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Endometrial cancer starts in the lining of the uterus. Symptoms can include vaginal bleeding, pelvic pain, unintended weight loss, nausea and fatigue. Endometrial cancer has a significant effect on both life expectancy and quality of life. People with advanced or recurrent endometrial cancer (meaning that the cancer has spread beyond the uterus or come back after previous treatment) have a poor prognosis; only 15% of people diagnosed at stage 4 live for 5 or more years. The patient experts explained that an endometrial cancer diagnosis is psychologically very challenging. The committee concluded that advanced or recurrent endometrial cancer has a devastating effect on life expectancy and quality of life.

Mismatch repair (MMR) is a system used by cells to correct the mutations in DNA that can cause cancer. Endometrial cancer can be mismatch repair deficient (dMMR; around 25% to 30% of cases) or proficient (pMMR; around 70% to 75% of cases). dMMR tumours are more likely to have high levels of mutation. The higher levels of mutation in dMMR tumours lead to more abnormal proteins being produced that are recognised by the immune system. dMMR endometrial cancer generally has a better prognosis than pMMR endometrial cancer. dMMR tumours also generally have a better response to immunotherapy treatments. The clinical experts explained that some pMMR tumours have biomarkers that are associated with a particularly poor prognosis and are unlikely to respond to treatment. But, some pMMR endometrial cancers can respond well to treatment. The committee concluded that, in general, dMMR endometrial cancer has a better prognosis and response to treatment than pMMR endometrial cancer.

KEYNOTE-868 is an ongoing multicentre, randomised, double-blind, phase 3 trial comparing pembrolizumab with carboplatin and paclitaxel followed by pembrolizumab maintenance against carboplatin and paclitaxel and followed by placebo maintenance. Initial treatment was for 18 weeks, followed by maintenance treatment for 84 weeks. Treatment continued until disease progression, unacceptable toxicity or the maximum treatment time was reached, which was approximately 24 months. The primary outcome of the trial was progression-free survival. Overall survival was a secondary outcome. The trial randomised 819 people with previously untreated advanced or recurrent endometrial cancer. A total of 408 people had pembrolizumab with carboplatin and paclitaxel and 411 had placebo with carboplatin and paclitaxel. Each intervention group was split into dMMR (222 people) and pMMR (597 people) subgroups. The results indicated that pembrolizumab with carboplatin and paclitaxel followed by pembrolizumab maintenance was significantly more effective at preventing progression or death than carboplatin and paclitaxel alone in both the dMMR subgroup and pMMR subgroups (the results from each subgroup are considered confidential by the company so cannot be reported here). Overall survival improved in each subgroup in people who had pembrolizumab with carboplatin and paclitaxel, but was not statistically significant in either subgroup. The committee noted that the relatively short follow-up time from the most recent data cut (the exact follow-up time is considered confidential by the company so cannot be reported here) may have affected the statistical significance of the overall survival results. The committee also noted that nobody from the UK was included in the trial, but clinical experts advised that this should not affect the generalisability of the results to NHS clinical practice. The clinical experts advised that stopping treatment after 2 years was appropriate because treatment response had occurred before this point. The committee concluded that pembrolizumab with carboplatin and paclitaxel is an effective treatment for improving progression-free survival in people with untreated advanced or recurrent endometrial cancer, but it was less certain how effective it was at prolonging overall survival. It also concluded that stopping pembrolizumab after 2 years was appropriate, in line with the clinical expert advice and trial evidence.

The company retrospectively combined the dMMR and pMMR subgroups to produce an 'all-comer' population, which it used for most of its analyses. In the all-comer population, pembrolizumab with carboplatin and paclitaxel improved both progression-free survival (the exact improvement in progression-free survival is considered confidential by the company so cannot be reported here) and overall survival (hazard ratio 0.74, 95% confidence interval 0.57 to 0.97). The EAG was concerned about combining results from both subgroups because the analysis was unplanned and retrospective. The company believed that the all-comer population better fitted the NICE scope and the marketing authorisation, and provided more statistical certainty because of the larger group size. The clinical experts advised that people with dMMR and pMMR endometrial cancer are treated differently in clinical practice because there are different subsequent treatments available for each subgroup. They advised that the groups have large differences in prognosis (see section 3.2) and that the 2 groups are likely to respond considerably differently to immunotherapy and should be considered separately. The committee agreed with the EAG and clinical experts, and concluded that the pMMR and dMMR subgroups should be considered separately.

