Pembrolizumab found Clinically Beneficial in Advanced Clear Cell Gynecological Cancer: JAMA

Advanced clear cell gynecological cancers (CCGCs), including clear cell ovarian cancer (CCOC), clear cell endometrial cancer (CCEC), and others, are associated with poor prognoses and limited treatment options, particularly in the second-line chemotherapy setting where response rates are notably low (under 8%). Recent study investigates the clinical activity of the programmed cell death 1 protein (PD-1) inhibitor pembrolizumab in a cohort of patients with advanced CCGC following initial chemotherapy.

Study Design and Participants

Conducted as a multicenter, single-arm phase 2 clinical trial, the PEACOCC study involved 49 enrolled patients, of which 48 were deemed eligible after excluding one due to a pre-treatment diagnosis of Graves disease. The participants included individuals aged 18 and older, diagnosed with advanced CCGC, who had received at least one course of platinum-based chemotherapy. Key exclusions were those with autoimmune disease or central nervous system metastases. The trial administered pembrolizumab (200 mg) intravenously every three weeks for up to 35 cycles, with treatment continuations contingent on progression-free status, adverse effects, or patient withdrawal.

Endpoints and Results

The primary endpoint was the 12-week progression-free survival (PFS) rate among patients, with secondary endpoints encompassing overall response rate (ORR), duration of response, overall survival (OS), and safety assessments. Following the analysis, the study reported a 12-week PFS rate of 42% (95% CI, 28-57), surpassing the anticipated lower bound threshold of 15%. The best ORR observed was 25%, with a median duration of response recorded at 13.1 months and median OS at 14.8 months. A total of 33 patients (69%) experienced treatment-related adverse events, primarily grade 1 or 2; however, 19% experienced grade 3 events, demonstrating tolerability in general. Notably, there were no grade 4 or 5 adverse events reported.

Biomarker Analysis

Exploratory biomarker analyses evaluated mismatch repair (MMR) proteins, ARID1A expression, and PD-L1/PD-1 levels in archival tumor samples from participants. The results indicated only one patient showed MMR deficiency, and while some tumors exhibited aberrant p53 and ARID1A loss, no definitive correlational patterns between PD-L1 expression and treatment response were established. Comparison with historical chemotherapy outcomes revealed that pembrolizumab's efficacy was favorable, especially considering the heavily pretreated nature of the study population. About 6% of participants completed two years of treatment, indicating sustained responses even among those with stable disease. The study emphasizes the unique histological and molecular characteristics of CCGC that differentiate it from other cancer types, advocating for the potential of PD-1 inhibition based on initial findings.

Conclusion and Future Directions

Despite limitations inherent in the single-arm design and moderate sample size, the results from this investigation support further exploration of anti-PD-1 therapies in randomized trials. Addressing a significant unmet clinical need, the findings indicate that patients with advanced CCGC could derive substantial, durable clinical benefits from pembrolizumab, marking a crucial step towards optimizing treatment strategies for this challenging cancer subtype. Further translational research is warranted to refine patient stratification for therapy effectiveness, leveraging ongoing studies of PD-1 inhibitors and emerging biomarkers to enrich treatment outcomes.

Key Points

- Advanced clear cell gynecological cancers (CCGCs), such as clear cell ovarian cancer (CCOC) and clear cell endometrial cancer (CCEC), present poor prognoses and limited options for second-line chemotherapy, prompting the investigation into pembrolizumab as a treatment option following initial chemotherapy.

- In a multicenter, single-arm phase 2 clinical trial (PEACOCC) involving 49 patients, 48 met eligibility criteria, including adults diagnosed with advanced CCGC who had undergone prior platinum-based chemotherapy, while those with autoimmune diseases or central nervous system metastases were excluded.

- The trial administered intravenous pembrolizumab (200 mg) every three weeks for up to 35 cycles, with key endpoints focused on the 12-week progression-free survival (PFS) rate, overall response rate (ORR), duration of response, overall survival (OS), and safety assessments.

- Results indicated a 12-week PFS rate of 42% (95% CI, 28-57) exceeding the expected lower threshold of 15%, with the best observed ORR at 25%, a median duration of response of 13.1 months, and median OS of 14.8 months; 69% of patients experienced treatment-related adverse events, primarily grade 1 or 2.

- Exploratory biomarker analysis showed limited MMR deficiency in one patient, with some tumors exhibiting abnormal p53 and ARID1A loss; however, no consistent correlations between PD-L1 expression and treatment response were identified.

- The findings suggest that pembrolizumab offers substantial, durable benefits for patients with advanced CCGC compared to historical chemotherapy outcomes, warranting further investigation through randomized trials to better evaluate anti-PD-1 therapy and refine patient stratification based on emerging biomarkers.

Reference –

R. Kristeleit et al. (2025). Pembrolizumab In Patients With Advanced Clear Cell Gynecological Cancer: A Phase 2 Nonrandomized Clinical Trial.. * R. Kristeleit et al. (2025). Pembrolizumab In Patients With Advanced Clear Cell Gynecological Cancer: A Phase 2 Nonrandomized Clinical Trial.. *JAMA Oncology*. https://doi.org/10.1001/jamaoncol.2024.6797.*. https://doi.org/10.1001/jamaoncol.2024.6797