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The company presented a 3‑state partitioned survival model to estimate the cost effectiveness of trifluridine–tipiracil plus bevacizumab compared with trifluridine–tipiracil alone, regorafenib and best supportive care. The 3 health states were progression free, progressed disease and death. The model had a time horizon of 15 years and a cycle length of 1 week with no half cycle correction. The committee concluded that the model structure was appropriate.
To estimate long-term overall survival for trifluridine–tipiracil plus bevacizumab and trifluridine–tipiracil alone, the company fitted independent parametric models to the SUNLIGHT overall survival data (see section 3.4). The company's base case used a log-logistic extrapolation because the company thought that the log-logistic function:
had the best statistical and visual fit to the data
was supported by the clinical expert opinion it had sought.
The EAG did not think that the log-logistic extrapolation was clinically plausible because:
the proportion of people alive at 5 years was too high, according to input from its clinical expert
the modelled overall survival increase for trifluridine–tipiracil plus bevacizumab compared with trifluridine–tipiracil alone at year 2 was greater than the overall survival benefit reported in SUNLIGHT at 1 year.
The EAG preferred to use a generalised gamma extrapolation because it produces a steeper decline in early survival, in line with clinical expert opinion. It noted that the overall survival curves for trifluridine–tipiracil plus bevacizumab and trifluridine–tipiracil alone crossed over at 4 years in the generalised gamma model. But the EAG highlighted that the number of people predicted to still be alive at this point was extremely small. This meant the curves crossing over had a minimal impact on the modelled outputs. The clinical experts commented that both the company's and EAG's overall survival curves could have potentially underestimated overall survival for trifluridine–tipiracil alone. But, they noted that this prediction was based on limited data from their own clinical practice. The committee considered that log-logistic and generalised gamma extrapolations could be plausible, but both were uncertain. It also thought that the differences in the tail ends of the extrapolation curves were the key drivers of cost-effectiveness estimates. It considered that it would be appropriate to consider analyses applying relative treatment effects from SUNLIGHT to observational survival data for trifluridine–tipiracil alone. This was because the proportional hazards assumption was likely to hold (see section 3.6). It concluded that, because of the important uncertainties in the overall survival modelling, additional analyses in which a hazard ratio from SUNLIGHT (see section 3.4) is applied to long-term survival data from UK clinical practice were needed to help resolve this uncertainty.
The company modelled overall and progression-free survival for regorafenib in its base case. It did this by applying HRs from a random-effects NMA (see section 3.6) to the overall and progression-free survival extrapolated curves for trifluridine–tipiracil plus bevacizumab. The EAG noted that the curves used for overall and progression-free survival were accelerated failure time models. It stated that proportional hazards assumptions do not hold for this type of model. The EAG provided an additional analysis in the form of a naive comparison with regorafenib. It did this by fitting independent survival curves to the Kaplan–Meier data for regorafenib from the CORRECT study. This was a phase 3 randomised controlled trial of regorafenib with best supportive care compared with placebo with best supportive care in adults who had previously had treatment for mCRC. The EAG acknowledged that neither approach was ideal. But, it considered that the naive comparison may have been less biased, so used it in its base case. The committee noted that this made minimal difference to the cost-effectiveness results. It also noted that, although the company had used accelerated failure time models as the reference curve, a hazard ratio assuming proportional hazards could reasonably be applied. The committee concluded that it might prefer the company's approach because it maintained randomisation. But, the committee also noted that using trifluridine–tipiracil plus bevacizumab as the reference curve meant that exploring treatment waning scenarios in the model would require artificial upwards adjustment of the hazard ratios of the comparator arms and may not represent a true waning effect. The committee thought that it would be more appropriate to use trifluridine–tipiracil alone as the reference curve, and apply the hazard ratios from the random-effects NMA for regorafenib to that curve. It concluded that additional analyses using this approach were needed, including exploration of treatment-waning scenarios, to provide more certainty when validating overall survival.
The company assumed that time on treatment for regorafenib was equal to progression-free survival for regorafenib in the company's base case. This was in line with the approach used in NICE's technology appraisal guidance on regorafenib for previously treated mCRC, in which people had regorafenib treatment until their cancer progressed. The EAG disagreed with this approach, stating that it overestimated the acquisition costs of treatment with regorafenib. The EAG's clinical expert stated that regorafenib treatment could be stopped before disease progression because of toxicity. The clinical experts confirmed that regorafenib can be stopped before progression because of tolerability issues. The EAG preferred to assume that:
a proportion of people who were progression free at any one time were having regorafenib
the proportion who were progression free and having regorafenib was equal to mean time on treatment from CORRECT divided by the mean modelled progression-free survival from the company's base-case analysis.
