| Autor: |
Soo-Chin Lee, Boon Cher Goh, Bee Choo Tai, Lingzhi Wang, Supriya Jain, Kritika Yadav, Raghav Sundar, Cheng Ean Chee, David S.P. Tan, Ross A. Soo, Wei Peng Yong, Hon Lyn Tan, Joan R.E. Choo, Matilda Lee, Yi Wan Lim, Siew Eng Lim, Wan Qin Chong, Yvonne L.E. Ang, Gloria H.J. Chan, Natalie Y.L. Ngoi, Samuel G.W. Ow, Andrea L.A. Wong, Joline S.J. Lim |
| Rok vydání: |
2023 |
| DOI: |
10.1158/1078-0432.c.6532424.v1 |
| Popis: |
Purpose:RET is an estrogen response gene with preclinical studies demonstrating cross-talk between the RET and estrogen receptor (ER) pathways. We investigate the role of lenvatinib, a multikinase 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 deescalating doses of lenvatinib from 20 to 14 mg were investigated. Lenvatinib 14 mg plus letrozole 2.5 mg 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% confidence interval (CI) 9.9%–42.3%], with median duration of response (DoR) of 6.9 months [interquartile range (IQR) 5.9 to 13.1]. Clinical benefit rate ≥6 months (CBR) was 50.0% (95% CI, 31.3%–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%–40.7%), median DoR 6.9 months (IQR 5.9–13.1), and CBR 52.0% (95% CI, 31.3%–72.2%)]. Pharmacodynamic studies showed target modulation, with paired tumor biopsies indicating downregulation of RET/pERK and improved vascular normalization index.Conclusions:Lenvatinib plus letrozole had manageable toxicity, with target engagement and preliminary antitumor activity observed, supporting further assessment in randomized studies. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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