Dostarlimab/Chemo/Niraparib Generates PFS Benefit in Primary/Recurrent Endometrial Cancer

Dostarlimab-gxly (Jemperli) plus carboplatin and paclitaxel, followed by dostarlimab plus niraparib (Zejula) maintenance therapy, elicited a statistically significant progression-free survival (PFS) benefit vs placebo plus chemotherapy in patients with primary advanced or recurrent endometrial cancer regardless of mismatch repair (MMR) status, histological subgroup, or molecular subgroup, according to findings from the first interim analysis of part 2 of the ENGOT-EN6-NSGO/GOG-3031/RUBY trial (NCT03981796). Findings were presented at the 2024 ESMO Gynecologic Cancers Congress.¹

In the overall population, at a median follow-up of 21.7 months, and a maturity rate of 56.4%, the median PFS with dostarlimab/chemotherapy/niraparib was 14.5 months (95% CI, 11.8-17.4) vs 8.3 months (95% CI, 7.6-9.8) with placebo plus chemotherapy (HR, 0.60; 95% CI, 0.43-0.82; P = .0007). The 12-month PFS rates were 57.0% in the dostarlimab arm vs 33.7% in the placebo arm.

Furthermore, in the MMR-proficient (pMMR)/microsatellite-stable (MSS) population, at a median follow-up of 21.8 months, and a maturity rate of 61.1%, the median PFS with dostarlimab/chemotherapy/niraparib was 14.3 months (95% CI, 9.7-16.9) vs 8.3 months (95% CI, 7.6-9.8) with placebo plus chemotherapy (HR, 0.63; 95% CI, 0.44-0.91; P = .0060). The 12-month PFS rates were 54.7% in the dostarlimab arm vs 31.1% in the placebo arm.

In the MMR-deficient (dMMR)/microsatellite instability–high (MSI-H) population, at a median follow-up of 21.2 months, and a maturity rate of 42.7%, the median PFS with dostarlimab/chemotherapy/niraparib was not evaluable (NE; 95% CI, 11.8-NE) vs 7.9 months (95% CI, 5.4-NE) with placebo plus chemotherapy (HR, 0.48; 95% CI, 0.24-0.96; P = .0174). The 12-month PFS rates were 64.4% in the dostarlimab arm vs 40.8% in the placebo arm.

“These outcomes demonstrate a potential role for PARP inhibitor maintenance in patients receiving dostarlimab plus chemotherapy, in particular in the pMMR population,” lead study author Mansoor Raza Mirza, MD, said in a presentation of the data. Dr Mirza is the chief oncologist in the Department of Oncology at Rigshospitalet, Copenhagen University Hospital, in Denmark.

In part 1 of RUBY, the dual primary end points of PFS and overall survival (OS) were met with dostarlimab plus chemotherapy, demonstrating a clinical benefit with the dostarlimab regimen regardless of patients’ MMR status. In the overall population, the 24-month PFS rate was 36.1% (95% CI, 29.3%-42.9%) with dostarlimab vs 18.1% (95% CI, 13.0%-23.9%) with placebo (HR, 0.64; 95% CI, 0.51-0.80; P < .001).2 Furthermore, patients with dMMR/MSI-H disease achieved substantial benefit with the dostarlimab regimen, with an estimated 24-month PFS rate of 61.4% (95% CI, 46.3%-73.4%) vs 15.7% (95% CI, 7.2%-27.0%) with placebo.

“When we planned RUBY part 2, we kept the inclusion/exclusion criteria…completely similar to what we [used] in part 1,” Mirza noted. “We kept the stratification factors similar; we kept the trial design similar.”

Part 2 of the RUBY trial enrolled patients with stage III/IV or first recurrent endometrial cancer of all histologies except sarcoma.¹ Eligible patients were naive to systemic anticancer therapies or had disease recurrence or progressive disease at least 6 months after completing systemic anticancer therapy. Patients also needed to be naive to PARP inhibitors.

