Dostarlimab with platinum-containing chemotherapy for treating primary advanced or recurrent endometrial cancer with microsatellite stability or mismatch repair proficiency

Endometrial cancer starts in the lining of the uterus and is the most common type of uterine cancer. At diagnosis, primary advanced endometrial cancer refers to stage 3 or 4 disease that has spread beyond the uterus. Recurrent endometrial cancer refers to cancer that is detected either radiologically or histologically, when there has been remission after initial treatment. Mismatch repair (MMR) status, the functionality of the DNA MMR system in tumours, is routinely tested in endometrial cancer. About 75% of people with endometrial cancer have tumours that are MMR proficient (MMRp) or microsatellite stable (MSS). In MMRp, the DNA repair mechanisms are intact and mutations can be corrected. In MSS, the length of microsatellites remains unchanged. People from Black ethnic backgrounds have a higher incidence of the p53‑abnormal (p53abn) subtype of endometrial cancer with MSS or MMRp. This may correlate with TP53-mutated (TP53mut) tumours (see section 3.4). This represents a small proportion of all endometrial cancers, but is often more aggressive and associated with poorer outcomes.

The clinical experts explained that endometrial cancer with MSS or MMRp is a molecularly heterogeneous group. They suggested that routinely available molecular testing cannot further identify subgroups of endometrial cancer with MSS or MMRp. They highlighted that the median survival for people with endometrial cancer with MSS or MMRp is usually less than 2 years. The patient experts explained that living with stage 3 or 4 endometrial cancer with MSS or MMRp has a substantial impact on all aspects of life for both the person and their family. This includes debilitating physical symptoms, psychological distress from the uncertainty of disease progression and financial burden. The committee concluded that primary advanced or recurrent endometrial cancer with MSS or MMRp can have a negative impact on people with the condition, as well as on their families and carers.

Standard care for primary advanced or recurrent endometrial cancer is platinum-containing chemotherapy, typically a combination of carboplatin and paclitaxel, followed by surveillance scans every 12 weeks. People whose cancer progresses after chemotherapy may be offered immunotherapy, further chemotherapy or, for a very small proportion, maintenance hormone treatment. Pembrolizumab plus lenvatinib is available as an option for people who have had treatment for endometrial cancer (see NICE's technology appraisal guidance on pembrolizumab with lenvatinib for previously treated advanced or recurrent endometrial cancer). The clinical experts explained that, once cancer has progressed after chemotherapy, about 35% to 40% of people are unable to tolerate further treatment at second line, including immunotherapy. They highlighted that the side effects are more often related to lenvatinib than to pembrolizumab.

The patient experts agreed and emphasised the high unmet need. They highlighted the limited treatment options for endometrial cancer with MSS or MMRp at this stage, which can leave people feeling frustrated, hopeless and abandoned. At the second committee meeting, NHS England's Cancer Drugs Fund lead noted that people with endometrial cancer with MSS or MMRp can now access immunotherapy at first line. This is because, since the first committee meeting, NICE recommended pembrolizumab with carboplatin and paclitaxel for untreated primary advanced or recurrent endometrial cancer. The committee noted the limited first-line treatment options available for endometrial cancer with MSS or MMRp. It concluded that people with the condition, and their families, would welcome safe and effective treatments that offer durable responses and are well tolerated.

For this evaluation, the company positioned dostarlimab as an add-on treatment to platinum-containing (also referred to as platinum-based) chemotherapy as a first-line option for primary advanced or recurrent endometrial cancer with MSS or MMRp, when systemic treatment is suitable. The company explained that its target population is narrower than the marketing authorisation. The committee noted that dostarlimab is recommended for a different subpopulation in NICE's technology appraisal guidance on dostarlimab with platinum-based chemotherapy for treating primary advanced or recurrent endometrial cancer with high MSS or MMR deficiency.

