“Robust and clinically meaningfulantitumor activity,” with durable responses and “encouraging survival outcomes,” were reported among patients with previously treated microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) endometrial tumors who received pembrolizumab in the KEYNOTE-158 trial.
These trial findings “are particularly encouraging in light of the low long-term survival rates typically observed in advanced endometrial cancer,” David M. O’Malley, MD, and colleagues reported in the Journal of Clinical Oncology.1 The results “support the use of pembrolizumab as a treatment option in patients with advanced MSI-H/dMMR endometrial cancer who had disease progression on prior therapy,” said the investigators.
“At this point, we can say that for patients with mismatch repair–deficient or MSI-high tumor, the standard of therapy in the recurrence setting is a PD-1 inhibitor.”— David M. O’Malley, MD
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That option can “absolutely” be exercised in the clinic now, the study’s lead author, Dr. O’Malley, said in an interview with The ASCO Post. As noted in the study report, “supported by findings from KEYNOTE-158,” the U.S. Food and Drug Administration previously approved pembrolizumab “for the treatment of patients with unresectable or metastatic MSI-H/dMMR solid tumors that have progressed after prior treatment and with no alternative treatment options.” More recently, dostarlimab was approved for patients with previously treated dMMR recurrent or advanced endometrial cancer.
“At this point, we can say that for patients with mismatch repair–deficient or microsatellite instability–high tumors, the standard of therapy in the recurrence setting is a PD-1 inhibitor,” Dr. O’Malley stated. Dr. O’Malley is Director of the Division of Gynecologic Oncology at The Ohio State University Wexner Medical Center and The James Comprehensive Cancer Center in Columbus. He is also Professor in the Department of Obstetrics and Gynecology at The Ohio State University College of Medicine.
“At the current time, we would recommend following the protocol outlined in the study,” Dr. O’Malley advised. The study protocol called for patients to receive pembrolizumab at 200 mg intravenously once every 3 weeks for 35 cycles (approximately 2 years). “Treatment continued until documented disease progression, unacceptable adverse events, intercurrent illness preventing further treatment administration, investigator decision, or patient withdrawal of consent,” the authors noted.
A total of 90 patients were enrolled between February 1, 2016, and September 23, 2020, from two separate cohorts of the multicohort KEYNOTE-158. “The initial KEYNOTE-158 had multiple-arm studies that have been published,” Dr. O’Malley explained. “Earlier aspects of the trial showed exciting activity” among patients with MSI-H/dMMR endometrial tumors, and so these patients were included in the expansion cohort.
Metastatic and/or Unresectable Disease
Trial participants were 18 years or older “with histologically or cytologically documented, advanced (metastatic and/or unresectable) disease that was incurable and had disease progression on or intolerance to standard therapies,” the authors reported. The median age was 64 years, with a range of 42 to 86 years; 48% had received two or more lines of prior therapy, and 68% had prior radiation therapy. Treatment was administered at 38 hospitals in 15 countries.
All 90 patients were included in the safety analysis, and 79 were included in the efficacy population—those who received at least one dose of pembrolizumab and had 26 weeks of additional follow-up prior to data cutoff.
As of the data cutoff (October 5, 2020), “18 of 90 treated patients (20%) had completed 35 cycles of pembrolizumab and 52 (58%) had discontinued treatment,” the researchers reported. However, just six patients (7%) discontinued treatment because of treatment-related adverse events. “Other patients discontinued treatment because of disease progression or because they completed 2 years of therapy,” Dr. O’Malley said. Some patients were still continuing on the trial.
Earlier Start to Therapy
The objective response rate in the efficacy population was 48%. The response rate was higher, however, among patients who had received one prior line of therapy—53% vs 44% for those who received two or more lines.
These findings support the earlier use of pembrolizumab among patients with advanced MSI-H/dMMR endometrial tumors, Dr. O’Malley said. “The treatment of patients with recurrent cancer who have had disease progression after prior therapy should be a PD-1 inhibitor like pembrolizumab, and it should be used earlier in therapy to have the opportunity for maximum benefit and to potentially impact survival.”
“When I counsel patients, I tell them that about 30% will experience some sort of immune-associated toxicity.”— David M. O’Malley, MD
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He added: “Multiple ongoing trials are looking at utilizing immunotherapy in the first-line setting, and I would strongly encourage participation in one of those studies.” Dr. O’Malley is actively involved with several such studies being conducted by the GOG Partners collaborative group.
A total of 11 patients (14%) achieved a complete response, and 27 (34%) had a partial response. “An additional 14 patients (18%) had stable disease, 13 of whom had a reduction in tumor size from baseline,” the researchers reported. “As of data cutoff, responses were ongoing in 21 of 38 patients who had a confirmed response, including 8 of 11 patients with a confirmed complete response.”
