Dostarlimab Plus Chemotherapy Opens Doors Across Endometrial Cancer Subtypes

Krishnansu S. Tewari, MD

Now that dostarlimab-gxly (Jemperli) plus chemotherapy followed by dostarlimab monotherapy is available for patients with primary advanced or recurrent endometrial cancer regardless of mismatch repair (MMR) status, the next frontier for this combination will be determining which patient subgroups benefit from the addition of a PARP inhibitor, according to Krishnansu S. Tewari, MD.

On August 1, 2024, the FDA approved dostarlimab plus carboplatin and paclitaxel followed by single-agent dostarlimab maintenance therapy for the treatment of all adult patients with primary advanced or recurrent endometrial cancer.¹ The regulatory decision expanded on the July 2023 approval of the combination for the treatment of patients with MMR-deficient (dMMR) or microsatellite instability–high disease,² and was supported by findings from part 1 of the phase 3 RUBY trial (NCT03981796). In RUBY, among all-comers who received the dostarlimab-based regimen (n = 245), the median overall survival (OS) was 44.6 months (95% CI, 32.6-not reached) vs 28.2 months (95% CI, 22.1-35.6) among those who received placebo plus chemotherapy (n = 249; HR, 0.69; 95% CI, 0.54-0.89; P = .002).¹

“This full approval of dostarlimab [for this population] came 13 months after we received the accelerated approval in July 2023 for patients with dMMR disease and has been well received,” Tewari said in an interview with OncLive®.

In the interview, Tewari discussed how this expanded approval has changed the endometrial cancer treatment landscape, and he detailed next steps for evaluating dostarlimab in combination with the PARP inhibitor niraparib (Zejula) in this population.

Tewari is a professor and chief of the Division of Gynecologic Oncology in the Department of Obstetrics and Gynecology at the University of California Irvine School of Medicine, as well as a member of the Chao Family Comprehensive Cancer Center and vice president of the Orange County Obstetrics & Gynecology Society.

OncLive: What is the significance of this approval?

Tewari: This expanded approval is fantastic because it’s based on the OS end point [of] the RUBY trial. [Besides the RUBY trial, other studies such as] the phase 3 NRG-GY018 [NCT03914612] and DUO-E [NCT04269200] trials examined different checkpoint inhibitors [in patients with endometrial cancer]. However, RUBY had OS as the primary end point, and it demonstrated a statistically significant and clinically meaningful OS benefit among patients who received chemotherapy plus dostarlimab followed by dostarlimab maintenance.

RUBY was well designed. In March 2023, the day the data were presented, [they were simultaneously] published in the New England Journal of Medicine. RUBY was published as a complete trial, because the OS end point was there, and the patient experience as measured through health-related quality of life was included in the study. [It was a] fantastic study, probably the most important clinical trial we’ve had in endometrial cancer.

What key efficacy findings from RUBY supported this expanded approval?

Initially progression-free survival was significantly improved [with the addition of dostarlimab to chemotherapy] when [earlier data from RUBY were] presented in March 2023 at that year’s SGO Annual Meeting. [This trial] had subsequent presentations, one at the 2023 ESMO Congress and one at the 2024 SGO Annual Meeting. [Findings from] RUBY part 2 showed that there’s a population of patients who are benefiting from dostarlimab plus niraparib.

Then, we saw the OS press release [from RUBY part 1 and additional] data showed that [progression] was not just delayed, but patients were living longer [with dostarlimab plus chemotherapy]. That’s a powerful end point. The only outcome better than OS is cure. Whenever we see an OS benefit, I am certain there are going to be patients amongst that group who are going to be cured.

How does dostarlimab fill a previously unmet need in the all-comer endometrial cancer population?

Not requiring a biomarker and having an all-comers indication will help [expand treatment to more patients]. We should still test patients for dMMR status because it helps us counsel them on their prognosis, but the all-comers indication allows us to not have to wait—we can go ahead and start patients on chemotherapy plus dostarlimab if they have advanced or recurrent disease not previously treated with chemotherapy. We still need to do molecular testing to understand the molecular signature of every patient’s tumor. However, the all-comers indication fulfills a high unmet need because previously, as of July 2023, the approval was only for the dMMR population. Now, we have good data demonstrating that in the intention-to-treat population, all patients benefitted [from the dostarlimab regimen].

The FDA recognized this, and hopefully this will lead [to similar approvals from] other regulatory agencies around the world, for example, the European Medicines Agency, the Cancer Drug Fund in the United Kingdom, and other health ministries. Hopefully they’ll recognize this and follow the FDA’s lead to offer this medicine to patients throughout the world.

What is the safety profile of dostarlimab in endometrial cancer?

The safety profile is always important to review with patients. Fortunately, we’ve been studying dostarlimab for many years in endometrial cancer. In the phase 1 GARNET study [NCT02715284], we learned about some of the inflammatory adverse effects [AEs] that [are associated with this agent]. Many different organ systems can be affected.

Fortunately, the grade 3/4 toxicology in the RUBY study with dostarlimab was low. Thyroiditis or hypothyroidism can occur. We saw [hypothyroidism] with dostarlimab in 11.2% of patients [in RUBY], however, we see [thyroid-related AEs] with other checkpoint inhibitors as well. For the most part, dostarlimab is well tolerated. [Rates of] autoimmune disease are low. [My patients have] been using the drug for over a year and have not had any significant toxicology.

What are the next steps for investigating dostarlimab in endometrial cancer?

At this point, our mission was accomplished with RUBY. We have the full approval, the OS end point, and an all-comers indication based on strong survival data. Now we need to better understand RUBY part 2 data and the cohort of patients who will benefit from dostarlimab plus a PARP inhibitor, specifically niraparib. That’s the next horizon.

The RUBY part 2 data need to continue to mature. Mansoor Mirza, MD, did a fantastic presentation of the part 2 data at the 2024 SGO Annual Meeting. Trying to figure out and characterize which patients at the molecular level are benefiting from dostarlimab plus a PARP inhibitor, specifically niraparib, is going to be critical so we can land RUBY part 2 like we did with RUBY and be able to say mission accomplished [for that trial as well]. The data are early. The presentation was provocative and interesting, but [we still have] lots of questions, and we need more follow-up time, data, and translational science on the specimens collected from the patients enrolled in the study.

References

1. FDA expands endometrial cancer indication for dostarlimab-gxly with chemotherapy. FDA. August 1, 2024. Accessed August 23, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-endometrial-cancer-indication-dostarlimab-gxly-chemotherapy
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 August 23, 2024. https://www.gsk.com/en-gb/media/press-releases/jemperli-plus-chemotherapy-approved-in-us-for-new-indication/