Dostarlimab With Carboplatin/Paclitaxel Shows Survival Benefits in dMMR/MSI-H Endometrial Cancer

Mansoor Raza Mirza, MD

A treatment combination of dorstarlimab (Jemperli) plus carboplatin and paclitaxel (CP) led to progression-free survival (PFS) and overall survival (OS) benefits in patients with mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) primary advanced or recurrent endometrial cancer (EC).

These findings were based on results from part 1 of the phase 3 RUBY trial (NCT03981796), which were presented at the 2024 ASCO Annual Meeting.¹

“These results support the understanding that mechanism of MMR protein loss does not appear to be a predictor of clinical benefit for dostarlimab treatment in patients with dMMR primary advanced or recurrent EC in part 1 of the RUBY trial,” the study authors wrote in a poster presentation of the data.

Part 1 of the RUBY trial — which was a randomized, double-blind, multicenter study —included 494 patients with dMMR/MSI-H primary advanced or recurrent EC. Patients were randomized 1:1 to receive 500 mg of dostarlimab plus CP (n=245) or placebo plus CP (n=249) every 3 weeks for 6 cycles. In addition, patients received 1,000 mg of dostalimab or placebo every 6 weeks for up to 3 years or until disease progression, toxicity, withdrawal of consent, investigator’s decision, or death (whichever occurred first).

The primary end points of the study included PFS per investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1 in the dMMR/MSI-H and overall populations and OS in the overall population.

The data cutoff for the post hoc PFS and OS analyses were September 28, 2022, and September 22, 2023, respectively, in which the respective end points were met.

At the first interim analysis for PFS on September 28, 2022, the PFS rates were statistically significant, with a 72% (HR, 0.28; 95% CI, 0.16-0.50; P<0.0001) reduction in risk of progression or death for patients in the dostarlimab arm.

At the second interim analysis for OS on September 22, 2023, the OS was clinically meaningful for patients treated with the dostarlimab regimen with a 68% (HR, 0.32; 95% CI, 0.17-0.63; nominal P=0.0002) reduced risk of death.

Mut-dMMR vs epi-dMMR

“No differences were seen in PFS or OS in patients with mut-dMMR (mutation dMMR) as compared with patients with epi-dMMR (epigenetic regulation) who were treated with dostarlimab plus CP or placebo plus CP,” the authors wrote in the poster.

The duration of response (DoR) was also improved among patients receiving the dostarlimab and placebo regimens with mut-dMMR and epi-dMMR. Among patients with mut-dMMR, 6 of 9 and 10 of 14 patients from the dostarlimab and placebo arms responded to treatment, respectively. Of the patients with epi-dMMR, 23 of 30 and 25 of 38 patients from the dostarlimab and placebo arms responded to treatment, respectively. The median DoR per month for patients with mut-dMMR was not reached (NR) in the dostarlimab arm (95% CI, 6.2-NR) and 4.8 months in the placebo arm (95% CI, 2/7-10.1). In patients with epi-dMMR, the median DoR was 36.7 months (95% CI, 5.4-NR) and 4.2 months (95% CI, 3.8-8.1) in the dorstarlimab and placebo arms, respectively.

Patients in the dostarlimab regimen arm had a higher probability of remaining in response at 12, 24, and 36 months, compared with patients treated with the placebo regimen.

Specifically, the probability of remaining in response at 12 months for patients with mut-dMMR was 80.0% (95% CI, 20.4-96.9) in the dostarlimab arm and 20.0% (95% CI, 3.1-47.5) in the placebo arm. In patients with epi-dMMR at 12 months, the probability of remaining in response was 50.3% (95% CI, 28.5-68.7) in the dostarlimab arm and 13.3% (95% CI, 3.4-30.1) in the placebo arm.

At both 24 months and 36 months in patients with mut-dMMR, the probability of remaining in responses was 80.0% (95% CI, 20.4-96.9) in the dostarlimab arm. At 24 months and 36 months, it was 10.0% (95% CI, 0.6-35.8) and not estimatable (NE) in the placebo arm, respectively.

In patients with epi-dMMR at both 24 months and 36 months, the probability of remaining in response was 50.3% (95% CI, 28.5-68.7) in the dostarlimab arm. For the placebo arm, both the 24-month and 36-month probability of remaining in responses in patients with epi-dMMR were 8.9% (95% CI, 1.6-24.5).

Safety

The safety was consistent overall with the full dMMR/MSI-H population, along with the safety profiles of the individual components. In particular for patients with mut-dMMR, 9 (100%) and 14 (100%) experienced any-grade treatment-emergent adverse events (TEAEs) in the dostarlimab and placebo arms, respectively. Of patients with epi-dMMR, 30 (100%) and 38 (100%) experienced any-grade TEAEs in the dostarlimab and placebo arms, respectively.

Discontinuations of treatment because of TEAEs were reported in both arms in the dMMR/MSI-H population, except for the placebo arm in patients with mut-dMMR. One patient with mut-dMMR in the dostarlimab arm discontinued treatment. In patients with epi-dMMR, 7 and 3 patients discontinued treatment due to TEAEs in the dostarlimab and placbo arms, respectively.

The only TEAEs with the outcome of death occurred in patients with epi-dMMR from the dostarlimab arm (n=2; 6.7%).

In the mut-dMMR and epi-dMMR subgroups, respectively, common TEAEs included nausea (66.7% vs 50.0%, dostarlimab; 57.1% vs 47.4%, placebo), fatigue (66.7% vs 50.0%, dostarlimab; 71.4% vs 52.6%, placebo), arthralgia (66.7% vs 36.7%, dostarlimab; 64.3% vs 26.3%, placebo), and alopecia (44.4% vs 60.0%, dostarlimab; 57.1% vs 65.8%, placebo).

Patient Characteristics

Of 118 patients in the dMMR/MSI-H population, 91 patients (77.1%) had MMR gene mutation data available. This included 39 of 53 patients (73.6%) and 52 of 65 patients (80.0%) in the dostarlimab plus CP and placebo plus CP arms, respectively.

“Patient characteristics were similar between arms and across the mut-dMMR and epi-dMMR subgroups,” the study authors wrote in the poster presentation.

In the mut-dMMR subgroup, there were 9 patients treated with the dostarlimab regimen and 14 patients treated with placebo regimen. In the edi-dMMR subgroup, 30 patients received the dostarlimab regimen and 38 patients received placebo regimen.

Reference

Mirza M, Sharma S, Roed H, et al. Post hoc analysis of progression-free survival (PFS) and overall survival (OS) by mechanism of mismatch repair (MMR) protein loss in patients with endometrial cancer (EC) treated with dostarlimab plus chemotherapy in the RUBY trial.J Clin Oncol. 2024;42(suppl 16): abstr5606. doi:10.1200/JCO.2024.42.16_suppl.5606