Behind the FDA Approval: Dostarlimab Plus Chemotherapy for Endometrial Cancer

Matthew A. Powell, MD

On July 31, 2023, dostarlimab-gxly (Jemperli) in combination with carboplatin and paclitaxel was approved by the FDA for patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H).¹

The approval of the PD-1 immune checkpoint inhibitor was driven by the global, randomized, double-blind placebo-controlled phase 3 RUBY trial (NCT03981796). The primary analysis of RUBY was published in the New England Journal of Medicine.² Dostarlimab was previously approved for use in patients with all dMMR/MSI-H solid tumors who progressed and have no satisfactory alternative treatment based on the GARNET trial (NCT02715284).³

The National Comprehensive Cancer Network (NCCN) guidelines for endometrial carcinoma have classified dostarlimab plus carboplatin and paclitaxel as a category 1 recommendation for stage III/IV tumors, particularly for “stage IIIA, IIIB, or IIIC1 with measurable disease, stage IIIC1 with carcinosarcoma, clear-cell, serous, or mixed histology regardless of the presence of measurable disease; and stage IIIC2 or stage IV regardless of the presence of measurable disease.”⁴

“This has become another tool we have in our armamentarium. Moving this to frontline therapy has been the big goal,” said Matthew A. Powell, MD, when discussing the impact of dostarlimab in an interview with Targeted Oncology^TM.

The RUBY investigators found that dMMR/MSI-H patients had a 24-month progression-free survival (PFS) rate of 61.4% with chemotherapy plus dostarlimab versus 15.7% with chemotherapy plus placebo (HR, 0.28; 95% CI, 0.162-0.495; P < .0001).^2,5

Powell presented additional data from the RUBY trial including efficacy by blinded independent central review (BICR) at the 2023 American Society of Clinical Oncology Annual Meeting (ASCO). By BICR, the 24-month PFS rate was 66.3% for the dostarlimab arm and 26.0% for the placebo arm in dMMR/MSI-H patients (HR, 0.29; 95% CI, 0.158–0.543).⁵ The overall patient population including those who have proficient mismatch repair status (pMMR) also benefited, with a BICR-assessed 42.5% PFS rate at 24 months with dostarlimab plus chemotherapy versus 25.4% with chemotherapy and placebo (HR, 0.66; 0.517-0.853).

The investigator-assessed and BICR-assessed end points were consistent for both PFS and overall survival (OS), emphasizing that dostarlimab plus chemotherapy is a new standard of care for patients with primary advanced or recurrent endometrial cancer.

During the interview, Powell, a professor of obstetrics and gynecology, chief of the division of gynecologic oncology at Washington University School of Medicine, and gynecologic oncologist at Siteman Cancer Center, discussed the significance of the FDA approval and his presentation of the results from the RUBY trial.

TARGETED ONCOLOGY: The FDA approved dostarlimab for adult patients with dMMR recurrent or advanced endometrial cancer. What can you tell me about the approval?

MATTHEW A. POWELL, MD: The FDA approval [was previously] for patients with dMMR recurrent endometrial cancer.³ They usually have progressed on prior therapies with carboplatin and paclitaxel typically, and they have this biomarker called dMMR, also known as MSI-H. These patients have a unique feature that they respond very well to checkpoint inhibition.

How has this approval impacted the space since then?

This has become another tool we have in our armamentarium. Moving this to frontline therapy has been the big goal.

What data did you present at ASCO?

We're providing further data on the RUBY trial, which is dostarlimab plus carboplatin and paclitaxel chemotherapy versus placebo and carboplatin/paclitaxel chemotherapy. This has led to transformative results, especially in the dMMR population, and…led to publication in the New England Journal of Medicine,² and now is NCCN Compendium-listed as an option for our patients with advanced or recurrent endometrial cancer.⁴

What are some of the methods and design of the study?

The study we presented at ASCO has to do with some additional end points or secondary end points of the BICR for the patients enrolled on the trial. It's important to not only evaluate the investigator assessment, which was our primary outcome of the trial, for both PFS and OS, but look at this in an independent subset of patients who underwent a BICR assessment. This was important not only to investigate possible bias among the investigators, but also to understand [since] those end points are important for regulatory purposes.

What can you discuss about the findings presented at ASCO?

The findings of the RUBY trial were a substantial benefit of a 71% reduction of progression or death in our patients with dMMR and similar overall benefits with a nice benefit for both patients with dMMR and pMMR.⁵ The entire population showed a benefit of the addition of dostarlimab to carboplatin and paclitaxel.

How do you think these findings will influence research moving forward?

This is transformative. [RUBY] plus another trial that was done…are consistent and show that adding checkpoint inhibition to the upfront treatment for patients with advanced recurrent endometrial cancer is the new standard of care.

What are the next steps for investigating dostarlimab?

The next steps are to further understand the molecular subtypes, and which patients benefit most, which patients maybe don't need this therapy, and to understand what we would do afterward if this regimen doesn't work. For second-line therapy, how do we add in some of the new therapies like antibody-drug conjugates, and other options we have beyond chemotherapy?

What unmet needs still exist in the space?

Unfortunately, there are a lot of unmet needs in endometrial cancer. One, it's a disease where the [incidence] rate is actually rising—and rising fast. A lot of that has to do with our obesity epidemic. Targeting patients before they develop cancer would be ideal and there are some preventative strategies we're working on. [We are] also focusing on the large disparity among our underrepresented groups, mostly Black patients who have [approximately twice as poor] survival. When they develop endometrial cancer, they tend develop a very aggressive type, and new interventions are needed, and understanding why these differences exist is also crucial.

_References:

_{1. FDA approves dostarlimab-gxly with chemotherapy for endometrial cancer. News release. FDA. July 31, 2023. Accessed August 3, 2023. https://tinyurl.com/52y3edc9}

_{2. Mirza MR, Chase DM, Slomovitz BM, et al; RUBY Investigators. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. 2023;388(23):2145-2158. doi:10.1056/NEJMoa2216334}

_{3. FDA grants accelerated approval to dostarlimab-gxly for dMMR advanced solid tumors. News release. FDA. August 17, 2021. Accessed June 19, 2023. https://tinyurl.com/mr32c99x}

_{4. NCCN. Clinical Practice Guidelines in Oncology. Uterine neoplasms, version 2.2023. Accessed August 3, 2023. https://tinyurl.com/bssx9uk7}

_{5. Powell MA, Hietanen S, Coleman RL, et al. Dostarlimab for primary advanced or recurrent (A/R) endometrial cancer (EC): Outcomes by blinded independent central review (BICR) of the RUBY trial (ENGOT-EN6-NSGO/GOG-3031/RUBY). J Clin Oncol. 2023;41(suppl 16):5503. doi:10.1200/JCO.2023.41.16_suppl.5503}