Background: 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 and methods: 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.

Results: 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.

Conclusion: Lenvatinib plus letrozole had manageable toxicity, with target engagement and preliminary antitumor activity observed, supporting further assessment in randomized studies.

PMID: 35363275  DOI: 10.1158/1078-0432.CCR-21-4179