E7386 plus lenvatinib in patients with advanced endometrial cancer that progressed on platinum-based chemotherapy and an anti-PD-(L)1 immunotherapy: a single-arm, open-label, global phase 1b/2 dose-expansion cohort

Abstract

Summary Background Novel therapies are needed for advanced endometrial cancer (aEC) that recurs after chemotherapy + immunotherapy. Lenvatinib has antitumour activity in patients with aEC after platinum-based chemotherapy and is approved in combination with pembrolizumab for aEC following prior systemic therapy. E7386, an oral anticancer agent, inhibits the interaction between β-catenin and CREB-binding protein (CBP). Preliminary results of a dose expansion cohort of Study 102 (n = 16) showed manageable safety and promising antitumour activity of E7386 + lenvatinib in aEC that progressed after platinum-based chemotherapy and anti-programmed cell death (ligand) 1, including responses in patients with prior lenvatinib. We report safety and antitumour activity for this complete dose expansion cohort. Methods In a dose expansion cohort of Study 102 (NCT04008797), patients with aEC that progressed after platinum-based chemotherapy and immunotherapy received E7386 120 mg twice daily plus lenvatinib 14 mg once daily (amended from 20 mg during enrolment). The primary endpoint was safety; secondary endpoints included objective response rate (ORR), duration of response, clinical benefit rate, and progression-free survival by investigator per RECIST v1·1). Findings Thirty patients were enrolled; 16 (53·3%) previously received lenvatinib. By data cut-off (4 June, 2025), five (16·7%) patients had treatment ongoing. All patients experienced treatment-emergent adverse events (TEAEs), most commonly vomiting (n = 22, 73·3%). Nineteen (63·3%) patients had grade 3 TEAEs, most frequently diarrhoea (n = 4). No grade 4–5 AEs were observed. TEAEs led to withdrawal of lenvatinib and/or E7386 in two patients. Overall, 11 patients (three with prior lenvatinib) had a confirmed response (one complete, ten partial) for an ORR of 36·7% (95% CI: 19·9–56·1). In patients without prior lenvatinib (n = 14), the ORR was 57·1% (95% CI: 28·9–82·3). Interpretation E7386 + lenvatinib showed promising antitumour activity with a manageable safety profile in heavily pretreated patients with aEC following platinum-based chemotherapy + immunotherapy. The dose-optimisation phase of Study 102 (E7386 + lenvatinib in patients with advanced endometrial carcinoma) is currently enrolling (NCT04008797). Funding Eisai Inc., Nutley, NJ, USA.