The Phase 3 REZILIENT3 trial met its PFS endpoint with zipalertinib plus chemotherapy in first-line EGFR exon 20 insertion-mutated NSCLC.
Written By: Anshu Gupta, PharmD
Reviewed By: Pharmacally Editorial Team
Taiho Pharmaceutical, Taiho Oncology and Cullinan Therapeutics announced on August 13, 2026, that the global Phase 3 REZILIENT3 trial met its primary endpoint of progression-free survival (PFS) at a planned interim analysis.
The trial evaluated zipalertinib in combination with platinum-based chemotherapy as first-line treatment for adults with previously untreated, locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion mutations.
At the planned interim analysis, the zipalertinib-containing regimen demonstrated a statistically significant and clinically meaningful improvement in PFS compared with chemotherapy alone. The observed safety profile of the zipalertinib-containing regimen was described as manageable.
Following the interim findings, the Independent Data Monitoring Committee recommended unblinding the study. The trial will continue to monitor efficacy and safety.
Full results from REZILIENT3 will be submitted for presentation at an upcoming international medical conference. Detailed efficacy and safety results from the interim analysis have not yet been disclosed.
REZILIENT3 Trial Design
REZILIENT3 (NCT05973773) is a multicenter, randomized, controlled, open-label, global Phase 3 trial evaluating zipalertinib plus platinum-based chemotherapy versus chemotherapy alone in the first-line treatment of adults with previously untreated, locally advanced or metastatic non-squamous NSCLC carrying EGFR exon 20 insertion mutations.
The study enrolled 285 patients. The primary endpoint was PFS, comparing patients receiving zipalertinib plus chemotherapy with those receiving chemotherapy alone.
The positive interim analysis established that the study met its primary endpoint. However, the announcement does not yet provide the median PFS, hazard ratio, confidence intervals, or other detailed efficacy measures.
Zipalertinib: An Investigational EGFR-Targeted Therapy
Zipalertinib, also known as 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. Zipalertinib is designed as a next-generation, irreversible EGFR inhibitor for the treatment of a genetically defined subset of patients with NSCLC.
Zipalertinib is investigational and has not been approved by any health authority.
The drug is being developed by Taiho Oncology, Inc., its parent company Taiho Pharmaceutical Co., Ltd., and in collaboration with Cullinan Therapeutics, Inc. in the United States.
EGFR Exon 20 Insertion Mutations in NSCLC
EGFR exon 20 insertion mutations represent a genetically defined subset of NSCLC. According to the companies, EGFR exon 20 insertions occur in up to 4% of NSCLC cases globally.
In the United States, approximately 16% of patients with NSCLC harbor EGFR mutations, while exon 20 insertions account for up to 12% of these EGFR mutations.
U.S. Regulatory Plans for Zipalertinib
The positive REZILIENT3 results represent an important development milestone for zipalertinib in the first-line treatment setting.
Based on the results, Taiho Pharmaceutical, Taiho Oncology, and Cullinan Therapeutics plan to pursue U.S. regulatory approval for zipalertinib in combination with chemotherapy as a first-line treatment, pending discussions with the U.S. Food and Drug Administration (FDA).
Fabio Benedetti, MD, Global Chief Medical Officer of Taiho Pharmaceutical, described the positive Phase 3 result as an important milestone for the zipalertinib program and said the companies would continue working together to advance the combination.
The companies will submit full REZILIENT3 results for presentation at an upcoming international medical conference.
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About the Writer
Anshu Gupta (LinkedIn) is a PharmD professional and healthcare writer with interests in clinical research, pharmacovigilance, regulatory affairs, and medical writing. She has presented research at academic conferences and completed certifications in Good Clinical Practice (GCP), ICH-GCP, and drug safety. Passionate about clinical trials and evidence-based medicine, she is committed to translating scientific evidence into accurate, reliable, and accessible healthcare content.