At the first committee meeting, the company explained that the only relevant comparator was carboplatin plus paclitaxel. This is standard NHS care for primary advanced or recurrent endometrial cancer with MSS or MMRp (see section 3.2). It also highlighted that, if recommended, people with primary advanced or recurrent endometrial cancer with MSS or MMRp who have had dostarlimab plus platinum-containing chemotherapy at first line would not be able to have pembrolizumab-based regimens at second line. This is because immunotherapies are not offered more than once for this condition in the NHS. At the first committee meeting, the clinical experts confirmed that the choice of comparator aligns with NHS practice for the company's target population.

The committee agreed with the company's positioning of dostarlimab plus platinum-containing chemotherapy. It noted that 5 days before the second committee meeting, NICE had recommended pembrolizumab with carboplatin and paclitaxel for people with untreated primary advanced or recurrent endometrial cancer (TA1092; see section 3.2), which would be considered a relevant comparator for the company's target population. The committee noted that NICE technology appraisal and highly specialised technologies guidance: the manual states that a comparator should be established clinical practice in the NHS for the population. But it concluded that the timing of TA1092 meant that, for this evaluation, the relevant comparator is carboplatin plus paclitaxel.

The key clinical-effectiveness evidence used in the company's submission and economic model came from RUBY‑1, an ongoing phase 3 multinational double-blind randomised trial. It compared 18 weeks of dostarlimab plus carboplatin and paclitaxel (from now, platinum-containing chemotherapy) followed by dostarlimab monotherapy for up to 3 years (from now, the dostarlimab arm) with 18 weeks of placebo plus platinum-containing chemotherapy followed by placebo for up to 3 years (from now, the placebo arm). Randomisation was stratified by MMR and MSS status, prior external pelvic radiotherapy and disease status. The trial included 494 adults (18 years and over) with primary stage 3 or 4, or recurrent endometrial cancer, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Of these, 76% (376 of 494) had endometrial cancer with MSS or MMRp. Mutational data was available for 400 people, of which 88 people had TP53mut tumours. The primary endpoints were overall survival (OS) and progression-free survival (PFS), assessed by the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1. The company presented results from 2 planned interim data cuts, which were used in the economic model:

• IA1 (28 September 2022) was done for PFS, health-related quality of life and time to treatment discontinuation at the first committee meeting The company considers the median follow-up for IA1 to be commercial-in-confidence, so this information cannot be reported here. In response to the draft guidance consultation, the company used PFS data at the IA2 data cut in its updated base case.

• IA2 (22 September 2023) had a median follow-up of 37.5 months for OS and adverse events.

The clinical experts noted that people in RUBY‑1 were generally younger than people likely to have dostarlimab in the NHS. But they thought that the RUBY‑1 population was broadly representative of NHS clinical practice. This was because people in the NHS would typically need to have an ECOG performance status of 0 or 1 to be considered fit enough for triplet therapy (chemotherapy and immunotherapy). About 64% (239 of 376) of people with endometrial cancer with MSS or MMRp in RUBY‑1 had a subsequent treatment after disease progression. These treatments included chemotherapy, immunotherapy (such as pembrolizumab plus lenvatinib and pembrolizumab monotherapy), radiation therapy, hormone treatment and bevacizumab. At the IA2 data cut, more people in the placebo arm (73%, 134 of 184) had a subsequent treatment compared with the dostarlimab arm (55%, 105 of 192). About 27% (102 of 376) of people with endometrial cancer with MSS or MMRp had subsequent immunotherapy. This was more common in the placebo arm (37%, 68 of 184) than in the dostarlimab arm (18%, 34 of 192).

The committee noted that some of the subsequent treatments used in RUBY‑1 were not fully representative of NHS practice. Specifically, bevacizumab monotherapy is not used for endometrial cancer in the NHS, and people whose cancer progresses after first-line immunotherapy would not usually have further immunotherapy. The EAG noted that few people had bevacizumab and, because proportions were similar between arms, this was unlikely to have affected outcomes. It agreed with the company that subsequent immunotherapy use in the placebo arm was similar to that seen in UK clinical practice. But it highlighted that the proportion of people having subsequent immunotherapies in the dostarlimab arm was higher than would be expected in NHS clinical practice. So, the treatment effect of the dostarlimab arm in the NHS may be lower than what was seen in RUBY‑1. This introduced uncertainty about the generalisability of the OS results (see section 3.7). The committee noted that RUBY‑1 was broadly representative of people likely to have dostarlimab in the NHS, But it concluded that differences in subsequent treatment use and retreatment with immunotherapy introduced uncertainty about the generalisability of the trial's findings to NHS clinical practice.

