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 Article
| Authors: | Kris, M. G.; Camidge, D. R.; Giaccone, G.; Hida, T.; Li, B. T.; O'Connell, J.; Taylor, I.; Zhang, H.; Arcila, M. E.; Goldberg, Z.; Jänne, P. A. |
| Article 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 |
| Abstract: | Background: 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. Patients and methods: 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. Results: 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. Conclusions: 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. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. |
| Keywords: | adult; cancer chemotherapy; clinical article; controlled study; overall survival; exon; missense mutation; fatigue; diarrhea; drug efficacy; cancer staging; gene; progression free survival; phase 2 clinical trial; gene amplification; randomized controlled trial; cohort analysis; lung cancer; tyrosine kinase inhibitors; drug fatality; multicenter study; mirtazapine; dermatitis; gene insertion; lung cancers; her2 gene; dacomitinib; her2 amplification; human; male; female; priority journal; article; her2 mutations |
| Journal Title: | Annals of Oncology |
| Volume: | 26 |
| Issue: | 7 |
| ISSN: | 0923-7534 |
| Publisher: | Oxford University Press |
| Date Published: | 2015-07-01 |
| Start Page: | 1421 |
| End Page: | 1427 |
| Language: | English |
| DOI: | 10.1093/annonc/mdv186 |
| PROVIDER: | scopus |
| PUBMED: | 25899785 |
| PMCID: | PMC5006511 |
| DOI/URL: | |
| Notes: | Export Date: 2 December 2015 -- Source: Scopus |
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