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Neratinib plus trastuzumab and fulvestrant for HER2-mutant, HR+ metastatic breast cancer

The latest update from the SUMMIT trial demonstrates that neratinib in combination with fulvestrant and trastuzumab offers promising results for patients with hormone receptor-positive, HER2-mutated metastatic breast cancer who have been previously exposed to a CDK4/6 inhibitor. In addition, neratinib in combination with trastuzumab also showed strong activity in patients with HER2-mutated triple negative breast cancer.

HER2 mutations are oncogenic drivers in a subset of metastatic breast cancers (mBC). Neratinib (N) is an oral, irreversible pan-HER tyrosine kinase inhibitor with preclinical and clinical activity against HER2 mutations. Genomic analyses from paired biopsies following N ± fulvestrant (F) suggest that resistance to N may occur via amplification of the mutant allele or by acquisition of secondary HER2 mutations. Addition of trastuzumab (T) to N+F showed encouraging clinical activity with durable responses in the SUMMIT trial in hormone receptor-positive (HR+), HER2-mutant mBC, including patients who had previously received CDK4/6 inhibitors (CDK4/6i). On the basis of these findings, and in order to better understand the contribution of N to the activity of the N+F+T combination, SUMMIT has recently been expanded to include a randomised Simon two-stage comparison of N+F+T vs. F+T vs. F in patients with HR+, HER2-mutated, HER2-negative mBC who were exposed to CDK4/6i.

SUMMIT study design

The phase II SUMMIT trial is an open-label, multicentre, multinational study to evaluate the safety and efficacy of neratinib administered daily to patients who have solid tumours with activating HER2 (ERBB2) mutations, identified by genomic sequencing. In the HER2-mutant, HR+ mBC cohort, patients who previously received CDK4/6 inhibitors were enrolled in a non-randomised cohort. They received 240 mg of neratinib per day, 500 mg fulvestrant on day 1 and 15 of cycle 1 and then once every four weeks (Q4W), and 8mg/kg trastuzumab Q4W initially and then 6mg/kg Q3W. Following initiation of the randomised portion of the trial, these patients received N+F+T, F+T or F in a 1:1:1 ratio with the same dose schedules as above. In the HER2-mutant, triple negative metastatic breast cancer (TNBC) cohort, patients received 240 mg of neratinib per day and 8mg/kg body weight trastuzumab initially and then 6mg/kg trastuzumab Q3W. All patients received anti-diarrheal prophylaxis with loperamide alone for the first two treatment cycles. There was no restriction on the number of prior lines of systemic therapy for mBC.


All patients enrolled in the non-randomised and randomised cohorts of the trial received a median of 3-6 prior anti-cancer regimens for locally advanced or metastatic disease and all received prior endocrine therapy. For patients with HR+/HER2-mutated mBC in the non-randomised cohort (N=26), the combination of N+F+T resulted in an objective response rate (ORR) of 46.2%, all of which were partial responses (PR). Furthermore, 57.7% of patients experienced clinical benefit (defined as confirmed complete response, partial response, or stable disease for at least 24 weeks). The median duration of response (DOR) was 14.4 months and the median progression-free survival (PFS) was 8.2 months.

In the HR+ randomised cohorts, there were two responses observed in the N+F+T cohort, including one complete response (CR). However, there were no responses in the F+T and F arms. This observation confirmed the hypothesis that neratinib appears to be critical for the inhibition of HER2-mutations. Based on these results, the Independent Data Monitoring Committee recommended to close the non-neratinib containing arms and further expand the neratinib arm. For all 33 patients with HR+, HER2-mutated mBC who received N+F+T (non-randomised and randomised cohorts combined), the ORR was 42.4%, including one complete response (3.0%). Seventeen patients (51.5%) experienced clinical benefit, the median DOR was 14.4 months and the median PFS was 7.0 months. Furthermore, patients in the neratinib cohorts had a deeper response and longer treatment duration as compared to patients not treated with neratinib. Despite required loperamide prophylaxis, diarrhoea was the most frequently observed adverse event, reported in 90.9% of patients in the combined N+F+T cohort (45.5% of grade 3, no grade 4). Median time to first diarrhoea event was 4 days and median duration of each grade 3 diarrhoea event was 2 days. One patient permanently discontinued neratinib due to diarrhoea.

For the 18 patients with HER2-mutant TNBC who received N+T, 6 patients (33.3%) experienced a confirmed objective response, including one CR (5.6%), and 7 patients (38.9%) experienced clinical benefit. The median DOR was not yet reached at time of analysis and the median PFS was 6.2 months. In this cohort, grade 3 diarrhoea was reported in three patients (16.7%).


The combination of N+F+T demonstrated encouraging clinical activity in patients with heavily pretreated HR+/HER2-, HER2-mutant mBC who previously received a CDK4/6i. Following guidance from the Independent Data Monitoring Committee, the F+T and F arms of SUMMIT were closed. In addition, the N+T combination showed promising clinical activity in heavily pretreated HER2-mutant TNBC. Grade 3 diarrhoea was higher than anticipated with the triplet combination of N+F+T and compliance with loperamide prophylaxis is imperative.


Jhaveri K, et al. Neratinib + fulvestrant + trastuzumab for hormone receptor-positive, HER2-mutant metastatic breast cancer and neratinib + trastuzumab for triple-negative disease: Latest updates from the SUMMIT trial. Presented at SABCS 2021; abstract GS4-10.

Speaker Komal Jhaveri

Komal Jhaveri

Komal Jhaveri, MD, FACP, Memorial Sloan Kettering Cancer Center, New York, USA


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