Pembrolizumab/Lenvatinib Show Efficacy, Safety in Clear Cell Gyn Cancers

The LARA trial (NCT04699071), a multi-center, single-arm, phase 2 study, found that combining pembrolizumab (Keytruda) with lenvatinib (Lenvima) in patients with recurrent clear cell gynecological cancer that had progressed after platinum-based chemotherapy was safe and efficacious.^1,2

The combination demonstrated promising antitumor activity, achieving a primary end point objective response rate (ORR) of 40% within the first 24 weeks of treatment.¹

In the primary analysis cohort, 10 of the 25 patients achieved a confirmed objective response within 24 weeks. This equates to an ORR at 24 weeks of 40% (95% CI, 21%-61%).

The safety profile was deemed manageable, with 52% of patients experiencing grade 3/4 treatment-related adverse events (TRAEs), most commonly hypertension. The analysis was based on the 27 patients who received at least 1 dose of treatment.

The trial yielded positive results regarding both antitumor activity and safety, meeting its primary end point.

Grade 3/4 TRAEs occurred in 14 patients (52%). The most common grade 3/4 TRAE was hypertension, reported in 6 patients (22%).

Other common TRAEs included decreased platelet count (n = 2, 7%), elevated aspartate aminotransferase (n = 2, 7%), and elevated alanine aminotransferase (n = 2, 7%).

Serious AEs occurred in 5 patients (19%). The most common serious AEs were immune-related hepatitis and decreased platelet count. There were no treatment-related deaths reported in the trial.

Study Overview and Rationale

The LARA trial was designed to investigate the combination of an immune checkpoint inhibitor (pembrolizumab) and an antiangiogenic agent (lenvatinib) for a specific subset of gynecological cancers.

The trial is predicated on the emerging strategy that combined targeting of angiogenic and immune pathways is particularly effective for clear cell gynecological cancers, given their unique molecular and microenvironmental characteristics.

The LARA trial is being conducted across 3 tertiary hospitals in Singapore and South Korea.

Patients received a combination therapy consisting of 200 mg intravenous pembrolizumab administered every 3 weeks and 20 mg oral lenvatinib taken daily. Treatment was continued for up to 2 years, or until disease progression, unacceptable toxicity, or withdrawal of consent occurred.

The primary end point was the ORR observed in the first 24 weeks of treatment. Responses were assessed by investigators according to the RECIST v 1.1.

Patient Characteristics

Between March 26, 2021, and October 10, 2023, 30 patients were assessed for eligibility. Of these, 27 received at least 1 dose of the treatment combination, and 25 were included in the primary outcome analysis. At the data cut-off date of March 19, 2025, the median follow-up period was 21.0 months.

Eligible patients were adult patients (aged ≥ 18 years) with histologically confirmed clear cell gynecologic cancer that had recurred or progressed after at least 1 previous line of platinum-based chemotherapy. Key inclusion criteria included an ECOG performance score of 0-1 and no prior exposure to immune checkpoint inhibitor therapy.

The median age of patients was 52 years (range, 40-66). Of the evaluable patients, 44% were Chinese, 44% were Korean, 7% were Malay, and 4% were Filipino. The majority of patients had ovarian cancer (89%), and 11% of patients had endometrial cancer. All tumors had proficient mismatch repair or were microsatellite stable.

Next Steps in Research

This efficacy was observed even in patients whose disease had progressed following previous treatment with anti-angiogenic therapy, suggesting a potent mechanism of action.

The positive findings from the LARA trial support the need for further evaluation of this drug combination in larger, randomized controlled trials to confirm its therapeutic benefit in this patient population.

“Pembrolizumab plus lenvatinib showed promising anti[tumor] activity and manageable safety in patients with recurrent [clear cell gynecologic cancers], including in patients with disease progression following previous treatment with antiangiogenic therapy,” concluded Ngoi et al, authors of the study. “These findings support further evaluation of this combination in [randomized] controlled trials.”

REFERENCES

1.Ngoi N, Lee JY, Lim D, et al. Pembrolizumab plus Lenvatinib in recurrent gynecological clear cell carcinoma (LARA): a multicenter, single-arm, phase 2 trial. The Lancet Oncology, Volume 0, Issue 0. January 15, 2026. Accessed January 30, 2026.

2.Trial of lenvatinib plus pembrolizumab in recurrent gynecological clear cell adenocarcinomas (LARA). ClinicalTrials.gov. Updated October 21, 2021. Accessed January 30, 2026. https://clinicaltrials.gov/study/NCT04699071