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Safety, Tolerability, and Antitumor Activity of Zipalertinib Among Patients With Non-Small-Cell Lung Cancer Harboring
Zofia Piotrowska1, Daniel Shao-Weng Tan2, Egbert F Smit3
1Massachusetts General Hospital, Boston, MA.
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.
Insights
Zipalertinib shows promising antitumor activity in patients with EGFR exon 20 insertion-mutant non-small-cell lung cancer. This targeted therapy demonstrated an acceptable safety profile, with fewer high-grade side effects like rash and diarrhea.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Targeted therapies for non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertions (ex20ins) face challenges due to wild-type (WT) EGFR toxicities.
- Zipalertinib (CLN-081, TAS6417) is an oral EGFR tyrosine kinase inhibitor (TKI) designed for enhanced selectivity against EGFR ex20ins mutations over WT EGFR.
Purpose of the Study:
- To evaluate the safety and efficacy of zipalertinib in patients with recurrent or metastatic EGFR ex20ins-mutant NSCLC.
- To determine the optimal dose and tolerability of zipalertinib in a heavily pretreated patient population.
Main Methods:
- A phase 1/2a study enrolled 73 patients with EGFR ex20ins-mutant NSCLC previously treated with platinum-based chemotherapy.
- Patients received zipalertinib at various oral doses (30-150 mg twice daily).
- Treatment-related adverse events and objective responses were assessed.
Main Results:
- The most common adverse events included rash (80%), paronychia (32%), and diarrhea (30%).
- No grade 3 or higher drug-related rash or diarrhea occurred at doses of 100 mg or below.
- Confirmed partial responses were observed in 38.4% of response-evaluable patients, with 41% response rate at 100 mg twice daily.
Conclusions:
- Zipalertinib exhibits encouraging preliminary antitumor activity in heavily pretreated NSCLC patients with EGFR ex20ins mutations.
- The drug demonstrates an acceptable safety profile, characterized by a low incidence of high-grade diarrhea and rash.
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