The EAG highlighted that this approach (in which a proportion of people who were progression-free were having regorafenib) resulted in a closer median time on treatment for regorafenib (median 8.8 weeks) to that seen in CORRECT (median 7.4 weeks) than the company's approach (median 14.0 weeks). The EAG calculated the proportion of the progression-free cohort on regorafenib treatment to be 68%, and the company considered that this was an underestimate. The EAG agreed to check its approach. The committee agreed that time on treatment with regorafenib would be overestimated if treatment was assumed until progression. But, it also acknowledged that the scenario provided by the EAG could have been an underestimate. It concluded that it would like to see further sensitivity analysis that increased the proportion of the progression-free cohort on regorafenib.
The company modelled regorafenib's relative dose intensity (RDI) as equal to that of trifluridine–tipiracil. This was in line with the preferred approach in NICE's technology appraisal guidance on regorafenib for previously treated mCRC. The EAG preferred to use data from CORRECT to reflect RDI, which was consistent with the preferred data source for progression-free survival, overall survival and time on treatment for regorafenib. The clinical experts noted that side effects with regorafenib would be managed with dose reductions in clinical trials and NHS practice. But, they thought that continuing with the full dose would be possible despite the side effects if the mCRC was responsive to the full dose of regorafenib. They considered that benefit was still possible in terms of progression-free survival with lower doses of regorafenib. The committee considered that the differences between the company's and EAG's assumptions for RDI had a minimal impact on cost-effectiveness estimates. But, in principle, it preferred an analysis that more closely matched regorafenib's use in clinical practice, which likely includes dose reductions in line with CORRECT.
In the company's base case (see section 3.7), utility values for the progression-free and progressed health states were derived from a regression model fitted to EQ‑5D data from SUNLIGHT (see section 3.4). The company assigned higher utility values for trifluridine–tipiracil plus bevacizumab. This was based on a higher overall response rate compared with trifluridine–tipiracil alone. The EAG noted that the interaction terms for the treatment arm and progression state were not statistically significant. It also noted that, when adjusted for baseline utility value, the treatment effect was no longer statistically significant. It preferred pooled utility values for the progression-free and progressed health states. It also provided additional scenarios with alternative sources of utility values from NICE's technology appraisal guidance on trifluridine–tipiracil for previously treated mCRC and NICE's technology appraisal guidance on regorafenib for previously treated mCRC. The committee agreed that the evidence for treatment-specific utility values was not convincing, and preferred pooled utility values for each health state. It considered the range of utility value sources, but noted that the source of pooled utility values had limited impact on the cost-effectiveness results.
In the company's base case, the costs of subsequent treatments were modelled using the proportion and distribution of subsequent treatments used in SUNLIGHT (see section 3.4). The EAG highlighted that the combinations of subsequent treatments in SUNLIGHT do not match UK clinical practice. It also noted that the high proportion of retreatment with regorafenib seen in SUNLIGHT would be unlikely in NHS practice. The EAG used the same proportion of people having subsequent treatments as in SUNLIGHT (58.3%). But, it preferred to assume that, based on expected UK clinical practice, everyone:
on trifluridine–tipiracil (with or without bevacizumab) had subsequent regorafenib
in the regorafenib arm had subsequent trifluridine–tipiracil alone.
The EAG also highlighted that increased progression-free survival with more effective treatments may have increased the chance of people being well enough to have another line of treatment. But it noted that the differences in subsequent treatments used across treatment arms in SUNLIGHT were small, and the impact of subsequent treatment distribution on cost-effectiveness estimates was minimal. The Cancer Drugs Fund clinical lead provided data on trifluridine–tipiracil and regorafenib treatment use at third and fourth lines in NHS England. They highlighted that the attrition rate currently between third- and fourth-line treatment is around 35%. The clinical experts said that differences in individual performance status and patient choice may affect treatment sequencing. They also said that improved survival may lead to increased use of subsequent treatments. The committee concluded that using the proportion of people having subsequent treatment data from NHS England was appropriate for decision making. But, it noted uncertainty because there was no data on how improved survival with trifluridine–tipiracil with bevacizumab would affect these proportions. It thought that this may have led to bias in favour of trifluridine–tipiracil with bevacizumab.
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