TA779 · STA
Recommended for use within the Cancer Drugs Fund only. Conditions in the managed access agreement must be followed.
Source documents
Intervention
Conditions
Comparators
| Name | Type | Established | Committee preferred |
|---|---|---|---|
| paclitaxel monotherapy | active drug | Yes | — |
| doxorubicin monotherapy | active drug | Yes | — |
| combination chemotherapy | active drug | Yes | — |
| hormone therapy | active drug | Yes | — |
| current clinical management | best supportive care | Yes | — |
| chemotherapy (various options) | active drug | Yes | — |
Clinical trials
| Trial | Design | Phase | Pivotal |
|---|---|---|---|
| GARNET | single_arm | Phase II | Yes |
| KEYNOTE-775 | RCT | unknown | — |
Economic model
ICER
Methodological decisions (11)
Choice between real-world evidence (RWE) GARNET-like subgroup from NCRAS registry vs KEYNOTE-775 chemotherapy arm as comparator for dostarlimab
Company: RWE registry subgroup should be used as primary evidence to evaluate comparative efficacy due to large sample size, alignment to GARNET patient characteristics, and real-world representation
ERG: RWE subgroup has serious generalisability concerns due to unknown biomarker prevalence, missing ECOG data, histology differences, and differences in prior therapy lines. KEYNOTE-775 would be a more reliable comparator as a biomarker-matched RCT
Committee: KEYNOTE-775 may provide better source of comparative data. RWE subgroup is not a robust comparator for GARNET due to unknown prevalence of high MSI/MMR deficiency, differences in histology (more endometrioid in GARNET), and variations in number of prior treatment lines
ICER impact: uncertain_direction
Validity of matching-adjusted indirect comparisons (MAIC) between GARNET and RWE/other chemotherapy studies
Company: MAIC scenarios (based on expert-identified prognostic variables and statistically significant variables) show dostarlimab benefits persist after adjustment, suggesting minimal differences between cohorts
ERG: Systematic differences remain that cannot be adequately adjusted by statistical methods, including methodological issues with data collection, case definition, and selection. Small sample size studies and poorly reported patient characteristics in chemotherapy comparisons severely limit validity
Committee: MAIC scenarios cannot be considered robust sources of evidence due to high levels of uncertainty. Better data needed for robust analysis of comparative efficacy
ICER impact: increases
Validity and reliability of matching-adjusted indirect comparisons (MAIC) between GARNET trial and UK real-world evidence (RWE) cohort to estimate comparative efficacy of dostarlimab versus current clinical management
Company: Two MAIC scenarios show dostarlimab superiority in overall survival; minimal differences between GARNET and RWE-matched populations
ERG: Systematic differences remain between cohorts due to methodological issues in data collection, case definition and selection; systematic biases cannot be adjusted for by statistical methods; supplementary endometrioid-only MAIC still highly uncertain due to remaining population differences
Committee: Agreed with ERG that MAIC scenarios had high levels of uncertainty and could not be considered robust source of evidence; concluded better data needed for robust comparative efficacy analysis
ICER impact: uncertain_direction
Robustness of matched-adjusted indirect comparison (MAIC) between GARNET and real-world evidence for current clinical management
Company: Used MAIC to indirectly compare dostarlimab to current clinical management
ERG: Expressed concern about uncertainty in MAICs and differences between GARNET and RWE populations
Committee: Committee agreed there was too much uncertainty in the MAICs to be confident about robustness of any ICERs from the economic model
ICER impact: increases
Generalisability of RWE GARNET-like subgroup to GARNET population
Company: The RWE subgroup is closely aligned to GARNET patient characteristics
ERG: Multiple differences limit generalisability: no biomarker data in NCRAS, ECOG performance status missing for ~50% of RWE patients, histology differences (lower proportion of endometrioid in RWE), and RWE had only 1 prior platinum treatment vs GARNET allowing 1 or more prior treatments
Committee: Concerns about matching populations are significant. Clinical experts noted differences in number of prior therapy lines would be key prognostic factor. Discrepancy often exists between RCT and RWE evidence with lower observed efficacy in RWE
ICER impact: increases
Treatment discontinuation estimates for dostarlimab. GARNET trial contained no stopping rule; company elicited clinical expert opinions on time to treatment discontinuation based on numbers remaining at risk.
Company: Presented numbers at risk to clinical experts to obtain range of TTD estimates
ERG: Modelled TTD curve bears no resemblance to numbers at risk; presenting numbers at risk treats data cut-off as discontinuation event, seriously biasing estimates; prefers more conservative value at upper end of range
Committee: Agreed with ERG that elicitation exercise was poorly constructed and results unreliable; concluded more conservative value preferred by ERG is appropriate
ICER impact: increases
Choice of parametric curve for extrapolating overall survival beyond trial data. Company preferred generalised gamma, ERG preferred Weibull. Both models associated with substantial uncertainty due to immature data.
Company: Generalised gamma model is most clinically plausible and aligns with clinical expert feedback; provides good fit to Kaplan-Meier data and longer-term survival estimates
ERG: Generalised gamma is overly optimistic and predicts survivors beyond 30 years implausibly; Weibull is preferred due to concerns about bias in clinical expert elicitation
Committee: Committee noted not enough evidence to prefer either curve; true survival lies within wide range of possibilities
ICER impact: increases
Choice of parametric curve for overall survival extrapolation
Company: Generalised gamma curve
ERG: Weibull curve preferred; noted uncertainty about whether Weibull or generalised gamma appropriate
Committee: Committee concluded not enough evidence to prefer either Weibull or generalised gamma; true survival lies within wide range of possibilities
ICER impact: uncertain_direction
Time to treatment discontinuation (TTD) values and stopping rules elicitation
Company: Company conducted TTD and stopping rules elicitation exercise; proposed values toward upper end of range
ERG: ERG viewed company elicitation exercise as poorly constructed with unreliable results; preferred more conservative values
Committee: Committee concluded more conservative value preferred by ERG is appropriate given high degree of uncertainty
ICER impact: increases
When and how the treatment benefit from dostarlimab diminishes after discontinuation. Company assumed maintenance of full treatment effect for extended duration beyond discontinuation; ERG assumed waning begins immediately at treatment discontinuation.
Company: Referenced previous NICE appraisals accepting 3-5 years treatment effect duration when people stop immunotherapy after 2 years
ERG: No evidence to support this waning profile in this population; prefers immediate waning beginning at treatment discontinuation with declining effect over longer period
Committee: Preferred ERG's more conservative approach given immaturity of data
ICER impact: increases
Whether dostarlimab treatment benefit wanes over time
Company: No modelling of treatment waning
ERG: Both treatment waning and treatment discontinuation should be modelled
Committee: Committee agreed with ERG's preference to model both treatment waning and treatment discontinuation
ICER impact: increases
Evidence gaps
Commercial arrangement
Special considerations
Cross-references