parametric method (Kaplan-Meier plus log-normal extrapolation from 6.9 months) while ERG used fully parametric log-logistic extrapolation.
Company: Semi-parametric approach better reflects changing hazard after 20 months with clear inflection point at 6 months
ERG: Parametric log-logistic extrapolation appropriate, with no clear inflection point in nivolumab arm and reasonable correspondence to observed landmarks
ICER impact: uncertain_direction
Parametric distribution choice for extrapolating progression-free and overall survival data from CheckMate 648.
Company: Semi-parametric extrapolation of PFS and OS data with log-normal distribution for OS
ERG: Different parametric extrapolation approach with modifications to PFS and OS modelling
ICER impact: increases
Company assumed no treatment waning of nivolumab effect; ERG included waning from 2.5-4 years after starting therapy and 6 months after stopping.
Company: Evidence of robust and durable treatment effect lasting beyond discontinuation; any waning assumed at 5 years after starting therapy
ERG: Treatment effect increase over time implausible; waning from 2.5-4 years is appropriate
ICER impact: increases
Whether nivolumab treatment effect wanes over time
Company: Excluded nivolumab treatment waning from base case
ERG: Included waning of nivolumab treatment effect between 2.5 and 4 years
ICER impact: increases
Adjustment to overall survival for subsequent therapy/switching
Company: Excluded any adjustments to OS for subsequent therapy
ERG: Same assumption as company in comparison with chemotherapy alone
ICER impact: negligible
Source of utility values and treatment-specific versus progression-based approaches. Company used average utility from both trial arms; ERG used treatment-specific utilities.
Company: Treatment-specific utilities not appropriate; use progression-based utilities independent of treatment
ERG: EQ-5D scores higher for chemotherapy than nivolumab plus chemotherapy; treatment-specific utilities more appropriate
ICER impact: decreases
Source and type of health-state utilities used in the model
Company: Using progression-based utilities independent of treatment received
ERG: Included treatment-specific progression utilities in the model
ICER impact: decreases
Evidence gaps
Commercial arrangement
Special considerations
Cross-references