Pembrolizumab Plus Lenvatinib Demonstrates Encouraging Activity in Recurrent Gynecologic Clear Cell Carcinomas

Clinical Summary: 

• Design/Population: The phase 2 LARA trial evaluated pembrolizumab plus lenvatinib in patients with recurrent clear cell carcinomas of gynecologic origin who had progressed after platinum-based chemotherapy and had no prior immune checkpoint inhibitor exposure. All tumors were mismatch repair proficient or microsatellite stable.
• Key Outcomes: Pembrolizumab plus lenvatinib demonstrated encouraging antitumor activity, achieving an objective response rate of 40% at 24 weeks. The regimen was associated with a manageable safety profile, although grade 3 or higher treatment-related adverse events occurred in approximately half of patients.
• Clinical Relevance: These findings support combined PD-1 and VEGF pathway inhibition as a potential treatment strategy for recurrent clear cell carcinomas of gynecologic origin and warrant further evaluation in randomized clinical trials.

Results from the phase 2 LARA trial demonstrated that pembrolizumab plus lenvatinib produced encouraging antitumor activity with a manageable safety profile in patients with recurrent clear cell carcinomas of gynecologic origin, supporting further evaluation of the combination in this difficult-to-treat population.

“Combined targeting of angiogenic and immune pathways is an emerging strategy in clear cell carcinomas arising from the gynaecological tract, given the unique molecular and microenvironmental features of this gynaecological cancer," stated Natalie Ngoi, MD, National University Cancer Institute, Singapore, and coauthors. “We aimed to evaluate the preliminary activity and safety of pembrolizumab plus lenvatinib in patients with recurrent [gynaecological clear cell carcinoma]." 

In this single-arm study, 25 patients with mismatch repair-proficient or microsatellite-stable ovarian clear cell carcinoma or primary endometrial clear cell carcinoma who experienced disease progression following at least 1 prior platinum-based chemotherapy regimen received 200 mg of pembrolizumab every 3 weeks plus 20 mg of once-daily lenvatinib for up to 2 years or until disease progression or unacceptable toxicity. Patients had not previously received immune checkpoint inhibitor therapy. The primary end point was objective response rate (ORR). A key secondary end point was safety. 

At the time of analysis, the 24-week ORR was 40%. Grade ≥3 treatment-related adverse events occurred in 52% of patients. The most common grade ≥3 events included hypertension (22%), decreased platelet count (7%), elevated aspartate aminotransferase (7%), and elevated alanine aminotransferase (7%). Serious treatment-related adverse events occurred in 19% of patients, most commonly immune-mediated hepatitis (7%) and decreased platelet count (7%). No treatment-related deaths were reported.

“Pembrolizumab plus lenvatinib showed promising anti-tumour activity and manageable safety in patients with recurrent [gynaecological clear cell carcinoma], including in patients with disease progression following previous treatment with anti-angiogenic therapy,” concluded Dr Ngoi et al. “These findings support further evaluation of this combination in randomised controlled trials.” 

Source: 

Ngoi NYL, Lee JY, Lim D, et al. Pembrolizumab plus lenvatinib in recurrent gynaecological clear cell carcinoma (LARA): A multicentre, single-arm, phase 2 trial. Lancet Oncol. Published online: January 15, 2025. doi:10.1016/S1470-2045(25)00662-X