Patients were stratified by MMR/MSI status (dMMR/MSI-H, 25%; pMMR/MSS, 75%), receipt of prior external pelvic radiotherapy, and disease status. A total of 291 patients were randomly assigned 2:1 to the dostarlimab (n = 192) or placebo (n = 99) arms. Patients in the investigational arm received intravenous (IV) dostarlimab at 500 mg plus chemotherapy every 3 weeks for 6 cycles, followed by IV dostarlimab at 1000 mg every 6 weeks plus niraparib at 200 mg or 300 mg daily for up to 3 years. Patients in the placebo arm received IV placebo plus chemotherapy every 3 weeks for 6 cycles followed by IV placebo every 6 weeks plus oral and IV placebo daily for up to 3 years.

The primary end point of RUBY part 2 is investigator-assessed PFS per RECIST v1.1 in both the overall and pMMR/MSS patient populations. Secondary end points include OS, PFS by blinded independent central review, overall response rate, duration of response, disease control rate, time to second progression, health-related quality of life/patient-reported outcomes, pharmacokinetics, and safety.

At a data cutoff of November 1, 2023, 77 patients randomly assigned to the dostarlimab arm discontinued the study because of death from any cause (n = 52), withdrawal of consent (n = 21), loss to follow-up (n = 2), and other reasons (n = 2). Seventy-one patients were in follow-up, and 44 remained on treatment. Among patients randomly assigned to the placebo arm, 36 discontinued the study because of death from any cause (n = 25), withdrawal of consent (n = 8), loss to follow-up (n = 2), and other reasons (n = 1). Forty-three patients were in follow-up, and 20 remained on treatment.

“The baseline characteristics were very well balanced,” Mirza said.

Notably, in the overall population, 63.1% and 69.7% of patients in the dostarlimab and placebo arms, respectively, had endometrioid carcinoma. These respective values were 54.2% and 62.2% in the pMMR/MSS population.

Among patients in the overall population in the dostarlimab arm, 1.6%, 19.3%, 20.3%, and 39.1% had POLE mutations, dMMR/MSI-H disease, TP53 mutations, and no specific molecular profile (NSMP), respectively; 19.8% of patients were NE for molecular subgroup. Furthermore, 64.1% and 33.3% of patients had PD-L1–positive and –negative disease, respectively; 2.6% were NE for PD-L1 status. BRCA-positive and -negative disease was reported in 3.1% and 77.1% of patients, respectively, and 19.8% of patients were NE for BRCA mutation status. Additionally, 10.4% and 69.8% of patients had homologous recombination repair (HRR)–positive and –negative disease; 19.8% of patients were NE. Regarding histologic subgroup, 59.4% and 39.6% of patients had endometrioid carcinoma and other histologies, respectively.

Among patients in the overall population in the placebo arm, 2.0%, 17.2%, 10.1%, and 46.5% had POLE mutations, dMMR/MSI-H disease, TP53 mutations, and NSMP, respectively; 24.2% of patients were NE for molecular subgroup. Furthermore, 62.6% and 31.3% of patients had PD-L1–positive and –negative disease, respectively, and 6.1% were NE for PD-L1 status. BRCA-positive and -negative disease was reported in 4.0% and 71.7% of patients, respectively; 24.2% of patients were NE for BRCA mutation status. Additionally, 14.1% and 61.6% of patients had HRR-positive and -negative disease, and 24.2% of patients were NE. Regarding histologic subgroup, 67.7% and 32.3% of patients had endometrioid carcinoma and other histologies, respectively.

Among patients with pMMR/MSS disease in the dostarlimab arm (n = 142), 62.0% and 37.3% of patients had PD-L1–positive and –negative disease, respectively, and 0.7% were NE for PD-L1 status. Moreover, 2.8% and 79.6% of patients had BRCA-positive and -negative disease, and 17.6% of patients were NE for BRCA mutation status. Additionally, 7.0% and 75.4% of patients had HRR-positive and -negative disease, and 17.6% of patients were NE.

