NDA Submission Begins for Zipalertinib Combo in First-Line EGFR+ NSCLC

A new drug application (NDA) submission has been initiated to the FDA for zipalertinib (CLN-081) in combination with platinum-based chemotherapy for the first-line treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, according to a news release from Cullinan Therapeutics.¹ The submission is being conducted under the FDA’s Real-Time Oncology Review (RTOR) program, following agreement with the agency, with completion of the NDA expected by the end of 2026.

What supports the zipalertinib NDA?

The submission is based on data from the phase 3 REZILIENT 3 trial (NCT05973773), which met its primary end point by demonstrating a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with zipalertinib plus chemotherapy vs chemotherapy alone. The results were presented at the IASLC 2026 World Conference on Lung Cancer (WCLC).²

At a prespecified interim analysis and a data cutoff of May 29, 2026, the median PFS by blinded independent central review (BICR) was 14.5 months (95% CI, 12.9-21.4) with zipalertinib plus chemotherapy vs 8.5 months (95% CI, 7.0-10.9) with chemotherapy alone (HR, 0.50; 95% CI, 0.34-0.73; P = .00015). The developer described this as the “longest median [PFS] observed to date in first-line NSCLC harboring EGFR exon 20 insertion mutations.”¹ The objective response rate (ORR) by BICR was 65.0% (95% CI, 56.49%-72.86%) vs 40.3% (95% CI, 32.06%-48.94%; P <.0001), the disease control rate (DCR) was 89.3% (95% CI, 82.94%-93.88%) vs 81.3% (95% CI, 73.81%-87.40%), and the median duration of response (DOR) was 14.2 months (95% CI, 10.51-not evaluable [NE]) vs 9.9 months (95% CI, 6.80-NE). The PFS benefit was observed across prespecified subgroups.

What was the REZILIENT 3 safety profile?

Treatment-related adverse events (TRAEs) occurred in 98.6% of patients receiving zipalertinib plus chemotherapy vs 88.2% receiving chemotherapy alone, with grade 3 or higher TRAEs in 80.7% vs 40.4%, respectively. Serious adverse events occurred in 50.7% vs 33.1% of patients. The investigators reported that although the combination resulted in more grade 3 AEs, these were largely related to cytopenias and associated sequelae, particularly during the first 4 cycles of combination with the platinum doublet, and were managed with patient selection, dose modifications, and supportive care.

AEs with an outcome of death occurred in 9.3% of patients in the combination arm vs 2.9% in the chemotherapy arm, including treatment-related deaths in 2.1% (all due to sepsis or septic shock) in the combination arm.

What is the REZILIENT 3 trial design?

REZILIENT 3 is a randomized phase 3 trial that enrolled patients with previously untreated, locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations and an ECOG performance status of 0 or 1; stable brain metastases were permitted. Following a safety lead-in, 280 patients were randomly assigned to zipalertinib at 100 mg twice daily plus pemetrexed and platinum (carboplatin or cisplatin) or to pemetrexed and platinum alone, with optional crossover to zipalertinib. The primary end point was PFS by BICR assessment; secondary end points included overall survival, investigator-assessed PFS, ORR, DOR, safety, and patient-reported outcomes. The trial was conducted at 122 clinical sites globally.

What is zipalertinib’s regulatory status?

Zipalertinib is an investigational, orally available, next-generation irreversible EGFR inhibitor designed to manage EGFR exon 20 insertion mutations. The agent holds FDA breakthrough therapy designation for patients with locally advanced or metastatic EGFR exon 20 insertion mutation–positive NSCLC who have previously received platinum-based chemotherapy. A separate NDA seeking accelerated approval for zipalertinib monotherapy in that previously treated population remains under FDA review, with a Prescription Drug User Fee Act target action date of February 27, 2027.

References

1. 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 October 5, 2026. https://tinyurl.com/3hryejjd
2. Tan DSW, Danchaivijitr P, Shinno Y, et al. Zipalertinib plus chemotherapy for 1st line mNSCLC with EGFR exon 20 insertions: results from the phase 3 trial (REZILIENT 3). Presented at: 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Abstract PL03.04.