TA866 · STA
Regorafenib is only recommended if the company provides it according to the commercial arrangement (simple discount patient access scheme)
Source documents
Intervention
Condition
Comparators
| Name | Type | Established | Committee preferred |
|---|---|---|---|
| trifluridine-tipiracil | active drug | Yes | — |
| best supportive care | best supportive care | Yes | — |
| trifluridine–tipiracil | active drug | — | — |
Clinical trials
| Trial | Design | Phase | Pivotal |
|---|---|---|---|
| CORRECT | RCT | 3 | Yes |
| CONCUR | RCT | 3 | Yes |
Economic model
ICER
Methodological decisions (16)
Relative dose intensity (RDI) modelling approach for regorafenib vs trifluridine-tipiracil
Company: RDI for regorafenib based on mean dose used in CORRECT and CONCUR; for trifluridine-tipiracil, cycle delay and dose reduction modelled separately
ERG: Mean dose from CORRECT and CONCUR already includes both dose delay and dose reduction; real-world evidence (Nakashima 2020) shows similar dose reduction for both treatments (54% vs 48%); EAG preferred equal RDI for both treatments
Committee: Both dose delay and dose reduction should be used for RDI estimation; preferred EAG's approach of applying equal RDI to trifluridine-tipiracil and regorafenib
ICER impact: decreases
Inclusion of grade 1 and 2 adverse events in economic model
Company: Only grade 3 and 4 adverse events (seen in over 2%) captured in base case; scenario analysis with grade 1 and 2 events had negligible impact (fixed cost £5 per event, disutility 0.01)
ERG: Not explicitly stated
Committee: Grade 1 and 2 adverse events should be included in the economic model, despite company scenario showing negligible impact
ICER impact: uncertain_direction
Equal relative dose intensity (RDI) for regorafenib and trifluridine–tipiracil
Company: Company base case did not reflect this preference
Committee: equal RDI for regorafenib and trifluridine–tipiracil
ICER impact: negligible
Inclusion of grade 1 and 2 adverse events in the model
Company: Company base case did not reflect this preference
Committee: include grade 1 and 2 adverse events
ICER impact: negligible
Indirect treatment comparison for regorafenib vs trifluridine-tipiracil using network meta-analysis and MAIC, but substantial heterogeneity between trial populations (CORRECT/CONCUR vs RECOURSE/TERRA/Yoshino 2012)
Company: Fixed effect NMA and MAIC show similar efficacy (HR 0.99); potential efficacy modifiers weighted by baseline characteristics
ERG: Concerns about differences in trial populations, particularly progression-free survival differences in Asia-only studies and heterogeneity in prior anti-VEGF treatment exposure and number of previous lines
Committee: Indirect treatment comparison associated with uncertainty due to heterogeneity; regorafenib likely to provide similar benefits but with uncertainty acknowledged
ICER impact: uncertain_direction
Use of indirect treatment comparison vs observational evidence to compare regorafenib and trifluridine-tipiracil
Company: Noted high risk of bias in observational studies
ERG: Reported results from observational studies but noted issues with baseline characteristics and potential immortal time bias
Committee: Preferred clinical-effectiveness estimates using indirect treatment comparison over observational studies; noted observational evidence compounds risk of bias due to differences in trial baseline characteristics
ICER impact: uncertain_direction
Whether 1.7 severity weighting should apply for trifluridine-tipiracil and best supportive care comparisons
Company: Provided evidence that previously treated mCRC is severe condition; calculated proportional QALY shortfall above 0.95 for both comparators, meeting criteria for 1.7 weighting
ERG: Not explicitly stated as different from company
Committee: 1.7 weighting should NOT be applied for trifluridine-tipiracil comparison due to uncertainty around data used to estimate QALYs (would have preferred real-world data); 1.7 weighting SHOULD be applied for best supportive care comparison as people receiving it would likely be less well with worse prognosis, giving greater face validity to estimates
ICER impact: decreases
Differences in baseline characteristics between CORRECT (global population, more prior biological therapy, more KRAS mutation, more ECOG 0) and CONCUR (Asia-only, longer metastatic disease duration) trials raised concerns about effect modification
Company: Pooled results from both trials are appropriate and generalisable to NHS clinical practice
ERG: Significant differences in trial populations create substantial uncertainty; concerns about anti-VEGF treatment history and baseline characteristics
Committee: Acknowledged differences in baseline characteristics increase uncertainty but concluded pooled results are likely generalisable to NHS practice in absence of further data
ICER impact: uncertain_direction
Choice of parametric survival curve for extrapolating overall survival beyond trial follow-up period
Company: Fully parametric models fit to pooled CORRECT and CONCUR trial data; Kaplan-Meier followed by parametric extrapolation for time-on-treatment and PFS
ERG: Preferred fully parametric models to avoid stepped nature of Kaplan-Meier curves causing overfitting; aligns with NICE DSU TSD14
Committee: Generalised gamma is the best visual fit to long-term overall survival data (up to 5 years) provided in clarification response; should be used for cost-effectiveness estimates instead of fitting only to trial data
ICER impact: increases
Choice of parametric survival curve for overall survival extrapolation
Company: Fitted parametric models to pooled CORRECT and CONCUR data; used Kaplan-Meier then parametric models for time-on-treatment and PFS
ERG: Preferred fully parametric models for base case, noting that stepped KM curves could cause overfitting; aligns with NICE DSU TA14
Committee: Generalised gamma was the best visual fit to company's long-term overall survival data (up to 5 years) for regorafenib and best supportive care; this should be used for cost-effectiveness estimates
ICER impact: uncertain_direction
Committee preferred fully parametric survival models for overall survival estimates using generalised gamma for both regorafenib and best supportive care
Company: Company base case did not reflect this preference
Committee: generalised gamma parametric model for OS
ICER impact: impacted the cost-effectiveness estimates
Committee preferred fully parametric survival models for progression-free survival estimates using log-logistic for both regorafenib and best supportive care
Company: Company base case did not reflect this preference
Committee: log-logistic parametric model for PFS
ICER impact: impacted the cost-effectiveness estimates
Committee preferred fully parametric model for regorafenib time-on-treatment estimates using log-logistic
Company: Company base case did not reflect this preference
Committee: log-logistic parametric model for time-on-treatment
ICER impact: impacted the cost-effectiveness estimates
Post-progression treatment costs and sequencing of regorafenib and trifluridine-tipiracil
Company: Post-progression treatment costs not included in base case; noted that fewer than 10% would have post-progression treatment; scenario analysis applied single cost of £1,633.18
ERG: Not explicitly stated
Committee: Subsequent treatments should be included in cost-effectiveness modelling; around 30% of people would be offered post-progression treatment; no difference in efficacy expected if trifluridine-tipiracil used at fourth line instead of best supportive care (due to different mechanisms of action)
ICER impact: increases
Inclusion of subsequent treatments in the cost-effectiveness model
Company: Company base case did not reflect this preference
Committee: include subsequent treatments
ICER impact: negligible
Source and applicability of utility values for trifluridine-tipiracil comparison
Company: Utility values from pooled EQ-5D-3L results in CORRECT and CONCUR; assumed pre-progression (0.72) and post-progression (0.59) utility values equal for trifluridine-tipiracil and regorafenib because trifluridine-tipiracil trials did not report quality-of-life results
ERG: Had concerns about plausibility of pooled end-of-treatment results being used to derive post-progression health state
Committee: Appropriate to use pooled estimates from clinical trials; utility values from CORRECT were used for NICE TA on trifluridine-tipiracil
ICER impact: uncertain_direction
Evidence gaps
Commercial arrangement
Special considerations
Cross-references