Dual Pathway Blockade Achieves 40% Response in Recurrent Clear Cell Gynaecological Cancer

The multicentre Phase 2 LARA trial reported encouraging activity for pembrolizumab plus lenvatinib in recurrent gynaecological clear cell carcinoma, achieving a 40% objective response rate within 24 weeks and a median progression-free survival of 6.4 months. Published in The Lancet Oncology, the trial evaluated the combination in patients with recurrent clear cell cancers arising from the ovary or endometrium. The findings suggest that dual blockade of immune and angiogenic pathways may offer a meaningful therapeutic strategy for patients whose disease has progressed after prior treatment.

“Our study points to the potential for immunotherapy plus targeted therapy to provide benefit in this hard-to-treat disease, and reinforces the need to explore this regimen further for patients with clear cell cancers of the ovary whose disease has progressed after previous treatment. Ovarian clear cell cancers are a clinically aggressive subtype that is rare in western countries but relatively common in Singapore where currently approved treatments often fall short,” said Assoc Prof David Tan said,  Senior Consultant at the Department of Haematology-Oncology, NU Cancer Institute, Singapore.

The LARA study enrolled adults with histologically confirmed recurrent gynaecological clear cell carcinoma after at least one prior line of platinum-based chemotherapy. Patients received pembrolizumab 200 mg intravenously every three weeks plus lenvatinib 20 mg orally once daily, until disease progression, unacceptable toxicity, withdrawal of consent, or for up to two years. The primary endpoint was objective response rate within the first 24 weeks, assessed by RECIST version 1.1.

After a median follow-up of 21 months, 10 of 25 patients achieved a confirmed objective response within 24 weeks, corresponding to an objective response rate of 40%, with a 95% confidence interval of 21% to 61%. Median progression-free survival was reported as 6.4 months.

These results compare favourably with historical outcomes in recurrent ovarian clear cell carcinoma. In the earlier APGOT MOCCA trial, response rates were 9.7% with immunotherapy alone and 18.8% with chemotherapy, with 50% of patients progressing by 1.7 months and 3.5 months, respectively.

Assoc Prof David Tan added, “The response rates from the LARA trial far exceeded historical data in this disease. Furthermore, a US study7 also recently presented similar results with this combination in recurrent clear cell ovarian cancers, hence providing further validation of our results. Currently approved therapeutic options have only shown limited activity in this tumour type, and we, as a scientific community, have a duty to advocate for our patients and adopt the treatments that provide the best available evidence for efficacy. We are currently working to try to get this combination into the US NCCN guidelines, which would then guide our subsequent efforts to make this treatment available for patients in Singapore.”

The safety profile was described as manageable, although treatment-related adverse events were common. Grade 3 or 4 treatment-related adverse events occurred in 14 of 27 patients, 52%. The most frequent were hypertension, reported in six patients, decreased platelet count in two, elevated AST in two, and elevated ALT in two. Serious adverse events occurred in five patients, including immune-related hepatitis and decreased platelet count. No treatment-related deaths were reported.

The authors conclude that pembrolizumab plus lenvatinib demonstrated promising anti-tumour activity and manageable safety in recurrent gynaecological clear cell carcinoma, including in patients previously treated with anti-angiogenic therapy. However, the LARA trial was single-arm and relatively small, so the findings require confirmation in randomised controlled trials.