Pembrolizumab Plus Lenvatinib Shows Promise in Recurrent Gynecologic Clear Cell Carcinomas

Clinical Summary:

• Design/Population: The phase 2 LARA trial enrolled 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 achieved a 40% objective response rate within 24 weeks, with over half of patients experiencing grade 3/4 treatment-related adverse events. The most common severe toxicity was hypertension, and no treatment-related deaths occurred.
• Clinical Relevance: These findings suggest that combined immune and angiogenic inhibition may represent a viable therapeutic strategy in recurrent clear cell carcinomas of gynecologic origin. Further randomized trials are warranted to confirm efficacy and define the role of this regimen in clinical practice.

According to results from the phase 2 LARA trial, pembrolizumab plus lenvatinib demonstrated promising antitumor activity and manageable safety among patients with recurrent clear cell carcinomas arising from the gynecological tract (CCGC). 

“Combined targeting of angiogenic and immune pathways is an emerging strategy in [CCGCs], 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 CCGC.” 

In this single-arm study, 25 patients with mismatch repair-proficient or microsatellite-stable ovarian clear cell carcinoma or primary endometrial cancer who experienced disease progression after at least one prior line of platinum-based chemotherapy received 200 mg of pembrolizumab once every 3 weeks plus 20 mg of once daily lenvatinib for up to 2 years or until disease progression or unacceptable toxicity. Patients had no prior exposure to immune checkpoint inhibitor therapy. The primary end point was objective response rate (ORR). A key secondary end point was safety.

At analysis, the 24-week ORR was 40%. Grade 3/4 treatment-related adverse events occurred in 52% of patients. The most common grade 3/4 events included hypertension (22%), decreased platelet count (7%), elevated aspartate aminotransferase (7%), and elevated alanine aminotransferase (7%). Serious adverse events occurred in 19% of patients, most frequently immune-related 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 CCGC, 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