Efficacy and Genomic Analysis of <i>HER2</i> -Mutant Metastatic Triple-Negative Breast Cancer Treated with Neratinib Alone or with Trastuzumab in the SUMMIT Basket Trial

PURPOSE: HER2 mutations occur in 1-3% of triple-negative breast cancers (TNBCs), representing a novel target for biomarker-directed treatment. In the SUMMIT basket trial (NCT01953926), patients with HER2-mutant, metastatic TNBC received neratinib (240 mg/day) or neratinib+trastuzumab (N+T; neratinib 240 mg/day, IV trastuzumab 8 mg/kg initially then 6 mg/kg q3w). We report final results from the neratinib and N+T TNBC cohorts. EXPERIMENTAL DESIGN: Primary endpoint: investigator-assessed objective response rate at first post-baseline tumor assessment (ORRfirst); secondary endpoints included: confirmed ORR by investigator; clinical benefit rate (CBR); progression-free survival (PFS); exploratory endpoint: circulating tumor (ct) DNA collected at baseline, during treatment, and at end of treatment. RESULTS: Twenty-seven patients were enrolled between July 2014 and September 2021. Confirmed ORRs were 40.0% (95%CI12.2-73.8) for neratinib (n=10) and 35.3% (95%CI 14.2-61.7) for N+T (n=17). CBRs were 40.0% (95%CI 12.2-73.8) and 47.1% (95%CI 23.0-72.2), respectively; median PFS was 2.89 (95%CI 0.95-5.52) and 6.24 months (95%CI 2.10-8.18), respectively. HER2 mutation variant allele frequencies in ctDNA from patients with response or stable disease decreased upon treatment and increased upon progression. Serial ctDNA sequencing revealed emergence or increase of on-pathway (ERBB3) and off-pathway (KRAS, TP53) mutations. The most common treatment-emergent adverse events were diarrhea, nausea, and constipation. CONCLUSIONS: N+T in patients with HER2-mutant metastatic TNBC appeared to prolong responses versus neratinib alone, representing a novel approach for biomarker-defined metastatic TNBC patients. Based on these and previously published data, neratinib-based combinations are endorsed by NCCN guidelines for patients with hormone receptor-positive or -negative metastatic breast cancer with activating HER2 mutations.