Dostarlimab plus chemo extends survival in advanced/recurrent endometrial cancer

Treatment with dostarlimab combined with carboplatin‒paclitaxel significantly improves overall survival (OS) among patients with primary advanced or recurrent endometrial cancer (EC), with no new safety signals, results of the RUBY trial have shown.

“[D]ostarlimab in combination with carboplatin–paclitaxel demonstrated a statistically significant and clinically meaningful OS benefit in the overall population of patients with primary advanced or recurrent EC while demonstrating an acceptable safety profile, representing a new standard of care,” the investigators said.

Part 1 of RUBY—a phase III, global, double-blind, randomized, placebo-controlled trial—enrolled patients with primary advanced stage III or IV or first recurrent EC. Eligible participants (n=494) were randomized 1:1 to receive either dostarlimab 500 mg (n=245) or placebo (n=249), plus carboplatin‒paclitaxel every 3 weeks for six cycles, followed by dostarlimab 1,000 mg or placebo every 6 weeks for up to 3 years.

In the overall population, with 51-percent maturity, patients treated with dostarlimab plus carboplatin‒paclitaxel achieved a statistically significant reduction in the risk of mortality (hazard ratio [HR], 0.69, 95 percent confidence interval [CI], 0.54‒0.89; p=0.002) compared with those treated with carboplatin‒paclitaxel alone. [Ann Oncol 2024;35:728-738]

In the mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) population, the risk of mortality was lower (HR, 0.32, 95 percent CI, 0.17‒0.63; p=0.0002). Additionally, a favourable trend was observed for dostarlimab in the mismatch repair-proficient/microsatellite stable population (HR, 0.79, 95 percent CI, 0.60‒1.04; p=0.0493).

Moreover, dostarlimab plus carboplatin‒paclitaxel had a safety profile that was consistent with the first interim analysis of RUBY.

Interim analyses

“At the first interim analysis, the trial met one of its dual primary endpoints with statistically significant progression-free survival benefits in the dMMR/MSI-H and overall populations,” the investigators said.

Subgroup analyses for OS at this second interim analysis were in favour of dostarlimab, except for patients with stage III EC, those with no disease at baseline, and those in Europe.

However, “[t]hese results should be interpreted with caution because of the low number of patients in these subgroups and potential confounding factors when evaluating populations in which stratification may be impacted,” the investigators said.

“Furthermore, there is no biological rationale for patients with stage III EC to respond differently to treatment than patients with stage IV or recurrent EC, which is supported by the literature,” they added. [J Clin Oncol 2020;38:3841-3850; JAMA Oncol 2019;5:833-840; J Clin Oncol 2006;24:36-44; Gynecol Oncol 2009;112:543-552; N Engl J Med 2019;380:2317-2326]

The RUBY trial provided substantial evidence for the use of dostarlimab plus chemotherapy, followed by dostarlimab maintenance, in patients with EC. However, there remains a lack of evidence regarding the efficacy of single-agent dostarlimab compared with chemotherapy.

Currently, two trials are trying to address this limitation: DOMENICA and KEYNOTE-C93. These open-label, phase III, randomized trials are assessing first-line dostarlimab or pembrolizumab, respectively, compared with carboplatin‒paclitaxel in patients with advanced or recurrent dMMR EC, according to the investigators. [J Clin Oncol 2023;41TPS5630; J Clin Oncol 2022;40TPS5623]