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Ref Type Journal Article
PMID (25899785)
Authors Kris MG, Camidge DR, Giaccone G, Hida T, Li BT, O'Connell J, Taylor I, Zhang H, Arcila ME, Goldberg Z, Jänne PA
Title Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors.
Journal Annals of oncology : official journal of the European Society for Medical Oncology
Vol 26
Issue 7
Date 2015 Jul
URL
Abstract Text HER2 mutations and amplifications have been identified as oncogenic drivers in lung cancers. Dacomitinib, an irreversible inhibitor of HER2, EGFR (HER1), and HER4 tyrosine kinases, has demonstrated activity in cell-line models with HER2 exon 20 insertions or amplifications. Here, we studied dacomitinib in patients with HER2-mutant or amplified lung cancers.As a prespecified cohort of a phase II study, we included patients with stage IIIB/IV lung cancers with HER2 mutations or amplification. We gave oral dacomitinib at 30-45 mg daily in 28-day cycles. End points included partial response rate, overall survival, and toxicity.We enrolled 30 patients with HER2-mutant (n = 26, all in exon 20 including 25 insertions and 1 missense mutation) or HER2-amplified lung cancers (n = 4). Three of 26 patients with tumors harboring HER2 exon 20 mutations [12%; 95% confidence interval (CI) 2% to 30%] had partial responses lasting 3+, 11, and 14 months. No partial responses occurred in four patients with tumors with HER2 amplifications. The median overall survival was 9 months from the start of dacomitinib (95% CI 7-21 months) for patients with HER2 mutations and ranged from 5 to 22 months with amplifications. Treatment-related toxicities included diarrhea (90%; grade 3/4: 20%/3%), dermatitis (73%; grade 3/4: 3%/0%), and fatigue (57%; grade 3/4: 3%/0%). One patient died on study likely due to an interaction of dacomitinib with mirtazapine.Dacomitinib produced objective responses in patients with lung cancers with specific HER2 exon 20 insertions. This observation validates HER2 exon 20 insertions as actionable targets and justifies further study of HER2-targeted agents in specific HER2-driven lung cancers.NCT00818441.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB2 exon 20 ins lung adenocarcinoma predicted - sensitive Dacomitinib Phase II Actionable In a Phase II trial, Vizimpro (dacomitinib) treatment resulted in an overall response rate of 25% (3/26) in patients with lung adenocarcinoma harboring ERBB2 (HER2) exon 20 mutations, including exon 20 insertions, indels, and missense mutations (23, 2, 1, respectively) (PMID: 25899785; NCT00818441). 25899785
ERBB2 M774delinsWLV lung adenocarcinoma sensitive Dacomitinib Case Reports/Case Series Actionable In a Phase II trial, a lung adenocarcinoma patient harboring ERBB2 (HER2) M774delinsWLV demonstrated a partial response to treatment with Vizimpro (dacomitinib) (PMID: 25899785; NCT00818441). 25899785
ERBB2 G778_P780dup lung adenocarcinoma sensitive Dacomitinib Case Reports/Case Series Actionable In a Phase II trial, two lung adenocarcinoma patients harboring ERBB2 (HER2) G778_780dup (reported as P780_Y781insGSP) demonstrated partial response to treatment with Vizimpro (dacomitinib) (PMID: 25899785; NCT00818441). 25899785
ERBB2 amp lung adenocarcinoma no benefit Dacomitinib Case Reports/Case Series Actionable In a Phase II trial, Vizimpro (dacomitinib) treatment resulted in an overall response rate of 0% (0/4) in patients with lung adenocarcinoma harboring ERBB2 (HER2) amplification (PMID: 25899785; NCT00818441). 25899785