Lenvatinib Plus Pembrolizumab Demonstrates Long-Term Efficacy, Safety in Advanced Endometrial Carcinoma

Updated Data From Study 111/KEYNOTE-775

Lenvatinib plus pembrolizumab yielded promising long-term results in efficacy and safety for patients with previously treated advanced endometrial carcinoma, according to updated results from the Study 111/KEYNOTE-146 trial published in the Journal of Clinical Oncology.

In earlier trials, lenvatinib plus pembrolizumab improved progression-free survival and overall survival compared with physician’s choice of chemotherapy (Study 309/KEYNOTE-775) and promising efficacy and safety (Study 111/KEYNOTE-146) among in patients with previously treated advanced endometrial cancer. The current analysis is an extended follow-up of the open-label, single-arm, phase 1b/2 Study 111/KEYNOTE-146, showing the long-term efficacy and safety of lenvatinib plus pembrolizumab within this patient population.

All analyses of enrolled patients (n = 108) were updated and completed by the new cutoff date of August 18, 2020. At that date, 32 (29.6%) patients were either on study treatment (both drugs or lenvatinib only, n = 8), or in survival follow-up (n = 24). The remaining 76 (70.4%) patients discontinued the study either because of death (n = 71), consent withdrawal (n = 4), or other reason (n = 1). End points of the study included overall survival (OS), progression-free survival (PFS), duration of response (DOR), and objective response rate (ORR).

After a median follow-up of 34.7 months, the updated ORR was 39.8%, with 9 complete responses and 34 partial responses. The updated median DOR for patients treated who received this treatment regimen was 22.9 months, with the upper range of DOR ongoing at years. Median PFS and OS were 7.4 months and 17.7 months, respectively.

The study also evaluated the efficacy and a tolerability of this treatment regimen based on microsatellite instability (MSI) and mismatch repair (MMR) tumor status. Patients were divided into 2 subgroups, high microsatellite instability and mismatch repair deficient (MSI-H/dMMR) or non-high microsatellite instability and mismatch repair proficient (non–MSI-H/pMMR). Patients with non–MSI-H/pMMR experienced an ORR of 38.3%, median DOR of 23 months (95% CI, 8.5 to NE), median PFS of 7.4 months, and median OS of 17.2 months. Comparatively, patients with MSI-H/dMMR experienced an OOR of 63.6%, median DOR of 21.2 months (95% CI, 7.3 to NE), median PFS of 26.4 months (95% CI, 4 to NE), and a median OS of NE (95 CI, 7.4 to NE). Upper ranges of DOR were ongoing at 4 years for both subgroups.

Any-grade treatment-related adverse events occurred in 104 (96.3%) patients, with 94 (87%) patients experiencing grade ≤3 treatment-related adverse events and 10 (9.3%) patients experiencing grade ≥ 4 treatment-related AEs. The most common grade ≥3 treatment-related adverse events were hypertension (33.3%), elevated lipase (9.3%), fatigue (8.3%), and diarrhea (7.4%). Aside from 2 treatment-related deaths reported in the primary analysis, no additional treatment-related deaths occurred. Treatment-related adverse events led to discontinuation of at least 1 study drug in 23 (21.3%) patients, discontinuation of both study drugs in 9 (8.3%) patients, lenvatinib dose reductions in 73 (67.6%) patients, and interruption of 1 or both study drugs in 80 (74.1%) patients.

Study authors concluded, “This follow-up analysis showed deep and durable tumor responses (with one additional complete response compared with the primary analysis) in patients with previously treated advanced [endometrial carcinoma] who received lenvatinib plus pembrolizumab,” adding “this combination continued to show compelling PFS and OS benefits in comparison with that would be expected on the basis of historical data for this treatment setting.

Source:

Makker V, Aghajanian C, Cohn AL, et al. A Phase Ib/II study of lenvatinib and pembrolizumab in advanced endometrial carcinoma (Study 111/KEYNOTE-146): long-term efficacy and safety update. J Clin Oncol. 2023;41(5):974-979. doi:10.1200/JCO.22.01021