Sunitinib for the treatment of gastrointestinal stromal tumours: a critique of the submission from Pfizer

Abstract

The submission's evidence for the clinical effectiveness and cost-effectiveness of sunitinib for the treatment of gastrointestinal stromal tumours (GISTs) is based on a randomised controlled trial (RCT) comparing sunitinib with placebo for people with unresectable and/or metastatic GIST after failure of imatinib and with Eastern Cooperative Oncology Group (ECOG) progression status 0-1, and an ongoing, non-comparative cohort study of a similar population but with ECOG progression status 0-4. The searches are appropriate and include all relevant studies and the RCT is of high quality. In the RCT sunitinib arm overall survival was 73 median weeks [95% confidence interval (CI) 61 to 83] versus 75 median weeks (95% CI 68 to 84) for the cohort study. However, time to tumour progression in the cohort study was different from that in the RCT sunitinib arm [41 (95% CI 36 to 47) versus 29 (95% CI 22 to 41) median weeks respectively]. Median progressionfree survival with sunitinib was 24.6 weeks (95% CI 12.1 to 28.4) versus 6.4 weeks (95% CI 4.4 to 10.0) on placebo (hazard ratio 0.333, 95% CI 0.238 to 0.467, p < 0.001). The manufacturer used a threestate Markov model to model the cost-effectiveness of sunitinib compared with best supportive care for GIST patients; the modelling approach and sources and justification of estimates are reasonable. The base-case incremental cost-effectiveness ratio (ICER) was £27,365 per quality-adjusted life-year (QALY) with the first cycle of sunitinib treatment not costed; when we included the cost of the first treatment cycle we estimated a base-case Discussion of ERG reports is invited. Visit the HTA website correspondence forum (www.hta.ac.uk/ correspond). DOI: 10.3310/hta13suppl2/10 Sunitinib for the treatment of gastrointestinal stromal tumours: a critique of the submission from Pfizer 70ICER of £32,636 per QALY. Pfizer's sensitivity analysis produced a range of ICERs from £15,536 per QALY to £59,002 per QALY. Weaknesses of the manufacturer's submission include that the evidence is based on only one published RCT; that 84% of the RCT control population crossed over to the intervention group, giving rise to the use of unusual rank preserved structural failure time (RPSFT) analysis to correct for possible bias; and that a number of errors and omissions were made in the probabilistic sensitivity analysis, meaning that it is not possible to come to firm conclusions about the cost-effectiveness of sunitinib for GIST in this patient population. In conclusion, during the blinded phase of the RCT, overall survival was significantly longer in the sunitinib arm than in the placebo arm (hazard ratio 0.491, 95% CI 0.290 to 0.831, p <0.007). However, intention-to-treat analysis of the entire study showed no statistically significant difference in overall survival for those who received sunitinib (73 weeks) versus those who received placebo (65 weeks) (hazard ratio 0.876, 95% CI 0.679 to 1.129, p = 0.306).

Health utility of patients with advanced gastrointestinal stromal tumors (GIST) after failure of imatinib and sunitinib: findings from GRID, a randomized, double-blind, placebo-controlled phase III study of regorafenib versus placebo

“…The previous GIST utility assessment also noted differences in utilities between actively treated subjects and BSC [ 12 ]. An appraisal of these data noted that the specific disutility of treatment-related events was not reported; however, it was acknowledged that the impact of such events was implicit in the lower utility values for actively treated subjects.…”

“…Previous HRQoL investigations of patients with GIST were derived from the investigational randomized studies of sunitinib for patients with unresectable and/or metastatic GIST and who had failed or were resistant to imatinib. In the PF state, a utility value of 0.731 was observed for sunitinib-treated subjects and 0.781 for those on BSC [ 12 ]. The previously reported BSC utility values are consistent with the nonsignificantly different baseline utility values reported here for regorafenib and BSC of 0.779 and 0.751, respectively, as well as the utility value obtained from the combined PF data set of 0.769 (SD 0.226).…”

“…Increasingly the patient experience is viewed as an important outcome for cancer patients where societal preferences for quantity and quality of life are recognized [ 11 ]. In GIST patients with advanced disease, maintaining quality of life is particularly important as many patients survive for many years with the targeted treatments, and current therapies used to treat GIST can cause side effects known to impair quality of life (QoL) [ 12 ]. This approach illustrates the advantages of measuring the consequences of therapeutic options to better understand whether side-effect profiles of new interventions pose any threat to QoL for progression-free and progressed patients [ 13 ].…”

Prevalence of gastrointestinal stromal tumour (GIST) in the United Kingdom at different therapeutic lines: an epidemiologic model

“…Another limitation we encountered was that data needed to inform the model parameters were sparse or unsuitable, which has also been reported in economic modelling studies [26-30]. This limitation is common in modelling studies since it is not always possible to inform all of the model parameters, considering that the samples of the available studies are small [27], the evidence for the model is obtained from only one study [26] or data are used from other countries and applied to the country of interest due to lack of local evidence [29]. …”

Adjusting Survival Time Estimates to Account for Treatment Switching in Randomized Controlled Trials—an Economic Evaluation Context

“…The RPSFTM method was designed specifically for an RCT context and has been used recently in HTAs. 10,11,17 It uses a counterfactual framework to estimate the causal effect of the treatment in question, 18 where counterfactual survival times refer to those that would have been observed if no treatment had been given. It is assumed that counterfactual survival times are independent of treatment group, and g-estimation is used to determine a value for the treatment effect that satisfies this constraint.…”