Imatinib for the adjuvant treatment of gastrointestinal stromal tumours

ACOSOG Z9001

3.5 At the primary outcome analysis of ACOSOG Z9001 (median follow‑up 19.7 months), 1‑year recurrence‑free survival was estimated to be 98% (95% confidence interval [CI] 96 to 100) in the imatinib group and 83% (95% CI 78 to 88) in the placebo group, which was a statistically significant difference (hazard ratio [HR] 0.35 [0.22 to 0.53], p<0.0001). Overall survival at 2 years was estimated to be 98.8% in the imatinib group and 97.6% in the placebo group with a hazard ratio of 0.66 (95% CI 0.22 to 2.03), which was not a statistically significant difference.

3.6 At the 5‑year follow‑up analysis of ACOSOG Z9001, approximately 75% of patients in both groups remained on study. The 5‑year follow‑up data showed that estimated 5‑year recurrence‑free survival (median follow‑up 46.3 months) was 72.8% (95% CI 67.1 to 78.4) in the imatinib group and 68.4% (95% CI 63.0 to 73.8) in the placebo group. Recurrence‑free survival for imatinib was statistically significantly greater in the imatinib group compared with the placebo group during follow‑up (HR 0.718 [95% CI 0.531 to 0.971], p=0.0305). The company advised that the follow‑up analysis was confounded by patients who had been randomised to placebo and were recurrence‑free at the time of study unblinding and had then opted to crossover to active treatment for 1 year. The company reported that a supporting analysis which removed these patients had a hazard ratio of 0.671 (95% CI 0.491 to 0.919, p=0.0123), but did not provide any further details about the methodology.

3.7 The 5‑year follow‑up analysis showed that 5‑year overall survival (median follow‑up of 60.2 months) in ACOSOG Z9001 was 91.3% for the imatinib group and 91.1% for the placebo group. There was no statistically significant difference in overall survival between treatment groups during follow‑up (HR 0.816 [95% CI 0.488 to 1.365], p=0.4385). A sensitivity analysis that censored for patients eligible for crossover to 1 year of imatinib treatment gave a hazard ratio of 0.746 (95% CI 0.441 to 1.262, p=0.2725).

SSGXVIII/AIO study

3.8 Median duration of follow‑up was 54 months for the full population. The median time to recurrence was 53.2 months for the 1‑year imatinib group, but it was not reached for the 3‑year imatinib group. Overall, recurrence‑free survival was statistically significantly longer in the 3‑year group than the 1‑year group (HR 0.46 [95% CI 0.32 to 0.65], p<0.0001; 5‑year recurrence‑free survival 65.6% and 47.9% respectively). There was no statistically significant difference in the risk of recurrence or death between the 1‑year and 3‑year treatment groups during the first year of treatment or after 3 years. However, a difference was evident from 1 to 2 years (HR 0.26 [95% CI 0.13 to 0.53]) and from 2 to 3 years (HR 0.17 [95% CI 0.07 to 0.39]) after randomisation.

3.9 Overall survival was statistically significantly greater in the 3‑year imatinib group than in the 1‑year group (HR 0.45 [95% CI 0.22 to 0.89], p=0.019; 5‑year overall survival 92.0% and 81.7% respectively). However, there was no statistically significant difference in 5‑year GIST‑specific survival between the 2 groups (88.5% in the 3‑year group compared with 95.1% in the 1‑year group; HR 0.46 [95% CI 0.19 to 1.14], p=0.09).

EORTC 62024

3.10 The EORTC 62024 interim analysis was for a median follow‑up of 4.7 years. Of the 908 patients who had been randomised to treatment, 835 were eligible for assessment. Recurrence‑free survival for the total study population was statistically significantly greater in the imatinib group than in the observation group at 3 years (84% compared with 66%, p<0.001) and 5 years (69% compared with 63%, p<0.001). There were no statistically significant differences in 5‑year imatinib failure‑free survival between the imatinib and observation groups (87% compared with 84%; HR 0.80 [98.5% CI 0.51 to 1.26], p=0.23). Overall survival at 5 years was similar in the imatinib and observation groups (100% and 99% respectively).

ACOSOG Z9001

3.11 Using the ACOSOG Z9001 primary analysis, the company identified 165 patients at high risk of disease recurrence according to the Miettinen 2006 criteria. For these patients, 1‑year recurrence‑free survival was 98.7% in the imatinib group and 56.1% in the placebo group. An analysis of overall survival showed no statistically significant difference between treatment groups overall (p=0.0764). Overall survival at 2 years was 100% in the imatinib group and 94.7% in the placebo group; at 4 years it was 100% and 90.9% respectively.

