Pembrolizumab plus lenvatinib in recurrent gynaecological clear cell carcinoma (LARA): a multicentre, single-arm, phase 2 trial

Abstract

BACKGROUND Combined targeting of angiogenic and immune pathways is an emerging strategy in clear cell carcinomas arising from the gynaecological tract (CCGCs), given the unique molecular and microenvironmental features of this gynaecological cancer. We aimed to evaluate the preliminary activity and safety of pembrolizumab plus lenvatinib in patients with recurrent CCGC. METHODS We conducted a multicentre, single-arm, phase 2 trial (LARA) across three tertiary hospitals in Singapore and South Korea. Adult patients (aged ≥18 years) with histologically confirmed CCGC, which had progressed or recurred after at least one previous line of platinum-based chemotherapy; an Eastern Cooperative Oncology Group performance status score of 0-1; and no previous exposure to immune checkpoint inhibitor therapy were eligible for inclusion. Patients received 200 mg intravenous pembrolizumab every 3 weeks plus 20 mg oral lenvatinib daily, until disease progression, unacceptable toxicity, or withdrawal of consent, whichever occurred first, for up to 2 years. The primary endpoint was objective response rate in the first 24 weeks of treatment, as per investigator-assessed Response Evaluation Criteria in Solid Tumours (RECIST; version 1.1), analysed by modified intention to treat. This trial is registered with ClinicalTrials.gov (NCT04699071) and is ongoing. FINDINGS Between March 26, 2021, and Oct 10, 2023, 30 patients were assessed for eligibility, of whom 27 (90%) participants received at least one dose of pembrolizumab plus lenvatinib. 25 (83%) patients were included in the primary outcome analysis. Median participant age was 52 years (IQR 40-66). Among the 27 patients, 12 (44%) were Chinese, 12 (44%) were Korean, two (7%) were Malay, and one (4%) was Filipino. 24 (89%) patients had primary ovarian clear cell carcinoma; three (11%) had primary endometrial cancer. All tumours had proficient mismatch repair or microsatellite stability. At data cutoff on March 19, 2025, median follow-up was 21middot;0 months (IQR 12middot;5-25middot;2). Ten of 25 patients had confirmed objective response within 24 weeks (objective response rate at 24 weeks 40% [95% CI 21-61]). Grade 3-4 treatment-related adverse events occurred in 14 (52%) of 27 patients, the most common of which were hypertension (six [22%] patients), decreased platelet count (two [7%]), elevated aspartate aminotransferase (AST; two [7%]), and elevated alanine aminotransferase (ALT; two [7%]). Serious adverse events occurred in five (19%) patients, the most common of which were immune-related hepatitis in two (7%) patients and decreased platelet count in two (7%) patients. No treatment-related deaths occurred. INTERPRETATION Pembrolizumab plus lenvatinib showed promising anti-tumour activity and manageable safety in patients with recurrent CCGC, including in patients with disease progression following previous treatment with anti-angiogenic therapy. These findings support further evaluation of this combination in randomised controlled trials. FUNDING National Medical Research Council (Singapore), Pangestu Family Foundation Gynaecological Cancer Research Fund, and MSD.