Lenvatinib in combination with pembrolizumab has demonstrated significant antitumor activity in patients with stage III/IV recurrent endometrial carcinoma. These findings come from an exploratory analysis of the phase 3 ENGOT-en9/LEAP-001 study, presented at the 2024 European Society for Medical Oncology (ESMO) Congress. The study highlights the potential of this combination therapy in addressing advanced endometrial cancer.
Objective Response and Duration
The data, with a cut-off date of October 2, 2023, revealed that 55.7% of patients treated with lenvatinib plus pembrolizumab achieved an objective response (ORR). Specifically, in the proficient mismatch repair (pMMR) population, the ORR was 50.6%. The median time to objective response was 2.1 months in both the overall group (range, 1.3-26.4) and the pMMR subgroup (range, 1.2-26.4).
The median duration of response (DOR) was 16.1 months (range, 1.0+-48.7+) for all patients and 23.2 months (1.0+-49.0+) for the pMMR population. These results indicate that the responses were not only significant but also durable, offering a potential long-term benefit for patients.
Investigator Insights
Dr. Anna Dańska-Bidzińska, a gynecologist from Warsaw Medical University in Warsaw, Poland, emphasized the broad applicability of the treatment. "Clinically meaningful response rates were seen regardless of baseline characteristics including MMR status, histology, and prior adjuvant therapy," she noted. She further added that patients who experienced a complete response (CR) to lenvatinib plus pembrolizumab showed promising progression-free survival (PFS) and overall survival (OS).
Progression-Free and Overall Survival
Kaplan-Meier estimates for PFS in the pMMR population showed 18.4 months (95% CI, 15.1-26.8) among all responders, 13.9 months (95% CI, 12.3-15.6) among patients with a partial response (PR), and not reached (NR; 95% CI, 29.1-NR) for those with a CR. Among all-comers, the PFS estimates were 27.3 months (95% CI, 20.9-36.8), 15.1 months (95% CI, 12.9-19.4), and NR (95% CI, NR-NR), respectively.
Overall survival (OS) estimates in the pMMR population were 43.6 months (95% CI, 37.9- NR) among all responders, 37.6 months (95% CI, 30.9-NR) among patients with a PR, and NR (95% CI, 39.5-NR) for those with a CR. For all-comers, OS estimates were NR (95% CI, 47.0-NR), 43.5 months (95% CI, 32.7-NR), and NR (95% CI, NR-NR), respectively.
Study Design
The ENGOT-en9/LEAP-001 study was a phase 3, multicenter, open-label trial. Patients with stage III to IV recurrent endometrial carcinoma were randomized 1:1 to receive either lenvatinib at 20 mg orally daily plus pembrolizumab at 200 mg intravenously every 3 weeks, or paclitaxel at 175 mg/m2 intravenously plus carboplatin at area under the curve 6 intravenously every 3 weeks for up to 7 cycles. The dual primary endpoints were PFS and OS, with secondary endpoints including ORR, safety, and health-related quality of life.
Safety Profile
Among responders in the lenvatinib combination group, all experienced adverse events (AEs). Any-grade and grade 3 or higher treatment-related AEs (TRAEs) occurred in 99.1% and 82.5% of patients, respectively. Discontinuation of lenvatinib, pembrolizumab, or both due to TRAEs occurred in 27.8%, 18.8%, and 3.4% of patients, respectively. A single treatment-related grade 5 instance of pneumonitis was reported.
Conclusions
The exploratory analysis of the ENGOT-en9/LEAP-001 study provides compelling evidence of substantial antitumor activity with lenvatinib plus pembrolizumab in advanced endometrial cancer. According to the investigators, responses were both deep and durable, and AEs were manageable with dose modifications and supportive care.
