Pembrolizumab Produces Durable Responses in Chemo-Pretreated Clear Cell Gynecologic Cancers

Pembrolizumab (Keytruda) monotherapy induced a 12-week progression-free survival (PFS) rate of 42% (95% CI, 28%-57%) in patients with advanced clear cell gynecologic cancers (CCGC) who were previously treated with chemotherapy, meeting the primary end point of the phase 2 PEACOCC trial (EudraCT 2017-004168-36), data from which were published in JAMA Oncology.1

At 12 weeks, among the 48 evaluable patients, best responses included partial response (PR; 21%), stable disease (SD; 21%), progressive disease (PD; 40%), and PD/death (56%); 3 patients had died, and 1 patient had missing data. This translated to a 12-week overall response rate (ORR) of 21% (95% CI, 10%-35%). Among patients with confirmed disease control at 12 weeks (n = 20; 42%), the median duration of disease control from the initiation of pembrolizumab was 11.7 months (95% CI, 5.5-16.5).

Additionally, among patients evaluable for a sensitivity analysis (n = 47), 43% (95% CI, 28%-58%) achieved disease control and were progression free at 12 weeks; the 12-week and best ORRs in this population were 21% (95% CI, 11%-36%) and 26% (95% CI, 14%-40%), respectively.

“Pembrolizumab [had] robust, durable clinical benefit in patients with heavily pretreated CCGC and was tolerated in the overall population,” Rebecca Kristeleit, MD, PhD, of Guy’s and St Thomas’ NHS Foundation Trust and Comprehensive Cancer Centre at King’s College London in the United Kingdom, and coauthors wrote in the paper.

Outcomes With Chemotherapy and Immunotherapy in CCGC

Patients with advanced CCGC have a poor prognosis; response rates to second-line chemotherapy are approximately 8%. Preliminary clinical activity with PD-1 inhibitors in patients with CCGC support the further investigation of this class of agents in this population.

For example, in the phase 2 NRG GY003 trial (NCT02498600), patients with clear cell epithelial ovarian cancer (CCOC; n = 12) were 5-fold more likely to respond to ipilimumab (Yervoy) plus nivolumab (Opdivo) compared with patients with other cell types (n = 88).2 However, the NRG GY003 study authors noted that this finding should be interpreted with caution because patients with CCOC comprised only 12% of the total study population.

PEACOCC Trial Design

The nonrandomized, single-arm PEACOCC trial was conducted across 5 centers in the United Kingdom.1 Between March 2019 and October 2021, this study enrolled patients at least 18 years of age with PD-1 inhibitor–naive, histologically confirmed, advanced CCGC (including ovarian [primary peritoneal and fallopian tube], endometrial, vaginal, vulval, and cervical cancers) with radiological disease progression following at least 1 prior course of platinum-based chemotherapy, including in the adjuvant setting. Patients with mixed histology were permitted to enroll if more than 50% of their tumor specimen was of clear cell histology. Patients needed to have an ECOG performance status of 0 or 1, measurable disease per RECIST 1.1 criteria, and disease that was amenable to biopsy.

Patients were excluded if they had a known diagnosis of autoimmune disease; central nervous system metastases and/or carcinomatous meningitis; second malignancy; grade 2 or higher hypercalcemia; untreated venous thrombosis; or if they had been hospitalized for bowel obstruction within 4 weeks of trial enrollment.

Patients received pembrolizumab at 200 mg intravenously every 21 days for a maximum of 2 years (35 cycles) until treatment completion, radiographic disease progression, discontinuation due to unacceptable toxic effects, or patient/clinician decision. Patients with confirmed radiological complete response (CR) could discontinue treatment after at least 24 weeks of pembrolizumab, including at least 2 treatment cycles beyond the date of CR. Patients with disease progression were eligible for a maximum of 1 year of retreatment if they had SD, PR, or CR at 2 years.

Twelve-week PFS rate served as the trial’s primary end point. The study was powered to detect a 12-week PFS rate of at least 33% and to exclude a rate of less than 15%. Secondary end points included ORR, duration of response (DOR), PFS, overall survival (OS), safety, and quality of life (QOL).

Additional Efficacy Data

Evaluable patients had a median age of 58.5 years (range, 32-77), and most (54%) had an ECOG performance status of 0. CCGC subtypes included ovarian cancer (85%), endometrial cancer (13%), and cervical cancer (2%). Patients had received a median of 3 prior courses of therapy (range, 1-6), including prior anti-angiogenic therapy (40%). Additionally, 40% of patients had a platinum-free interval of longer than 12 months. Most patients (98%) had mismatch repair–proficient (pMMR) tumors.

In the total population, the best ORR was 25% (95% CI, 14%-40%), including best responses of PR (25%), SD (33%), and PD (33%). Among responders (n = 12), the median time to response from the start of pembrolizumab was 2.2 months (95% CI, 1.3-2.8), and the median DOR was 13.1 months (95% CI, 4.2-26.5).

