Zipalertinib Combo Meets PFS End Point in First-Line EGFR Exon 20+ NSCLC

Zipalertinib (CLN-081/TAS6417) plus platinum-based chemotherapy met the primary end point of progression-free survival (PFS) at a planned interim analysis of the phase 3 REZILIENT3 trial (NCT05973773).¹ The global, randomized, open-label trial is evaluating the combination vs chemotherapy alone in the first-line treatment of adults with previously untreated, locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion (ex20ins) mutations.

At the interim analysis, the study demonstrated a statistically significant and clinically meaningful improvement in PFS with zipalertinib plus chemotherapy compared with chemotherapy alone; the sponsors did not disclose the hazard ratio, 95% CI, P value, or median PFS in either arm in the topline announcement. Safety in the zipalertinib-containing arm was described as manageable. Based on these findings, the trial's independent data monitoring committee recommended unblinding the study, and the trial will continue to monitor efficacy and safety. Full results are planned for submission to an upcoming international medical conference.

"The positive topline results from the planned interim analysis of REZILIENT3 further support the potential of zipalertinib to meet the high unmet medical need in patients with NSCLC harboring EGFR exon 20 insertion mutations. We look forward to pursuing regulatory approval of zipalertinib in combination with chemotherapy in the first-line treatment setting with the goal of providing a new treatment option for this group of patients,” said Harold Keer, MD, PhD, chief medical officer, Taiho Oncology, in a news release.

Study Design

REZILIENT3 is a multicenter, randomized, controlled, open-label global trial that enrolled 285 adults with previously untreated, locally advanced or metastatic non-squamous NSCLC harboring EGFR ex20ins mutations.² Patients were randomized to zipalertinib, an oral, next-generation, irreversible EGFR inhibitor, plus platinum-based chemotherapy, or to platinum-based chemotherapy alone, with the primary objective of comparing PFS between the 2 arms.

EGFR ex20ins mutations occur in up to 4% of NSCLC cases globally; 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.^3,4

Regulatory Path Forward

Pending discussions with the FDA, the sponsors plan to pursue US regulatory approval of zipalertinib plus chemotherapy in the first-line setting based on the REZILIENT3 results.¹ The agent previously received FDA breakthrough therapy designation, in January 2022, for use after prior platinum-based chemotherapy in patients with locally advanced or metastatic NSCLC harboring EGFR ex20ins mutations.⁵ Separately, the FDA in April 2026 accepted a new drug application for zipalertinib monotherapy in that previously treated population, based on phase 2b data from the REZILIENT1 trial (NCT04036682); that application carries a Prescription Drug User Fee Act target action date of February 27, 2027.⁶

REFERENCES

1. Zipalertinib Plus Chemotherapy Meets Primary Endpoint of Progression-Free Survival in Planned Interim Analysis of Phase 3 REZILIENT3 Trial in First-Line EGFR Exon 20 Insertion Mutation Non-Small Cell Lung Cancer. News release. Taiho Oncology, Taiho Pharmaceutical, Cullinan Therapeutics. August 12, 2026. Accessed August 13, 2026. https://tinyurl.com/4rw94k7k

2. REZILIENT3 (REsearching ZIpaLertinib In Egfr Non-small Cell Lung Cancer Tumors) (REZILIENT3). ClinicalTrials.gov. Updated July 30, 2026. Accessed August 13, 2026. https://clinicaltrials.gov/study/NCT05973773

3. Burnett H, Emich H, Carroll C, et al. Epidemiological and clinical burden of EGFR exon 20 insertion in advanced non-small cell lung cancer: a systematic literature review. PLoS One. 2021;16(3):e0247620. doi:10.1371/journal.pone.0247620

4. Riess JW, Gandara DR, Frampton GM, et al. Diverse EGFR exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC. J Thorac Oncol. 2018;13(10):1560-1568. doi:10.1016/j.jtho.2018.06.019

5. FDA Grants Breakthrough Therapy Designation for Cullinan Oncology's CLN-081 in Patients with Locally Advanced or Metastatic EGFR-Mutated Non-Small Cell Lung Cancer. News release. Cullinan Oncology, Inc. January 4, 2022. Accessed August 13, 2026. https://tinyurl.com/yfvy32pz

6. U.S. Food and Drug Administration Accepts New Drug Application for Zipalertinib for the Treatment of Locally Advanced or Metastatic Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations. News release. Taiho Oncology, Taiho Pharmaceutical, Cullinan Therapeutics. April 28, 2026. Accessed August 13, 2026. https://tinyurl.com/2parwj9f