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

purposeHuman epidermal growth factor receptor 2 (HER2) mutations occur in 1% to 3% of triple-negative breast cancers (TNBC), 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, intravenous trastuzumab 8 mg/kg initially and then 6 mg/kg every 3 weeks). We report final results from the neratinib and N + T TNBC cohorts. PATIENTS AND

methodsPrimary endpoint: investigator-assessed objective response rate at first postbaseline tumor assessment (ORRfirst); secondary endpoints included confirmed ORR by investigator, clinical benefit rate (CBR), and progression-free survival (PFS); exploratory endpoint included circulating tumor DNA (ctDNA) collected at baseline, during treatment, and at the end of treatment.

resultsTwenty-seven patients were enrolled between July 2014 and September 2021. Confirmed ORRs were 40% [95% confidence interval (CI), 12.2-73.8] for neratinib (n = 10) and 35.3% (95% CI, 14.2-61.7) for N + T (n = 17). CBRs were 40% (95% CI, 12.2-73.8) and 47.1% (95% CI, 23-72.2), respectively; median PFS times were 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 in on-pathway (ERBB3) and off-pathway (KRAS and TP53) mutations. The most common treatment-emergent adverse events were diarrhea, nausea, and constipation.

conclusionsN + T in patients with HER2-mutant metastatic TNBC seemed to prolong responses versus neratinib alone, representing a novel approach for patients with biomarker-defined metastatic TNBC. Based on these and previously published data, neratinib-based combinations are endorsed by the National Comprehensive Cancer Network guidelines for patients with hormone receptor-positive or -negative metastatic breast cancer with activating HER2 mutations. See related commentary by Lloyd et al., p. 3715.