NDA Submission Is Initiated for Zipalertinib Plus Chemotherapy in Frontline EGFR Exon 20 Insertion+ NSCLC

Submission of a new drug application (NDA) to the FDA has been initiated for zipalertinib (CLN-081/TAS6417) in combination with platinum-based chemotherapy for the treatment of patients with previously untreated, locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations.¹

The application is being submitted under the FDA’s Real-Time Oncology Review (RTOR) program, which allows sponsors to submit clinical data in advance of the complete application, and Cullinan Therapeutics anticipates completing the submission by the end of 2026.

The filing is supported by data from the phase 3 REZILIENT3 trial (NCT05973773), which were presented during a Presidential Symposium at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (WCLC).^1-3 At the interim analysis, zipalertinib plus chemotherapy (n = 140) produced a median progression-free survival (PFS) of 14.5 months (95% CI, 12.9-21.4) per blinded independent central review vs 8.5 months (95% CI, 7.0-10.9) with chemotherapy alone (n = 139), a 6.0-month improvement (HR, 0.50; 95% CI, 0.34-0.73; P = .00015).^2,3

The objective response rate (ORR) was 65.0% with the combination vs 40.3% with chemotherapy alone (P < .0001), and the median duration of response (DOR) was 14.2 months vs 9.9 months, respectively.² At the interim overall survival (OS) analysis, which was conducted at 30% event maturity, the HR for death was 0.72 (95% CI, 0.42-1.23). The PFS benefit was consistent across subgroups, including among patients with brain metastases (HR, 0.38).

“The combination of zipalertinib plus platinum-based chemotherapy in the REZILIENT3 trial demonstrated a statistically significant and clinically meaningful improvement in PFS for patients with advanced NSCLC harboring EGFR exon 20 insertion mutations,” Helena A. Yu, MD, thoracic medical oncologist at Memorial Sloan Kettering Cancer Center and a study investigator, said in a news release.² “The combination also produced significantly higher response rates compared with chemotherapy alone. These findings support the potential of zipalertinib plus platinum-based chemotherapy as a first-line treatment option for this patient population.”

What is the mechanism of action of zipalertinib?

Zipalertinib is an orally available, next-generation, irreversible EGFR inhibitor designed to target activating EGFR mutations, specifically variants with exon 20 insertion mutations.^1,2 The agent has a pyrrolopyrimidine scaffold that forms an irreversible covalent bond with C797 and is highly selective for EGFR exon 20 insertions over EGFR wild-type.³

How was the REZILIENT3 trial designed?

REZILIENT3 was a multicenter, randomized, controlled, open-label, global phase 3 trial that enrolled patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC with EGFR exon 20 insertion mutations.²

Following a safety lead-in, 279 patients were randomly assigned 1:1 to receive zipalertinib at 100 mg twice daily plus pemetrexed and carboplatin or cisplatin (n = 140) or pemetrexed plus platinum chemotherapy alone (n = 139), with optional crossover to zipalertinib at progression. Randomization was stratified by ECOG performance status, brain metastases, and region.^2,3

The primary end point was PFS by blinded independent central review; secondary end points included OS, investigator-assessed PFS, ORR, DOR, safety, and patient-reported outcomes.^2,3

What is the safety profile of zipalertinib plus chemotherapy?

Grade 3 or higher adverse effects (AEs) occurred more frequently with the combination than with chemotherapy alone (87.1% vs 54.4%), and these were primarily hematologic AEs (58.6% vs 28.7%).² Grade 3 or higher EGFR-related toxicities were observed only in the combination arm and included rash (10.7%), stomatitis (5.0%), pneumonitis (2.1%), and diarrhea (1.4%). No new safety signals were observed.

In the combination arm, AEs led to zipalertinib discontinuation in 17.1% of patients, and treatment-related AEs with an outcome of death—sepsis or septic shock—occurred in 3 patients (2.1%) vs none in the chemotherapy arm.³

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. October 1, 2026. Accessed October 2, 2026. https://investors.cullinantherapeutics.com/news-releases/news-release-details/new-drug-application-submission-initiated-zipalertinib-plus
2. Zipalertinib plus chemotherapy demonstrates 6-month median progression-free survival benefit in REZILIENT3 phase 3 trial in first-line EGFR exon 20 insertion mutation non-small cell lung cancer. News release. Cullinan Therapeutics. September 13, 2026. Accessed October 2, 2026. https://investors.cullinantherapeutics.com/news-releases/news-release-details/zipalertinib-plus-chemotherapy-demonstrates-6-month-median
3. Tan DSW. Zipalertinib plus chemotherapy for 1st line NSCLC with EGFR exon 20 insertions: results from the phase 3 trial (REZILIENT 3). Presented at: International Association for the Study of Lung Cancer 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Abstract PL03.04.