Rolling NDA Submission Begins for Zipalertinib in EGFR Exon 20+ NSCLC

The rolling submission of a new drug application (NDA) to the FDA has been initiated for zipalertinib (CLN-081) for treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) with EGFR exon 20 insertion (ex20ins) mutations who have previously received platinum-based systemic chemotherapy.¹

In January 2022, the FDA granted breakthrough therapy designation to zipalertinib in this indication. This designation enables rolling review of the NDA, a process during which components of the NDA will be submitted and reviewed as they are completed. The sponsors, Taiho Oncology and Cullinan Therapeutics, expect to finalize NDA submission by early 2026 along with a request for priority review, with an ultimate goal of securing accelerated approval.

The NDA submission is motivated by promising primary efficacy data from the phase 1/2 REZILIENT1 trial (NCT04036682) presented this year at the American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in the Journal of Clinical Oncology, followed by the IASLC World Conference on Lung Cancer (WCLC).

As of the published data cutoff on December 10, 2024, durable, clinically meaningful responses were observed with zipalertinib in the overall treated patient population, with a 35.2% confirmed objective response rate (ORR) (95% CI, 28.2%–42.8%) and a median duration of response (DOR) of 8.8 months (95% CI, 8.3–12.7).² These figures compare favorably with the historical benchmark ORR of approximately 20%.

Of note, differential benefits in ORR and DOR were observed across treatment subgroups. Those who had received only prior platinum-based chemotherapy achieved a higher ORR (40%; 95% CI, 31%–49%), while those who had received only prior amivantamab [Rybrevant] had a notably prolonged DOR (14.7 months; 95% CI, 4.2–not evaluable).

Zipalertinib’s safety profile was manageable with a low treatment discontinuation rate due to treatment-related adverse events (TRAEs), facilitated by its oral route of administration. Anemia was the most common grade ≥3 TRAE (7%). Two TRAEs, pneumonitis and hypoxia, led to death.

“These findings support zipalertinib as a potential treatment option for patients with EGFR ex20ins-mutant NSCLC after progression on platinum-based chemotherapy, including those who are unresponsive to or experience disease progression on amivantamab,” concluded authors Piotrowska et al in the publication.²

More recently at WCLC, a confirmed ORR of 27.4% and median DOR of 8.5 months were reported for the overall population, continuing the positive trends observed a few months prior.

About the REZILIENT1 Trial

The REZILIENT1 trial is a first-in-human, open-label, multicenter, dose escalation and dose-expansion study of zipalertinib, an oral tyrosine kinase inhibitor, in patients with recurrent or metastatic NSCLC harboring EGFR ex20ins mutations.³ The specific objectives of the study are to evaluate zipalertinib’s safety, tolerability, antitumor activity, and pharmacokinetics.

As of the ASCO presentation, 244 patients were enrolled across 2 cohorts: patients who had progressed on platinum-based chemotherapy but had not received prior exon 20-targeted treatment (n = 143), and those who received both prior platinum-based chemotherapy and prior exon 20-targeted therapy, including amivantamab (n = 101). Patients are receiving 100 mg of zipalertinib twice daily, the recommended dose determined in phase 1.

The trial also includes 3 distinct modules, one of which is assessing the preliminary effect of food on zipalertinib’s pharmacokinetic profile.

Beyond REZILIENT1, the randomized phase 3 REZILIENT3 trial (NCT05973773) is evaluating zipalertinib in the first-line setting, comparing chemotherapy plus zipalertinib with chemotherapy alone.

REFERENCES

1. Taiho Oncology, Taiho Pharmaceutical and Cullinan Therapeutics initiate rolling submission of new drug application to U.S. Food and Drug Administration for zipalertinib for treatment of locally advanced or metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations. News release. Taiho Oncology. November 20, 2025. Accessed November 20, 2025. https://tinyurl.com/8sby3ppt

2. Piotrowska Z, Passaro A, Nguyen D, et al. Zipalertinib in Patients With Epidermal Growth Factor Receptor Exon 20 Insertion-Positive Non–Small Cell Lung Cancer Previously Treated With Platinum-Based Chemotherapy With or Without Amivantamab. J Clin Oncol. 2025;43(21):2387-2397. doi:10.1200/jco-25-00763

3. A phase 1/2 trial of CLN-081 in patients with non-small cell lung cancer (REZILIENT1). ClinicalTrials.gov. Updated March 13, 2025. Accessed November 20, 2025. https://clinicaltrials.gov/study/NCT04036682