The Phase II MutHER Study of Neratinib Alone and in Combination with Fulvestrant in HER2-Mutated, Non-amplified Metastatic Breast Cancer

Abstract

Purpose: HER2 mutations (HER2mut) induce endocrine resistance in estrogen receptor–positive (ER+) breast cancer. Patients and Methods: In this single-arm multi-cohort phase II trial, we evaluated the efficacy of neratinib plus fulvestrant in patients with ER+/HER2mut, HER2 non-amplified metastatic breast cancer (MBC) in the fulvestrant-treated (n = 24) or fulvestrant-naïve cohort (n = 11). Patients with ER-negative (ER−)/HER2mut MBC received neratinib monotherapy in an exploratory ER− cohort (n = 5). Results: The clinical benefit rate [CBR (95% confidence interval)] was 38% (18%–62%), 30% (7%–65%), and 25% (1%–81%) in the fulvestrant-treated, fulvestrant-naïve, and ER− cohorts, respectively. Adding trastuzumab at progression in 5 patients resulted in three partial responses and one stable disease ≥24 weeks. CBR appeared positively associated with lobular histology and negatively associated with HER2 L755 alterations. Acquired HER2mut were detected in 5 of 23 patients at progression. Conclusions: Neratinib and fulvestrant are active for ER+/HER2mut MBC. Our data support further evaluation of dual HER2 blockade for the treatment of HER2mut MBC.

Current and future diagnostic and treatment strategies for patients with invasive lobular breast cancer

“…59 A significantly higher number of HER2 mutations have also been reported in ILC versus NST, especially in grade 3 ILC and in the metastatic setting, 60 of relevance for treatment with second-generation HER2 tyrosine kinase inhibitors. 61 While alterations in the HER2 and phosphoinositide 3kinase (PI3K) pathway are frequently observed in ILC, Teo All alterations in the table are somatic unless otherwise specified. Red and darkgreen, respectively, denote the alterations that were found to be statistically significantly more and less prevalent in ILC versus IDC tumours, respectively.…”

“…2022.05.006). 61,169 While in HER2-mutated non-small-cell lung cancer impressive response rates to the HER2-targeting ADC trastuzumab-deruxtecan were observed, 170 no data are available yet on HER2-targeting ADCs in HER2-non-amplified ILC. An increased frequency of HER3 (ERBB3) mutations was reported in ILC as compared to NST; however, it is unknown whether these HER3-mutated tumours could benefit from second-generation HER2 tyrosine kinase inhibitors or ADCs targeting HER3.…”

Mechanisms of neratinib resistance in HER2-mutant metastatic breast cancer

“…Genome sequencing efforts have recently identified recurrent somatic mutations in the HER2 (ERBB2) gene in HER2-negative (non-amplified) breast cancer. Recurrent HER2 mutations have been proven to be oncogenic drivers in both preclinical experiments and clinical trials [2][3][4][5][6][7][8][9] . Activating HER2 mutations typically fall into four categories, with distribution dependent on tumor type: single nucleotide variants (SNVs) in the extracellular domain, particularly S310F/Y; SNVs in the transmembrane domain; SNVs in the kinase domain; and small insertions in exon 20 [4,10,11] .…”

“…HER2 mutations are rare in primary cancers, occurring in 2%-12% of solid tumors depending on tumor type and disease stage. In breast cancer, HER2 mutations vary in frequency from ~2% to 8% depending on disease stage and histology (higher in lobular) [7,10,11,13,14] and have been associated with poor prognosis [15,16] . The prevalence of HER2 mutations is higher in patients with metastatic breast cancer (MBC) that has progressed after primary endocrine therapy (~6%), and these mutations have been causally associated with antiestrogen resistance [12,13,17] .…”

“…Clinically, the utility of neratinib, alone or in combination with other agents, in patients with heavily pretreated HER2-mutant breast and other cancers was explored in the phase II SUMMIT and MutHER trials [4,7] . The SUMMIT trial demonstrated clinical benefit from single-agent neratinib in patients with several solid tumor types, including HER2-mutant breast cancers [4] .…”