Taiho Oncology, Taiho Pharmaceutical and Cullinan Therapeutics have announced positive topline results from the Phase 3 REZILIENT3 trial, evaluating zipalertinib in combination with platinum-based chemotherapy as first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion (ex20ins) mutations.
At a planned interim analysis, REZILIENT3 met its primary endpoint of progression-free survival (PFS). The zipalertinib-containing arm demonstrated a statistically significant and clinically meaningful improvement in PFS. The observed safety profile of the combination was reported as manageable.
Based on the interim findings, the trial’s Independent Data Monitoring Committee recommended unblinding the study. The trial will continue to monitor efficacy and safety.
Detailed efficacy and safety results, including median PFS and the magnitude of the treatment effect, have not yet been disclosed. Full results from REZILIENT3 are planned for submission for presentation at an upcoming international medical conference.
Following the positive findings, and pending discussions with the U.S. Food and Drug Administration (FDA), Taiho Oncology, Taiho Pharmaceutical and Cullinan Therapeutics plan to pursue U.S. regulatory approval for zipalertinib plus chemotherapy in the first-line setting.
Harold Keer, MD, PhD, Chief Medical Officer of Taiho Oncology, said the findings further support the potential of zipalertinib to address the “high unmet medical need” among patients with NSCLC harboring EGFR exon 20 insertion mutations. He also highlighted the company’s intention to pursue regulatory approval of the combination in the first-line setting.
Fabio Benedetti, MD, Global Chief Medical Officer of Taiho Pharmaceutical, described the positive Phase 3 results as “an important milestone for this program” and emphasized the continued collaboration among Taiho Pharmaceutical, Taiho Oncology and Cullinan Therapeutics to advance the combination.
Jeffrey Jones, MD, MBA, Chief Medical Officer of Cullinan Therapeutics, noted that reaching the primary endpoint at the planned interim analysis “supports the potential role of zipalertinib in the first-line treatment setting.”
About the REZILIENT3 Trial
REZILIENT3 (NCT05973773) is a multicenter, randomized, controlled, open-label global Phase 3 trial evaluating zipalertinib plus platinum-based chemotherapy versus chemotherapy alone.
The study enrolled 285 adults with previously untreated, locally advanced or metastatic non-squamous NSCLC harboring EGFR exon 20 insertion mutations. Its primary objective is to assess PFS with zipalertinib plus chemotherapy compared with chemotherapy alone.
The study evaluates zipalertinib in combination with standard chemotherapy consisting of pemetrexed and a platinum agent, either carboplatin or cisplatin.
The rationale and design of REZILIENT3 were previously described in a peer-reviewed publication in Future Oncology in 2025. The newly announced positive interim findings, however, represent topline Phase 3 results and have not yet been published as a full peer-reviewed efficacy analysis.
About Zipalertinib
Zipalertinib (CLN-081/TAS6417) is an orally available small molecule designed to target activating mutations in EGFR. The drug was selected for its ability to inhibit EGFR variants containing exon 20 insertion mutations and is designed as a next-generation, irreversible EGFR inhibitor for a genetically defined subset of patients with NSCLC.
Zipalertinib is being developed by Taiho Oncology and its parent company, Taiho Pharmaceutical, in collaboration with Cullinan Therapeutics in the United States.
The therapy remains investigational and has not been approved by any health authority.
EGFR Exon 20 Insertions in NSCLC
EGFR exon 20 insertion mutations represent a distinct molecular subset of NSCLC. According to data cited in the announcement, up to 4% of NSCLC cases globally harbor EGFR exon 20 insertion mutations.
In the United States, approximately 16% of patients with NSCLC harbor EGFR mutations, with exon 20 insertions accounting for up to 12% of EGFR mutations.
Further details on the magnitude of the PFS benefit and the safety profile of the zipalertinib combination are expected when the full REZILIENT3 results are presented.
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