Pembrolizumab Combo Yields Activity in Recurrent Gyn Clear Cell Carcinoma

Pembrolizumab (Keytruda) plus lenvatinib (Lenvima) demonstrated promising anti-tumor activity and a manageable safety profile in patients with recurrent gynecological clear cell carcinoma (CCGC), according to findings from the multicenter, single-arm, phase 2 LARA trial (NCT04699071) published in The Lancet Oncology.

Clinical Efficacy and Subgroup Analysis

The primary outcome analysis included 25 evaluable patients and reported a confirmed investigator-assessed objective response rate (ORR) of 40% (95% CI, 21%-61%) within the first 24 weeks of treatment. Among these responders, all 10 patients achieved a partial response, with 1 unconfirmed partial response. The median duration of response was 6.6 months (95% CI, 6.0-not available [NA]). The clinical benefit rate (CBR) at 24 weeks, which encompassed patients with confirmed objective responses or stable disease, reached 84% (95% CI, 64%-96%). These results were notable given the heavily pretreated nature of the study population; the median number of previous lines of therapy was 2, and 59% of patients had a treatment-free interval of less than 6 months.

The combination demonstrated consistent efficacy across various clinical subgroups. Anti-tumor activity was observed in patients regardless of whether they had previously received anti-angiogenic therapy, a common standard for recurrent CCGC. Specifically, 63% of the cohort had experienced disease progression following prior treatment with agents such as bevacizumab, yet the regimen remained active in this subgroup. At a median follow-up of 21.0 months (IQR 12.5-25.2), the trial met its primary end point of achieving at least 6 responders out of 25 patients.

As of the data cutoff of March 19, 2025, 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). The investigators highlighted that 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).

“…[P]embrolizumab plus lenvatinib showed clinically meaningful anti-tumor activity. This activity is encouraging given that most enrolled patients had disease progression following previous anti-angiogenic therapy and showed resistance to platinum-based chemotherapy with a short therapy-free interval,” wrote lead study author Natalie Ngoi, MD, of the Department of Hematology-Oncology at the National University Cancer Institute Singapore in Singapore, with coauthors. “Treatment-related toxicities were manageable with dose modifications and close supportive measures.”

Trial Breakdown

The LARA trial utilized a standardized treatment regimen consisting of 200 mg of intravenous pembrolizumab administered every 3 weeks in combination with 20 mg of oral lenvatinib daily. Treatment was continued for up to 2 years or until disease progression, unacceptable toxicity, or withdrawal of consent. To manage treatment-related toxicities, the protocol allowed for stepwise dose reductions of lenvatinib, though no dose reductions were planned for pembrolizumab.

Eligible patients included adults with histologically confirmed primary ovarian or endometrial CCGC that had progressed or recurred after at least 1 previous line of platinum-based chemotherapy. Patients were required to have an ECOG performance status of 0 or 1 and no previous exposure to immune checkpoint inhibitor therapy. The study population was predominantly Asian, with equal representation of Chinese (44%) and Korean (44%) patients. All tumors included in the analysis were proficient in mismatch repair status or exhibited microsatellite stability.

Safety and Tolerability

Safety results indicated that the combination was generally well-tolerated, with no treatment-related deaths reported. Grade 3 to 4 treatment-related adverse events occurred in 14 (52%) of the 27 patients who received at least 1 dose of the study treatment. The most frequently observed high-grade events were hypertension (22%) followed by decreased platelet counts (7%) and elevations in aspartate aminotransferase or alanine aminotransferase (7% each).

Serious adverse events were recorded in 19% of the patients, with the most common being immune-related hepatitis (7%) and decreased platelet counts (7%). While 85% of patients eventually discontinued treatment due to disease progression, 7% discontinued due to toxicity, suggesting that the adverse event profile is manageable for most patients when dose adjustments for lenvatinib are employed.

Treatment-related adverse events led to lenvatinib dose interruptions in 93% and dose reductions or discontinuation in 89%. By the end of treatment, the median dose of lenvatinib was 10 mg (range, 4-20) daily.

“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.

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