Dostarlimab Plus Chemotherapy Elicits PFS Benefit in Recurrent Endometrial Cancer

Dostarlimab-gxly (Jemperli) plus standard-of-care chemotherapy with carboplatin/paclitaxel generated a significant improvement in progression-free survival (PFS) vs chemotherapy alone for patients with recurrent endometrial cancer, including those with mismatch repair–deficient (dMMR), microsatellite instability–high (MSI-H) tumors, according to updated data from the phase 3 RUBY trial (NCT03981796).¹

Results of the randomized, double-blind, multicenter study presented at the 2023 Society of Gynecological Oncology (SGO) Annual Meeting on Women's Cancer displayed that the trial met its primary end point of PFS in the overall patient population of patients on the immune checkpoint inhibitor (ICI) plus chemotherapy treatment (n = 245) compared with patients on placebo and chemotherapy (n = 249) by increasing PFS from 18.1% (95% CI, 13%-23.9%) in the placebo group to 36.1% (95% CI, 29.3%-42.9%) at 24 months in the treatment group (HR, 0.64; 95% CI, 0.51-0.80, P < .001).

Moreover, in the dMMR/MSI-H population of patients on dostarlimab and chemotherapy (n = 53), estimated PFS at 24 months was 61.4% (95% CI, 46.3%-73.4%) compared with 15.7% (95% CI, 7.2%-27.0%) in the placebo group (n = 65; HR, 0.28; 95% CI, 0.16-0.50; P < .001). In the mismatch repair proficient (MMRp)/microsatellite stable (MSS) population of patients, a PFS benefit was observed for patients in the treatment group at 28.4% PFS at 24 months vs 18.8% in the placebo group, but these results did not meet the criteria for statistical significance (HR, 0.76; 95% CI, 0.59-0.98). According to the researchers, dMMR and MSI-H tumors account for 25% to 30% of endometrial cancer and due to the increased mutational burden of these tumors they are potentially vulnerable to anti–PD-1 and anti–PD-L1 therapies, which results of this study show.²

Through the course of the current study up to data cut off on September 28, 2022, separation of patients’ PFS results in the overall population and dMMR/MSI-H showed a steady increase of survival, explained Mansoor Raza Mirza, MD, who presented these data at the 2023 SGO Annual Meeting, which demonstrates further evidence for the hypothesis that ICI combined with chemotherapy is effective in this patient population.

At the time of the analysis the overall survival (OS) data were at 33% maturity. In the overall population and the dMMR/MSI-H population a trend toward improved OS was observed. In the overall population the 24-month OS rate was 71.3% (95% CI, 64.5%-77.1%) for patients who received dostarlimab compared with 56% for those who received placebo (HR 0.64%; 95% CI, 0.46-0.87; P = .021). In the dMMR/MSI-H population the 24-month OS rate was 83.3% (95% CI, 66.8%-92.0%) with dostarlimab vs 58.7% (95% CI, 43.4%-71.2%) with placebo (HR 0.30; 95% CI, 0.13-0.69). In the pMMR/MSS population these rates were 67.7% (95% CI, 59.8%-74.4%) and 55.1% (95% CI, 46.8%-62.5%) for patients who received the ICI combination and placebo combinations, respectively (HR 0.73; 95% CI, 0.52-1.02).^1,2

Strong Responses Show Validity of ICIs in Endometrial Cancer

In the overall population 34.5% of patients in the placebo arm were then given subsequent therapy and 38.5% of patients in the placebo arm with dMMR/MSI-H tumors received the same treatment compared with approximately 15% of patients in the dostarlimab arm in both groups.

Secondary end points of the trial included the objective response rate (ORR) and duration of response (DOR).^1,2

In the overall population, patients treated with the dostarlimab combination had an ORR of 70.3% (95% CI, 63.6%-76.3%) with a complete response (CR) rate of 25% and a partial response (PR) rate of 45.3%. The median DOR was 10.6 months (95% CI, 8.2-17.6). In the placebo arm, the ORR was 64.8% (95% CI, 58.1%-71.2%) with a CR rate of 19.6% and a PR rate of 45.2%, with a median DOR of 6.2 months (95% CI, 4.4-6.7). Stable disease was reported among 19.8% and 22.4% of patients in the dostarlimab and placebo arms, respectively. The disease control rate (DCR) was 90.1% (95% CI, 85.3%-93.8%) in the dostarlimab arm. In the placebo arm the DCR was 87.7% (95% CI, 82.6%-91.7%).²