The company used a partitioned survival model with 3 health states: progression free, progressed disease, and death. The committee agreed that the partitioned survival model is a standard approach for estimating the cost effectiveness of cancer drugs and is suitable for decision making.

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 believed 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 been previously treated, 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 the small sample size meant that the data has limited generalisability, is associated with wide confidence intervals, and may under- or overestimate utility values. The EAG was also concerned that the 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 believed 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 the use of the KEYNOTE-158 endometrial cancer subgroup health-related quality of life data in the pMMR population.

Treatment effect waning was not included in the company's base case model. The company said that the mechanism of action of pembrolizumab and the available trial data supported a sustained treatment effect. For the all-comer population, the company provided a scenario including treatment effect waning in overall survival starting 7 years after starting pembrolizumab treatment for people who did not obtain an objective response (24.8% of pembrolizumab with carboplatin and paclitaxel arm). It chose this point based on long-term follow-up in KEYNOTE-006, which showed no treatment effect waning up to 7 years after starting pembrolizumab. The EAG noted the lack of longer-term evidence around treatment effect waning, but also that previous technology appraisals considered it plausible that treatment effect waning began 3 to 5 years after stopping immunotherapy. So, it did scenarios including treatment effect waning in overall survival 5 and 6 years from starting pembrolizumab. The committee recalled its preference for analysing the data by MMR subgroup (see section 3.5). It noted that the treatment effect waning scenarios were done only on the all-comer population and should be repeated separately for the dMMR and pMMR subgroups. The committee also noted that the impact of adjusting for treatment effect waning on quality-adjusted life years (QALYs) gained was smaller than expected in the all-comer population. It requested a rationale for this. The committee also requested a scenario in the dMMR and pMMR subgroups where treatment effect waning applies to everyone, regardless of response status, in the pembrolizumab with carboplatin and paclitaxel arm.

The company determined resource use in the model by consulting clinical experts and an advisory board, and considering other technology appraisals related to similar cancers. The EAG was concerned that blood tests and outpatient visits appeared to be underestimated in the pembrolizumab with carboplatin and paclitaxel group. It noted that the use of these resources was lower in the pembrolizumab with carboplatin and paclitaxel group than in the carboplatin and paclitaxel group, even though it would be expected that people having pembrolizumab would have more frequent blood tests and outpatient visits. The EAG provided 2 scenarios for resource use. One used estimates from the EAG's clinical experts. The other used resource use from NICE's technology appraisal on dostarlimab with platinum-based chemotherapy for treating advanced or recurrent endometrial cancer with high microsatellite instability or mismatch repair deficiency. The clinical experts agreed that blood test and outpatient visit resource use appeared to be underestimated in the company's base case. They believed that the scenario using estimates from the EAG's clinical experts was most suitable. This is because the frequency of blood tests and outpatient visits (initially every 3 weeks, then every 6 weeks from week 18 while having treatment) aligned with the dosing schedule for chemotherapy followed by maintenance pembrolizumab. The Cancer Drugs Fund clinical lead noted that, in some cases, pembrolizumab is given on a 3-weekly rather than a 6-weekly cycle, and this would be expected to increase the resource use assumed in the EAG's scenario. The committee agreed with the clinical experts and concluded that the scenario using estimates from the EAG's clinical experts was most suitable, but that this may underestimate the resource used while on treatment.

