Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer

Abstract

PURPOSE Patients with advanced endometrial carcinoma have limited treatment options. We report final primary efficacy analysis results for a patient cohort with advanced endometrial carcinoma receiving lenvatinib plus pembrolizumab in an ongoing phase Ib/II study of selected solid tumors. METHODS Patients took lenvatinib 20 mg once daily orally plus pembrolizumab 200 mg intravenously once every 3 weeks, in 3-week cycles. The primary end point was objective response rate (ORR) at 24 weeks (ORRWk24); secondary efficacy end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Tumor assessments were evaluated by investigators per immune-related RECIST. RESULTS At data cutoff, 108 patients with previously treated endometrial carcinoma were enrolled, with a median follow-up of 18.7 months. The ORRWk24 was 38.0% (95% CI, 28.8% to 47.8%). Among subgroups, the ORRWk24 (95% CI) was 63.6% (30.8% to 89.1%) in patients with microsatellite instability (MSI)–high tumors (n = 11) and 36.2% (26.5% to 46.7%) in patients with microsatellite-stable tumors (n = 94). For previously treated patients, regardless of tumor MSI status, the median DOR was 21.2 months (95% CI, 7.6 months to not estimable), median PFS was 7.4 months (95% CI, 5.3 to 8.7 months), and median OS was 16.7 months (15.0 months to not estimable). Grade 3 or 4 treatment-related adverse events occurred in 83/124 (66.9%) patients. CONCLUSION Lenvatinib plus pembrolizumab showed promising antitumor activity in patients with advanced endometrial carcinoma who have experienced disease progression after prior systemic therapy, regardless of tumor MSI status. The combination therapy had a manageable toxicity profile.

Immune Checkpoint Blockade in Gynecologic Cancers: State of Affairs

“…KEYNOTE-146/Study 111 was a single-arm, open label, phase Ib/II study to evaluate the safety and efficacy of lenvatinib plus pembrolizumab in advanced solid tumors, including endometrial carcinoma [73]. Patients received lenvatinib 20 mg once daily orally plus pembrolizumab 200 mg IV once every three weeks, based on the recommended dosing from the phase Ib portion of the study.…”

“…The ORR Wk24 was 38% in the cohort of 108 patients who were previously treated with conventional therapy. For 94 patients with MSS/MMRp tumors, ORR as measured by immune-related RECIST (irRECIST) was 37.2% versus 63.6% for 11 patients with MSI-H/MMRd tumors [73].…”

“…Grade 3/4 treatment-related adverse events were seen in 68% of patients, and 17.7% of patients discontinued one or both therapies because of treatment-related adverse events. Overall, 19 patients (15.3%) discontinued lenvatinib, 15 (12.1%) discontinued pembrolizumab, and 11 (8.9%) discontinued both study drugs [73]. Based on the outcome of these studies, lenvatinib in combination with pembrolizumab was granted accelerated approval by the FDA in September of 2019 for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or MMRd, and who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation [73].…”

Metastatic endometrial carcinoma responsive to pembrolizumab

“…In KEYNOTE-146/study 111 (a single-arm, openlabel trial) involving 94 patients with MSI-H or dMMR metastatic endometrial cancers who had progressed on one prior systemic therapy, the objective response rate to pembrolizumab with lenvatinib was 36%, with a complete response rate of 2%. [9] For those responding, the probability of having a response duration of ≥6 months was 85%. e abscopal effect is mediated by a systemic anti-tumor immune response and reflects the regression of nonirradiated metastatic lesions at a distance from the primary site of irradiation.…”

A multicenter phase II randomized trial of durvalumab (MEDI-4736) versus physician’s choice chemotherapy in recurrent ovarian clear cell adenocarcinoma (MOCCA)

“…Recent data showing efficacy for lenvatinib plus pembrolizumab in patients with advanced recurrent clear cell endometrial cancer also suggests that the combination of vascular endothelial growth factor and PD-1 pathway inhibition should also be studied in ovarian clear cell carcinoma in the future. 15 Crucially, it is hoped that translational studies from the aforementioned trials will also help to determine the relevant biomarkers of sensitivity and resistance to immune checkpoint inhibitors in ovarian clear cell carcinomas and help transform the treatment for patients affected by this challenging disease.…”