Efficacy and genomic analysis of

Background: Genomic analyses of the SUMMIT metastatic breast cancer (mBC) cohorts suggested that resistance to neratinib (N) occurred primarily via acquisition of additional HER2alterations [Smyth et al. Cancer Discovery 2020]; this finding was independently confirmed in the MutHER clinical trial [Ma et al. Clin Cancer Res 2022]. Addition of trastuzumab (T) to N + fulvestrant (F) in HR+, HER2-negative, HER2-mutant mBC revealed increased efficacy compared to N+F [Jhaveri et al. Ann Oncol 2023]. Here, we report final data from SUMMIT evaluating whether the addition of T to N could improve outcomes in patients (pts) with HER2-mutant, triple-negative mBC (representing up to 3% of triple-negative mBCs) and performed next-generation sequencing (NGS) of serial biopsies to evaluate mechanisms of sensitivity and resistance. Methods: Pts with HER2-mutant triple-negative mBC received N (original SUMMIT cohort) or N+T (in the subsequent cohort): oral N 240 mg/d, i.v. T 8 mg/kg initially followed by 6 mg/kg q3w. Loperamide prophylaxis was mandatory during the first two cycles. Efficacy endpoints: confirmed objective response rate and clinical benefit rate (RECIST v1.1 or modified PERCIST); duration of response; progression-free survival. Retrospective central NGS was performed by MSK-IMPACT (tissue) or MSK-ACCESS (plasma). Results: 10 and 17 pts with triple-negative mBC were enrolled in the N and the N+T cohorts, respectively. Median no. of prior systemic regimens for metastatic disease was 2.5 (range 0–6) for the N and 2 (range 0–7) for the N+T cohort. Efficacy findings are summarized (Table). Diarrhea was the most commonly reported adverse event (N 80% any grade; 20% grade 3; N+T 100% any grade; 18% grade 3; no grade 4/5 or permanent discontinuations in either cohort). Correlation of efficacy to central NGS analysis is ongoing and will be reported. Conclusions: Treatment with either N and/or N+T yielded promising clinical efficacy and has been included in recent NCCN guidelines for HER2-mutant, triple-negative mBC. Molecular mechanisms of intrinsic or acquired sensitivity/resistance per genomic analysis will be reported.