Immunotherapy as the new standard of care for advanced endometrial cancer

Since the publication of the Gynecologic Oncology Group (GOG) 209 trial, the combination of carboplatin plus paclitaxel has been the standard treatment for advanced endometrial cancer (EC) with a median overall survival (OS) of approximately 40 months (1). More recently, immunotherapy has demonstrated favorable outcomes and has been incorporated in the first-line treatment.

In a systematic review and meta-analysis that included three studies with 1,431 patients in the setting of primary advanced or recurrent EC, the combination of programmed death ligand 1 (PD-1)/programmed cell death protein 1 (PD-L1) inhibitors with carboplatin and paclitaxel demonstrated benefit in progression-free survival (PFS) and OS, especially in those patients with deficient mismatch repair (dMMR) and high microsatellite instability (MSI-H) [PFS: hazard ratio (HR) =0.32; 95% confidence interval (CI): 0.23–0.44; P<0.001 and OS in 30 months: risk ratio (RR) =3.13; 95% CI: 1.26–7.78; P=0.01] (2).

The RUBY trial (Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer) was the first phase III trial to demonstrate OS improvement with an immune checkpoint inhibitor in EC (3). It is a randomized, global, double-blind, placebo-controlled trial, in which patients with advanced EC not able to be cured with surgery or radiotherapy were included if they had measurable primary advanced stage IIIA, IIIB, or IIIC1 disease by Response Evaluation Criteria in Solid Tumors (RECIST), or stage IIIC1 disease with unfavorable histologies (including serous, carcinosarcoma, or clear cell), irrespective of whether the disease could be assessed or measured, or stage IIIC2 or IV. Recurrent disease was allowed if there was no previous systemic therapy or recurrence at least 6 months after neoadjuvant or adjuvant treatment completion. Patients were randomly assigned to receive either dostarlimab or placebo, administered alongside carboplatin and paclitaxel every three weeks for a total of six cycles. After the chemotherapy phase, in the intervention group, dostarlimab was continued as maintenance every 6 weeks for up to 3 years. A total of 494 patients were randomized and around 48% of the included patients had recurrent disease. Among patients with primary disease, 18.9% were stage III, and 33.3% were stage IV. Carcinosarcomas were allowed and represented about 10% of the population while endometrioid (54.7%) and serous adenocarcinoma (20.4%) were the most common histologies. In the overall population, dostarlimab improved the median PFS when compared to placebo (HR =0.64; 95% CI: 0.51–0.80; P<0.0001) (3). The dostarlimab group had an improvement of 16.4 months in the median OS (44.6 versus 28.2 months) (HR =0.69; 95% CI: 0.54–0.89; P=0.0020) (4). A prespecified exploratory analysis of OS was planned according to MMR status. In the dMMR population, the median OS was not reached for the dostarlimab arm and was 31.4 months for the placebo arm (HR =0.32, 95% CI: 0.17–0.63, P=0.0002). In the proficient mismatch repair group (pMMR), the median OS was 34.0 and 27.0 months for dostarlimab and placebo, respectively (HR =0.79; 95% CI: 0.60–1.04; P=0.0493). The subgroup analysis for OS did not show benefit with immunotherapy in the stage III population (HR =1.32; 95% CI: 0.65–2.65) and the group of patients with no disease at baseline (HR =1.53; 95% CI: 0.5–4.68). Although these results should be interpreted carefully as it is an exploratory analysis with a small group of patients, there is a biological rationale for better efficacy of immunotherapy in the presence of tumor or measurable disease. The concept that administering immune checkpoint inhibitors while the primary tumor remains present will induce a more robust systemic antitumor immune response primarily derives from studies conducted on melanoma. Previous evidence indicates that an increased tumor burden may improve antigen presentation by tumor cells, thereby eliciting a stronger T-cell response. Removing the tumor before initiating immune checkpoint inhibitor reduces the number of tumor-specific antigens available for targeting by CD8⁺ T cells, which can consequently lead to poorer clinical outcomes (5).