At the first committee meeting, the company presented PFS results from the IA1 and IA2 data cuts. At IA1, the median PFS was 9.9 months in the dostarlimab arm compared with 7.9 months in the placebo arm. The difference was statistically significant (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.59 to 0.98). But the difference in PFS was not statistically significant at the IA2 data cut. The company considers the PFS results at IA2 to be commercial-in-confidence, so they cannot be reported here. The company also presented results for PFS2. This was defined as the time from treatment randomisation to the date of assessment of progression on the first subsequent anticancer treatment after study treatment or death by any cause (whichever is earlier). Median PFS2 at IA2 was 24.6 months in the dostarlimab arm compared with 15.9 months in the placebo arm (HR 0.74, 95% CI 0.57 to 0.97). The committee noted the difference in whether there was a statistically significant benefit for dostarlimab in PFS between IA1 and IA2. It concluded that there was uncertainty about the clinical effectiveness of dostarlimab plus platinum-containing chemotherapy in improving PFS in people with endometrial cancer with MSS or MMRp compared with platinum-containing chemotherapy.

In its submission, the company did not present OS results at IA1. At IA2, the median OS was 34 months in the dostarlimab arm compared with 27 months in the placebo arm. But the difference was not statistically significant (HR 0.79, 95% CI 0.60 to 1.04). The company highlighted that the OS data at this interim analysis was still immature, with 54.8% data maturity. The clinical experts thought that the OS data was relatively mature and that it was unlikely that the OS estimates would change substantially by the final follow-up in 2026. The EAG highlighted concerns about the reliability of the OS data from RUBY‑1, particularly the data beyond 30 months, because of heavy censoring. The committee noted the use of subsequent treatments in RUBY‑1 and questioned their potential impact on OS (see section 3.5). The company explained that, for most people in RUBY‑1, the cancer had progressed in the first 12 months. So, it thought that the impact of subsequent treatments would have been captured in the IA2 post-progression outcomes. The clinical experts highlighted that there was no data on the clinical effectiveness of second-line immunotherapy after progression on first-line immunotherapy. But they thought it unlikely that this would have a substantial impact on OS in RUBY‑1 because they did not expect later lines of immunotherapy to be clinically effective. The committee questioned why 18% (34 of 192) of people in the dostarlimab arm of RUBY‑1 had subsequent immunotherapy if it was not expected to be clinically effective. The company explained that RUBY‑1 was a double-blind trial, so investigators were unaware of treatment group allocations.

In response to the draft guidance consultation, the company reiterated that the proportion of people having subsequent treatment, and the lines and types of regimens in RUBY‑1, were largely consistent with what would be expected in clinical practice. The exception was for bevacizumab use. It clarified that RUBY‑1's protocol had not included guidelines for post-progression treatment strategies. Instead, decisions on subsequent treatments were based on physicians' clinical judgement. The company also provided post-hoc analyses exploring the effect of subsequent treatments on survival outcomes in RUBY‑1:

• An analysis of the treatment effect of dostarlimab plus platinum-containing chemotherapy compared with placebo plus platinum-containing chemotherapy on OS by subsequent immunotherapy or chemotherapy use: The company explained that this suggested that subsequent immunotherapy did not improve OS in the dostarlimab arm compared with subsequent chemotherapy alone. It considers the results to be commercial-in-confidence, so they cannot be reported here. The EAG highlighted limitations of the analysis, including small sample sizes, broken randomisation, lack of baseline comparability and a focus only on pembrolizumab plus lenvatinib immunotherapy. So, it remained unclear whether any differences reflected treatment effects or patient characteristics. The EAG also highlighted that the company had not provided evidence from any previous trials on the impact of retreatment with immunotherapy on post-progression outcomes.

