Health-related quality-of-life data was collected in KEYNOTE‑868, but the data was not collected using the EQ‑5D. The company advised that it had been unable to find a suitable method for converting the data collected in KEYNOTE‑868 to EQ‑5D data. The company then assessed other sources of health-related quality-of-life data. It thought that the endometrial cancer subgroup of KEYNOTE‑158 was the most suitable source of health-related quality-of-life data. The company noted that, although it included only people with dMMR cancer and people who had had previous treatment, the endometrial cancer subgroup population of KEYNOTE‑158 aligned reasonably well with the population of KEYNOTE‑868. The resulting utility values were used for the all-comer population and were also used in the company's analysis of the dMMR and pMMR subgroups. The EAG was concerned about the small sample size of the endometrial cancer subgroup in KEYNOTE‑158 (the exact population size is considered confidential by the company so cannot be reported here). It noted that, because of the small sample size, the data has limited generalisability, is associated with wide confidence intervals and may under- or overestimate utility values. The EAG was also concerned that health-related quality-of-life data was collected only in people with dMMR cancer, and that people with pMMR cancer may have different utility values. At the committee meeting, a clinical expert advised that they were not aware of any evidence of differences in quality of life between people with dMMR and pMMR cancer. Another clinical expert advised that dMMR cancer would be expected to respond better to immunotherapy, so might have a higher utility value than pMMR cancer if both respond to treatment. The committee recalled its preference for analysing the data by MMR subgroup (see section 3.5). It thought that the company's choice of source for health-related quality-of-life data was the most suitable for the dMMR population, but was concerned that it would not adequately represent the pMMR population. So, the committee requested that the company and EAG explore sources for health-related quality-of-life data in people with pMMR cancer or justify using the KEYNOTE‑158 endometrial cancer subgroup health-related quality-of-life data in the pMMR population.
In response to the draft guidance consultation, the company presented evidence that suggested similar utility values between the dMMR and pMMR subgroups. This included a comparison of the all-comer population and pMMR subgroup (which was 84% of the all-comer population) from KEYNOTE‑775, which showed similar health-related quality-of-life results between the 2 groups. The company also provided an analysis from the RUBY study, which showed a slightly higher utility in the overall population than in the dMMR subgroup. It also used utility values from KEYNOTE‑B21, which became available after the first committee meeting. KEYNOTE‑B21 is a study of people with previously untreated, post-surgical, endometrial cancer. The company thought that the results for the disease-free health state were very similar between the dMMR and pMMR cohorts but noted that it was an earlier stage of cancer. The company also noted that the progressed-disease health state has a lower utility value than the progression-free state, so the impact of lower response rate in the pMMR subgroup is already accounted for in the model. The company noted that, in the long term, the progression-free health state will mostly comprise responders. So, it thought that dMMR utilities should still be reflective of people with pMMR cancer who remain progression free in the long term, because these are also people whose cancer had a good response to treatment. The company used health-related quality-of-life data from the pMMR subgroup in KEYNOTE‑B21 to derive utilities for the progression-free health state in the model. The company thought that the disease recurrence health state from KEYNOTE‑B21 was largely aligned with the model's progression-free health state. An equivalent of the progressed-disease health state was not available from KEYNOTE‑B21, so the company continued to use the value from KEYNOTE‑158 for the progressed-disease utility value.
The EAG had several concerns about the company's updated approach. It noted that the dMMR utility values from KEYNOTE‑B21 lack face validity, which may question the validity of the pMMR values. The EAG also thought that the people in the disease recurrence health state in KEYNOTE‑B21 were not identical to the starting population of KEYNOTE‑868, noting that they may have had different previous treatments and have different current treatments. The EAG also preferred not to mix the source of utility values for each health state without good justification. So, it preferred to maintain using KEYNOTE‑158 sourced utility values in its base case.
At the second committee meeting, the clinical expert advised that the trial population of KEYNOTE‑868 was dissimilar to the KEYNOTE‑B21 population. But, they expected dMMR and pMMR utility values to be different because the groups respond differently to treatment. The committee noted the clinical expert's view that dMMR and pMMR utility values are expected to be different. But, it was reassured by the evidence presented by the company that indicated that, within each health state, utility values between subgroups were similar. It also noted the limited impact on the cost-effectiveness results when using either the company's or the EAG's preferred approach. So, it agreed that using the KEYNOTE‑158 utilities for both subgroups in the progression-free and progressed-disease health states was the best available approach for estimating utility values in the model.