What question did this study set out to answer?

This research focuses on evaluating the efficacy of neratinib alone or in combination with trastuzumab in HER2-mutant metastatic triple-negative breast cancer (TNBC).

April 8, 2026Open Access

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

Key Points

This research focuses on evaluating the efficacy of neratinib alone or in combination with trastuzumab in HER2-mutant metastatic triple-negative breast cancer (TNBC).
Patients with HER2-mutant metastatic TNBC were treated with either neratinib alone or neratinib plus trastuzumab.
Objective response rates and clinical benefit rates were the primary endpoints assessed post-treatment.
Circulating tumor DNA (ctDNA) was collected to monitor mutations during treatment.
Confirmed objective response rates were 40.0% for neratinib alone and 35.3% for the combination therapy.
Median progression-free survival was better for the combination therapy at 6.24 months compared to 2.89 months for neratinib alone.
Circulating tumor DNA studies showed changes in mutation frequencies correlating with treatment responses.

Abstract

Abstract 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.

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