• An analysis of the time between first and second progression event (PFS2 minus PFS1). The company suggested that this showed that upfront use of dostarlimab increases time between first and progression events. This is despite using immunotherapies after progression in people who initially had chemotherapy. The EAG highlighted that PFS2 reflects the time to a person's second progression event, rather than the length of time from controlled disease to a second progression. The EAG explained that post-progression benefit should be interpreted with caution because PFS2 does not isolate the treatment effect of dostarlimab. This is because it includes the additional effects of different subsequent treatments. Also, the PFS2 analysis included everyone, not just people who had had a first progression event. So, the dostarlimab arm mainly reflected people who had had an early failure on initial dostarlimab treatment. Conversely, the placebo arm likely included a greater number of people who had progressed on initial chemotherapy. So, the populations between arms were not balanced for PFS2.

• An analysis of the treatment effect of dostarlimab plus platinum-containing chemotherapy compared with placebo plus platinum-containing chemotherapy for PFS2 at IA2, by subsequent immunotherapy or any subsequent anticancer treatment use. The company noted that the results suggested that people in the dostarlimab arm who had subsequent immunotherapy had a similar median PFS2 as people in the same arm who had any subsequent anticancer treatment. The company considers the results to be commercial-in-confidence so they cannot be reported here. The EAG highlighted the limitations of the post-hoc subgroup analysis. These limitations included no explanation from the company on choice of subsequent treatment offered to people at disease progression and concerns about using PFS2 as an outcome measure. So, it was also unclear whether any differences in median PFS2 were because of the type of subsequent treatment or differences in patient characteristics.

• Treatment-switching analyses using rank-preserving structural failure time models (RPSTMs) on OS, which adjusted for switching to all subsequent immunotherapies or only pembrolizumab plus lenvatinib in both trial arms. The company explained that, in the analyses, there was a modest reduction in the OS hazard ratio compared with the unadjusted hazard ratios from the trial. These treatment-switching analyses showed that the hazard ratios adjusted for all subsequent immunotherapies (HR 0.76; 95% CI 0.542 to 1.061) and for pembrolizumab plus lenvatinib only (HR 0.77; 95% CI 0.564 to 1.057) were similar to the unadjusted hazard ratios (HR 0.79; 95% CI 0.602 to 1.044) used in the company's base case. The EAG suggested that Inverse Probability of Censoring Weights (IPCW) models may be more appropriate than RPSTMs if immunotherapy effects are likely to vary and treatment is started at different times. At the second committee meeting, the company explained that it had explored both methods but preferred the RPSFTM. This choice reflected a concern that the IPCWs may have been unstable because of the moderate sample size in RUBY‑1. Also, there were concerns that the censoring and treatment switching could have violated the no-unmeasured-confounders assumption essential to IPCWs. The EAG agreed that IPWCs were less sensitive to the 'common treatment-effect' assumption for previous subsequent treatment. But it explained that this assumption remains a critical vulnerability of RPSFTMs.
  
  The committee noted the lack of statistical significance on OS estimates, data immaturity and the issues of subsequent immunotherapy use in RUBY‑1. It acknowledged the company's attempts to analyse the impact of subsequent treatments on survival estimates. It also noted that the direction of the treatment effect for dostarlimab plus platinum-containing chemotherapy in these post-hoc analyses was broadly consistent with what had been previously presented in the ITT population. But it thought that there was still uncertainty. The committee concluded that there is uncertainty about the effectiveness of dostarlimab plus platinum-containing chemotherapy in improving OS in people with endometrial cancer with MSS or MMRp compared with platinum-containing chemotherapy alone.

