Phase Ib/II dose expansion study of lenvatinib combined with letrozole in post-menopausal women with hormone receptor positive breast cancer.

RET is an estrogen response gene with preclinical studies demonstrating cross talk between RET and estrogen receptor (ER) pathways. We investigate the role of lenvatinib, a multi-kinase inhibitor with potent activity against RET, in patients with metastatic breast cancer.Patients with advanced ER+/HER2- breast cancer were treated with lenvatinib plus letrozole in a phase Ib/II trial. Primary objectives included safety and recommended phase II dose (RP2D) determination in phase Ib, and objective response rates (ORR) in phase II dose expansion.Sixteen patients were recruited in dose finding, where de-escalating doses of lenvatinib from 20mg to 14mg were investigated. Lenvatinib 14mg plus letrozole 2.5mg daily was determined as RP2D. Thirty-one patients with 5 median lines of prior therapy in the metastatic setting (range 0-11) were recruited in dose expansion. In this cohort, ORR was 23.3% (95% CI 9.9 to 42.3%), with median duration of response (DoR) of 6.9 months (Interquartile range(IQR) 5.9 to 13.1). Clinical benefit rate {greater than or equal to}6 months (CBR) was 50.0% (95% CI 31.3 to 68.7%). Similar efficacy was observed in the subgroup of 25 patients who progressed on prior CDK4/6 inhibitor therapy (ORR 20.0% (95% CI 6.8 to 40.7%), median DoR 6.9 months (IQR 5.9 to 13.1) and CBR 52.0% (95% CI 31.3 to 72.2%). Pharmacodynamic studies showed target modulation, with paired tumor biopsies indicating downregulation of RET/pERK and improved vascular normalisation index.Lenvatinib plus letrozole had manageable toxicity, with target engagement and preliminary antitumor activity observed, supporting further assessment in randomized studies.