SUMMIT Basket Trial — Neratinib in HER2/HER3-Mutant Cancers (2018)

Overview

SUMMIT (NCT01953926) is a multi-histology, genomically selected basket trial of the irreversible pan-HER tyrosine kinase inhibitor neratinib in patients with advanced solid tumours harbouring somatic ERBB2 (HER2) or ERBB3 (HER3) mutations. The dataset deposited in cBioPortal covers 141 patients (125 HER2-mutant, 16 HER3-mutant) across 21 cancer types; data were interim as of March 2017. Central sequencing used the MSK-IMPACT panel at mean 738x coverage; local mutation testing from 30 unique assays across 25 laboratories was accepted for enrollment. The trial established that HER2-mutant sensitivity to neratinib is jointly determined by tumour lineage and specific mutant allele. PMID:29420467

Composition

  • 141 patients (125 ERBB2-mutant, 16 ERBB3-mutant) across 21 cancer types; most common: BRCA (breast), NSCLC/LUAD, BLCA (bladder/urinary tract), and COAD (colorectal) — 61% of treated patients. PMID:29420467
  • Pre-specified disease cohorts: endometrial, gastroesophageal, ovarian, colorectal, bladder/urinary tract, plus a histology-agnostic “Solid tumour (NOS)” cohort. Breast, CESC, CHOL, SACA, and lung accrued sufficient patients in NOS for independent efficacy analysis. PMID:29420467
  • Treatment: neratinib 240 mg PO daily continuous with mandatory loperamide prophylaxis during cycle 1. PMID:29420467
  • Primary endpoint: ORR at week 8 (ORR8) by RECIST v1.1; PET Response Criteria (PRC, modified PERCIST v1.0) used for non-RECIST-evaluable patients. PMID:29420467
  • Data interim cut: 10 March 2017 (enrollment through 16 December 2016). PMID:29420467

Assays / panels (linked)

Papers using this cohort

  • PMID:29420467 — Hyman et al. 2018, Nature — “HER kinase inhibition in patients with HER2- and HER3-mutant cancers”

Notable findings derived from this cohort

  • Breast cancer met its pre-specified efficacy endpoint with ORR8 32% (8/25, 95% CI 15–54%) across extracellular and kinase domain mutations and ER subtypes, all in centrally HER2-non-amplified tumours. PMID:29420467
  • Bladder (n=16) and colorectal (n=12) cohorts produced no RECIST responses, establishing lineage-based resistance to single-agent pan-HER kinase inhibition independent of allele. PMID:29420467
  • No responses among 16 ERBB3-mutant patients; 95% (70/74) of HER2 mutations were clonal (CCF >0.85 by ABSOLUTE); no subclonal HER2 patient achieved benefit. PMID:29420467
  • Concurrent TP53 mutation was enriched in non-responders (nominal p=0.018); concurrent ERBB3 mutation also enriched in non-responders (p=0.064). PMID:29420467
  • PI3K/AKT/mTOR activation did NOT adversely affect benefit (p=0.753), diverging from its established negative-predictor role in HER2-amplified breast cancer. PMID:29420467
  • 17% (15/86) of centrally profiled patients had concurrent ERBB2 mutation + amplification; amplification did not correlate with clinical benefit (p=0.50). PMID:29420467
  • Grade 3 diarrhoea rate 22% with mandatory prophylaxis; only 2.8% permanently discontinued due to diarrhoea. PMID:29420467

Sources

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