In the dMMR/MSI-H population, the ORR with dostarlimab was 77.6% (95% CI, 63.4%-88.2%) compared with 69.0% (95% CI, 55.5%-80.5%) with placebo. Among the responders in the dostarlimab arm, 30.6% had a CR and 46.9% had a PR; the median DOR was not estimable (NE; 95% CI, 10.1-NE). The DCR was 89.8% (95% CI, 77.8%-96.6%).² In the placebo arm, CRs and PRs reported in 20.7% and 48.3% of patients, respectively, with 17.2% of patients having SD, for a DCR of 87.9% (95% CI, 76.7%-95.0%). The median DOR was 5.4 months (95% CI, 3.9-8.1).²

Finally, for patients in the pMMR/MSS population the ORR was 68.1% (95% CI, 60.4%-75.2%) with a CR and PR rate of 23.3% and 44.8%, respectively, with dostarlimab. The median DOR was 8.6 months (95% CI, 6.9-13.1). Among those who received placebo, the ORR was 63.4% (95% CI, 55.4%-70.8%) with a CR rate of 19.3% and a PR rate of 44.1%, with a median DOR of 6.3 months (95% CI, 4.4-6.9). The DCR was 90.2% (95% CI, 84.5%-94.3%) in the dostarlimab arm vs 87.6% (95% CI, 81.5%-92.2%) in the placebo arm.²

“These [data are] very important because we look here at the [ORR] and the hypothesis we have that if you give chemotherapy, you get a better response with immune therapy,” explained Mirza, Chief Oncologist at the Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Denmark, in his presentation. “As you can see...the separation of the curves from the very beginning gives us a hint that probably this is the right hypothesis that chemotherapy plus immunotherapy is beneficial.”

Safety Signals Present Manageable Outcomes

Among the patients with endometrial cancer patients in the treatment arm were on treatment for a median of 43 weeks compared with 36 weeks for patients on placebo with serious treatment-emergent adverse events (TEAEs) observed in 37.8% of patients in the combination arm compared with 27.6% in the placebo arm.

Patients were randomly assigned 1:1 to either 500 mg of dostarlimab given intravenously with 5 mg/mL/min or carboplatin or 175 mg/m² once every 3 weeks for 6 cycles, then dostarlimab was given at 1000 mg intravenously once every 6 weeks up to 3 years. Of the 494 patients initially randomized 52 remained on treatment with dostarlimab at the time of data cut off compared with 36 on placebo. Most patients in either arm had recurrent disease but 33.9% of patients in the overall population had primary stage IV disease and 18.4% had primary stage III disease. The majority of patients had measurable disease at the time of baselines with just 19.6% given prior chemotherapy.

Seventeen percent of patients discontinued therapy in the dostarlimab arm, whereas discontinuation occurred in 9.3% of patients on placebo. Moreover, around 10% in the treatment arm discontinued either chemotherapy option due to a TEAE and 5 patients died due to any TEAE.

The most common AEs that occurred, or worsened during the treatment, in the dostarlimab group vs placebo group included nausea (53.9% vs 45.9%), alopecia (53.5% vs 50.0%), and fatigue (51.9% vs 54.5%). The AEs with the largest difference in incidences between the groups were rash and maculopapular rash with both AEs reported more frequently in the ICI and chemotherapy arm vs the placebo and chemotherapy arm at 22.8% vs. 13.8% and 14.1% vs. 3.7%, respectively. Rash and maculopapular rash accounted for the most common AEs that led to discontinuation of treatment with 1.2% each, while thrombocytopenia (1.2%) was the most common in the placebo group that led patients to discontinue.

The most common immune-related AEs were hypothyroidism (11.2% vs 2.8%), rash (6.6% vs 2.0%), arthralgia (5.8% vs 6.5%), and increase in alanine aminotransferase levels (5.8% vs 0.8%). At the meeting, Mirza provided patient reported outcomes on quality of life that were in the works and were set to be presented later this year but believed they favored patients on the ICI as dostarlimab did not interrupt the use of chemotherapy.

“Substantial unprecedented benefit in dMMR patients and clinically meaningful long-term benefit observed in the MMR proficient patients along with the safety profile of the [combination] was manageable and generally consistent with that of the individual drugs,” concluded Mirza. “[Therefore,] dostalimab plus carboplatin/paclitaxel represents a new standard of care for patients with primary advanced and recurrent endometrial cancer.”

References

1. Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab in combination with chemotherapy for the treatment of primary advanced or recurrent endometrial cancer: a placebo-controlled randomized phase 3 trial (ENGOT-EN6-NSGO/GOG-3031/RUBY). Presented at: 2023 SGO Annual Meeting on Women’s Cancer; March 25-28, 2023; Tampa, FL.
2. Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. Published online March 27, 2023. doi:10.1056/NEJMoa2216334