Zipalertinib (CLN-081), an oral small molecule EGFR inhibitor, has demonstrated promising efficacy in patients with non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations. The Phase 1/2 REZILIENT1 trial met its primary endpoint of overall response rate (ORR), offering a potential new treatment option for this difficult-to-treat population. The study results, based on the Phase 2b portion of the trial, indicate a manageable safety profile consistent with previous data presentations.
The REZILIENT1 trial (NCT04036682) evaluated the efficacy and safety of zipalertinib monotherapy in NSCLC patients with EGFR exon 20 insertion mutations who had received prior therapy. The topline results are from the Phase 2b part of the study. Patients enrolled had locally advanced or metastatic NSCLC with documented EGFR exon 20 insertion mutations and had experienced disease progression on or after treatment with amivantamab. All patients received oral zipalertinib at a dose of 100 mg twice daily.
Efficacy Results
Data from the Phase 2b study, with a data cutoff of March 29, 2024, showed that efficacy-evaluable patients who received zipalertinib (n = 30) achieved a confirmed ORR of 40.0% (95% CI, 22.7%-59.4%), including a 3.3% complete response (CR) rate (95% CI, 0.1%-17.2%). The disease control rate (DCR) was 90.0% (95% CI, 73.5%-97.9%). The median duration of response (DOR) was not estimable (NE), and the median progression-free survival (PFS) was 9.7 months (90% CI, 4.1-NE).
Notably, evaluable patients who received prior amivantamab-vmjw (Rybrevant) only (n = 18) experienced a confirmed ORR of 50.0% (95% CI, 26.0%-74.0%), with a CR rate of 5.6% (95% CI, 0.1%-27.3%) and a DCR of 88.9% (95% CI, 65.3%-98.6%). Evaluable patients who received prior amivantamab and other exon 20 insertion–directed agents (n = 12) achieved a confirmed ORR of 25.0% (95% CI, 5.5%-57.2%) and a DCR of 91.7% (95% CI, 61.5%-99.8%).
Safety Profile
The safety profile of zipalertinib was generally consistent with prior data presentations. Any-grade treatment-related adverse effects (TRAEs) occurring in at least 10% of the overall population (n = 45) included rash (38%), paronychia (36%), anemia (24%), dry skin (20%), dermatitis acneiform (16%), nausea (16%), and stomatitis (11%). Grade 3 or higher TRAEs in the overall population included anemia (9%), rash (7%), and pneumonitis or interstitial lung disease (ILD; 7%). Seven percent of patients reduced the dose of and/or discontinued treatment with zipalertinib.
Regulatory Plans
Taiho Pharmaceutical Co., Ltd., Taiho Oncology, Inc., and Cullinan Therapeutics, Inc. plan to submit zipalertinib for regulatory approval in the United States in the second half of 2025, pending discussions with the FDA. Zipalertinib has already received Breakthrough Therapy Designation from the FDA.
About Zipalertinib
Zipalertinib (development code: CLN-081/TAS6417) is an orally available small molecule designed to target activating mutations in EGFR. The molecule was selected because of its ability to inhibit EGFR variants with exon 20 insertion mutations, while sparing wild-type EGFR. Zipalertinib is designed as a next generation, irreversible EGFR inhibitor for the treatment of a genetically defined subset of patients with non-small cell lung cancer.
EGFR Exon 20 Insertion Mutations in NSCLC
NSCLC is a common form of lung cancer, and up to 4% of all cases have EGFR exon 20 insertions, making them the third most common EGFR mutation subtype. In the United States, approximately 16% of patients with NSCLC harbor EGFR mutations, with insertions at exon 20 accounting for up to 12% of these mutations.