The committee noted that subgroup analyses in the TP53mut population (see section 3.4) showed better PFS benefit compared with that in the overall population at IA1 (HR 0.55, 95% CI 0.30 to 0.99). But the OS benefit in this subgroup was not statistically significant (HR 0.59, 95% CI 0.33 to 1.03). The committee agreed that these subgroup analyses were post hoc and involved a small cohort, so they were not statistically powered to detect differences. But it recalled that endometrial cancer with the p53abn subtype is associated with poorer outcomes (see section 3.1). Having seen the relative clinical-effectiveness evidence from RUBY‑1 for the TP53mut subgroup, the committee thought that it would be useful to see exploratory analyses in the p53abn and TP53mut subgroups. In response to the draft guidance consultation, the company explained that it was not informative to explore cost-effectiveness scenarios in any subgroup, including p53abn. This was because it did not think that the potential for dostarlimab to disproportionately benefit a single subgroup in endometrial cancer with MMRp or MSS was supported by evidence from RUBY‑1, external expert opinion, underlying clinical rationale or external evidence. The committee acknowledged the company's rationale but concluded that they would preferred to have seen analyses specific to this subgroup.

The company used a partitioned survival model to estimate the cost effectiveness of adding dostarlimab to platinum-containing chemotherapy. This had 3 health states (progression-free, progressed disease and death), a 1‑week cycle with no half-cycle correction and a 36‑year time horizon. Data from the placebo arm of RUBY‑1 was used to inform the comparator arm in the model (that is, platinum-containing chemotherapy). In line with the marketing authorisation, a 3‑year stopping rule was applied for dostarlimab (see section 2.2). The committee concluded that the company's model was suitable for decision making.

The company extrapolated the long-term effects of dostarlimab plus platinum-containing chemotherapy, and of platinum-containing chemotherapy alone, on PFS and OS in people with primary advanced or recurrent endometrial cancer with MSS or MMRp beyond the trial data. It assumed non-proportional hazards for PFS and OS. This was because dostarlimab has a different mechanism of action than platinum-containing chemotherapy. There was a longer time on treatment with dostarlimab but only 6 cycles of platinum-containing chemotherapy in RUBY‑1. There was also the commonly observed delayed response with immunotherapies. To extrapolate the long-term effects, the company fitted independent parametric distributions to model PFS and OS in the 2 treatment arms. The EAG agreed with the company that the proportional hazard assumption did not hold. It also agreed that fitting independent parametric distributions to model PFS and OS in the 2 arms was reasonable. The committee concluded that using independent parametric distributions to model PFS and OS was appropriate for decision making.

In its base case, the company assumed that treatment-effect waning was captured in the modelled OS. This assumption was based on RUBY‑1, which the company suggested had shown a sustained OS benefit in the dostarlimab arm compared with the placebo arm. The company also highlighted that its independent modelling of OS curves should have implicitly captured any waning of the treatment effect. The EAG thought that the company's modelling of OS was generally appropriate, and agreed with the company that treatment-effect waning was likely captured in the OS extrapolations. This was because the PFS plots showed that the risk of progression was similar for both arms after about 2 years. But the EAG noted that, at IA2, the Kaplan–Meier curve for OS in the 2 treatment arms appeared to converge from month 30 then diverge again from month 36 onwards. So, it thought that a scenario of gradual treatment-effect waning may be informative. The company also provided 2 treatment-effect waning scenarios:

• a scenario with a 2‑year stopping rule

• a scenario with a 3‑year stopping rule that was in line with dostarlimab's marketing authorisation (see section 2.2).
  
  The committee did not think that treatment-effect waning was implicitly captured in the model. This was because the company's extrapolated OS curves with and without incorporated treatment-effect waning were different. The committee recalled the uncertainties associated with the evidence on OS (see section 3.7 and section 3.12). It thought that there was high uncertainty related to the treatment-effect waning assumptions. At the first committee meeting, the committee requested additional evidence and analyses in which:

• including or excluding treatment-effect waning in the model was sufficiently justified

• the impact of second-line treatment effect on OS was adjusted for the potential interplay between the impact of subsequent treatments on OS and treatment-effect waning is explored.
  