The endpoints in the RUBY trial are presented after a long follow-up (37.2 months), which is a key strength of this study. Besides, dostarlimab was administered for up to 3 years, not until progression, and this is also a strong point of the study, especially for low- and middle-income countries, where the cost-effectiveness of a treatment must be considered. On the other hand, the improvements in PFS and OS are less pronounced in the pMMR cohort, and a remaining question and limitation of the trial is identifying which patients from this subgroup derive benefit from the addition of immunotherapy to chemotherapy.

Durvalumab is also an option in this scenario following the results of DUO-E (6). This multicenter, double-blind, placebo-controlled study included three investigational arms: carboplatin/paclitaxel combined with durvalumab placebo followed by placebo maintenance; carboplatin/paclitaxel combined with durvalumab followed by maintenance with durvalumab and olaparib placebo; or carboplatin/paclitaxel combined with durvalumab followed by maintenance with durvalumab and olaparib. The maintenance treatment was done until disease progression or unacceptable toxicity. Eligibility criteria were measurable stage III and stage IV disease or recurrent EC of epithelial histology. Recurrent EC was allowed if the recurrence had occurred at least 12 months after the last dose of primary systemic treatment. The randomization involved 718 patients, 241 for the control group, 238 for the durvalumab group, and 239 for the durvalumab/olaparib arm. In the control, durvalumab, and durvalumab/olaparib arms, the proportions of patients with pMMR tumors were 80%, 81%, and 80%, respectively, while 67.7%, 71.4%, and 63.8% had PD-L1 positive tumors. About 8% of all patients had carcinosarcoma histology. The median follow-up for the first analysis of PFS was 12.6 months. In the intention-to-treat population, PFS was 10.2 and 9.6 months in the durvalumab arm and control arm, respectively (HR =0.71; 95% CI: 0.57–0.89; P=0.003). PFS of durvalumab/olaparib arm was 15.1 months versus 9.6 months for control arm (HR =0.55; 95% CI: 0.43–0.69; P<0.0001). When durvalumab is compared to control, the HRs for PFS were 0.42 [95% CI: 0.22–0.80, median PFS: not reached (NR) vs. 7.0 months] in the dMMR population and 0.77 (median PFS: 9.9 vs. 9.7 months) in the pMMR subgroup. For durvalumab/olaparib versus control, the HRs for PFS were 0.41 (95% CI: 0.21–0.75, median PFS: 31.8 vs. 7.0 months) and 0.57 (15.0 vs. 9.7 months) for the dMMR and pMMR subgroups, respectively. The OS trend to benefit both interventional arms but results are not mature yet.

Another trial with immunotherapy in EC is the NRG-GY018 (Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer), which evaluated the addition of pembrolizumab to chemotherapy (7). This phase III, randomized, double-blind, placebo-controlled trial included patients with stage III to IVB EC with detectable disease, as well as those with recurrent EC, regardless of the presence of measurable disease. For the recurrent setting, the treatment-free interval needed to be a minimum of 12 months from adjuvant chemotherapy. A total of 816 patients was assigned to receive carboplatin/paclitaxel with pembrolizumab (n=407) or placebo (n=409) every 3 weeks for 6 cycles, followed by maintenance with pembrolizumab or placebo every 6 weeks for up to 2 years. In the dMMR population, the median follow-up was 12 months, with a risk of disease progression or death reduced by 70% with pembrolizumab compared to placebo—median PFS NR in the pembrolizumab arm and 7.6 months in the placebo arm (HR =0.3; 95% CI: 0.19–0.48; P<0.001). Regarding the pMMR cohort, the follow-up was 7.9 months and the addition of pembrolizumab resulted in a median PFS of 13.1 against 8.7 months in the placebo group (HR =0.54; 95% CI: 0.41–0.71; P<0.001).

