Pembrolizumab-Lenvatinib Combination Shows 40% Response Rate in Recurrent Gynecologic Clear Cell Carcinoma

The combination of pembrolizumabView drug details and lenvatinibView drug details demonstrated promising antitumor activity in patients with recurrent gynecologic clear cell carcinoma (search)Search disease, achieving a 40% objective response rate in a phase II trial published in The Lancet Oncology. The LARA trial addresses a significant unmet medical need in this rare cancer subtype, which historically shows poor response rates of 0-19% to standard chemotherapy in the recurrent setting.

Study Design and Patient Population

The multicenter, single-arm phase II trial enrolled 27 patients across three tertiary hospitals in Singapore and South Korea between March 2021 and October 2023. The efficacy-evaluable population included 25 patients with histologically confirmed ovarian or endometrial clear cell carcinoma (search)Search disease who had progressed after at least one prior platinum-based chemotherapy regimen and had no previous immune checkpoint inhibitor exposure.

The patient population reflected the challenging nature of this disease, with a median age of 52 years and heavy pretreatment burden. Most participants (89%) had ovarian clear cell carcinoma (search)Search disease, while 11% had endometrial clear cell carcinoma (search)Search disease. The median number of prior therapy lines was 2, with 22% having received three or more prior treatments. Notably, 63% had previously received anti-angiogenic therapy, predominantly bevacizumabView drug details (59%).

The cohort demonstrated aggressive disease characteristics, with 59% experiencing progression within 6 months after platinum therapy and 30% progressing within 3 months, indicating platinum-resistant disease. Biomarker analysis revealed typical "immune-cold" features, with 85% of patients having PD-L1 (search)Search target CPS of 0 and a median tumor mutational burden of only 3 mutations per megabase.

Treatment Protocol and Primary Outcomes

Patients received pembrolizumabView drug details 200 mg intravenously every 3 weeks plus lenvatinibView drug details 20 mg orally once daily, continued until progression, unacceptable toxicity, or for a maximum of 2 years. The primary endpoint was investigator-assessed objective response rate within the first 24 weeks using RECIST v1.1 criteria.

At the March 2025 data cutoff, with a median follow-up of 21.0 months, 10 of 25 efficacy-evaluable patients achieved confirmed objective partial responses within 24 weeks, yielding the primary endpoint of 40% objective response rate (95% CI: 21-61%). An additional 10 patients (40%) achieved stable disease, resulting in a clinical benefit rate of 84% (95% CI: 64-96%).

Efficacy and Survival Outcomes

The median duration of response was 6.6 months (95% CI: 6.0 months to not reached), with a median time to response of 2.8 months. Median progression-free survival reached 6.4 months (95% CI: 3.4-9.5 months), with a 24-week progression-free survival rate of 53% (95% CI: 37-77%).

Importantly, the combination maintained activity in patients previously exposed to anti-angiogenic therapy. Among 17 patients who had progressed on bevacizumabView drug details or another anti-angiogenic agent, the objective response rate was 47% (95% CI: 23-72%).

By data cutoff, 16 deaths (64%) were observed, all attributed to progressive disease, with a median overall survival of 15.6 months (95% CI: 7.9 months to not available). In exploratory subgroup analysis, patients with ovarian clear cell carcinoma (search)Search disease had a median progression-free survival of 6.5 months and overall survival of 19.4 months.

Safety Profile and Dose Modifications

Treatment-related adverse events occurred in 93% of patients, with grade 3-4 events in 52%. The most common all-grade treatment-related adverse events included palmar-plantar erythrodysaesthesia (59%), hypertension (48%), anorexia (48%), oral mucositis (44%), fatigue (44%), and diarrhea (37%).

Grade 3-4 treatment-related adverse events occurred most commonly as hypertension (22%), with less frequent hematologic and liver enzyme abnormalities (approximately 7% each for elevated AST/ALT and thrombocytopenia). Serious adverse events occurred in 19% of patients, including immune-related hepatitis in 7% and grade 3 immune-related primary adrenal insufficiency in 4%. No treatment-related deaths were reported.

Dose modifications were frequently required, with lenvatinibView drug details interruptions occurring in 93% of patients and dose reductions or discontinuation in 89%. The median lenvatinib dose by treatment end was 10 mg daily (range 4-20 mg), though dose reduction did not appear to reduce objective response rate in post-hoc assessment.

Clinical Implications

The study's corresponding author, David S. P. Tan, MD, PhD, of the Department of Haematology-Oncology at National University Cancer Institute (search)Search term, Singapore, noted that the findings support further evaluation of this combination in randomized controlled trials.

The investigators concluded that "pembrolizumabView drug details plus lenvatinibView drug details showed promising anti-tumour activity and manageable safety in patients with recurrent clear cell gynecologic carcinoma," emphasizing the combination's potential in a disease setting with limited treatment options.

Notably, responses occurred largely independent of classic immunotherapy biomarkers, with most tumors having PD-L1 (search)Search target CPS of 0 and low tumor mutational burden, suggesting the combination may extend immunotherapy benefit beyond traditional biomarker-selected populations. This finding has important implications for treatment selection in clear cell gynecologic cancers, where standard predictive biomarkers may not adequately identify patients who could benefit from immunotherapy approaches.