Abstract CT235: REPLOT Trial: Phase II study of repotrectinib with or without fulvestrant in patients with HR+ HER2- metastatic invasive lobular carcinoma previously treated with endocrine therapy and CDK4/6 inhibition

Abstract Background: Invasive lobular carcinoma (ILC) is the second most common histologic subtype of invasive breast cancer, accounting for 10-15% of cases. The majority of ILCs (93%) are hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-). While both metastatic ILC (mILC) and invasive ductal carcinoma (IDC) benefit from endocrine therapy (ET) combined with CDK4/6 inhibitors, mILC shows poor responses to subsequent therapies, with reported median progression-free survival (mPFS) <3 months and objective response rates (ORR) <10% to single-agent ET (e.g., fulvestrant) or chemotherapy. A hallmark of ILC is the universal loss of E-cadherin, most often due to mutations in the CDH1 gene (present in ∼70% of cases). Beyond its role in cell adhesion, E-cadherin is essential for spindle apparatus formation during cell division. Preclinical ILC models demonstrate that in the absence of E-cadherin, cells rely on ROS1 for spindle stability. Inhibiting ROS1 induces synthetic lethality, identifying ROS1 as a promising therapeutic target in ILC.Repotrectinib (REPO) is a potent, next-generation tyrosine kinase inhibitor (TKI) targeting ROS1, NTRK, and ALK, with >90-fold greater ROS1 inhibition compared to crizotinib. In the TRIDENT-1 Phase I/II trial, REPO showed remarkable efficacy in ROS1 fusion-positive metastatic non-small cell lung cancer, achieving an ORR of 79%, median duration of response (mDOR) of 34.1 months, and mPFS of 35.7 months. REPO was well tolerated, with primarily Grade 1/2 adverse events (AEs), including dizziness (58%), and dysgeusia (50%). No Grade 4/5 AEs were reported. Methods: NCT06408168 is the first U.S.-based trial dedicated to metastatic ILC. This Phase II study will enroll 58 patients with HR+ HER2- mILC who progressed on at least one prior ET + CDK4/6 inhibitor. Cohort 1 (29 patients) includes fulvestrant-naïve participants treated with REPO + fulvestrant; Cohort 2 (29 patients) includes those previously exposed to fulvestrant, treated with REPO monotherapy. Patients may have received unlimited prior ET combinations and up to two lines of chemotherapy/antibody-drug conjugates.The primary objective is to assess the 6-month PFS, with a doubling from 20% to 40% considered clinically meaningful. Secondary endpoints include mPFS, 12-month PFS, mDOR, overall survival (mOS), ORR, clinical benefit rate (CBR), and safety/tolerability. Correlative studies will assess changes in circulating tumor DNA (ctDNA) and serum thymidine kinase 1 activity (TKa). Enrollment began in October 2024 to Cohort 1. After 15 patients have been followed for six months, the Kaplan-Meier estimate of 6-month PFS will determine if Cohort 2 enrollment proceeds. Citation Format: Jason A. Mouabbi, Amy Hammell, Shailaja Suryawanshi, Lavinia Middleton, Roland Bassett, Toni Zaayman, Livia Geoffrey, Funda Meric-Bernstam. REPLOT Trial: Phase II study of repotrectinib with or without fulvestrant in patients with HR+ HER2- metastatic invasive lobular carcinoma previously treated with endocrine therapy and CDK4/6 inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT235.