RUBY update: Dostarlimab strengthens spot in the endometrial cancer treatment arena

The addition of dostarlimab to a carboplatin-paclitaxel (CP) chemotherapy regimen confers an overall survival (OS) benefit in women with primary advanced or recurrent endometrial cancer (EC), according to the second interim analysis of the ENGOT-EN6/GOG-3031/RUBY trial part 1.

“Dostarlimab-CP demonstrated a statistically significant and clinically meaningful OS improvement in the overall population,” said study investigator Dr Robert Coleman from Sarah Cannon Research Institute, Nashville, Tennessee, US, during his presentation at ESMO Gyn 2024.

After a median follow-up of 37.2 months, the risk of death with dostarlimab-CP dropped by 31 percent as opposed to placebo-CP in the overall cohort (hazard ratio [HR], 0.69, 95 percent CI, 0.54–0.89; p=0.002).

The median OS was markedly longer with the investigational vs placebo regimen (44.6 vs 28.2 months). A comparison between arms yielded a clinically meaningful improvement of 16.4 months favouring the former vs the latter, despite 38 percent of placebo recipients crossing over to receive subsequent immunotherapy, noted Coleman.

The OS benefit was substantial and unprecedented in the subgroup of patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) disease (median not estimable vs 31.4 months; HR, 0.32, 95 percent CI, 0.17–0.63; p_nominal=0.0002).

Among those with mismatch repair-proficient/microsatellite stable (MMRp/MSS) disease, the 7-month difference in median OS was considered clinically meaningful (median 34 vs 27 months; HR, 0.79, 95 percent CI, 0.60–1.04; p_nominal=0.0493). [ESMO Gyn 2024, abstract 37MO]

Furthermore, the OS benefit was consistent across most post hoc exploratory molecular subgroups, including dMMR/MSI-H (HR, 0.40, 95 percent CI, 0.19–0.83), TP53-mutated (HR, 0.59, 95 percent CI, 0.33–1.03), and no specific molecular profile (HR, 0.89, 95 percent CI, 0.61–1.29). According to Coleman, these findings aligned with those reported during the first interim analysis.

There were also clinically meaningful benefits in progression-free survival 2 (PFS2) in the overall cohort (HR, 0.66, 95 percent CI, 0.52–0.84) and the dMMR/MSI-H (HR, 0.33, 95 percent CI, 0.18–0.63) and MMRp/MSS (HR, 0.74, 95 percent CI, 0.57–0.97) subgroups.

“The PFS2 results support the observed OS outcomes and suggest the importance of utilizing immunotherapy early given the inability of subsequent immunotherapy to essentially catch up,” said Coleman.

The incidences of adverse events (AEs) were generally higher with dostarlimab-CP vs placebo-CP, such as any grade ≥3 treatment-emergent AEs (TEAEs; 72.2 percent vs 60.2 percent), serious TEAEs (39.8 percent vs 28 percent), any treatment-related immune-related AE (40.7 percent vs 16.3 percent), and drug discontinuation due to any TEAE (19.1 percent vs 8.1 percent). Nonetheless, Coleman noted that no new safety signals were seen with additional follow-up.

A new standard therapy

“CP served as the principal backbone of therapy for primary advanced or recurrent EC for many years, yet this combination has been associated with poor long-term outcomes,” said Coleman. [Discov Med 2011;12:205-212; J Clin Oncol 2004;22:2159-2166]

In this phase III trial, 494 participants (median age 64.5 years) were randomized 1:1 to receive IV dostarlimab 500 mg plus CP or placebo-CP Q3W for six cycles, followed by dostarlimab 1,000 mg or placebo Q6W for ≥3 years or until disease progression. About a quarter of participants had dMMR/MSI-H disease. Nearly half had recurrent disease and a third were at primary stage IV.

The first interim analysis showed a PFS benefit and an early OS trend with the investigational regimen in both overall and dMMR/MSI-H cohorts. [N Engl J Med 2023;388:2145-2158] The results paved the way for the approval of dostarlimab-CP in the US, EU, and Canada* for primary advanced or recurrent dMMR/MSI-H EC.

The updated OS results and other findings reinforce those reported in the first interim analysis, said Coleman. “RUBY is the only trial to demonstrate a statistically significant OS benefit in patients with primary advanced or recurrent EC.”

“These data confirm dostarlimab-CP as a new standard of care for patients with primary advanced or recurrent EC regardless of MMR status,” he concluded.

Molecular subgroup data needs validation

However, discussant Dr Ramez Eskander from the University of California San Diego Moores Cancer Center, La Jolla, California, US, underlined the need to validate the molecular subgroup data. “These findings are hypothesis-generating, but there is limited clinical utility in prospectively using [the investigational regimen] until we validate it in appropriately designed trials.”

“Importantly, [we need to know] what we can do better to make sure that these patients all receive subsequent anticancer therapy in the context of the amazing data we are seeing, and the work being done in the EC arena,” Eskander added.