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
Open accessAbstract
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.Clinicaltrialsgov NCT00818441.
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NSCLC tumors carrying EGFR or HER2 exon 20 insertion mutations rarely show clinical responses to dacomitinib or afatinib.
“Non-small cell lung cancer (NSCLC) patients with tumors harboring these mutations seldom achieve clinical responses to dacomitinib and afatinib, two covalent quinazoline-based inhibitors of EGFR or HER2, respectively.”
From Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors (2017) · cites this paper as [26]
In a phase II study, 3 of 26 patients with HER2 mutant NSCLC (12%) had a partial response to dacomitinib.
“In a phase II study, 3 of 26 patients with HER2 mutant NSCLC (12%) had a partial response (26).”
From Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors (2017) · cites this paper as [26]
None of the three HER2 mutant NSCLC patients who responded to dacomitinib harbored the common A775_G776insYVMA mutation.
“None of the three responders harbored the common A775_G776insYVMA HER2 mutation.”
From Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors (2017) · cites this paper as [26]
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- 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.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- University of Colorado Denver (US)
- Georgetown University (US)
- Aichi Cancer Center (JP)
- Pfizer (United States) (US)
- Pfizer (China) (CN)
- Corresponding author
- Kris, M.G.
- Venue
- Annals of Oncology
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 26
- Issue
- 7
- Pages
- 1421-1427
- ISSN
- 0923-7534 (ISSN-L)
- PMC
- PMC5006511
- OpenAlex
- W2159192794
- Cited by
- 334
- References
- 32
- Citations by year
- 2026: 18 · 2025: 26 · 2024: 24 · 2023: 27 · 2022: 35 · 2021: 48 · 2020: 43 · 2019: 25 · 2018: 42 · 2017: 30 · 2016: 12 · 2015: 3 · 2014: 1
- FWCI
- 22.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Annals of Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Pfizer, Inc.
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- dacomitinib, HER2 mutation, HER2 amplification, lung cancer, HER2 exon 20 insertion, pan-HER tyrosine kinase inhibitor, EGFR, ErbB4, partial response, overall survival, diarrhea, skin inflammation
- MeSH terms
- Adenocarcinoma, Administration, Oral, Carcinoma, Non-Small-Cell Lung, Drug Administration Schedule, Follow-Up Studies, Gene Amplification, Humans, Lung Neoplasms, Mutation, Neoplasm Staging, Prognosis, Survival Rate, Erb-b2 Receptor Tyrosine Kinases, Quinazolinones
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