At a median follow-up of 46.9 months (95% CI, 43.4-55.0) and a data cutoff in July 2024, 40 patients had died, 7 patients were alive following disease progression, and 1 patient was alive and progression free. The median PFS was 2.7 months (95% CI, 1.3-5.4), with 1- and 2-year PFS rates of 20.8% (95% CI, 10.8%-33.2%) and 8.3% (95% CI, 2.7%-18.2%), respectively.

The median OS was 14.8 months (95% CI, 6.7-28.2); the respective 1- and 2-year OS rates were 54.2% (95% CI, 39.2%-67.0%) and 37.5% (95% CI, 24.1%-50.9%).

In total, 3 patients completed the maximum 2 years of treatment; best responses in these patients included PR (n = 2) and SD (n = 1). One of these patients who achieved PR was eligible for and enrolled in pembrolizumab retreatment following their first progression. This patient was treated with 6 additional cycles of pembrolizumab, after which they stopped treatment due to grade 3 immune-related hepatitis. This patient’s best response to retreatment was SD, and their second progression occurred 7.1 months after their first progression. The second patient who completed 2 years of treatment did not undergo retreatment at disease progression. The third patient continued in the trial with PR.

In the overall population, patients received a median of 4.5 cycles of pembrolizumab (IQR, 2.5-12). Patients stopped treatment because of disease progression (81%), toxic effects (6%; toxic effects included grade 3 acute kidney injury, grade 3 encephalitis, and grade 3 metabolic ketoacidosis), and death due to CCGC (6%).

Safety and QOL Findings

A total of 69% of patients experienced at least 1 treatment-related adverse effect (TRAE), and grade 3 TRAEs were seen in 19% of patients. No grade 4 or 5 AEs were observed. The most common grade 3 TRAEs included increased alanine aminotransferase levels and hyperthyroidism (4% each); and acute kidney injury, increased alkaline phosphatase levels, anemia, increased aspartate aminotransferase levels, increased gamma-glutamyltransferase levels, immune-related hepatitis, ketoacidosis, and noninfective encephalitis (2% each).

Overall, 96% of patients completed baseline QOL Functional Assessment of Cancer Therapy—Ovarian Cancer questionnaires, and 60% of patients completed these questionnaires at end of treatment. Investigators did not note strong evidence of change in the total score or in the physical, social, emotional, or functional wellbeing subscales over time.

Exploratory Biomarker Analysis Findings

Investigators performed immunohistochemistry (IHC) analyses of diagnostic formalin-fixed paraffin-embedded tumor samples for MMR protein, ARID1A, and p53 expression status in 46 patients. IHC analyses of tumor samples for PD-1, PD-L1, and combined PD-1/PD-L1 expression were performed in 45 patients.

One patient had MMR-deficient (dMMR) disease with isolated loss of PMS2 expression. This patient achieved a PR with pembrolizumab, had PD at 2.8 months, and died at 28.2 months. “[This finding ruled] out dMMR as an explanation for the clinical activity observed in the PEACOCC trial,” the authors wrote.

Investigators also observed tumors with aberrant p53 expression (13%), ARID1A loss (22%), PD-1 positivity (9%), PD-L1 positivity (22%), and combined PD-1/PD-L1 positivity (9%). The investigators did not observe differences in PFS or OS for patients with dMMR, ARID1A loss, aberrant p53 expression, PD-1 expression, PD-L1 expression, or combined PD-1/PD-L1 expression. However, they noted that “small numbers limit interpretation of these exploratory biomarkers with immune checkpoint inhibitor response, and no definitive conclusions can be reached.”

Research Limitations and Next Steps

The authors explained that key limitations of this study include its single-arm design and the moderate sample size.

However, they noted that the clinical outcomes seen in this trial are superior to historical findings with current standard-of-care chemotherapy.

“Translational research to identify those patients who benefit most is underway. Further evaluation of anti–PD-1 monotherapy or PD-1 inhibitor combinations in randomized clinical trials is justified for this poor-prognosis gynecological cancer population with a significant unmet clinical need,” the authors concluded.

References

1. Kristeleit R, Devlin MJ, Clamp A, et al. Pembrolizumab in patients with advanced clear cell gynecological cancer: a phase 2 nonrandomized clinical trial. JAMA Oncol. Published online February 6, 2025. doi:10.1001/jamaoncol.2024.6797
2. Zamarin D, Burger RA, Sill MW, et al. Randomized phase II trial of nivolumab versus nivolumab and ipilimumab for recurrent or persistent ovarian cancer: an NRG Oncology study. J Clin Oncol. 2020;38(16):1814-1823. doi:10.1200/JCO.19.02059