Safety, tolerability, and antitumor activity of zipalertinib among patients with non-small-cell lung cancer harboring epidermal growth factor receptor exon 20 insertions Journal Article


Authors: Piotrowska, Z.; Tan, D. S. W.; Smit, E. F.; Spira, A. I.; Soo, R. A.; Nguyen, D.; Lee, V. H. F.; Yang, J. C. H.; Velcheti, V.; Wrangle, J. M.; Socinski, M. A.; Koczywas, M.; Janik, J. E.; Jones, J.; Yu, H. A.
Article Title: Safety, tolerability, and antitumor activity of zipalertinib among patients with non-small-cell lung cancer harboring epidermal growth factor receptor exon 20 insertions
Abstract: PURPOSE: Although several agents targeting epidermal growth factor receptor (EGFR) exon 20 insertions (ex20ins) have recently been approved by the US Food and Drug Administration, toxicities related to the inhibition of wild-type (WT) EGFR are common with these agents and affect overall tolerability. Zipalertinib (CLN-081, TAS6417) is an oral EGFR tyrosine kinase inhibitor (TKI) with a novel pyrrolopyrimidine scaffold leading to enhanced selectivity for EGFR ex20ins-mutant versus WT EGFR with potent inhibition of cell growth in EGFR ex20ins-positive cell lines. METHODS: This phase 1/2a study of zipalertinib enrolled patients with recurrent or metastatic EGFR ex20ins-mutant non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. RESULTS: Seventy-three patients were treated with zipalertinib at dose levels including 30, 45, 65, 100, and 150 mg orally twice a day. Patients were predominantly female (56%), had a median age of 64 years, and were heavily pretreated (median previous systemic therapies 2, range 1-9). Thirty six percent of patients had received previous non-ex20ins EGFR TKIs and 3/73 (4.1%) patients received previous EGFR ex20ins TKIs. The most frequently reported treatment-related adverse events of any grade included rash (80%), paronychia (32%), diarrhea (30%), and fatigue (21%). No cases of grade 3 or higher drug-related rash or diarrhea were observed at 100 mg twice a day or below. Objective responses occurred across all zipalertinib dose levels tested, with confirmed partial response (PR) observed in 28/73 (38.4%) response-evaluable patients. Confirmed PRs were seen in 16/39 (41%) response-evaluable patients at the dose of 100 mg twice a day. CONCLUSION: Zipalertinib has encouraging preliminary antitumor activity in heavily pretreated patients with EGFR ex20ins-mutant NSCLC, with an acceptable safety profile, including low frequency of high-grade diarrhea and rash.
Keywords: middle aged; exon; genetics; mutation; exons; diarrhea; protein kinase inhibitor; carcinoma, non-small-cell lung; lung neoplasms; epidermal growth factor receptor; pathology; protein kinase inhibitors; lung tumor; non small cell lung cancer; erbb receptors; humans; human; male; female
Journal Title: Journal of Clinical Oncology
Volume: 41
Issue: 26
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2023-09-10
Start Page: 4218
End Page: 4225
Language: English
DOI: 10.1200/jco.23.00152
PUBMED: 37384848
PROVIDER: scopus
DOI/URL:
Notes: Article -- Source: Scopus
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  1. Helena Alexandra Yu
    283 Yu