Subsequent treatments in the model were calculated as a one-off cost on entry into the progressed disease health state. The company used a weighted average of the proportion of people having each subsequent treatment in KEYNOTE-868, which was then validated and adjusted by clinicians to produce the cost on entry into the progressed disease health state. The company presented the combined treatment mix for the all-comer population, but also provided separate treatment mixes for the dMMR and pMMR subgroups. The EAG noted that it had received advice that it was standard for pembrolizumab with lenvatinib to be given at second line after carboplatin and paclitaxel at first line. It did a scenario analysis where all pembrolizumab monotherapy use was replaced with pembrolizumab with lenvatinib for second-line treatment. The clinical experts explained that pembrolizumab with lenvatinib is available for second line treatment of dMMR or pMMR cancer, but pembrolizumab monotherapy is available as second-line treatment only for people with dMMR cancer. Because of lenvatinib's toxicity, most people with dMMR endometrial cancer would have pembrolizumab monotherapy. They explained that almost everyone with pMMR cancer who had chemotherapy as first-line treatment started pembrolizumab with lenvatinib at second line. But, they also noted that lenvatinib was associated with significant toxicity, so many people have reduced doses of lenvatinib, with some people completely stopping lenvatinib. The Cancer Drugs Fund clinical lead noted that almost everyone with dMMR cancer now has dostarlimab at first line, so would be ineligible for treatment with pembrolizumab monotherapy or pembrolizumab with lenvatinib at second line. But, because dostarlimab is currently funded by the Cancer Drugs Fund, it cannot be considered as part of this appraisal. The committee recalled its preference for analysing the data by MMR subgroup (see section 3.5). The committee noted that people with dMMR and pMMR cancer would have different treatments. The committee concluded that subsequent treatments should be based on MMR subgroups. It requested that the EAG consider the appropriateness of the company's subsequent treatment mix for the pMMR and dMMR subgroups.

The committee's preference was for separate analyses for the dMMR and pMMR subgroups (see section 3.5). The committee requested further analysis of the following key issues by MMR subgroup:

• overall survival extrapolation (see section 3.7)

• starting age in the model (see section 3.8)

• health state utility values (see section 3.9)

• treatment effect waning (see section 3.10)

• subsequent treatment mix (see section 3.12).

Both the company's and the EAG's base cases were based on the all-comer population. They differed in choice of overall survival extrapolation (see section 3.7) and choice of starting age in the model (see section 3.8). The company also presented subgroup analyses by MMR status. But, the committee noted these analyses did not include health state utility values by MMR subgroup and treatment effect waning was not fully explored. The committee also noted that the EAG did not assess the suitability of the company's subgroup analyses. So, it agreed that it was not suitable to rely on either the all-comer population analysis or the company's subgroup analyses by MMR status without further consideration and justification for the assumptions included in each subgroup.

The committee could not identify a plausible ICER because further analyses are needed. The committee could also not determine a preferred ICER threshold for pembrolizumab with carboplatin and paclitaxel for untreated primary advanced or recurrent endometrial cancer.

The committee noted that endometrial cancer affects people with female reproductive organs. It also noted concerns raised by the company that:

• incidence rates for endometrial cancer are higher among the Black ethnic group than the White ethnic group

• people from the Black ethnic group are more likely than people from other ethnic groups to be

  • diagnosed with higher-risk, non-endometrioid endometrial cancer subtypes

  • given a late-stage diagnosis of endometrial cancer

• the diagnostic method for endometrial cancer (transvaginal ultrasound) is less reliable when fibroids are present and in high-risk, non-endometrioid endometrial cancer tumours, both of which are more common in Black people.

The committee discussed whether there were any uncaptured benefits of pembrolizumab with carboplatin and paclitaxel. It did not identify additional benefits of pembrolizumab with carboplatin and paclitaxel that had not already been captured in the economic modelling. So, the committee concluded that all the benefits of pembrolizumab with carboplatin and paclitaxel had been taken into account.

The committee believed that analyses of pembrolizumab with carboplatin and paclitaxel should be done separately in the dMMR and pMMR subgroups, and that further analysis of key issues by MMR subgroups was needed (see section 3.5). So, it was unable to establish that pembrolizumab with carboplatin and paclitaxel is a cost-effective use of NHS resources. The committee concluded that pembrolizumab with carboplatin and paclitaxel should not be used, within its marketing authorisation, for untreated primary advanced or recurrent endometrial cancer in adults, and that further analysis is needed.