Responses were durable. “The median duration of response was not reached after a median follow-up of 42.6 months, and approximately two-thirds of patients were estimated to have a response duration of at least 3 years,” the authors noted.
Median progression-free survival was 13.1 months and was estimated to be 51% at 1 year, 41% at 2 years, and 37% at 3 and 4 years. Median overall survival was not reached but estimated to be “69% at 1 year and 64% at 2 years, with a plateau at 60% at 3 and 4 years,” the authors reported.
“These findings suggest a long-term benefit to patients,” Dr. O’Malley stated. “The potential for curative intent may now be possible in patients with recurrent or metastatic uterine cancer.”
No New Safety Signals
Although “no new safety signals were identified,” adverse events considered related to study treatment occurred in 68 patients (76%), the most common being pruritus (24%), fatigue (21%), and diarrhea (16%). Grade 3 or 4 treatment-related adverse events occurred in 11 patients (12%).
Immune-mediated adverse events and infusion reactions, “regardless of attribution to study treatment or immune relatedness by the investigator, occurred in 25 patients (28%),” the researchers reported. “The most frequently occurring of these events were hypothyroidism (14%), hyperthyroidism (8%), and infusion reactions (4%).”
These adverse events “were managed as standard immunotherapy toxicities would be managed,” Dr. O’Malley said. “For grade 2 or above, that usually would entail a steroid therapy to minimize the toxicity.”
Over 42.6 months of follow-up, the occurrence of adverse events was fairly consistent with that seen with pembrolizu-mab across solid tumors. “The occurrence of some toxicity—that includes fatigue and things that we don’t think of as being immune-related—is what we’ve seen in patients when we look at immune-associated toxicities. The occurrence is about 20% to 30% across most solid tumors. In this study, we have shown it is 28% for immune-associated toxicities of any grade and 7% for grade 3 or 4.” Dr. O’Malley noted.
“When I counsel patients, I tell them that about 30% will experience some sort of immune-associated toxicity,” Dr. -O’Malley commented. “This trial is very consistent with previously published reports of solid tumors that have a strong response to immune therapy.”
Previous studies have shown that approximately 25% to 31% of patients with endometrial cancer have tumors with high levels of MSI and dMMR, the study report noted. Would the findings from the current study be limited to these patients, or might other patients with advanced endometrial cancer also benefit from pembrolizumab?
“Single-agent PD-1 inhibitors are for those with mismatch repair–deficient or microsatellite instability–high tumors,” Dr. O’Malley said. In combination therapy, however, lapatinib plus pembrolizumab “has been approved for patients who don’t meet the MSI-high/dMMR criteria but who have MSI-low or mismatch repair–proficient tumors.”
DISCLOSURE: KEYNOTE-158 was sponsored by Merck, the manufacturer of pembrolizumab. Dr. O’Malley served as a consultant or advisor to Janssen Oncology, AstraZeneca, Clovis Oncology, Tesaro, Novocure, AbbVie, Genentech/Roche, OncoQuest, Immunogen, GOG Foundation, Translational Genomics Research Institute, Agenus, Marker Therapeutics, Eisai, Genelux, Iovance Biotherapeutics, Ambry Genetics, Tarveda Therapeutics, Leap Therapeutics, Myriad Genetics, GlaxoSmithKline, Regeneron, Sorrento Therapeutics, Rubius Therapeutics, Elevar Therapeutics, Novartis, Seattle Genetics, BBI Healthcare, Arquer Diagnostics, Toray Medical, Takeda, InxMed, Celsion, and Roche Diagnostics MSA; and has received institutional research funding from Amgen, AstraZeneca, Genentech/Roche, Regeneron, Immunogen, Janssen Research & Development, Clovis Oncology, EMD Serono, Ergomed, Ajinomoto, Immunogen, Cerulean Pharma, PharmaMar, Array BioPharma, Bristol Myers Squibb, Agenus, Tesaro, TRACON Pharma, Genmab, Seattle Genetics, Iovance Biotherapeutics, Leap Therapeutics, Merck, AbbVie/Stemcentrx, AbbVie, Mersana, Eisai, BBI Healthcare, and Sumitomo Dainippon Pharma Oncology.
1. O’Malley DM, Bariani GM, Cassier PA, et al: Pembrolizumab in patients with microsatellite instability–high advanced endometrial cancer: Results from the KEYNOTE-158 study. J Clin Oncol. January 6, 2022 (early release online).
Findings from the international phase II KEYNOTE-158 trial of pembrolizumab among women with previously treated microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) endometrial tumors “suggest a long-term benefit to patients,” stated the trial’s lead author David M. O’Malley, ...