Expert Point of View: Rebecca Arend, MD, MSH and Ilaria Colombo, MD

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“Endometrial cancer is the most frequently diagnosed gynecologic malignancy in the United States, and it is the only one where the mortality has actually risen over the past 40 years,” noted Rebecca Arend, MD, MSH, Associate Professor at the University of Alabama and Associate Scientist in the Experimental Therapeutics Program at O’Neal Comprehensive Cancer Center, Birmingham. Dr. Arend was the invited discussant of two recent phase III studies presented at the Society of Gynecologic Oncology (SGO) 2023 Annual Meeting on Women’s Cancer.

Rebecca Arend, MD, MSH

Rebecca Arend, MD, MSH

Pembrolizumab and dostarlimab are approved as single agents in mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H) endometrial cancer. They have yielded overall response rates of almost 50%, but both have had modest activity in unselected populations or in patients with mismatch repair–proficient (pMMR) tumors.

Investigators for both the ENGOT-EN6-NSGO/GOG-3031/RUBY trial and the NRG GY018/KEYNOTE-868 trial hypothesized that the addition of chemotherapy could improve the response to checkpoint inhibitors. “Both these trials hit a home run,” Dr. Arend commented.

Important Differences

Dr. Arend cautioned against comparing the results of these two trials, as there were important differences between the studies. RUBY included more patients with nonmeasurable disease, carcinosarcoma, and pMMR tumors; GY018 included more patients with performance status 2 and more who completed prior adjuvant chemotherapy at least 12 months ago. There were also differences in stratification and in the statistical design of the clinical trials.

Nevertheless, the studies had the same chemotherapy backbone, and both switched to maintenance dosing every 6 weeks. GY018 allowed for up to 10 cycles of chemotherapy but limited maintenance to 14 cycles, whereas RUBY allowed maintenance to continue for up to 3 years. Both trials used investigator assessment, though their primary endpoints were different, as were their statistical analytic plans and frequency of imaging. Taken together, she said, the studies’ message was clear and consistent: The efficacy of checkpoint inhibition plus chemotherapy in advanced endometrial cancer is robust.

“In the MSI-H population, median progression-free survival in the control arms in both trials was almost exactly the same (7.6 and 7.7 months) and has not been reached in the experimental arm of either trial, with almost unprecedented hazard ratios (0.30 and 0.28),” Dr. Arend noted. The effect on overall survival is still a work in progress. “We don’t know how to accurately interpret overall survival, as it’s not available for one trial, it’s not mature on the other, and the confidence intervals for the point estimates overlap,” she added.

Lingering Questions

One lingering question now pertains to checkpoint inhibition in the pMMR population, she said. Acknowledging the differences between the studies, Dr. Arend nevertheless noted that outcomes for this subset were different between the trials. In GY018, where progression-free survival in the pMMR subset was a primary endpoint, the hazard ratio favoring pembrolizumab was 0.54. As a prespecified subgroup in RUBY, the hazard ratio favoring dostarlimab was 0.76.

Although different immune checkpoint inhibitors are known to vary in their efficacy in distinct populations and in different disease settings, she said, the larger question is why they would be effective at all in pMMR endometrial tumors. One hypothesis is that chemotherapy may enhance immunogenicity through the release of tumor-specific neoantigens. In addition, there are microsatellite-stable tumors that have high tumor mutation burdens or mutations in the POLE gene, she pointed out.

Several other questions will be the focus of further investigations: Is immunotherapy best for all patients? Can other agents be added or sequenced to improve the efficacy of immune checkpoint inhibition in pMMR tumors? How will analysis of overall survival impact decision-making? How will regulatory approval affect the endometrial trial landscape going forward? Future questions aside, Dr. Arend concluded, ENGOT-EN6-NSGO/GOG-3031/RUBY and NRG GY018/KEYNOTE-868 are “a win for our patients.”

Additional Commentary

At the European Society for Medical Oncology (ESMO) Virtual Plenary, Ilaria Colombo, MD, Attending Physician at the Oncology Institute of Southern Switzerland, EOC, in Bellinzona, offered some comments on the RUBY trial. “The RUBY trial results have significant implications for the treatment of advanced or recurrent endometrial cancer, suggesting a new standard of care with the combination of immunotherapy and standard chemotherapy. These findings also pave the way for further research to explore the potential benefits of other immunotherapy combinations and their application in various stages of endometrial cancer.”

Ilaria Colombo, MD

Ilaria Colombo, MD

Dr. Colombo also highlighted the improved quality of life for patients receiving the immunotherapy and chemotherapy combination: “The beneficial effect on quality of life is important because we need to know that patients are not only living longer, but also living better, especially when we use maintenance therapy and patients remain on treatment for a long time.”

Finally, Dr. Colombo mentioned the need for further research to determine the best duration of maintenance immunotherapy, its effectiveness compared with chemotherapy in patients with dMMR/MSI-H tumors, and the need to identify other biomarkers of resistance and of sensitivity beyond mismatch repair and microsatellite status. Additionally, ongoing trials are investigating other immunotherapy combinations for advanced endometrial cancer, including triple therapy with chemotherapy, immunotherapy, and an inhibitor of poly (ADP-ribose) polymerase (PARP), as well as for patients with early-stage endometrial cancer. 

DISCLOSURE: Dr. Arend has served as a consultant or advisor to Merck, Seagen, Sutro, GSK, VBL Therapeutics, and Kiyatec. Dr. Colombo has served as a speaker, consultant, or advisor to GSK, AstraZeneca, Novartis, and MSD; has received travel funding from Tesaro, GSK, Astra Zeneca, and Janssen; and has received research funding from MSD, Bayer, Incyte, Astra Zeneca, and Vivesto.

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