  In response to the draft guidance consultation, the company reiterated that fitting independent OS curves implicitly captured treatment-effect waning in the model, as evidenced by the hazard ratios for OS over time. These OS estimates were consistent with clinical expectation and RUBY‑1 data. It noted that this approach was consistent with previous NICE appraisals in similar indications with less mature OS data. But it also provided scenarios of gradual treatment-effect waning. These reduced the treatment effect to the same level as the platinum-containing chemotherapy arm after 3 years, and at 3 and 5 years after dostarlimab's stopping rule (that is, 6 to 8 years and 8 to 10 years after starting dostarlimab).
  
  The company provided analyses in which the waning assumptions were applied to everyone and also just to people without a complete response (74.2% in dostarlimab arm). The EAG suggested that treatment-effect waning was likely captured in the data for the observed period of RUBY‑1 that informed the PFS and OS extrapolations. It explained that the main effect of dostarlimab is to reduce the risk of progression. It highlighted that the hazard rate plot for PFS showed that treatment effect peaks at about 1 year and then diminishes, until it is equal to the platinum-containing chemotherapy arm. It also noted that the follow-up period for RUBY‑1 was about 4 years and that most people in the dostarlimab arm had stopped treatment before the maximum duration of 3 years. So, the EAG did not apply any additional treatment-effect waning assumptions in its base case. The committee noted that the implied hazard ratio over time showed that the relative treatment effect over time increased sharply then decreased during the observed period of RUBY‑1 at 4 years. The company explained that the implied hazard ratio reached 1 at about 20 years, meaning no difference in treatment effect in the 2 arms. The committee acknowledged that treatment-effect waning may have been largely captured during the observed period of RUBY‑1 and the independent extrapolations. But it considered that there was uncertainty in assuming that dostarlimab benefit would continue for up to about 15 years after stopping treatment. So, the committee preferred not to apply any additional treatment-effect waning assumptions in the base case. But it concluded that treatment-effect waning was unlikely to have been fully captured in the modelled OS estimates and took this into account in its decision making.

The company modelled time on treatment by using weighted completion rates for platinum-containing chemotherapy from RUBY‑1 for the first 6 cycles across both treatment arms. For dostarlimab, it used completion rates for the first 6 cycles, followed by time to treatment discontinuation Kaplan–Meier data adjusted for relative dose intensity up to 3 years. The EAG thought that using completion rates did not fully capture the cost of starting treatment in either arm. This was because the intention-to-treat population included people who were randomised but did not start treatment. So, the completion rate for the first treatment cycle in the model was less than 100%. To capture the full treatment costs in its base case, the EAG preferred to use time to treatment discontinuation Kaplan–Meier data for both arms. In addition, for dostarlimab, it used the relative dose intensity from cycle 1 up to 3 years. The committee concluded that the EAG's approach to modelling time on treatment was appropriate.

In its original base case, the company modelled health-state resource use for the dostarlimab arm based on advice from 6 UK healthcare professionals. It assumed that, after the first 18 weeks of treatment, people having dostarlimab who were progression-free would have specific resource use that differed from people in the platinum-containing chemotherapy arm. The EAG disagreed and thought that, after 3 years of dostarlimab monotherapy, resource use would be the same. The clinical experts thought that the level of surveillance would be similar for people who are progression-free after treatment, regardless of whether they have had had dostarlimab or platinum-containing chemotherapy. At the committee meeting, the company explained that it agreed with the EAG's modelling. In response to the draft guidance consultation, the company adopted the EAG's approach to modelling health-state resource use for the dostarlimab arm. The committee concluded that the EAG's approach to modelling health-state resource use for the dostarlimab arm in the company's updated base case was appropriate for decision making.

The company's original base case included an oral administration cost for lenvatinib to account for specialist oversight related to procurement, prescribing, dispensing and administration. The EAG disagreed and excluded this cost from its base case. It noted that, based on published advice, people are likely to take lenvatinib at home. So, there would likely be no administration cost to the NHS. It highlighted that these administration costs only affect the platinum-containing chemotherapy arm because pembrolizumab plus lenvatinib is not used after dostarlimab treatment. The clinical experts agreed that there is likely no cost associated with administering lenvatinib. But they noted there would be costs related to managing its side effects. The EAG confirmed that these were accounted for in the monitoring costs already included in the model. The committee thought that the oral administration cost of lenvatinib should be excluded from the model. In response to the draft guidance consultation, the company adopted the EAG's approach of excluding the oral administration cost of lenvatinib from the model. The committee concluded that the company's updated base case excluding oral administration cost of lenvatinib was appropriate for decision making.

