In a single-arm multicentre phase II PEACOCC study, conducted at 5 centres in UK, pembrolizumab showed robust, durable clinical benefit in patients with heavily pretreated clear cell gynaecological cancers and was tolerated in the overall population. The clinical activity was observed in a predominantly population of patients with mismatch repair (MMR)-proficient tumours.
Clinical outcomes are superior to historical data for current standard-of-care chemotherapy. Translational research to identify those patients who benefit most is underway. The findings were reported by Dr. Rebecca Kristeleit of the Guy’s and St Thomas’NHS Foundation Trust and Comprehensive Cancer Centre, King’s College London in London, UK and colleagues, who published the findings on 6 February 2025 in the JAMA Oncology.
Clear cell gynaecological cancers represent a subgroup of malignant tumuors characterised by distinct clinicopathological features, including an association with endometriosis, which is present pathologically in 50% of cases. Patients with clear cell cancer tend to be younger, present more commonly with early-stage disease, and have a higher risk of arterial venous thrombosis and hypercalcaemia.
While clear cell ovarian cancers (including fallopian tube and primary peritoneal cancers) are most common, representing up to 15% of all epithelial ovarian cancers, 5-8% of clear cell tumours of the endometrium, and less than 5% of clear cell gynaecological cancers of the vagina, vulva, and cervix.
Advanced clear cell ovarian cancers studies consistently demonstrate significantly poorer prognosis than other subtypes, with response rates to first-line carboplatin/paclitaxel chemotherapy of 25% and to second-line chemotherapy of less than 8%. Clear cell tumours of the endometrium represents a difficult to treat subgroup, which are relatively resistant to radiotherapy or chemotherapy and have poorer survival than other.
These anatomically distinct tumours have overlapping gene expression profiles and possess similar mutational landscapes, with frequent variants in ARID1A (around 50% of clear cell ovarian cancers), PIK3CA, and PTEN, which supports treating them together as a single histopathological entity. Clear cell gynaecological cancers have an immune-rich tumour microenvironment contributed to by various mechanisms, including MMR deficiency, estimated at 5-10% of clear cell ovarian cancers, frequent ARID1A variants, and upregulation of IL-6 and other pro-inflammatory cytokine signalling.
The authors wrote in the background that these features as well as a high level of PD-L1 and PD-L2 expression suggest a possible role for immune checkpoint inhibitors (ICIs). Furthermore, anecdotal evidence from studies with ICI performed in epithelial ovarian cancers suggested a superior response rate in clear cell ovarian cancers than other epithelial ovarian cancers subtypes. For example, in the randomised phase II NRG GY003 study, comparing ipilimumab and nivolumab with nivolumab in patients with epithelial ovarian cancer, patients with clear cell ovarian cancers were 5-fold more likely to respond than other subtypes. PEACOCC is the only study examining pembrolizumab monotherapy in clear cell gynaecological cancers to date.
The PEACOCC is a single-arm multicentre phase II study conducted at 5 centres in UK investigating the clinical benefit and safety of pembrolizumab. PD1 inhibitor-naive patients with histologically confirmed advanced clear cell gynaecological cancer, radiological disease progression following one or more prior courses of chemotherapy, and an ECOG performance status (PS) score of 0 to 1 were included. Patients were enrolled from March 2019 to October 2021, with data collected until July 2024.
Patients received pembrolizumab 200 mg intravenously every 21 days up to 2 years until progression, discontinuation due to side effects, or patient/clinician decision. They received up to 1 year of retreatment on diseases progression, in case of stable disease, partial response, or complete response at 2 years. The primary endpoint was progression-free survival (PFS) rate at 12 weeks using RECIST v1.1 to detect a 12-week PFS rate of 33% or greater and exclude a PFS rate of less than 15%, with 90% power and 1-sided 5% significance level. Secondary endpoints included objective response rate, duration of response, PFS, overall survival (OS), safety, and quality-of-life.
A total of 48 patients were eligible. The median (range) age was 58.5 (32-77) years, and 26 (54%) had an ECOG PS score of 0 and 22 (46%) had an ECOG PS score of 1; 41 (85%) had ovarian, 6 (13%) had endometrial, and 1 (2%) had cervical advanced clear cell gynaecological cancer. The median (range) courses prior therapy was 3 (1-6); 19 patients (40%) received prior anti-angiogenic therapy, and 19 (40%) had a platinum-free interval of more than 12 months. Grade 3 treatment-related adverse events were observed in 9 patients (19%), and no patients had grade 4 or 5 adverse events.
A total of 45 of 46 patients (98%) had MMR–proficient tumours. The 12-week PFS rate was 42% (95% confidence interval [CI] 28-57), and the best objective response rate was 25% (95% CI 14-40), with 12 partial responses. After a median follow-up of 46.9 months (95% CI 43.4-55.0), the median PFS was 2.7 months (95% CI 1.3-5.4), and the median OS was 14.8 months (95% CI 6.7-28.2).
The study team investigated MMR, ARID1A, p53, PD-1, PD-L1 (combined positive score ≥1 deemed PD-L1-positive; combined positive score <1 deemed PD-L1-negative) and combined PD1/PD-L1 protein expression in archival tumour samples to explore their relationship with clinical outcome following ICI treatment. Only 1 of 46 patients with evaluable diagnostic tumour tissue had an MMR-deficient pattern, ruling out MMR deficiency as an explanation for the clinical activity observed in the PEACOCC study. Small numbers limit interpretation of these exploratory biomarkers with ICI response and no definitive conclusions can be reached. Specifically, no clear association with PD-L1 positivity and pembrolizumab response as observed in Keynote-100 was seen.
The authors wrote that they have demonstrated that a study of a rare histological subtype of gynaecological cancer is feasible even with mandated translational sample collection including tumour biopsies, with enrolment occurring over a 30-month span in large part during the COVID19 pandemic. Tissue collection including contemporaneous trial biopsies allows further translational study of the molecular and immune landscape. Further evaluation of anti–PD1 monotherapy or PD1 inhibitor combinations in randomised clinical trials is justified for this poor-prognosis population with gynaecological cancers of significant unmet clinical need.
Funding was provided by Merck Sharp & Dohme who also provided trial investigational medicinal product to all participating Trust Hospital Sites. Support for translational research was provided by Queen Mary University of London, Health Services Laboratory, and London and Kings College London.
Reference
Kristeleit R, Devlin M-J, Clamp A, et al. Pembrolizumab in Patients With Advanced Clear Cell Gynecological Cancer A Phase 2 Nonrandomized Clinical Trial. JAMA Oncology; Published online 6 February 2025. doi:10.1001/jamaoncol.2024.6797