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Pulse Afatinib for ERBB2 Exon 20 Insertion-Mutated Lung Adenocarcinomas.

ABSTRACT: 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.

SUBMITTER: Costa DB

PROVIDER: S-EPMC4877224 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Pulse Afatinib for ERBB2 Exon 20 Insertion-Mutated Lung Adenocarcinomas.

Costa Daniel B DB Jorge Susan E SE Moran Jason P JP Freed Jason A JA Zerillo Jessica A JA Huberman Mark S MS Kobayashi Susumu S SS

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 20160308 6

<h4>Introduction</h4>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 tolera ...[more]

PMID: 26964772

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Project description:BACKGROUND:Epidermal growth factor receptor (EGFR) exon 20 insertions (exon20ins) represent approximately 10% of EGFR-mutant lung adenocarcinomas, and are associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Clinical outcomes in comparison with patients with sensitizing EGFR mutations are not well established. METHODS:Patients with stage IV lung adenocarcinomas with EGFR exon20ins were identified through routine molecular testing. Clinicopathologic data were collected. Overall survival (OS) was measured from the diagnosis of stage IV disease, and in patients treated with EGFR TKIs, the time to progression (TTP) on erlotinib was measured. RESULTS:One thousand eight hundred and eighty-two patients with stage IV lung adenocarcinomas were identified: 46 patients had EGFR exon20ins (2%), and 258 patients had an EGFR exon 19 deletion (exon19del)/L858R point mutation (14%). Among 11 patients with lung adenocarcinomas with EGFR exon20ins who received erlotinib, 3 patients (27%) had a partial response (FQEA, 1; ASV, 1; and unknown variant, 1). TTP for patients with EGFR exon20ins and patients with EGFR exon19del/L858R on erlotinib were 3 and 12 months, respectively (P?<?.01). Responses to chemotherapy were similar for patients with lung adenocarcinomas with EGFR exon20ins and patients with lung adenocarcinomas with EGFR exon19del/L858R. Median OS from the diagnosis of stage IV disease for patients with EGFR exon20ins and patients with EGFR exon19del/L858R was 26 months (95% confidence interval, 19 months-not reached n?=?46) and 31 months (95% confidence interval, 28-33 months; n?=?258), respectively (P?=?.53). CONCLUSIONS:The majority of patients with advanced lung adenocarcinomas harboring EGFR exon20ins do not respond to EGFR TKI therapy. Standard chemotherapy should be used as first-line therapy. These patients have an OS similar to that of patients with sensitizing EGFR mutations. Individuals with certain variants such as FQEA and ASV may respond to erlotinib.

Dataset Information

Pulse Afatinib for ERBB2 Exon 20 Insertion-Mutated Lung Adenocarcinomas.

Publications

Pulse Afatinib for ERBB2 Exon 20 Insertion-Mutated Lung Adenocarcinomas.

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