Efficacy of histology-agnostic and molecularly-driven HER2 inhibitors for refractory cancers

Abstract

A targeted therapy is recommended in case of ERBB2 alteration for breast and gastric carcinomas, but miscellaneous other tumor types are ERBB2-altered at low prevalence. Broadening the administration of HER2 inhibitors across tumor types and genomic alterations could benefit to patients with refractory metastatic tumors.Targeted next-generation-sequencing (tNGS) and comparative genomic hybridization array (CGH) have been performed on fresh tumor biopsies of patients included in the MOSCATO-01 and ongoing MOSCATO-02 trials to administrate HER2 inhibitors in case of ERBB2 pathogenic mutation of amplification.Between December 2011 and January 2017 a molecular analysis was performed for 934 patients (759 CGH and 912 tNGS). A novel ERBB2 alteration has been found in 4.7% (n = 44/934), including 1.5% (n = 14/912) ERBB2 mutations, and 4% (n = 30/759) ERBB2 amplifications.A matched HER2 inhibitor was administrated to 70% (31/44) of patients and consisted in trastuzumab plus chemotherapy for 90% of them (28/31). On the 31 evaluable patients, 1 complete response (CR), 10 partial response (PR) and 2 stable disease (SD) >24 weeks were observed accounting for a clinical benefit rate (CBR) of 42% (n = 13/31, 95% CI 25–61%). Besides breast and oesogastric carcinomas, 19 patients affected by 8 different tumor types had a CBR of 25% for ERBB2 mutations (n = 2/8, 95% CI 3%–65%, with 2 PR) and 64% for ERBB2 amplifications (n = 7/11, 95% CI 31%–89%; with 1 CR, 4 PR, 2 SD).ERBB2 genomic alterations were diffuse across metastatic tumor types and signs of efficacy emerged for HER2 targeted treatments, especially in case of ERBB2 amplifications or a p.S310Y ERBB2 mutation.

Disease characterization in liquid biopsy from HER2-mutated, non-amplified metastatic breast cancer patients treated with neratinib

“…We observed an average response to neratinib treatment for Patients 2, 4, and 5, all of whom harbored mutations in the tyrosine kinase domain, confirming sensitivity previously reported in other studies 13,[45][46][47][48] . Additionally, Patient 1 presented with the S310F mutation and was found to be an excellent responder to neratinib, supporting the hypothesis that the S310F/Y mutation in the extracellular domain is sensitive to anti-HER2 therapy containing neratinib [49][50][51] . Contrary to the outcome observed for Patient 3, neratinib efficacy has been reported in a ERBB2 I655V transmembrane domain mutation in different lung cancer cell lines 52 , suggesting the S653C mutation may be functionally different than the I655V mutation.…”

Cancer Therapy Guided by Mutation Tests: Current Status and Perspectives

“…ALK, ROS1 and RET rearrangements, although not formally classified as agnostic markers, occur in multiple tumor types and render sensitivity to appropriate inhibitors [63,[109][110][111][112]. HER2 amplification accompanied by gene overexpression may also be considered as an example of a more or less agnostic druggable event [113][114][115].…”

Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive Breast Cancer

“…Both mutations appear to have a homologous effect. Of the two, S310F has been most studied in different tumor tissues (both HER2-positive breast and HER2-negative lobular breast, lung, colorectal, ovarian, bladder, micropapillary urothelial, and endometrial) [29,33,54,[68][69][70] while S310Y has been more commonly associated with pulmonary adenocarcinoma while it has been also found in HER2-positive and HER2-negative breast cancer [29,33,55,71]. e fact that mutations in this position are present in different cancers suggests it could be an oncogenic mutation [72].…”

“…ey are therefore mutations that activate HER2 protein via elevated phosphorylation of the C-terminal tail, as is the case of mutation S310F/Y, or inducing covalent dimerization sustained by intermolecular disulfide bridges [73], as in the case of mutations G309E/A, only described in HER2-negative breast cancer and other cancers [28,73]. In the presence of an S310F/Y mutation, it has been noted that protein HER2 seems more sensitive to anti-HER2 therapy containing neratinib and possibly trastuzumab in patients with HER2+ breast cancer [33,54,55]. Accordingly, in cells featuring ECD mutations, trastuzumab may bind to this region and prevent homodimerization and activation of the receptor.…”