Combining neratinib with trastuzumab is associated with longer duration of response and progression-free survival (PFS) vs neratinib alone in patients with HER2-mutant metastatic triple-negative breast cancer (TNBC), according to the results of the open-label phase II SUMMIT trial.
Rationale
TNBC, which accounts for approximately 15–20 percent of all newly diagnosed breast cancers, is a highly aggressive disease with a poorer prognosis than other breast cancer subtypes. Somatic activating mutations in HER2 gene can act as oncogenic drivers in the absence of gene amplification or overexpression. “HER2 mutations have been reported in 1–3 percent of TNBC tumours and may represent a novel target for biomarker-directed treatment,” wrote SUMMIT investigators. [Clin Cancer Res 2026;32:3735-3745]
Trial population
Patients with metastatic TNBC and activating HER2 mutations (median age, 61 years; female, 92.6 percent) were enrolled across 17 sites globally between July 2014 and September 2021 and received either neratinib 240 mg orally daily (n=10) or neratinib plus trastuzumab (N + T) 8 mg/kg intravenously followed by 6 mg/kg intravenously every 3 weeks (n=17). Patients in the neratinib monotherapy cohort had a median of 2.5 (range, 0–6) prior lines of systemic therapy in the metastatic setting, while those in the N + T cohort had a median of 2.0 (range, 0–7) prior lines. The respective median values for prior lines of chemotherapy in the metastatic setting were 1.0 (range, 0–6) and 2.0 (range, 0–7).
Efficacy
The median duration of response was 3.78 months for patients treated with neratinib and 6.14 months for those treated with N + T. The median PFS was 2.89 vs 6.24 months, respectively. “This encouraging clinical activity supports the previously reported benefit of N + T plus fulvestrant in patients with hormone receptor–positive, HER2-mutant metastatic breast cancer – an observation consistent with the hypothesis that dual HER2 targeting may address the previously reported emergence of additional HER2 mutations and amplifications as the dominant mechanism of acquired resistance to neratinib-containing regimens,” commented the investigators. [Ann Oncol 2023;34:885-898]
Although responses seemed to be deepened and prolonged with the combination, the addition of trastuzumab to neratinib did not preclude eventual emergence or increase of either on-pathway (ERBB3) or off-pathway (KRAS and TP53) mutations.
Confirmed objective response rates were 40 percent for neratinib and 35.3 percent for N + T. “Responses to neratinib or N + T were histology-independent, occurring in patients with ductal and lobular histologies,” noted the investigators.
Safety
Although all patients received mandatory loperamide prophylaxis for diarrhoea for the first one to two 28-day cycles and as needed thereafter, diarrhoea of any grade was reported in 80 percent of patients treated with neratinib and in all patients treated with N + T. Grade 3 diarrhoea was reported in 20 and 17.6 percent of patients, respectively, occurred early after treatment initiation (median time to onset, 7 days) and was of short duration (cumulative median, 2.0 days). Among the 25 patients who experienced diarrhoea, four were managed with temporary dose interruption and three with dose reduction; none of these patients discontinued treatment.
NCCN endorsement
Based on these and previously published data, neratinib-based combinations are endorsed by the National Comprehensive Cancer Network (NCCN) guidelines for patients with hormone receptor–positive or –negative metastatic breast cancer with activating HER2 mutations. [NCCN Clinical Practice Guidelines in Oncology, Breast Cancer, version 6.2026]