Pembrolizumab and Lenvatinib Present Promise in Recurrent Gynecological Clear Cell Carcinoma

A combination therapy of pembrolizumab (Keytruda) and lenvatinib (Lenvima) has demonstrated encouraging anti-tumor activity and a manageable safety profile in patients with recurrent gynecological clear cell carcinoma (CCGC), according to results from the phase 2 LARA trial (NCT04699071). The findings, published in The Lancet Oncology, offer a potential new treatment option for this rare and challenging cancer subtype.

Understanding Clear Cell Carcinoma

Clear cell carcinomas of the gynecological tract, including ovarian and endometrial cancers, are uncommon but often resistant to standard chemotherapy, particularly when the disease recurs. This lack of effective treatment options creates a significant unmet need for patients.

The LARA Trial Design

The LARA trial was a multicenter, single-arm, phase 2 study conducted across tertiary hospitals in Singapore and South Korea. The trial evaluated the combination of pembrolizumab, a PD-1 immune checkpoint inhibitor and lenvatinib, a multi-kinase anti-angiogenic inhibitor. Eligible patients had histologically confirmed primary ovarian or endometrial CCGC that had progressed or recurred after at least one prior line of platinum-based chemotherapy and an ECOG performance status of 0 or 1. Patients had not previously received immune checkpoint inhibitor therapy.

Participants received 200 mg of intravenous pembrolizumab every three weeks, combined with 20 mg of oral lenvatinib daily. Treatment continued for up to two years or until disease progression, unacceptable toxicity, or withdrawal of consent. Dose reductions of lenvatinib were permitted to manage treatment-related side effects, but no dose adjustments were planned for pembrolizumab.

Key Findings: Efficacy and Survival

Analysis of 25 evaluable patients revealed a confirmed investigator-assessed objective response rate (ORR) of 40% (95% CI, 21%-61%) within the first 24 weeks of treatment. All 10 patients who responded achieved a partial response, with one additional unconfirmed partial response.

The median duration of response was 6.6 months (95% CI, 6.0-not available). The clinical benefit rate (CBR) at 24 weeks, encompassing patients with objective responses or stable disease, reached 84% (95% CI, 64%-96%).

At a median follow-up of 21.0 months, the trial met its primary endpoint of achieving at least 6 responders out of 25 patients. The median progression-free survival (PFS) was 6.4 months (95% CI, 3.4-9.5), with a 24-week PFS rate of 53% (95% CI, 37%-77%). The median overall survival (OS) was 15.6 months (95% CI, 7.9-NA). Patients with primary ovarian clear cell carcinoma had a median PFS of 6.5 months (95% CI, 3.6-9.6) and a median OS of 19.4 months (95% CI, 10.0-NA).

Safety and Tolerability

The combination of pembrolizumab and lenvatinib was generally well-tolerated. No treatment-related deaths were reported. Grade 3 to 4 treatment-related adverse events occurred in 52% of patients who received at least one dose of the study treatment. The most common high-grade events were hypertension (22%), followed by decreased platelet counts (7%) and elevations in liver enzymes (7% each).

Serious adverse events were recorded in 19% of patients, including immune-related hepatitis (7%) and decreased platelet counts (7%). Lenvatinib dose interruptions occurred in 93% of patients, and dose reductions or discontinuation were necessary in 89%. However, 7% of patients discontinued treatment due to toxicity, suggesting that adverse events are manageable with dose adjustments.

Implications for Treatment

“Given that only a few treatment options are available for patients with relapsed CCGC, pembrolizumab plus lenvatinib represents a promising therapy,” the study authors concluded. The combination demonstrated consistent efficacy across various clinical subgroups, including patients who had previously received anti-angiogenic therapy.

Reference: 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, 2026. doi:10.1016/S1470-2045(25)00662-X