At the second committee meeting, the company's updated base case included:

• PFS extrapolations using more mature data from IA2 (see section 3.11)

• subsequent treatment proportions from the IA2 data cut

• the committee's preferences from the first committee meeting in modelling time on treatment (see section 3.14)

• health-state resource use for dostarlimab arm (see section 3.15)

• excluding the cost for oral administration of lenvatinib (see section 3.16).
  
  The EAG's preferred base case was mostly aligned with the company's updated base case, except for corrections it had done in the first committee meeting. These were to:

• use the Office for National Statistics life tables from 2017-2019 (see guidance in NICE's Decision Support Unit's technical support document 23)

• source nurse and GP costs directly from the Unit Costs of Health and Social Care Manual, 2023

• use the unit cost of carboplatin 450 mg for subsequent treatment cost.
  
  The committee noted the uncertainty in the clinical evidence (see section 3.5, section 3.6 and section 3.7) and economic modelling (see section 3.12). But it concluded that the EAG's preferred base case including the corrections to the company's updated base case, reflected its preferred assumptions.

NICE technology appraisal and highly specialised technologies guidance: the manual notes that, above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. But it will also take into account other aspects including uncaptured health benefits. The committee noted the substantial uncertainty in the evidence and company's modelling, specifically:

• that the longer data cut of PFS was not statistically significant and OS data was immature (see section 3.6)

• that subsequent treatments from RUBY‑1 may not be generalisable to NHS clinical practice and may affect the OS estimates (see section 3.5 and section 3.7)

• whether treatment-effect waning has been fully captured in the company's base case (see section 3.13).
  
  The committee considered the uncertainties in the evidence and modelling and whether there are any benefits not fully captured (see section 3.22). It concluded that an acceptable ICER would be towards the lower end of the range NICE considers a cost-effective use of NHS resources, that is, around £20,000 per QALY gained.

The committee noted that there was little difference between the cost-effectiveness estimates in the company's updated base case and the EAG's preferred base case. The exact figures cannot be reported because of confidential discounts for dostarlimab, pembrolizumab and lenvatinib. Both the company's and EAG's updated base case ICERs were within the range that NICE normally considers an acceptable use of NHS resources.

Stakeholders highlighted that people from Black ethnic backgrounds have a higher incidence of the more aggressive p53‑abn subtype of endometrial cancer with MSS or MMRp, which is associated with poorer outcomes (see section 3.1). Although the committee requested further analyses for consideration in the p53‑abnormal or TP53mut subgroups, the company did not provide these (see section 3.8). The committee noted that the company's target population meant this subgroup would have been included. So, the recommendations would apply to everyone with endometrial cancer with MMRp or MSS. The committee thought that equality issues relating to differences in incidence of a condition cannot be addressed in a technology appraisal. It concluded that although the incidence of p53‑abnormal subtype was higher in people from Black ethnic backgrounds, there were no equality issues that would need changes to the recommendation.

The committee acknowledged that there are limited options for early treatment of primary advanced or recurrent endometrial cancer with MSS or MMRp (see section 3.2). It considered whether there were any uncaptured benefits of dostarlimab plus platinum-containing chemotherapy and did not identify additional benefits not captured in the economic modelling. So, it concluded that all additional benefits of dostarlimab plus platinum-containing chemotherapy had already been taken into account.

The most likely cost-effectiveness estimates were within the range considered to be a cost-effective use of NHS resources. So, dostarlimab plus platinum-containing chemotherapy can be used to treat primary advanced or recurrent endometrial cancer with MSS or MMRp in adults when systemic treatment is suitable.