The Phase III LEAP-001 trial (ENGOT-en9) has revealed that the combination of lenvatinib and pembrolizumab, when used as a first-line treatment, did not significantly improve progression-free survival (PFS) or overall survival (OS) compared to standard chemotherapy in patients with advanced or recurrent endometrial cancer, specifically those with mismatch repair-proficient (pMMR) tumors. The study, involving 842 patients, aimed to address the need for more effective and tolerable therapies for this patient population, where the prognosis remains poor.
Study Design and Patient Population
The LEAP-001 trial was a multicenter, open-label study in which patients with stage III to IV or recurrent endometrial cancer, who had not received prior chemotherapy (or had disease progression ≥ 6 months after neoadjuvant or adjuvant platinum-based chemotherapy), were randomized to receive either lenvatinib (20 mg daily) plus pembrolizumab (200 mg every 3 weeks) or paclitaxel (175 mg/m²) plus carboplatin (AUC 6) every 3 weeks. The primary endpoints were PFS and OS in the pMMR population and in all patients.
Efficacy Outcomes
In the pMMR population, the median PFS was 9.6 months (95% CI: 8.2-11.9 months) in the lenvatinib/pembrolizumab group and 10.2 months (95% CI: 8.4-10.5 months) in the chemotherapy group (HR: 1.01, 95% CI: 0.83-1.24). The median OS was 30.9 months (95% CI: 25.4-37.7 months) in the lenvatinib/pembrolizumab group and 29.4 months (95% CI: 26.2-35.4 months) in the chemotherapy group (HR: 1.02, 95% CI: 0.83-1.26). These results indicated that the lenvatinib/pembrolizumab combination did not meet the prespecified statistical criteria for superiority compared to chemotherapy in the pMMR subgroup.
In the total population, the median PFS was 12.5 months (95% CI: 10.3-15.1 months) in the lenvatinib/pembrolizumab group and 10.2 months (95% CI: 8.4-10.4 months) in the chemotherapy group (HR: 0.91, 95% CI: 0.76-1.09). The median OS was 37.7 months (95% CI: 32.2-43.6 months) in the lenvatinib/pembrolizumab group and 32.1 months (95% CI: 27.2-35.7 months) in the chemotherapy group (HR: 0.93, 95% CI: 0.77-1.12). Although there was a trend towards improved survival in the overall population, the difference was not statistically significant.
Safety and Tolerability
The combination therapy was associated with a higher incidence of adverse events. Grade ≥3 treatment-related adverse events occurred in 79% of patients in the lenvatinib/pembrolizumab group compared to 67% in the chemotherapy group. Common adverse events in the combination group included hypertension (43%), diarrhea (8%), and proteinuria (7%), while the chemotherapy group experienced decreased neutrophils (26%), neutropenia (23%), and anemia (15%). Treatment-related adverse events led to discontinuation of any study drug in 39% of patients receiving lenvatinib/pembrolizumab versus 17% receiving chemotherapy. Adverse events led to death in 12 patients in the combination arm and 1 patient in the chemotherapy arm.
Implications for Clinical Practice
The results from the LEAP-001 trial suggest that first-line lenvatinib plus pembrolizumab did not meet the prespecified statistical criteria for PFS or OS compared to chemotherapy in patients with pMMR advanced endometrial cancer. While there was a trend toward improved outcomes in the overall population, the increased toxicity associated with the combination therapy warrants careful consideration. Further research is needed to identify subgroups of patients who may benefit from this combination and to optimize treatment strategies for advanced endometrial cancer.
