The session’s invited discussant at the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer was Gini F. Fleming, MD, Professor of Medicine, and Medical Director of Gynecologic Oncology at the University of Chicago. She was elated with the findings of several studies showing the addition of a PD-1 inhibitor to chemotherapy could improve outcomes in advanced or recurrent endometrial cancer, particularly for women with mismatch repair–deficient/microsatellite instability–high (dMMR/MSI) disease.

Gini F. Fleming, MD

According to Dr. Fleming, this new approach is “a huge win for our patients.” The overall survival benefit achieved with dostarlimab-gxly plus chemotherapy in RUBY Part 1 for women with dMMR/MSI disease “is something none of us has seen before, over many years of working with endometrial cancer, and it should be incorporated into everyone’s practice yesterday!” She maintained the data for pembrolizumab in NRG GY018 are “on a par with RUBY but are simply less mature.”

What Next?

With the value of front-line PD-1 inhibitors no longer in question for those with dMMR/MSI disease, there are other “new directions” and issues to be settled, according to Dr. Fleming:

• Can PD-1 inhibitors be used with no chemotherapy without compromising survival? KEYNOTE-C93 and DOMENICA are comparing them with chemotherapy in dMMR populations.
• What is the best option for patients who do experience disease progression on front-line chemotherapy plus checkpoint inhibition? Lenvatinib plus pembrolizumab and immunotherapy combinations should be evaluated.
• What about the use of checkpoint inhibitors in earlier-stage disease? GY020 and RAINBO are evaluating them, given with radiotherapy, for stage 1, 2, and 3 disease.
• What about the addition of PARP inhibitors? DUO-E and RUBY Part 2 are evaluating their use.

Further commenting on RUBY Part 2, Dr. Fleming noted: “It is not possible to untangle the benefit of the PARP inhibitor per se, since patients on the treatment arm received both immunotherapy and a PARP inhibitor, while patients on the control arm received neither.” The RAINBO RED trial will evaluate the addition of olaparib in patients with TP53-mutant disease. And an update on the phase III DUO-E trial, presented at this meeting,¹ showed a 45% reduction in risk of disease progression for patients receiving maintenance durvalumab plus olaparib after first-line durvalumab plus chemotherapy (vs carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance), regardless of mismatch repair status.

For patients with MMR-proficient (pMMR)/microsatellite-stable tumors, an overall survival trend toward benefit for use of front-line immunotherapy was observed in both RUBY and NRG GY018, “but it’s not as dramatic” as for dMMR/microsatellite instability–high tumors, Dr. Fleming noted. “It begs us to figure out what subset of those patients might actually benefit, but we have not found a predictive biomarker. Unfortunately, as presented by Dr. Eskander for the GY018 trial, PD-L1 status did not predict benefit of immunotherapy in the pMMR/MSS population,” she commented. For this population, novel strategies being explored include the addition of upfront antiangiogenic therapy, the addition of inhibitors of nuclear export protein exportin-1 (XPO1, such as selinexor) as maintenance, anti-HER2 therapy for HER2 3+ or amplified tumors, and endocrine therapy.

“Multiple agents are being tested and may prove useful in subgroups,” Dr. Fleming said. Meanwhile, she maintained, anti–PD-1 agents in combination with chemotherapy “should be considered in the front-line setting for patients with microsatellite-stable endometrial cancer.” 

DISCLOSURE: Dr. Fleming has served as an institutional principal investigator for industry-sponsored trials with Roche, Iovance Biotherapeutics, Sermonix Pharmaceuticals, Compagen, Celldex Therapeutics, Corcept Therapeutics, AstraZeneca, Molecular Templates, Astellas, K-Group Beta, Pfizer, Artios Pharma, and Blueprint Medicines.

REFERENCE

1. Chon HS, et al: Durvalumab plus carboplatin/paclitaxel followed by durvalumab with or without olaparib as first-line treatment for endometrial cancer (DUO-E/GOG-3041/ENGOT-EN10). Society of Gynecologic Oncology 2024 Annual Meeting on Women’s Cancer. Late-Breaking Abstract. Presented March 18, 2024.