Among patients with pMMR/MSS disease in the placebo arm (n = 74), 59.5% and 35.1% of patients had PD-L1–positive and –negative disease, respectively, and 5.4% were NE for PD-L1 status. Moreover, 4.1% and 74.3% of patients had BRCA-positive and -negative disease, and 21.6% of patients were NE for BRCA mutation status. Additionally, 14.9% and 63.5% of patients had HRR-positive and -negative disease, and 21.6% of patients were NE.

Further analysis of PFS in the overall population according to patient subgroups demonstrated benefit with dostarlimab among all patients regardless of molecular or histology subgroup (HR, 0.59; 95% CI, 0.43-0.81). Patients with TP53-mutated disease benefitted the most from treatment with dostarlimab/chemotherapy/niraparib (HR, 0.29; 95% CI, 0.13-0.63).

In the overall population, findings from exploratory PFS analyses also favored the dostarlimab arm regardless of PD-L1, BRCA mutation, or HRR mutation status (HR, 0.59; 95% CI, 0.43-0.81). Similarly, in the pMMR/MSS population, exploratory analysis results favored the dostarlimab arm across these patient subgroups (HR, 0.62; 95% CI, 0.44-0.88).

Regarding safety in the overall population, among evaluable patients in the dostarlimab arm (n = 191), 99.5% experienced any treatment-emergent adverse effects (TEAEs), and 96.3% reported any treatment-related TEAEs. TEAEs of grade 3 or higher were observed in 84.8% of patients, and any treatment-related TEAEs of grade 3 or higher were observed in 70.7% of patients. Forty-four percent of patients reported any serious TEAEs, and 23.6% of patients experienced any treatment-related serious TEAEs. Any dostarlimab-related immune-related AEs were seen in 36.6% of patients. TEAEs led to treatment discontinuation and death in 36.6% and 2.1% of patients, respectively; however, no treatment-related TEAEs led to death. The median duration of overall treatment was 45.0 weeks (range, 0.9-136.3).

All evaluable patients in the placebo arm (n = 96) experienced any TEAEs, 97.9% of which were treatment-related TEAEs. Any TEAEs of grade 3 or higher were observed in 49.0% of patients, and any treatment-related TEAEs of grade 3 or higher were observed in 36.5% of patients. In total, 19.8% of patients had any serious TEAEs, and 9.4% of patients had any treatment-related serious TEAEs. Any dostarlimab-related immune-related AEs were seen in 6.3% of patients. TEAEs led to treatment discontinuation in 13.5% of patients. No deaths were observed in this arm.

“For the OS [outcomes]…we still have events, so we are following that…” Mirza concluded, adding that, “The safety profile observed [with the dostarlimab regimen] was generally consistent with the known safety profiles of the individual agents.”

Disclosures: Dr Mirza reports receiving consulting fees from AstraZeneca, Biocad, GSK, Karyopharm, Merck, Roche, and Zailab; receiving speakers’ bureau fees from AstraZeneca and GSK; receiving institutional research funding from Apexigen, AstraZeneca, Deciphera (trial chair), GSK, and Ultimovacs; and having personal financial interest in the form of stocks/shares or membership on the board of directors with Karyopharm.

References

1. Mirza MR, Ghamande S, Hanker LC, et al. Progression-free survival (PFS) in primary advanced or recurrent endometrial cancer (pA/rEC) in the overall and mismatch repair proficient (MMR/MSS) populations and in histological and molecular subgroups: results from part 2 of the RUBY trial. Ann Oncol. 2024;9(suppl_5):1-8. doi:10.1016/esmoop/esmoop103499
2. Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. 2023;388(23):2145-2158. doi:10.1056/NEJMoa2216334