NDA Completed for Zipalertinib Plus Chemo in Frontline EGFR Exon 20 NSCLC

A new drug application has been submitted to the FDA for zipalertinib (CLN-081/TAS6417) in combination with platinum-based chemotherapy for adults with previously untreated, locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, according to a news release.¹ Zipalertinib is an investigational oral, irreversible, next-generation EGFR inhibitor selected for its activity against exon 20 insertion variants.¹

The application is supported by the phase 3 REZILIENT3 trial (NCT05973773), in which the combination improved median progression-free survival (PFS) to 14.5 months vs 8.5 months with chemotherapy alone (HR, 0.50; 95% CI, 0.34-0.73; P = .00015) at a planned interim analysis. The objective response rate (ORR) was 65.0% vs 40.3%, respectively.²

Regulatory Path

The submission was made through the FDA’s Real-Time Oncology Review (RTOR) program, under which sponsors can provide clinical data before the full application is complete so the agency can begin evaluating efficacy and safety earlier. Taiho initiated the RTOR submission in October 2026 and had projected completion by the end of the year.² The completed application will now go through a standard review, and a Prescription Drug User Fee Act (PDUFA) date will be set if the FDA accepts it.¹

The first-line filing follows a separate application for zipalertinib monotherapy in patients with EGFR exon 20 insertion–positive NSCLC who have received prior systemic therapy, which the FDA accepted in April 2026 with a PDUFA target action date of February 27, 2027. That application is primarily supported by the phase 2b portion of REZILIENT1 (NCT04036682), in which the confirmed ORR was 35% and the median duration of response was 8.8 months among 176 patients treated with zipalertinib 100 mg twice daily.³

REZILIENT3 Findings

REZILIENT3 is an open-label, randomized phase 3 trial that enrolled 285 previously untreated adults with advanced nonsquamous NSCLC harboring EGFR exon 20 insertion mutations and compared 100 mg twice daily zipalertinib plus platinum-based chemotherapy vs chemotherapy alone.^2,4 Patients with asymptomatic untreated brain metastases measuring under 2 cm were considered eligible. Patients were permitted to cross over from chemotherapy alone to zipalertinib following disease progression. The full data were reported during a Presidential Symposium at the 2026 World Conference on Lung Cancer on September 14, 2026.⁵

The patient population was well-balanced across the arms, with a median age of 66.5 years in the experimental arm vs 64 years with chemotherapy alone, with 31.4% and 31.7% of patients in each arm having brain metastases.⁵ The trial met its PFS primary end point at the interim analysis, after which the independent data monitoring committee recommended unblinding.⁴ The PFS benefit was consistent across subgroups including those with brain metastases, with an HR of 0.38 favoring zipalertinib. The median duration of response was 14.2 months with zipalertinib plus chemotherapy vs 9.9 months with chemotherapy alone.⁵

Overall survival (OS) data were immature at the interim analysis, with 30% maturity and an HR of 0.72 favoring the combination; follow-up continues.²

Safety

The observed safety profile of the combination was consistent with that of the known safety profiles of the individual components. Grade 3 or higher adverse events occurred in 87.1% of patients receiving zipalertinib plus chemotherapy vs 54.4% of those receiving chemotherapy alone, and most were hematologic (58.6% vs 28.7% in the respective study arms). Grade 3 or higher EGFR-related adverse events were only reported in the combination arm, including rash in 10.7% of patients and diarrhea in 1.4%.²

REFERENCES

1. New Drug Application Submission Completed for Zipalertinib Plus Chemotherapy in First-Line EGFR Exon 20 Insertion Mutation Non-Small Cell Lung Cancer. News release. Cullinan Therapeutics. November 12, 2026. Accessed November 13, 2026. https://tinyurl.com/bddnyd2h

2. New drug application submission initiated for zipalertinib plus chemotherapy in first-line EGFR exon 20 insertion mutation NSCLC for review under FDA Real-Time Oncology Review program. News release. Cullinan Therapeutics, Inc. October 1, 2026. Accessed November 13, 2026. https://tinyurl.com/42r7e5p4

3. 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. Cullinan Therapeutics. April 28, 2026. Accessed November 13, 2026. https://tinyurl.com/4n8ehf6e

4. 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. August 12, 2026. Accessed November 13, 2026. https://tinyurl.com/4rw94k7k

5. Tan DS, Danchaivijitr P, Shinno Y, et al. Zipalertinib Plus Chemotherapy for 1st Line NSCLC with EGFR Exon 20 Insertions: Results From the Phase 3 Trial (REZILIENT 3). Presented at: IASLC 2026 World Conference on Lung Cancer, September 12-15, 2026; Seoul, Republic of Korea. PL03.04