Immunotherapy in dMMR/MSI-H endometrial cancer – a true game-changer?

Sustained benefit and durable remissions in patients with mismatch repair deficient/microsatellite-high (dMMR/MSI-H) advanced/recurrent endometrial cancer treated with the anti-PD-1 immune checkpoint inhibitor, dostarlimab, were reported at ESMO Gynaecological Cancers 2026 (Copenhagen, 17–19 June) in two oral presentations, further consolidating the role of immunotherapy for these difficult-to-treat tumours.

Patients with advanced/recurrent endometrial cancer have limited treatment options following disease progression on frontline platinum-based chemotherapy, resulting in a poor prognosis with an estimated median survival of less than 3 years (N Engl J Med. 2023;388:2145–2158). However, approximately 25–30% of endometrial cancers are classed as dMMR (or ‘hot’ tumours) and have a high probability of responding to immunotherapy (N Engl J Med. 2023;388:2145–2158; Clin Cancer Res. 2023;29:4564–4574).

Over the last 3 years, the clinical benefits of immunotherapy in endometrial cancer have been reported in four randomised phase III trials: RUBY (dostarlimab; N Engl J Med. 2023;388:2145–2158), KEYNOTE-868 (pembrolizumab; N Engl J Med. 2023;388:2159–2170), AtTEnd (atezolizumab; Lancet Oncol. 2024;25:1135–1146) and DUO-E (durvalumab; J Clin Oncol. 2024;42:283–299). “We see a class effect with these agents, but there are some nuances and these studies can help us decide which agent to use for different patients,” notes Dr Brian M. Slomovitz from Mount Sinai Medical Center, Miami Beach, FL, USA.

Earlier results from the open-label, single-arm GARNET trial (JAMA Oncol. 2020;6:1766–1772; J Immunother Cancer. 2022;10:e003777) previously led to dostarlimab approvals in the European Union (for dMMR/MSI-H advanced/recurrent endometrial cancer) and the USA (for dMMR advanced solid tumours). At one oral presentation, 6-year data from the previously published GARNET trial (JAMA Netw Open. 2023;6:e2341165; Clin Cancer Res. 2023;29:4564–4574) confirmed earlier observations of robust clinical benefit and durable antitumour activity of dostarlimab, with an objective response rate (ORR) of 45.5% and disease control rate (DCR) of 60.1% in 143 efficacy-evaluable patients (Abstract 69O). A complete response (CR) was reported in 9 patients who previously achieved a partial response, suggesting a deepening of response over time.

“These are unprecedented results in the second-line management of endometrial cancer,” says Slomovitz. “Neither median duration of response (DOR) nor median overall survival (OS) was reached at a median follow-up of 69 months with single-agent immunotherapy: this is remarkable. These are pre-treated patients who are experiencing a durable response and potentially being cured of their disease.”

Also presented at the Congress, an updated analysis of the phase III RUBY trial (N Engl J Med. 2023;388:2145–2158) showed that dostarlimab in combination with carboplatin–paclitaxel chemotherapy (n=53) was associated with a 4-year OS rate of 72.8% (versus 40.3% in the chemotherapy arm [n=65]) in patients with dMMR/MSI-H primary advanced/recurrent endometrial cancer (Abstract 71RO). At a median follow-up of 55.6 months, only 4 new progression events were reported with an additional 2.5 years of follow-up since the primary progression-free survival (PFS) analysis. Notably, almost one-third (17/53; 32%) of patients treated with the dostarlimab combination achieved a CR; of these, only 3 patients subsequently progressed and 1 patient died. Median PFS and median OS were not reached with dostarlimab plus chemotherapy at 4 years.

Slomovitz points out: “Patients with proficient (p)MMR/microsatellite stable (MSS) endometrial cancer (so-called ‘cold’ tumours) also derived PFS and OS benefit at 24 months in the RUBY trial, although survival benefits were smaller in magnitude than in the dMMR/MSI-H population.” Among patients with dMMR/MSI-H tumours, a 72% lower risk of progression or death (hazard ratio 0.28) was reported compared with the placebo regimen (N Engl J Med. 2023;388:2145–2158). “The data are game-changing for all patients, but there is a tremendous advantage for patients with dMMR/MSI-H or ‘hot’ tumours,” he adds. The long-term results provide further evidence for the benefit of adding immunotherapy to a chemotherapy backbone in this setting and may support this regimen as first-line standard of care in this tumour type.

Despite progress in the field, in patients with pMMR/MSS endometrial cancer there remains an unmet need for more effective therapies. According to Slomovitz, major advances will come from the ongoing studies in pMMR/MSS that are focusing on combinations of immunotherapy with targeted agents, such as antibody–drug conjugates. For instance, the TroFuse-033 study is investigating a combination of pembrolizumab with sacituzumab tirumotecan as first-line maintenance treatment, while DESTINY-Endometrial01 is evaluating first-line trastuzumab deruxtecan plus immunotherapy (rilvegostomig – a bispecific antibody targeting PD-1 and TIGIT – or pembrolizumab) in patients with HER2-expressing pMMR advanced/recurrent endometrial cancer as a potential chemotherapy-free regimen.

Concluding, Slomovitz notes that, “Immunotherapy has significantly changed the way we treat endometrial cancer, and all patients - (regardless of whether they have a ‘hot’ or ‘cold’ tumour -) deserve to receive immunotherapy at some point during their treatment course. In the years ahead, the hope is that first-line immunotherapy, likely in combination with other novel agents, will negate the need for a second-line option by increasing the number of patients considered cured of their disease.”