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      Pulse afatinib for ERBB2 exon 20 insertion mutated lung adenocarcinomas

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          Abstract

          Introduction

          Genomic aberrations involving erb-b2 receptor tyrosine kinase 2 ( ERBB2) are driver oncogenes in ∼2% of lung adenocarcinomas. However, the use of daily dosing of ERBB2 tyrosine kinase inhibitors (TKIs) - including afatinib - has been fraught by 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.

          Methods

          We profiled lung cancer cell lines against TKIs and retrospectively evaluated the toxicity/response to pulse afatinib (280mg once weekly) in lung cancers with ERBB2 mutations.

          Results

          An ERBB2 exon 20 insertion mutated lung cancer cell line had 50% inhibitory concentration to afatinib higher than the reported plasma concentration of afatinib 40mg daily. Three patients with advanced ERBB2 mutated lung adenocarcinomas were treated with off-label pulse afatinib. The 280mg weekly dose was well tolerated with no reported rash and minimal diarrhea. One TKI-naïve patient achieved a partial response for 5 months and another stable disease for 11 months.

          Conclusions

          Pulse afatinib at a weekly dosing scheme induced anti-tumor 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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          Author and article information

          Journal
          101274235
          33311
          J Thorac Oncol
          J Thorac Oncol
          Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
          1556-0864
          1556-1380
          11 March 2016
          08 March 2016
          June 2016
          01 June 2017
          : 11
          : 6
          : 918-923
          Affiliations
          [1 ]Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
          Author notes
          [* ]Correspondence to: Daniel B. Costa, MD, PhD - Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Av., Boston, MA 02215, Phone: 617-667-9236, Fax: 617-975-5665, dbcosta@ 123456bidmc.harvard.edu
          Article
          PMC4877224 PMC4877224 4877224 nihpa766638
          10.1016/j.jtho.2016.02.016
          4877224
          26964772
          1b96a25a-8131-4693-a906-dbf44b93ae72
          History
          Categories
          Article

          pulse,afatinib,exon 20,HER2,ERBB2,adenocarcinoma,lung cancer,mutation
          pulse, afatinib, exon 20, HER2, ERBB2, adenocarcinoma, lung cancer, mutation

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