Dostarlimab Plus Chemo Followed by Dostarlimab/Niraparib Improves PFS in Endometrial Cancer

Dostarlimab-gxly (Jemperli) paired with carboplatin and paclitaxel, followed by maintenance dostarlimab and niraparib (Zejula), significantly improved progression-free survival (PFS) vs placebo plus chemotherapy followed by placebo in patients with primary advanced or recurrent endometrial cancer, according to data from part 2 of the phase 3 RUBY/ENGOT-EN6/GOG3031/NSGO trial (NCT03981796).¹

The PFS improvement with dostarlimab was observed in the overall patient population and in a subset of patients with mismatch repair–proficient (MMRp) or microsatellite stable (MSS) tumors, meeting the primary end point of the study. Data pertaining to overall survival (OS), a key secondary end point, are immature but will continue to be followed.

The dostarlimab combination’s toxicity profile was aligned with what has previously been reported with each agent.

“Patients with MMRp/MMS primary advanced or recurrent endometrial cancer have few approved treatment options,” Hesham Abdullah, senior vice president and global head of Oncology, R&D at GlaxoSmithKline, stated in a press release. “Today’s positive topline results reinforce our approach of building combination therapies with dostarlimab as the backbone in an effort to improve patient outcomes and options.”

The global, double-blind, placebo-controlled phase 3 RUBY study enrolled female patients with histologically or cytologically confirmed endometrial cancer who are in first recurrence or who have primary advanced disease.² Patients were at least 18 years of age, an ECOG performance status of 0 or 1, and acceptable organ function. They needed to provide a tumor sample to determine MMR status.

Those with primary advanced disease could not have previously received chemotherapy in the adjuvant or neoadjuvant settings. Those who experienced recurrence within 6 months following chemotherapy completion, at least 1 disease recurrence, concomitant malignancies within the past 3 years, or uncontrolled central nervous system metastases, they were excluded. They also could not have had prior exposure to a PD-1, PD-L1, or PD-L2 inhibitor, nor could they have had immunocompromised or active autoimmune disease.

The study was comprised of 2 parts. In part 1, patients were randomly assigned 1:1 to receive dostarlimab at 500 mg plus carboplatin at an area under the curve (AUC) of 5 mg/mL/min and paclitaxel at 175 mg/m² every 3 weeks for the first 6 cycles, followed by dostarlimab monotherapy at 1000 mg or placebo every 6 weeks.³ The primary end points were PFS by investigator assessment and RECIST v1.1 criteria in the overall population and a subset of patients with mismatch repair­–deficient (dMMR) or microsatellite instability­­–high (MSI-H) disease and OS in the overall population.

Data from an interim analysis of part 1 indicated that at a median follow-up of 24.8 months (range, 19.2-36.9), dostarlimab plus chemotherapy reduced the risk of disease progression or death by 72% compared with placebo plus chemotherapy in the dMMR/MSI-H subset (HR, 0.28; 95% CI, 0.16-0.50; P < .001). The estimated 24-month PFS rates were 61.4% (95% CI, 46.3%-73.4%) vs 15.7% (95% CI, 7.2%-27.0%), respectively. Moreover, the 24-month OS rates were 83.3% (95% CI, 66.8%-92.0%) vs 58.7% (95% CI, 43.4%-71.2%), respectively (HR, 0.30; 95% CI, 0.13-0.70).

The findings supported the July 2023 FDA approval of dostarlimab plus carboplatin/paclitaxel, followed by single-agent-dostarlimab, for the treatment of adult patients with primary advanced or recurrent endometrial cancer that is dMMR or MSI-H.⁴

Part 2 was slated to include approximately 270 patients who were randomly assigned 2:1 to receive placebo or dostarlimab at 500 mg plus carboplatin at an AUC of 5 mg/mL/min and paclitaxel at 175 mg/m² followed by placebo or dostarlimab at 1000 mg every 6 weeks plus niraparib at 200 mg once daily for those with a baseline body weight of less than 77 kg or platelet count below 150,000/μL or 300 mg once daily for those with baseline body weight of 77 kg or more and platelet count of at least 150,000/μL.

They were stratified by MMR/MSI status (dMMR/MSI-H vs MMRp/MSS), prior external pelvic radiotherapy (yes vs no), and disease status (recurrent vs primary stage III vs primary stage IV).

In addition to PFS by blinded independent review committee and RECIST v1.1 criteria in the overall population followed by the MMRp/MSS subset serving as the primary end point of part 2 of the study, secondary end points include investigator-assessed PFS, OS, objective response rate, duration of response, disease control rate, time to second disease progression, and patient-reported outcomes. Safety will also be evaluated.

Full data from the planned analysis of part 2 will be shared at an upcoming scientific meeting, published in a journal, and discussed with regulatory authorities.¹

References

1. Jemperli (dostarlimab) plus Zejula (niraparib) combination significantly improved progression-free survival in primary advanced or recurrent endometrial cancer in RUBY part 2 phase III trial. News release. GlaxoSmithKline. December 18, 2023. Accessed December 19, 2023. https://www.gsk.com/media/10741/jemperli-plus-zejula-combination-significantly-improved-progression-free-survival-in-endometrial-cancer-phase-iii-trial.pdf
2. Mirza MR, Coleman RL, Hanker L, et al. 820 TiP ENGOT-EN6/GOG-3031/NSGO-CTU-RUBY part 2: a phase III, randomized, double-blind, study of dostarlimab + carboplatin-paclitaxel followed by dostarlimab + niraparib versus placebo (PBO) + carboplatin-paclitaxel followed by PBO in recurrent or advanced endometrial cancer (EC). Ann Oncol. 2021;32(suppl 5):S770-S771. doi:10.1016/j.annonc.2021.08.1262
3. 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
4. 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 December 19, 2023. https://www.gsk.com/en-gb/media/press-releases/jemperli-plus-chemotherapy-approved-in-us-for-new-indication/