A fourth option of immune checkpoint inhibitor in EC is atezolizumab based on the AtTEnd trial (atezolizumab and chemotherapy for advanced or recurrent endometrial cancer), a multicenter, randomized, placebo-controlled, double-blind, phase III trial. In this study, 551 patients with advanced or recurrent EC were randomly assigned to either atezolizumab (362 patients) or placebo (189 patients) given intravenously with chemotherapy (carboplatin and paclitaxel) for 6–8 cycles, then continued until progression. With a follow-up of 28.3 months, the median PFS in the intention-to-treat population was 10.1 months in the immunotherapy group versus 8.9 months in the placebo group (HR =0.74, 95% CI: 0.61–0.91; P=0.022). In the dMMR population, the median PFS was not reached for the immunotherapy group versus 6.9 months in the placebo group (HR =0.36, 95% CI: 0.23–0.57; P=0.0005). In patients with pMMR tumors, atezolizumab treatment did not improve PFS (HR =0.92, 95% CI: 0.73–1.16; P=0.38). The results of OS are not mature, but there is a trend for benefit for the immunotherapy group, although the P value is not statistically significant yet (8).

It is important to highlight the differences among the study populations (Table 1). Regarding the inclusion criteria, the RUBY trial included patients with aggressive histologies IIIC1 or IIIC2, and stage IV of any histology, without the requirement for measurable disease. The DUO-E trial permitted the enrollment of patients with primary diagnoses involving measurable disease, as well as those with any disease recurrence. In the NRG-GY018 the presence of measurable disease for stages III and IVA was required. In the AtTend trial, eligible patients were those with EC presenting with either measurable or evaluable residual disease after surgery or inoperable stage III–IV EC. RUBY, DUO-E and AtTend included carcinosarcoma, but NRG-GY018 did not.

The time between the adjuvant therapy and the recurrence also differed among the trials. In the dostarlimab and atezolizumab studies, patients were enrolled if the interval was equal to or greater than 6 months, whereas in the durvalumab and pembrolizumab trials, participation was permitted only if the interval was at least 12 months. The number of patients with dMMR was similar, about 20% in RUBY and DUO-E studies, around 27% in the NRG-GY018 trial, and approximately 23% in AtTend.

Furthermore, the duration of maintenance treatment with immunotherapy was different across the studies. Dostarlimab was administered for a duration of up to three years, whereas durvalumab and atezolizumab were used until disease progression or unacceptable toxicity occurred. Pembrolizumab was continued for a maximum of two years.

Regarding efficacy outcomes, the AtTend trial is the only study that did not demonstrate an improvement in PFS in the pMMR group. The DUO-E trial aimed to enhance patient outcomes, particularly for those with MMR proficiency, by combining treatment approaches. With the addition of a poly (ADP-ribose) polymerase (PARP) inhibitor, the pMMR group achieved a PFS of 15 months, a result that had not been observed previously. The combination emerges as a potential new approach for this population, which comprises approximately 80% of patients with advanced EC.

All four studies demonstrated that immunotherapy provides the most substantial benefit for the dMMR group. Cancers with dMMR are marked by extremely high mutation rates, especially in repetitive microsatellite regions that are susceptible to replication mistakes, resulting in MSI-H. This increased mutation burden in MSI-H/dMMR tumors is believed to contribute to the formation of numerous tumor-specific neoantigens, which the immune system can target through immune checkpoint blockade (9). This principle is broadly applicable to solid tumors. In EC, approximately 20% of patients have dMMR tumors (10). For this patient population, immunotherapy represents a transformative treatment option.

Regarding stage III patients, we have already mentioned the subgroup analysis of DUO-E. The KEYNOTE-B21 (a randomised, double-blind, phase III study of pembrolizumab or placebo plus adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed, high-risk endometrial cancer) evaluated the addition of pembrolizumab to adjuvant treatment for high-risk EC patients who had no residual disease after surgical treatment. Immunotherapy in this setting resulted in similar disease-free survival (DFS) compared to standard adjuvant treatment. In the dMMR group, incorporating pembrolizumab led to improved DFS, with the median not reached (HR =0.31; 95% CI: 0.14–0.69). This data reinforces the hypothesis that, in the general population, the greatest benefit of immunotherapy occurs in the presence of measurable disease (11).

