Pembrolizumab Provides Clinical Benefit in Previously Treated Advanced Clear Cell Gynecologic Cancer

Treatment with pembrolizumab (Keytruda) demonstrated efficacy and tolerability in patients with previously treated advanced clear cell gynecologic cancer (CCGC), meeting the primary end point of the phase 2 nonrandomized PEACOCC trial (NCT03425565) published in JAMA Oncology.1

Results indicated that 42% (95% CI, 28%-57%) of eligible patients (n = 48) who received the immunotherapy achieved disease control and were free of disease progression at 12 weeks, with the confidence interval exceeding the pre-stated lower bound of 15%.

The 12-week objective response rate (ORR) was 21% (95% CI, 10%-35%); the best ORR was 25% (95% CI, 14%-40%) with 12 partial responses. Moreover, at a median follow-up of 46.9 months (95% CI, 43.4-55.0), the median progression-free survival (PFS) was 2.7 months (95% CI, 1.3-5.4) and the median overall survival (OS) was 14.8 months (95% CI, 6.7-28.2).

“The PEACOCC trial showed clinical benefit with pembrolizumab in patients with previously treated advanced CCGC, of whom all except 1 had mismatch repair–proficient [MMR] disease,” Rebecca Kristeleit, MD, PhD, of Guy’s and St Thomas’ NHS Foundation Trust and Comprehensive Cancer Centre, Kings College London, in London, United Kingdom, and colleagues, wrote in the paper. “Clinical outcomes were durable with an overall tolerable safety profile, justifying further evaluation of pembrolizumab monotherapy for advanced CCGC in a randomized clinical trial.”

The multicenter, single-arm trial enrolled patients with CCGC, including ovarian, endometrial, vaginal, vulval, and cervical cancer who were at least 18 years of age who had received 1 or more prior courses of platinum chemotherapy, including in the adjuvant setting. They had an ECOG performance status of 0 or 1, measurable disease by RECIST v1.1 criteria and investigator assessment, and disease amenable to biopsy. Patients were excluded if they had known autoimmune disease, second malignancy, central nervous system metastases and/or carcinomatous meningitis, untreated venous thrombosis, or hospitalization for bowel obstruction within 4 weeks.

Study participants were given 200 mg of pembrolizumab intravenously, once every 3 weeks for up to 35 cycles. They continued to receive the immunotherapy until radiographic progression, intolerable toxicity, withdrawn consent, physician decision, or 35 cycles were completed.

In addition to PFS at 12 weeks serving as the trial’s primary end point, secondary end points included ORR, duration of response (DOR), PFS, OS, safety, and quality of life.

The median patient age was 58.5 years (range, 32-77). Regarding clear cell cancer type, 85% had ovarian, 13% had endometrial, and 2% had cervical. In terms of ECOG performance status, 54% had a status of 0 and the remainder had a status of 1. Patients had a FIGO stage of I (38%), II (19%), III (29%), or IV (15%) at the time of diagnosis. Most previously underwent surgery (90%) but had not previously received radiotherapy (77%). All received prior systemic treatment, with a median of 3 prior courses (range, 1-6). Forty percent of patients had a platinum-free interval of longer 12 months; 31% had an interval ranging from 6 to 12 months and 29% had an interval of less than 6 months. The median cancer antigen 125 was 117.5 U/mL (range, 5-4375).

Additional efficacy data showed that in the 20 patients who had confirmed disease control at 12 weeks, the median duration of control from the initiation of pembrolizumab was 11.7 months (95% CI, 5.5-16.5). In the 12 patients who experienced response, the median time from pembrolizumab initiation to disease response was 2.2 months (95% CI, 1.3-2.8); the median DOR was 13.1 months (95% CI, 4.2-26.5).

The 1-year PFS rate was 21% (95% CI, 11%-33%) and the 2-year PFS rate was 8% (95% CI, 3%-18%); the OS rates at 1 and 2 years were 54% (95% CI, 39%-67%) and 38% (95% CI, 24%-51%), respectively.

One patient enrolled for retreatment with the immunotherapy after their disease progressed. They received 6 cycles of the immunotherapy and stopped treatment because of immune-related hepatitis that was grade 3 in severity. Their best response to retreatment with pembrolizumab was disease stability, and they progressed for the second time 7.1 months from their first progression.

Patients had received a median of 4.5 cycles (interquartile range, 1.5-12) of pembrolizumab. Eighty-one percent of patients discontinued treatment because of disease progression. The most common treatment-related adverse effects were diarrhea (grade 1, 17%; grade 2, 2%; grade 3, 0%), fatigue (17%; 13%; 0%), pruritus (17%; 4%; 0%), maculopapular rash (13%; 2%; 0%), nausea (10%; 4%; 0%), oral mucositis (8%; 0%; 0%), dry skin (8%; 0%; 0%), dry mouth (8%; 2%; 0%), anorexia (8%; 6%; 0%), vomiting (6%; 0%; 0%), hypothyroidism (6%; 15%; 0%), hyperthyroidism (6%; 4%; 4%), dysgeusia (6%; 0%; 0%), cough (6%; 0%; 0%), increased alkaline phosphatase (4%; 4%; 2%), rash (4%; 2%; 0%), increased alanine aminotransferase (2%; 4%; 4%), increased aspartate aminotransferase (2%; 4%; 2%), acute kidney injury (0%; 0%; 2%), anemia (0%; 0%; 2%), increased y-glutamyltransferase (0%; 0%; 2%), immune-related hepatitis (0%; 0%; 2%), ketoacidosis (0%; 0%; 2%), and noninfective encephalitis (0%; 0%; 2%).

The single-arm design and moderate sample size represent the key limitations of the study.

“Pembrolizumab has robust, durable clinical benefit in patients with heavily pretreated CCGC and was tolerated in the overall population. The clinical activity was observed in a predominantly MMR-proficient population,” the study authors concluded. “Clinical outcomes are superior to historical data for current standard-of-care chemotherapy, and 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 gynecologic cancer population with a significant unmet clinical need.”

Reference

Kristeleit R, Devlin M-J, Clamp A, et al. Pembrolizumab in patients with advanced clear cell gynecological cancer: A phase 2 randomized clinical trial. JAMA Oncol. Published online February 6, 2025. doi:10.1001/jamaoncol.2024.6797