Reference Detail

Ref Type Journal Article
PMID (26964772)
Authors Costa DB, Jorge SE, Moran JP, Freed JA, Zerillo JA, Huberman MS, Kobayashi SS
Title Pulse Afatinib for ERBB2 Exon 20 Insertion-Mutated Lung Adenocarcinomas.
Journal Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
Vol 11
Issue 6
Date 2016 Jun
URL
Abstract Text Genomic aberrations involving the erb-b2 receptor tyrosine kinase 2 gene (ERBB2) are driver oncogenes in approximately 2% of lung adenocarcinomas. However, the use of daily dosing of ERBB2 tyrosine kinase inhibitors (TKIs)-including afatinib-has been fraught with plasma concentrations that barely achieve preclinical model inhibition, significant patient-reported toxicities, and limited clinical activity. We hypothesized that alternative dosing strategies could improve tolerability and efficacy.We profiled lung cancer cell lines against TKIs and retrospectively evaluated the toxicity of and response to pulse afatinib (280 mg once weekly) in lung cancers with ERBB2 mutations.An ERBB2 exon 20 insertion-mutated lung cancer cell line had a 50% inhibitory concentration in response to afatinib that was higher than the reported plasma concentration of afatinib, 40 mg daily. Three patients with advanced ERBB2-mutated lung adenocarcinomas were treated with off-label pulse afatinib. The 280-mg weekly dose was well tolerated with no reported rash and minimal diarrhea. One TKI-naive patient achieved a partial response for 5 months and another achieved stable disease for 11 months.Pulse afatinib at a weekly dosing scheme induced antitumor activity in ERBB2 exon 20 insertion-mutated lung adenocarcinomas. Future clinical trials of alternative dosing schemes of ERBB TKIs as monotherapy or in combination with other therapies are warranted for ERBB2-mutated tumors.

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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
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 Y772_A775dup lung adenocarcinoma conflicting Afatinib Case Reports/Case Series Actionable In a clinical study, a lung adenocarcinoma patient harboring ERBB2 Y772_A775dup (also referred to as A775_G776insYVMA and E740_A741insAYVM) achieved a partial response for 5 months following treatment with pulse Gilotrif (afatinib), however, a second patient harboring ERBB2 Y772_A775dup treated with pulse Gilotrif (afatinib) demonstrated progressive disease (PMID: 26964772). 26964772
ERBB2 G778_P780dup lung adenocarcinoma predicted - sensitive Afatinib Case Reports/Case Series Actionable In a clinical study, a lung adenocarcinoma patient harboring ERBB2 (HER2) G778_P780dup (also referred to as V747_G748insGSP and G748_P750dup), demonstrated a 13% regression of target lesions and stable disease for 11 months following treatment with pulse Gilotrif (afatinib) (PMID: 26964772). 26964772
ERBB2 exon 20 ins lung adenocarcinoma predicted - sensitive Afatinib Case Reports/Case Series Actionable In a clinical study, treatment with pulse Gilotrif (afatinib) resulted in an objective response rate of 33.3% (1/3) in lung adenocarcinoma patients with ERBB2 (HER2) exon 20 insertion mutations (PMID: 26964772). 26964772