Dostarlimab/Chemo Shows OS Benefit Regardless of MMR Status in Endometrial Cancer

Robert L. Coleman, MD, FACOG, FACS

The addition of dostarlimab-gxly (Jemperli) to chemotherapy, followed by dostarlimab monotherapy, demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) vs placebo plus chemotherapy in patients with primary advanced or recurrent endometrial cancer, with benefits observed across molecular subgroups and irrespective of mismatch repair (MMR) status, according to updated findings from part 1 of the phase 3 RUBY trial (NCT03981796) presented at the 2024 ESMO Gynecologic Cancers Congress.¹

At a median follow-up of 37.2 months for the overall population, patients treated with dostarlimab plus chemotherapy followed by dostarlimab (n = 245) achieved a median OS of 44.6 months (95% CI, 32.6–not evaluable [NE]) compared with 28.2 months (95% CI, 22.1-35.6) in those treated with placebo plus chemotherapy (n = 249; HR, 0.69; 95% CI, 0.54-0.89; P = .002). Notably, 38.2% of patients in the placebo arm received subsequent immunotherapy.

In the mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) population, the median OS was NE (95% CI, NE-NE) in the dostarlimab arm (n = 53) vs 31.4 months (95% CI, 20.3-NE) in the placebo arm (n = 65; HR, 0.32; 95% CI, 0.17-0.63; nominal P = .0002) at a median follow-up of 36.6 months. In the placebo arm, 41.5% of patients in the dMMR/MSI-H population received subsequent immunotherapy.

There was also a clinically meaningful OS difference in the mismatch repair–proficient (pMMR)/microsatellite stable (MSS) population at a median follow-up of 37.5 months. The median OS was 34.0 months (95% CI, 28.6-NE) in the dostarlimab group (n = 192) vs 27.0 months (95% CI, 21.5-35.6) in the placebo group (n = 184; HR, 0.79; 95% CI, 0.60-1.04; nominal P = .0493). Notably, 37.0% of patients in the placebo arm in this subgroup received subsequent immunotherapy.

"These data confirm dostarlimab plus chemotherapy as a new standard of care for patients with primary advanced or recurrent endometrial cancer, regardless of MMR status,” presenting author Robert L. Coleman, MD, FACOG, FACS, of Sarah Cannon Research Institute in Nashville, Tennessee, said in a presentation of the data.

In July 2023, prior data from RUBY supported the FDA approval of dostarlimab in combination with carboplatin and paclitaxel, followed by dostarlimab monotherapy, for adult patients with primary advanced or recurrent endometrial cancer that is dMMR or MSI-H.²

The updated analysis included data for OS, time to second progression (PFS2), and safety. Coleman and colleagues also conducted an exploratory analysis on OS outcomes by molecular classification.¹

During RUBY, 494 patients with primary advanced or recurrent endometrial cancer were randomly assigned to either dostarlimab plus carboplatin and paclitaxel, followed by dostarlimab monotherapy; or placebo plus carboplatin and paclitaxel, followed by placebo monotherapy.

At the September 22, 2023, data cutoff, 130 patients in the dostarlimab arm discontinued treatment due to death from any cause (n = 96), consent withdrawal (n = 26), loss of follow-up (n = 5), or other reasons (n = 3). Eighty-eight patients remained in follow-up, and 27 patients were still receiving dostarlimab. In the placebo arm, 160 patients discontinued study treatment due to death from any cause (n = 133), consent withdrawal (n = 20), loss of follow-up (n = 5), or other reasons (n = 2). Sixty-seven patients were in follow-up, and 22 remained on placebo.

Enrolled patients presented with either dMMR/MSI-H (dostarlimab arm, 21.6%; placebo arm, 26.1%) or pMMR/MSS disease (78.4%; 73.9%), and were White (77.1%; 76.7%), Black (11.4%; 12.4%), or Asian (2.9%; 3.2%). Patients in the dostarlimab had a median age of 64 years (range, 41-81) vs 65 years (range, 28-85) in the placebo arm. Notably, 48.2% and 54.2% of patients, respectively, were at least 65 years of age.

Moreover, some patients received prior external pelvic radiation (dostarlimab arm, 16.7%; placebo arm, 18.1%). Disease status included primary stage II (18.4%; 18.9%), primary stage IV (33.9%; 33.3%), or recurrent (47.8%; 47.8%). The majority of patients had an ECOG performance status of 0 (60.2%; 65.0%).

Additionally, patients had a median BMI of 30.8 (range, 17.6-60.6) and 32.8 (range, 17.7-68.0) in the dostarlimab and placebo arms, respectively, and 86.5% and 88.0% of patients had measurable disease at baseline in these respective groups. A minority of patients received prior anticancer treatment (dostarlimab arm, 19.6%; placebo arm, 20.9%), including carboplatin-paclitaxel (14.7%; 15.7%). Histology types included carcinoma (10.2%; 7.6%), endometrioid (54.7%; 54.6%), serous adenocarcinoma (20.4%; 20.9%), or other (14.7%; 16.9%).

