Data confirm benefit of dostarlimab regimen for women with advanced endometrial cancer
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Key takeaways:
- Results by blinded independent central review showed clinically meaningful PFS improvement with dostarlimab plus chemotherapy.
- The regimen represents a new standard for primary advanced or recurrent disease.
CHICAGO — Assessment of RUBY trial outcomes by blinded independent central review confirmed the benefits of adding dostarlimab to chemotherapy for women with primary advanced or recurrent endometrial cancer.
The findings, presented at ASCO Annual Meeting, showed clinically meaningful PFS improvement with the dostarlimab (Jemperli, GSK) regimen vs. chemotherapy alone among women with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) tumors and the overall study population. The HRs for PFS mirrored those per investigator assessment — a primary endpoint of the RUBY trial — which supports the reliability of investigator-assessed PFS in endometrial cancer trials, according to researchers.
“This is such a step forward for our patients,” Matthew A. Powell, MD, chief of gynecologic oncology and professor of obstetrics and gynecology at Siteman Cancer Center and Washington University School of Medicine in St. Louis, said during a presentation.
Background, methodology
The global, double-blind, randomized RUBY trial examined the safety and efficacy of dostarlimab plus standard-of-care carboplatin and paclitaxel vs. carboplatin and paclitaxel alone among 494 women with primary advanced stage III (18.6%), stage IV (33.6%) or first recurrent (47.8%) endometrial cancer. Overall, 118 (23.9%) of women had dMMR/MSI-H tumors.
Researchers randomly assigned women 1:1 to either dostarlimab, an anti-PD-1 antibody, dosed at 500 mg or placebo plus carboplatin (AUC-time curve, 5 mg/mL/minute) and paclitaxel (175 mg/m2 body-surface area), every 3 weeks for six cycles, followed by 1,000 mg dostarlimab or placebo every 6 weeks for up to 3 years.
Results presented at this year’s Society of Gynecologic Oncology Annual Meeting on Women’s Cancer showed significantly longer PFS by investigator assessment per RECIST version 1.1 with the dostarlimab regimen among women with dMMR/MSI-H tumors (HR = 0.28; 95% CI 0.16-0.5) and the overall population (HR = 0.64; 95% CI, 0.51-0.8).
Powell presented results of secondary efficacy endpoints assessed by blinded independent central review [BICR].
“Both investigator and BICR assessment have been shown as valid estimates of treatment effect in endometrial cancer,” Powell said. “Concordance between both investigator and BICR can provide more confidence in results.”
Results
The findings by BICR again showed longer PFS with dostarlimab in the dMMR/MSI-H group (HR = 0.29; 95% CI, 0.15-0.54) and overall (HR = 0.66; 95% CI, 0.51-0.85). Women who received the dostarlimab regimen also had higher rates of PFS probability at 24 months (dMMR/MSI-H, 66.3% vs. 26%; overall, 42.5% vs. 25.4%) and objective response (dMMR/MSI-H, 77.1% vs. 63.3%; overall, 68.2% vs. 59.4%).
Researchers observed high concordance between investigator assessment and BICR for both the dMMR group and the overall population.
The treatment groups had the same disease control rate among women with dMMR/MSI-H tumors (91.7%), but the dostarlimab group had a higher disease control rate overall (88.3% vs. 86.9%) and higher median duration of response both in the dMMR/MSI-H subgroup (not estimable vs. 6.9 months) and overall (12.9 months vs. 6.7 months).
Safety results showed similar rates of grade 3 or higher treatment-emergent adverse events in the dostarlimab group (70.5%) and placebo group (59.8%). Treatment-related immune-related adverse events occurred among 38.2% of patients in the dostarlimab group vs. 15.4% of the placebo group.
Five patients in the dostarlimab group experienced a treatment-emergent event that led to death, with two deaths due to treatment-emergent adverse events related to dostarlimab.
The dostarlimab group had a longer median duration of overall treatment (43 weeks vs. 36 weeks).
Next steps, implications
Powell emphasized the “transformative” PFS benefit observed among patients with dMMR/MSI-H tumors.
“Overall, efficacy assessments by both investigator and BICR, along with a manageable safety profile, support a favorable benefit-to-risk profile for dostarlimab plus chemotherapy in patients with primary advanced or recurrent endometrial cancer,” he said.
Perspective
Back to TopLynda D. Roman, MD and Koji Matsuo, MD, PhD
The results of the RUBY trial appeared consistent with those of another randomized phase 3 trial that assessed the addition of pembrolizumab (Keytruda, Merck), another class of anti-PD-1 monoclonal antibody, to cytotoxic chemotherapy.
The antitumor effect of immunotherapy with cytotoxic chemotherapy for dMMR tumors in these two trials was robust. This leads to more tumor surface neoantigen with increased tumor-infiltrating T lymphocyte accumulation. Use of an anti-PD-1 monoclonal antibody is thus effective by blocking the PD-1/PD-L1 immunoinhibitory effect.
Collectively, the results of two trials endorse the importance of awareness of DNA mismatch-repair status as a predictive biomarker of immunotherapy in endometrial cancer.
Endometrial cancer is one of the few malignancies that is steadily rising in incidence. The RUBY trial has changed the standard of care for women with advanced stages of this disease, especially those with dMMR tumors. We look forward to future innovations in this increasingly common disease.
Reference:
Eskander RN, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2302312.
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Powell MA, et al. Abstract 5503. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
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