TA1027 · STA
Source documents
Intervention
Conditions
Comparators
| Name | Type | Established | Committee preferred |
|---|---|---|---|
| pembrolizumab | active drug | Yes | Yes |
| ipilimumab | active drug | Yes | — |
| nivolumab | active drug | Yes | — |
| dacarbazine | active drug | Yes | — |
| investigator's choice | standard of care | Yes | — |
| ipilimumab plus nivolumab | active drug | — | — |
| best supportive care | best supportive care | — | — |
Clinical trials
| Trial | Design | Phase | Pivotal |
|---|---|---|---|
| IMCgp100-202 | RCT | Phase 3 | Yes |
| IMCgp100-102 | single_arm | 2 | — |
Economic model
ICER
Methodological decisions (13)
Which comparator to use from investigator's choice arm (pembrolizumab 82%, ipilimumab 13%, dacarbazine 6%)
Company: investigator's choice reflected lack of standard care
ERG: all scope comparators should be included in model
Committee: pembrolizumab is most relevant comparator, use subgroup of 82% who had pembrolizumab
ICER impact: decreases
Subsequent treatment costs: company applied one-off cost at progression plus 4 months best supportive care (based on McKendrick et al. 2016); ERG preferred per-cycle costs while in progressive disease state
Company: One-off costs at progression appropriate. 4-month BSC duration based on McKendrick study
ERG: Per-cycle costs more appropriate. One-off costs inappropriate and 4-month duration not related to time in progressive disease state
Committee: Some uncertainty in estimates but limited impact on results. Clinical experts noted treatment usually stops at progression so costs would not accrue
ICER impact: negligible
Treatment adherence consistency: company assumed 92% adherence in tebentafusp arm but 100% in pembrolizumab arm
Company: 92% adherence applied to tebentafusp only
ERG: Adherence unlikely 100% in either arm. Should either apply same adherence to both arms or apply no adherence correction to either
Committee: Adherence would not be 100% for pembrolizumab; some adjustment should be applied to maintain consistency
ICER impact: negligible
Best supportive care costs modelled as one-off costs versus per-cycle costs
Company: One-off costs for best supportive care
ERG: Per-cycle costs for best supportive care
ICER impact: negligible
Whether to adjust for crossover from investigator's choice to tebentafusp in overall survival analysis
Company: crossover adjustment not feasible using standard methods; trial protocol did not mandate crossover; statistical analysis inappropriate due to too few crossovers
ERG: crossover adjustment preferred; company's approach was methodologically most robust as it mirrored clinical practice
Committee: accept company's unadjusted approach as methodologically most robust
ICER impact: uncertain_direction
Progression-free survival and time on treatment extrapolation: company used piecewise approach (Kaplan-Meier data then generalised gamma tail at 15% at risk); ERG preferred fully parametric generalised gamma for both arms
Company: Piecewise approach appropriate: rapid decrease phase followed by flattening. Data shows 15% cut-point appropriate for extrapolation tail
ERG: Fully parametric generalised gamma more appropriate. Kaplan-Meier may overfit and cut-points are arbitrary
Committee: Both approaches reasonable. Given mature PFS data, differences have little impact on cost-effectiveness results
ICER impact: negligible
Piecewise versus fully parametric progression-free survival and time on treatment extrapolation
Company: Piecewise extrapolation
ERG: Fully parametric extrapolation
ICER impact: negligible
Choice of parametric model for extrapolating overall survival beyond trial data
Company: 3-knot spline model for tebentafusp arm (captures change in survival profile) and Weibull for investigator's choice arm
ERG: standard parametric models (log-logistic or generalised gamma) applied to both arms preferred
Committee: standard parametric approaches most appropriate; acknowledged different approach in each arm reasonable given novel mechanism, but concerned about plateau suggesting cure
ICER impact: increases
Overall survival extrapolation approach: company used 3-knot spline for tebentafusp (allowing plateau) and Weibull for investigator's choice; updated to piecewise model for tebentafusp with different parametric models for each arm; ERG preferred standard parametric models (log-logistic or generalised gamma) applied to both arms without plateau
Company: Spline model with plateau justified by novel mechanism of action and atypical hazard profile in tebentafusp arm (hazard increases then decreases). Piecewise model with Kaplan-Meier data for early phase and parametric tail for late phase
ERG: Standard parametric curves should be applied to both arms. Plateau assumption is inappropriate as uveal melanoma is not curative disease. Log-logistic or generalised gamma curves preferred
Committee: Standard parametric approach should be starting point. Company's approach appears to overestimate long-term survival. Standard parametric extrapolation preferred for both arms
ICER impact: increases
Choice of parametric curve for extrapolating overall survival: company preferred piecewise approach, ERG preferred standard parametric curves (generalised gamma or log-logistic)
Company: Piecewise extrapolation for overall survival
ERG: Standard parametric curves (generalised gamma or log-logistic) for overall survival extrapolation
Committee: Standard parametric curves for overall survival extrapolation
ICER impact: increases
2-year stopping rule: company included rule because <5% remained on treatment at 2 years; ERG and committee opposed
Company: 2-year stopping rule appropriate because model predicts <5% of people still on treatment beyond 2 years
ERG: No stopping rule should be applied; no clinical justification for stopping effective treatment
Committee: No stopping rule appropriate; clinical rationale not justified. Patient and clinical experts noted treatment is well-tolerated and no evidence treatment effect would wane after stopping
ICER impact: decreases
Whether and how to apply adherence correction for pembrolizumab relative to tebentafusp
Company: 92% adherence in tebentafusp arm with different assumption for pembrolizumab
ERG: Either include adherence correction for pembrolizumab to maintain consistency with tebentafusp arm, or apply no adherence correction to either arm
Committee: Treatment adherence would not be at 100% for pembrolizumab and some adjustment should be applied
ICER impact: uncertain_direction
Approach to derive utility values: company used time-to-death approach based on Hatswell et al. 2014, applied utilities from NICE's pembrolizumab guidance for advanced melanoma. ERG preferred health state utilities differentiated by progression-free vs progressed states using EQ-5D data from IMCgp100-202
Company: Time-to-death approach more appropriate because disease progression not good marker of quality of life in tebentafusp patients. EQ-5D data from trial had insufficient observations by time-to-death category and high missing data requiring imputation
ERG: Time-to-death approach inconsistent with partitioned survival model structure. Should use progression-state-specific utilities from trial EQ-5D data despite imputation needed
Committee: Time-to-death approach not consistent with model structure but clinical/patient experts agreed disease progression not good QoL marker. Choice of approach unlikely to be important driver of cost-effectiveness results
ICER impact: negligible
Evidence gaps
Commercial arrangement
Special considerations
Cross-references