Molecular classification was performed for all patients with whole-exome DNA sequencing (WES) results (n = 400/494), and an exploratory analysis examined OS difference in patients with dMMR/MSI-H disease who underwent WES (HR for dostarlimab vs placebo, 0.40; 95% CI, 0.19-0.83), those harboring TP53 mutations (HR, 0.59; 95% CI, 0.33-1.03), and patients with no specific molecular profile (HR, 0.89; 95% CI, 0.61-1.29). Notably, HR for patients with POLE mutations was not applicable, since all patients in the dostarlimab arm (n = 2) and placebo arm (n = 3) were alive at data cutoff. Coleman noted that the findings from molecular subgroup analysis were consistent with findings from the first interim analysis.

Additional data from the overall population showed that 49.0% of patients on the dostarlimab arm received any follow-up anticancer therapy vs 69.5% of patients in the placebo arm. Subsequent therapies included immunotherapy (dostarlimab arm, 35.0%; placebo arm, 54.9%) with either pembrolizumab (Keytruda; 10.8%; 23.7%), pembrolizumab plus lenvatinib (Lenvima; 20.8%; 26.0%), dostarlimab (0%; 1.7%), or other (4.2%; 6.9%).

Furthermore, a clinically meaningful PFS2 benefit was observed for the dostarlimab regimen in the overall population (HR, 0.66, 95% CI, 0.52-0.84). The median PFS2 was 32.3 months (95% CI, 24.6-NE) in the dostarlimab group vs 18.4 months (95% CI, 14.9-22.0) in the placebo group.

In the dMMR/MSI-H population, the median PFS2 was NE (95% CI, NE-NE) for the dostarlimab arm and 21.6 months (95% CI, 13.4-39.1) for the placebo arm (HR, 0.33; 95% CI, 0.18-0.63). In the pMMR/MSS population, the median PFS2 was 24.6 months (95% CI, 20.1-32.6) for the dostarlimab arm vs 15.9 months (95% CI, 13.6-22.0) for the placebo arm (HR, 0.74; 95% CI, 0.57-0.97).

Regarding safety, all patients in the dostarlimab arm (n = 241) and placebo arm (n = 246) experienced any treatment-emergent adverse effect (TEAE); 72.2% and 60.2% experienced grade 3 or higher TEAEs; 39.8% and 28.0% experienced serious TEAEs; and 40.7% and 60.3% had any treatment-related immune-related AE.

TEAEs that led to discontinuation of dostarlimab or placebo in 19.1% and 8.1% of patients, respectively. Additionally, 8.3% and 6.1% of patients had any TEAE that led to discontinuation of carboplatin in the dostarlimab and placebo arms, respectively; 10.8% and 10.2% had any TEAE leading to discontinuation of paclitaxel; 2.1% and 0% had any TEAE leading to death. Notably, 0.8% of patients in the experimental arm experienced any TEAE related to dostarlimab that led to death. Notably, the median duration of overall treatment was 43.0 weeks (range, 3.0-192.6) for the dostarlimab arm vs 36.0 weeks (range, 2.1-193.1) for the placebo arm.

Disclosures: Dr Coleman reported receiving grants or contracts from AstraZeneca, Clovis, Genelux, Genmab, Immunogen, Merck, and Roche/Genentech; consulting fees from AbbVie, Agenus, Alkermes, AstraZeneca, Clovis, Deciphera, Genelux, Genmab, GSK, Immunogen, Novocure, Merck, OncoQuest, Onxerna, Regeneron, and Roche/Genentech; honoraria from AstraZeneca, Clovis, Merck, and Roche/Genentech; and participation on a data safety monitoring board or advisory board with Eisai/BMS and VBL Therapeutics.

References

1. Powell MA, Auranen A, Willmott L, et al. Dostarlimab plus chemotherapy in primary advanced or recurrent endometrial cancer in the RUBY trial: overall survival by MMR status and molecular subgroups. Presented at: 2024 ESMO Gynecological Cancers Congress; June 20-22, 2024; Florence, Italy. Abstract 37MO.
2. Jemperli (dostarlimab) plus chemotherapy approved in the US as the first new frontline treatment option in decades for dMMR/MSI-H primary advanced or recurrent endometrial cancer. News release. GlaxoSmithKline. July 31, 2023. Accessed July 2, 2024. https://www.gsk.com/en-gb/media/press-releases/jemperli-plus-chemotherapy-approved-in-us-for-new-indication/