3.12 At the 5‑year follow‑up analysis, 103 high‑risk patients had been identified in the imatinib group and 98 high‑risk patients in the placebo group. An improvement in recurrence‑free survival was observed in the imatinib group compared with the placebo group (HR 0.608 [95% CI 0.417 to 0.886], p=0.009). The difference between the imatinib and placebo groups was at its greatest 18 months after randomisation (86.7% [95% CI 79.6 to 93.7] compared with 49.9% [95% CI 39.7 to 60.2] respectively), and then decreased over time (reaching 37.9% [95% CI 25.9 to 49.9] and 32.1% [95% CI 21.6 to 42.6] respectively at 5 years). The company noted that, unlike the primary analysis, the 5‑year follow‑up analysis was confounded by placebo patients who were recurrence‑free at the time of study unblinding opting to crossover to active treatment for 1 year.

3.13 At the clarification stage, the company provided a report that used different methods of adjusting for treatment crossover in ACOSOG Z9001. The methods were: a rank‑preserving structural failure time model, the iterative parameter estimation algorithm, inverse probability of censoring weights (IPCW) and per‑protocol analyses that censored crossovers at the time of switching or excluded them altogether. The report concluded that the IPCW method was the most reliable for recurrence‑free survival and overall survival. In patients at high risk of disease recurrence, the IPCW hazard ratio for recurrence‑free survival was 0.50 (95% CI 0.3 to 0.78), which was similar to the simple, unweighted, per‑protocol censoring approach (HR 0.52 [95% CI 0.35 to 0.77]). Both provide a numerically lower hazard ratio for recurrence‑free survival than the intention‑to‑treat analysis (HR 0.61 [95% CI 0.42 to 0.89]). For overall survival, the IPCW hazard ratio in the high‑risk group was 0.76 (95% CI 0.36 to 1.62), which was similar to the simple, unweighted per‑protocol censoring approach (HR 0.79 [95% CI 0.40 to 1.55]). The report stated that these were numerically lower than the hazard ratio for the intention‑to‑treat analysis (0.93 [95% CI 0.47 to 1.83]).

SSGXVIII/AIO study

3.14 Overall, 70% of patients were at high risk of recurrence according to the Miettinen 2006 criteria (142 in the 1‑year imatinib group and 139 in the 3‑year imatinib group). At the 5‑year follow‑up, recurrence‑free survival was longer in the 3‑year group than in the 1‑year group (HR 0.43 [95% CI 0.30 to 0.62], p<0.0001). Median time to recurrence was 35.9 months in the 1‑year adjuvant imatinib group and 71.8 months in the 3‑year adjuvant imatinib group.

3.15 Overall survival was greater in the 3‑year imatinib group compared with the 1‑year imatinib group (HR 0.39 [95% CI 0.19 to 0.79], p=0.007). Overall survival rates were higher with 3‑year imatinib than 1‑year imatinib at 4 years (94.5% [95% CI 88.6 to 97.3] compared with 83.0% [95% CI 73.8 to 89.1] respectively) and at 5 years (89.5% compared with 74.2%).

EORTC 62024

3.16 The EORTC 62024 interim analysis showed that for a subgroup of patients with high‑risk disease according to the National Institutes of Health consensus criteria, there was no statistically significant difference in 5‑year imatinib failure‑free survival between the imatinib and observation groups (77% and 73% respectively, p=0.44).

ERG's comments

3.21 The ERG stated that the company's submission contained a generally unbiased estimate of imatinib's treatment effect, and noted that the randomised controlled trials had been well conducted (although 2 trials were open label and 2 had experienced a change in the primary outcome). It indicated that the main limitation of the clinical evidence was that the treatment effect for high‑risk patients was based on retrospective subgroup analyses that varied in the proportion of total number of randomised patients (the lowest being 28%), meaning that these are most likely underpowered.

3.22 The ERG stated that differences in baseline patient characteristics between the treatment arms were more pronounced in the Miettinen high‑risk subgroups in than the full trial populations, indicating selection bias. However, the ERG was unclear if the imbalances were statistically significant. Although results were similar for the full population and high‑risk subgroups (in terms of statistically significant recurrence‑free and overall survival differences between trial arms), the ERG concluded that caution was necessary when interpreting the subgroup results.

