Zipalertinib plus chemotherapy has met the primary PFS endpoint in the Phase III REZILIENT3 trial in previously untreated EGFR exon 20 insertion-mutated NSCLC, setting up a potential first-line US filing for Taiho Pharmaceutical and Cullinan Therapeutics' oral EGFR inhibitor. According to an announcement from Massachusetts-based Cullinan (Nasdaq: CGEM), the result came from a planned interim analysis of the trial and could extend zipalertinib into first-line treatment while an NDA is already under US FDA review for patients whose disease progressed after platinum-based chemotherapy.
The REZILIENT3 trial is a multicenter, randomized, open-label study that enrolled 285 adults with previously untreated, locally advanced or metastatic non-squamous NSCLC harboring EGFR ex20ins mutations. Patients received zipalertinib plus platinum-based chemotherapy or chemotherapy alone. The companies described the PFS improvement in the combination arm as statistically significant and clinically meaningful; no quantitative data — median PFS, hazard ratio, or p-value — were disclosed. The Independent Data Monitoring Committee recommended unblinding the study following the interim analysis, and the trial will continue to collect efficacy and safety data. Full results are to be submitted to an international medical conference. Safety in the zipalertinib-containing arm was described as manageable.
Zipalertinib is designed as a covalent, irreversible inhibitor that selectively targets EGFR variants carrying exon 20 insertion mutations while sparing wild-type EGFR, a property intended to reduce the class-effect toxicities associated with broader EGFR inhibition. Taiho is co-developing the molecule outside the US under a 2022 license deal.
The REZILIENT3 result adds a first-line data package to a program already advanced in the second-line setting. The FDA accepted an NDA for zipalertinib in April 2026 for patients with locally advanced or metastatic EGFR ex20ins NSCLC whose disease progressed on or after platinum-based chemotherapy, with a PDUFA target action date of February 27, 2027. That submission was supported by the Phase I/II REZILIENT1 trial, which met its primary overall response rate endpoint and demonstrated a confirmed ORR of 35% across 176 patients, including those with prior amivantamab exposure. Zipalertinib holds FDA Breakthrough Therapy Designation for the previously treated indication.