Preliminary pembrolizumab–lenvatinib activity reported in recurrent gynaecological clear cell carcinoma

Evidence before this study

We searched the American Society of Clinical Oncology Annual Meeting database, the European Society of Medical Oncology Congress database, and PubMed, without language restrictions, for conference abstracts or clinical trials published between database inception and Sept 20, 2025, using the following terms: “ovarian clear cell carcinoma”, “ovarian clear cell cancer”, “endometrial clear cell carcinoma”, “uterine clear cell carcinoma”, “endometrial clear cell cancer”, “uterine clear cell cancer”, “gynaecological clear cell carcinoma”, “gynaecological clear cell cancer”, OR “extra-renal clear cell carcinoma” AND “immunotherapy”, “immune checkpoint blockade”, OR “immune checkpoint inhibitors” OR “anti-angiogenic”, “angiogenesis inhibitor” OR “vascular endothelial growth factor (VEGF) pathway inhibitor”. We found three phase 2 trials that had evaluated the preliminary activity of anti-PD-1 or anti-PD-L1 immune checkpoint blockade in patients with recurrent ovarian or gynaecological clear cell carcinoma, suggesting modest activity overall. We found three other non-comparative phase 2 trials that had evaluated nivolumab combined with ipilimumab in patients with recurrent gynaecological clear cell carcinoma, reporting objective response rates between 21·1% and 54·0% and suggesting promising activity. We found one single-arm phase 2 trial that had evaluated the anti-PD-1 inhibitor, sintilimab, in combination with bevacizumab in patients with recurrent ovarian clear cell carcinoma, reporting promising activity with an objective response rate of 40·5%. We also found one single-arm phase 2 trial that had evaluated pembrolizumab–lenvatinib in patients with recurrent ovarian clear cell carcinoma, reporting preliminary activity with an objective response rate of 36·7%.

Added value of this study

The LARA trial evaluated the preliminary activity and safety of an immune checkpoint inhibitor, pembrolizumab, in combination with a multi-kinase angiogenesis inhibitor, lenvatinib, in Asian women with recurrent gynaecological clear cell carcinoma, most of whom had previously received anti-angiogenic therapy. This combination showed promising anti-tumour activity and an acceptable safety profile, supporting further investigation of this regimen in randomised trials.

Implications of all the available evidence

Recurrent gynaecological clear cell carcinoma represents a rare and aggressive histological subtype of gynaecological cancer. No immunotherapy or targeted therapy is currently approved for clear cell ovarian cancer, and only few efficacy data exist for immunotherapy against clear cell endometrial cancer. The preliminary activity observed in this trial of pembrolizumab–lenvatinib aligns with previously reported results of sintilimab–bevacizumab, collectively reinforcing the therapeutic rationale for combining immune checkpoint inhibition with anti-angiogenic strategies in this setting. These findings underscore the urgent need for randomised controlled trials to formally compare pembrolizumab–lenvatinib with standard chemotherapy in patients with recurrent gynaecological clear cell carcinoma.

Source: The Lancet Oncology