3.23 The ERG highlighted that there were differences in the results for overall survival between ACOSOG Z9001 and the SSGXVIII/AIO study, and that neither of these trials was statistically powered to detect a difference in this outcome. In ACOSOG Z9001, there were few deaths overall and there was no statistically significant difference in overall survival for imatinib for 1 year compared with placebo at 2 years and 5 years. It further noted that even in the additional analyses that removed patients who had crossed over to active treatment, the difference between trial arms generally remained non‑statistically significant. In the SSGXVIII/AIO study, there were comparatively more deaths and at 5 years there was statistically significantly longer overall survival associated with 3‑year imatinib treatment compared with 1‑year treatment. The ERG stated that although the differences in the overall death rates could potentially be explained by differences in patient characteristics (or other variables) between the 2 trials, the available evidence suggested that extending imatinib treatment to 3 years was associated with longer overall survival than 1‑year treatment.

3.24 The ERG was concerned that the high degree of crossover at study unblinding in ACOSOG Z9001 may have confounded the results and was aware that the company had presented analyses in which patients were censored at the time of crossover. The ERG also reviewed the supplemental report that used various statistical methods to adjust for patient crossover in ACOSOG Z9001, which was provided as part of the company's response to clarification. The ERG agreed that all the methods had advantages and limitations in the assumptions made and their applicability to ACOSOG Z9001, but that the IPCW method appeared to be appropriate. The ERG noted that all methods produced hazard ratios that were lower than the intention‑to‑treat analysis and therefore more favourable to imatinib. It also noted that the IPCW method produced hazard ratios that were similar to a per‑protocol analysis that simply censors switchers at the time of crossover. The ERG considered this to be conservative because both of these approaches gave hazard ratios that were slightly lower (approximately 0.1 to 0.2) than the intention‑to‑treat analysis, compared with bigger differences for some of the other methods.

3.25 The ERG noted that although the company did not present subgroup analyses mentioned in the NICE scope, the SSGXVIII/AIO study reported recurrence‑free survival for predefined exploratory subgroup analyses according to tumour site, tumour size and tumour mutation site for the full population discussed in the company's submission. The ERG noted, however, that no results for the high‑risk group in the SSGXVIII/AIO study had been reported in the journal publication. The results of these subgroup analyses were similar to those of the full population. In the genetic mutational status subgroup, there was a statistically significant treatment effect favouring imatinib for 3 years for patients with the KIT exon 11 mutation, but not for other mutations or for patients with no mutation (but the numbers in these latter groups were smaller). The ERG advised that these analyses were exploratory and were likely to be underpowered.

ERG's comments

3.39 The ERG stated that the model structure and methodology used by the company was a reasonable approach to modelling the cost effectiveness of imatinib as adjuvant treatment for GISTs. It observed that the company had made some amendments to the model in response to comments during the original appraisal of Imatinib for the adjuvant treatment of gastrointestinal stromal tumours (NICE technology appraisal guidance 196). However, the ERG raised several concerns with the estimates and assumptions in the current model.

3.40 The ERG noted that the company's model did not explicitly model disease progression and instead defined the health states based on treatment. As a result, the ERG considered that some of the later progressions in the model did not seem appropriate (for example, patients discontinuing treatment because of adverse events may transition to best supportive care without experiencing disease recurrence).

3.41 The ERG had reservations about the validity of some utility values. It stated that although the majority of these were based on the only published set of values for patients with advanced GISTs, insufficient methodological detail had been reported and there was a lack of information about respondents such as baseline characteristics of respondents, sample size, response rate or the valuation method adopted.

3.42 The ERG stated that there was substantial uncertainty over the company's methods used to derive the baseline risk of recurrence and relative treatment effects for adjuvant imatinib in its economic model. The ERG was aware that the company had adopted these methods to avoid confounding by crossover in the placebo arm of ACOSOG Z9001. The ERG agreed that the Kaplan–Meier curves indicated changes in the shape of the survival curves after stopping adjuvant imatinib treatment, but stated that these trends might have been more apparent, and the cut‑points more easily identified and justified, by plotting the hazard function rather than the Kaplan–Meier curves. Regarding the approach to estimating 'on‑treatment' treatment effect, the ERG was concerned that the company had derived the treatment effects using a semi‑parametric model (Cox proportional hazards) then applied these to fully parametric survival functions used to derive baseline risk of recurrence (that is, with surgery alone). The ERG noted that the on‑treatment recurrence‑free hazard ratio for the high‑risk population, using the Cox proportional hazards model with the data truncated at 12 months, was 0.111 (95% CI 0.043 to 0.281). The ERG noted that this was lower than the hazard ratio of 0.265 (95% CI 0.148 to 0.477) that was reported in the clinical‑effectiveness section of the company's submission, and was unclear whether the difference was caused by truncating the data at 12 months or the retrospective reclassification of additional high‑risk patients. The ERG noted that the company's submission does not state clearly the maximum follow‑up for placebo patients before cross‑over (censoring), so it was unable to judge the duration over which the baseline survival function was modelled. The ERG noted that the company's overall approach had required considerable post‑hoc reorganisation of the trial data and was uncertain if this had introduced biases into the estimated effects. The ERG concluded that it may be more appropriate to use the crossover‑adjusted recurrence‑free survival estimates to derive clinical effectiveness parameters from ACOSOG Z9001.

