The prognosis for patients with advanced or recurrent endometrial cancer is poor. Until recently, the treatment options after progression on first-line, platinum-based chemotherapy were limited to single-agent chemotherapy, hormone therapy, and PD-1 inhibitor, pembrolizumab, for patients with microsatellite instability-high (MSI-H) tumors. The combination of pembrolizumab and the multikinase inhibitor, lenvatinib, demonstrated potent antitumor activity in preclinical studies and in the single arm phase Ib/II KEYNOTE-146/Study 111 that evaluated this combination in patients with advanced tumors, including advanced endometrial cancers. Based on an objective response rate (ORR) of 38%, durable responses, and favorable progression-free survival (PFS) from this study in a cohort of patients with endometrial cancer, the US Food and Drug Administration granted accelerated approval, in September 2019, of the combination of lenvatinib plus pembrolizumab for pretreated patients with advanced endometrial cancer whose tumors are not MSI-H or deficient in mismatch repair (dMMR).

The efficacy and safety of this combination in platinum-pretreated endometrial cancer was further evaluated in the open-label, randomized, phase III KEYNOTE-775/Study-309, which compared lenvatinib plus pembrolizumab with treatment of physician’s choice (TPC; single-agent doxorubicin or paclitaxel). Results from this pivotal study were presented by Vicky Makker, MD (Memorial Sloan Kettering Cancer Center, New York, US) at the plenary session of the Society of Gynecologic Oncology (SGO) Virtual Annual Meeting, held in March 2021. The co-primary endpoints of the trial were PFS (by blinded independent central review) and overall survival (OS). The study enrolled 827 platinum-pretreated patients: 697 with proficient MMR (pMMR) tumors and 130 with dMMR tumors. Patients were randomly assigned to receive pembrolizumab (200 mg intravenously, every 3 weeks for up to 35 cycles) in combination with lenvatinib (20 mg orally, once daily) or TPC. The dual primary endpoints of the trial were met. At a median follow-up of 11.4 months, median PFS for all patients (i.e. regardless of MMR status) was 7.2 versus 3.8 months in the combination versus TPC arm, respectively (hazard ratio [HR], 0.56; P <0.0001). For the pMMR cohort, median PFS was 6.6 versus 3.8 months (HR, 0.6). Despite informal crossover that occurred when lenvatinib plus pembrolizumab was approved, median OS for all patients was 18.3 versus 11.4 months, respectively (HR, 0.62; P <0.0001). For the pMMR cohort, median OS was 17.4 months versus 12.0 months (HR, 0.68). Comparable benefits in PFS and OS were observed across all analyzed subgroups, including MMR status, histology, and prior lines of therapy. Objective response rate (ORR) for all patients was 31.9% with lenvatinib plus pembrolizumab versus 14.7% with TPC, and complete responses were achieved by 6.6% and 2.6%, respectively, with a duration of response of 14.4 versus 5.7 months. Of note, the median duration of treatment was doubled with the combination (231 days versus 104.5 days). The safety profile of the combination treatment was consistent with those previously reported for the individual monotherapies. Treatment-related adverse events (TRAEs) of grade ≥3 were observed in 89% of patients in the combination arm versus 73% in the TPC arm, and the most common were hypertension (38%), weight decrease, decreased appetite, and diarrhea, each occurring in ≤10% of patients. In the combination arm, discontinuation rates due to TRAEs were 31% for lenvatinib, 19% for pembrolizumab, and 14% for both study treatments.

In conclusion, the combination of lenvatinib and pembrolizumab showed statistically significant and clinically meaningful improvements in PFS, OS, and ORR versus TPC, irrespective of MMR status, in patients with advanced endometrial cancer after progression on platinum-based chemotherapy, and it had a manageable safety profile. These data justify the approval of the combination for pMMR patients after failure on front-line chemotherapy. 

Reference

Maker V, et al. Presented at 2021 SGO Virtual Annual Meeting on Women’s Cancer; Abstract 11512.