Dacomitinib in lung cancer: a “lost generation” EGFR tyrosine-kinase inhibitor from a bygone era?

Ou, Sai-Hong; Soo, Ross

doi:10.2147/dddt.s52787

Cited by 29Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchLung Cancer Diagnosis and Treatment

Dacomitinib in lung cancer: a “lost generation” EGFR tyrosine-kinase inhibitor from a bygone era?

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Ou, Sai-Hong, Soo, Ross·2015·Drug Design, Development and Therapy

DOI 10.2147/dddt.s52787PMC PMC4610796

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Abstract

EGFR tyrosine-kinase inhibitors (TKIs) have now been firmly established as the first-line treatment for non-small-cell lung cancer (NSCLC) patients harboring activating EGFR mutations, based on seven prospective randomized Phase III trials. However, despite significantly improved overall response rate and improved median progression-free survival when compared to platinum-doublet chemotherapy, EGFR-mutant NSCLC patients treated with EGFR TKIs invariably progress due to the emergence of acquired resistances, with the gatekeeper T790M mutation accounting for up to 60% of the resistance mechanisms. Second-generation irreversible EGFR TKIs were developed in part to inhibit the T790M mutation, in addition to the common activating EGFR mutations. Dacomitinib is one such second-generation EGFR TKI designed to inhibit both the wild-type (WT) EGFR and EGFR T790M. Afatinib is another second-generation EGR TKI that has been now been approved for the first-line treatment of EGFR-mutant NSCLC patients, while dacomitinib continues to undergo clinical evaluation. We will review the clinical development of dacomitinib from Phase I to Phase III trials, including the two recently published negative large-scale randomized Phase III trials (ARCHER 1009, NCIC-BR-26). Results from another large-scale randomized trial (ARCHER 1050) comparing dacomitinib to gefitinib as first-line treatment of advanced treatment-naïve EGFR-mutant NSCLC patients will soon be available and will serve as the lynchpin trial for the potential approval of dacomitinib in NSCLC. Meanwhile, third-generation EGFR TKIs (eg, CO-1686 [rociletinib], AZ9291, HM61713, EGF816, and ASP8273) that preferentially and potently inhibit EGFR T790M but not WT EGFR are in full-scale clinical development, and some of these EGFR TKIs have received "breakthrough" designation by the US Food and Drug Administration and will likely be approved in late 2015. Given the rapid development of third-generation EGFR TKIs and the approval of gefitinib, erlotinib, and afatinib as first-line treatment of EGFR-mutant NSCLC patients, the future role of dacomitinib in the treatment of NSCLC seems to be limited.

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Dacomitinib is an irreversible second-generation EGFR TKI originally developed by Pfizer and co-developed by SFJ Pharmaceuticals in 2012, and was approved by the FDA in 2018 for metastatic NSCLC with exon 19 deletion and exon 21 replacement.
“Dacomitinib (VizimproTM, PF-299804) (46), also an irreversible second-generation EGFR TKI originally developed by Pfizer and co-developed by SFJ Pharmaceuticals in 2012, was approved by the FDA in 2018 for the treatment of metastatic NSCLC with exon 19 deletion and exon 21 replacement.125–128”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [126]

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Authors: Ou, S.-H., & Soo, R.
Affiliations: University of California, Irvine (US)
National University Cancer Institute, Singapore (SG)
Corresponding author: Ou, Sai-Hong
ORCID: Ou, Sai-Hong
Soo, Ross
Venue: Drug Design, Development and Therapy
Publisher: Informa UK Limited
Published: 2015-10
Volume: 9
Pages: 5641
ISSN: 1177-8881 (ISSN-L)
DOI: 10.2147/dddt.s52787
PMC: PMC4610796
OpenAlex: W1940324115
Cited by: 28
References: 57
Citations by year: 2026: 1 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 1 · 2020: 3 · 2019: 4 · 2018: 3 · 2017: 4 · 2016: 5
FWCI: 0.71
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc
creativecommons.org/licenses/by-nc/3.0/ (vor)
Locations: Drug Design Development and Therapy (publishedVersion, cc-by-nc)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
Dove Medical Press (Taylor and Francis Group) (submittedVersion, cc-by-nc)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
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 › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
Keywords: dacomitinib, EGFR tyrosine kinase inhibitors, non-small cell lung cancer, EGFR-mutant non-small cell lung cancer, T790M mutation, acquired drug resistance, third-generation EGFR-TKI, afatinib, gefitinib, erlotinib, first-line therapy
MeSH terms: Animals, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mutation, Drug Design, Signal Transduction, Treatment Outcome, Patient Selection, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, Quinazolinones, ErbB Receptors

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Dacomitinib in lung cancer: a “lost generation” EGFR tyrosine-kinase inhibitor from a bygone era?

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