3.43 The ERG also expressed substantial uncertainty about the most appropriate assumptions for extrapolating the effectiveness of adjuvant imatinib beyond the follow‑up period of the randomised controlled trials providing baseline and relative treatment effects for adjuvant imatinib. The maximum follow‑up in the randomised controlled clinical trials was around 9 years, and these effects were extrapolated over a lifetime (40‑year) time horizon in the model. In particular, the ERG was concerned about the face validity of these survival extrapolations based on the Gompertz function, which suggested a long‑term maintenance of recurrence‑free survival in around 30% of patients who received 3 years' adjuvant imatinib treatment. The ERG was concerned that this may not be appropriate in a population initially identified as being at high risk of recurrence. This compares with approximately 20% recurrence‑free survival at 20 years using the log‑logistic model or approximately 5% using the other functions.

3.44 The ERG assessed the validity of the results generated using the company's model compared with the clinical trials. The ERG considered that there was a reasonable fit for recurrence‑free survival compared with the clinical trials at 5 years for patients who had received adjuvant imatinib (for 1 year or 3 years) and at 2 years for patients who had received no adjuvant treatment. However, the ERG considered the fit for overall survival to be poorer and noted that the company's model underestimated overall survival at 5 years for patients who had received 1‑ or 3‑year adjuvant imatinib treatment, and at 2 years for patients who had received no adjuvant treatment. The ERG added that there was uncertainty around estimated long‑term extrapolation of recurrence‑free survival, and noted that long‑term recurrence‑free survival differed widely according to the parametric distribution chosen. The ERG noted that the parametric distribution chosen by the company produced the most favourable ICER for adjuvant imatinib treatment.

3.45 The ERG expressed uncertainty over the company's approach to incorporating costs for sunitinib in the model. It noted that the company estimated sunitinib use by allowing for a 21% probability of discontinuation per month, which resulted in an estimated mean duration of treatment of 3.48 cycles. The ERG considered that the company had over‑estimated sunitinib use because the 2 clinical trials for sunitinib reported a median of 2 cycles of treatment. Based on the clinical trial results, the ERG calculated that 2.89 cycles would be a more appropriate mean estimate for use in the model. Using the ERG's estimate instead of the company's reduced the monthly cost of sunitinib (with a patient access scheme) from £1615.34 to £1231.17.

3.46 The ERG reviewed how the company had explored uncertainty in its economic model. It considered that both the parameters that were varied and the ranges used in the one‑way sensitivity analyses were appropriate and comprehensive. The ERG indicated that the company's probabilistic sensitivity analyses included most of the variables within the model, that the probability distributions had been correctly applied and that the methods used to assess parameter uncertainty were appropriate. Nevertheless, the ERG noted that the sensitivity analyses in the company's submission did not include varying either the cost of imatinib, or the proportion receiving sunitinib or best supportive care after recurrence.

ERG exploratory analyses

3.47 The ERG identified some errors in the utility values and management costs used in the company's submission and provided corrected base‑case results. In a fully incremental analysis, the ERG's ICER for 1‑year imatinib treatment compared with no adjuvant treatment was £3612 per QALY gained (incremental costs £7819; incremental QALYs 2.16). The ERG's ICER for 3 years' treatment with imatinib compared with 1 year was £16,663 per QALY gained (incremental costs £22,928; incremental QALYs 1.38). These corrected base‑case ICERs were similar to the original base‑case results provided by the company (see section 3.33).

3.48 The ERG explored issues and uncertainties that it had identified in the company's submission, including the assumption of a continuing off‑treatment effect of adjuvant imatinib, the parametric distribution used for modelling recurrence‑free survival, resistance to imatinib and the mortality estimates used for the recurrence health states. The ERG did the following analyses:

3.49 Full details of all the evidence are in the committee papers.