Pembrolizumab (Keytruda) in combination with lenvatinib (Lenvima) is showing promise as a treatment option for patients with recurrent gynecological clear cell carcinoma (CCGC), a relatively rare and often aggressive cancer. Results from the phase 2 LARA trial, published in in The Lancet Oncology, demonstrate significant anti-tumor activity and a manageable safety profile with this combination therapy.
Clinical Efficacy and Subgroup Analysis
The LARA trial evaluated 25 patients with recurrent CCGC who had previously undergone platinum-based chemotherapy. The primary endpoint, assessed at 24 weeks, revealed an objective response rate (ORR) of 40% (95% CI, 21%-61%). All responders experienced a partial response, with one additional patient showing an unconfirmed partial response. The median duration of response was 6.6 months (95% CI, 6.0-not available [NA]). Importantly, 84% of patients (95% CI, 64%-96%) experienced clinical benefit, defined as either an objective response or stable disease.
These findings are particularly encouraging given the challenging nature of treating recurrent CCGC and the heavily pretreated status of the study participants. The median number of prior therapies was two, and a substantial proportion – 59% – had experienced disease progression within six months of their last treatment. The combination therapy demonstrated efficacy across various subgroups, including patients who had previously received anti-angiogenic agents like bevacizumab, with 63% of those patients still responding to the pembrolizumab/lenvatinib regimen.
At a median follow-up of 21.0 months (IQR 12.5-25.2), the trial met its primary endpoint of achieving at least six responders out of 25 patients. Further analysis revealed a median progression-free survival (PFS) of 6.4 months (95% CI, 3.4-9.5), with 53% of patients remaining progression-free at 24 weeks (95% CI, 37%-77%). The median overall survival (OS) reached 15.6 months (95% CI, 7.9-NA). Patients with primary ovarian clear cell carcinoma experienced 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).
“Pembrolizumab plus lenvatinib showed clinically meaningful anti-tumor activity,” noted lead study author Natalie Ngoi, MD, of the National University Cancer Institute Singapore. “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.” Dr. Ngoi and coauthors also emphasized that treatment-related toxicities were manageable with appropriate dose modifications and supportive care.
Trial Breakdown
The LARA trial employed a standardized treatment protocol: 200 mg of pembrolizumab administered intravenously every three weeks, combined with 20 mg of lenvatinib taken orally each day. Treatment continued for up to two years, or until disease progression, unacceptable toxicity, or patient withdrawal. The protocol allowed for stepwise dose reductions of lenvatinib to mitigate treatment-related side effects, but no dose adjustments were planned for pembrolizumab.
Patients eligible for inclusion in the trial had histologically confirmed primary ovarian or endometrial CCGC that had recurred or progressed after at least one prior line of platinum-based chemotherapy. They also needed to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no prior exposure to immune checkpoint inhibitors. The study population was predominantly Asian, with roughly equal representation of Chinese (44%) and Korean (44%) patients. All tumors analyzed were proficient in mismatch repair or exhibited microsatellite stability.
Safety and Tolerability
The combination of pembrolizumab and lenvatinib was generally well-tolerated, with no treatment-related deaths reported. Grade 3 to 4 adverse events occurred in 52% of the 27 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 elevated liver enzymes (7% each).
Serious adverse events were observed in 19% of patients, with immune-related hepatitis (7%) and decreased platelet counts (7%) being the most frequent. While 85% of patients ultimately discontinued treatment due to disease progression, only 7% discontinued because of toxicity, suggesting that the adverse event profile can be effectively managed through dose adjustments of lenvatinib.
Lenvatinib dose interruptions were required in 93% of patients, and dose reductions or discontinuation were necessary in 89%. At the end of treatment, the median lenvatinib dose was 10 mg daily (range, 4-20 mg).
“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 . Doi:10.1016/S1470-2045(25)00662-X
