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Clinical effectiveness

Key clinical trial: SUNLIGHT

3.4

The clinical evidence for trifluridine–tipiracil plus bevacizumab came from an open-label phase 3 randomised controlled trial, SUNLIGHT (n=492). It included people with unresectable, refractory mCRC who had had a maximum of 2 previous chemotherapy regimens. It evaluated trifluridine–tipiracil plus bevacizumab compared with trifluridine–tipiracil alone, and the primary outcome was overall survival. Other outcomes included progression-free survival, overall response rate, disease control rate, adverse events and health-related quality of life. The results showed that there was a statistically significant increase for trifluridine–tipiracil plus bevacizumab compared with trifluridine–tipiracil alone for overall survival (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.49 to 0.77) and progression-free survival (HR 0.44, 95% CI 0.36 to 0.54). The clinical experts said that the estimates of overall and progression-free survival in the trial were plausible and were likely generalisable to NHS practice. They also highlighted that the rate of adverse events associated with bevacizumab in the trial was relatively low and considered that trifluridine–tipiracil plus bevacizumab is well tolerated. The committee concluded that there was a clear survival benefit of adding bevacizumab to trifluridine–tipiracil.

Previous bevacizumab use

3.5

The company's base-case analysis used data from the intention-to-treat population in SUNLIGHT. This included a large proportion of people who had previously had bevacizumab (72%). The company highlighted that, although this does not reflect clinical practice in England because bevacizumab is not currently recommended at earlier lines of mCRC treatment, it thought that:

  • previous bevacizumab was not a treatment effect modifier

  • the intention-to-treat population in SUNLIGHT was generalisable to people with mCRC in the NHS.

The EAG agreed that the ITT population in SUNLIGHT was generalisable to people in the NHS. It pointed out that although a subgroup analysis of people who had not had bevacizumab in SUNLIGHT suggested the treatment effect of trifluridine–tipiracil plus bevacizumab in SUNLIGHT was potentially larger in people who had not had bevacizumab before, this effect was not statistically significant. The clinical experts suggested that the treatment effect of trifluridine–tipiracil plus bevacizumab in SUNLIGHT may have underestimated the treatment effect in people with mCRC in the NHS. But, they thought that the size of the additional treatment effect was unquantifiable. The clinical experts also clarified that, if bevacizumab is recommended at earlier lines of treatment in the future, a clear benefit of trifluridine–tipiracil plus bevacizumab would still be seen. The committee concluded that it was appropriate to consider the SUNLIGHT intention-to-treat population regardless of previous bevacizumab use. It also concluded that, if bevacizumab is added to earlier treatment lines in future clinical practice, the SUNLIGHT treatment effects will become more generalisable to people with mCRC in NHS clinical practice.

Indirect treatment comparison

3.6

The company did not have direct clinical-effectiveness evidence for trifluridine–tipiracil plus bevacizumab compared with regorafenib or best supportive care. So, it did a network meta-analysis (NMA) to provide estimates of relative treatment effectiveness for overall and progression-free survival. The results of the NMA favoured trifluridine–tipiracil plus bevacizumab compared with regorafenib for overall survival (HR 0.60, 95% CI 0.38 to 0.95) and progression-free survival (HR 0.49, 95% CI 0.31 to 0.84). The EAG noted that the NMA was based on reported HRs that assumed proportionality in hazards. The company acknowledged that this may have biased the results and associated extrapolations at certain time points. Although the EAG agreed, it also stated that was unlikely to have had a significant effect on the results because long-term overall survival for mCRC is low. The committee thought that the proportional hazards assumption was likely to hold for overall and progression-free survival for trifluridine–tipiracil plus bevacizumab. It concluded that the results of the NMA were appropriate for decision making.