There is no doubt that the addition of immunotherapy to first-line chemotherapy has changed the long-term results of patients diagnosed with advanced EC. All the studies demonstrated improved PFS with chemotherapy and immunotherapy; this treatment became the gold standard for advanced EC. The RUBY trial has a longer follow-up and showed, for the first time, a consistent result of OS with the addition of immunotherapy in this setting.

For the decision on which immunotherapy associate in the first line, it is essential to check which study the patient meets the eligibility criteria, verify the regulatory approval in the country, and assess the financial toxicity of the treatment.

Some challenges and next research directions are the development of phase III trials to analyze if immune checkpoint inhibitors in monotherapy can result in equivalent or even better results in dMMR population in the first line of advanced EC when compared with the combination of platin-based chemotherapy and immunotherapy. The use of immunotherapy as an adjuvant treatment for high-risk dMMR EC remains also a subject of ongoing investigation.

Patients with pMMR represent a highly heterogeneous group, and the benefit of immune checkpoint inhibitors in this population is less pronounced compared to those with dMMR. It is crucial to identify which patients within the pMMR subgroup may derive significant benefit from combination therapy. Additionally, further research is needed to explore other treatment strategies that could improve their prognosis.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-213/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-213/coif). A.C.d.M. reports grants from Amgen, AstraZeneca, Bristol Myers Squibb, Clovis Oncology, GSK, MSD, Novartis, Regeneron, and Roche; honoraria from AstraZeneca, Bristol Myers Squibb, GSK, MSD, Novartis, Adium, Daiichi, and Pfizer; support for attending meetings and/or travel from MSD, Daiichi; and has participated in advisory boards for AstraZeneca, Bristol Myers Squibb, GSK, MSD, Novartis, Roche, and Daiichi. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Miller DS, Filiaci VL, Mannel RS, et al. Carboplatin and Paclitaxel for Advanced Endometrial Cancer: Final Overall Survival and Adverse Event Analysis of a Phase III Trial (NRG Oncology/GOG0209). J Clin Oncol 2020;38:3841-50. [Crossref] [PubMed]
2. de Moraes FCA, Pasqualotto E, Lopes LM, et al. PD-1/PD-L1 inhibitors plus carboplatin and paclitaxel compared with carboplatin and paclitaxel in primary advanced or recurrent endometrial cancer: a systematic review and meta-analysis of randomized clinical trials. BMC Cancer 2023;23:1166. [Crossref] [PubMed]
3. Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer. N Engl J Med 2023;388:2145-58. [Crossref] [PubMed]
4. Powell MA, Bjørge L, Willmott L, et al. Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin-paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial. Ann Oncol 2024;35:728-38. [Crossref] [PubMed]
5. Witt RG, Erstad DJ, Wargo JA. Neoadjuvant therapy for melanoma: rationale for neoadjuvant therapy and pivotal clinical trials. Ther Adv Med Oncol 2022;14:17588359221083052. [Crossref] [PubMed]
6. Westin SN, Moore K, Chon HS, et al. Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial. J Clin Oncol 2024;42:283-99. [Crossref] [PubMed]
7. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer. N Engl J Med 2023;388:2159-70. [Crossref] [PubMed]
8. Colombo N, Biagioli E, Harano K, et al. Atezolizumab and chemotherapy for advanced or recurrent endometrial cancer (AtTEnd): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2024;25:1135-46. [Crossref] [PubMed]
9. Chow RD, Michaels T, Bellone S, et al. Distinct Mechanisms of Mismatch-Repair Deficiency Delineate Two Modes of Response to Anti-PD-1 Immunotherapy in Endometrial Carcinoma. Cancer Discov 2023;13:312-31. [Crossref] [PubMed]
10. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts the response of solid tumors to PD-1 blockade. Science. 2017;357:409-413. [Crossref] [PubMed]
11. Van Gorp T, Cibula D, Lv W, et al. ENGOT-en11/GOG-3053/KEYNOTE-B21: a randomised, double-blind, phase III study of pembrolizumab or placebo plus adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed, high-risk endometrial cancer. Ann Oncol 2024;35:968-80. [Crossref] [PubMed]