NDA for Zipalertinib in Pretreated NSCLC With EGFR Exon 20 Insertion Mutations Is Submitted to the FDA

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

The NDA is supported by data from the phase 1/2 REZILENT1 study (NCT04036682).2 Findings from REZILENT1 presented during the 2025 ASCO Annual Meeting and simultaneously published in the Journal of Clinical Oncology showed that patients who received the EGFR inhibitor in the primary efficacy population (n = 176) achieved a confirmed overall response rate (ORR) of 35.2% (95% CI, 28.2%-42.8%) and a median duration of response (DOR) of 8.8 months (95% CI, 8.3-12.7). One patient experienced a complete response (CR). The disease control rate (DCR) was 89.2% (95% CI, 83.7%-93.4%), and the median time to response was 44 days (range, 31-295).

What were the key design characteristics of REZILENT1?

REZILENT1 was open-label, multicenter trial that examined the safety and efficacy of zipalertinib in patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations who received prior platinum-based chemotherapy. Eligible patients needed to be at least 18 years of age, have measurable disease per RECIST 1.1 criteria, have an ECOG performance status of 0 or 1, and have adequate organ function.

Patients included in the Journal of Clinical Oncology publication received at least 1 dose of zipalertinib 100 mg twice daily and were enrolled by April 25, 2024. The data cutoff was December 10, 2024.

The coprimary end points were ORR and DOR per independent central review (ICR). Secondary end points included investigator-assessed ORR and DOR, DCR, clinical benefit rate (CBR), progression-free survival (PFS) per ICR and investigator assessment, overall survival (OS), antitumor activity in patients with central nervous system (CNS) disease, and safety and tolerability.

What was the safety profile of zipalertinib and the additional efficacy data?

At a median follow-up of 9.3 months, additional efficacy data from REZILENT1 demonstrated that the median PFS per ICR in the primary efficacy cohort was 9.4 months (95% CI, 7.4-10.0). The 6- and 12-month PFS rates were 63.8% and 29.9%, respectively. Although OS data were immature at the time of the analysis, the 6- and 12-month OS rates were 84.1% and 69.3%, respectively.

The DCR and CBR per ICR were 89.2% (95% CI, 83.7%-93.4%) and 64.2% (95% CI, 56.6%-71.3%), respectively. These respective rates per investigator assessment were 90.9% (95% CI, 85.7%-94.7%) and 67% (95% CI, 59.6%-73.9%).

The confirmed ORRs per ICR and investigator assessment among patients who received prior platinum-based chemotherapy (n = 125) were 40% (95% CI, 31.3%-49.1%) and 40.8% (95% CI, 32.1%-49.9%), respectively. The median DORs were 8.8 months (95% CI, 8.3-12.7) per ICR and 10.4 months (95% CI, 8.3-29.0) per investigator assessment.

In the safety population (n = 244), the median duration of treatment exposure was 6.4 months (range, 0.03-51.8), and the median relative dose intensity was 94.1%. Most patients had at least 1 any-grade treatment-emergent adverse effect; 29.5% experienced a grade 3 or higher treatment-related adverse effect (TRAE). The most common any-grade TRAEs that were reported in at least 20% of patients included paronychia (38.5%), rash (30.3%), dermatitis acneiform (24.6%), dry skin (24.6%), diarrhea (21.7%), and stomatitis (20.1%).

Dose modifications due to TRAEs occurred in 42.2% of patients, including dose reductions (14.3%) and interruptions (39.3%). Twenty patients discontinued treatment due to a TRAE.

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 21, 2025. https://www.taihooncology.com/us/news/taiho-oncology-taiho-pharmaceutical-and-cullinan-therapeutics-initiate-rolling-submission-of-new-drug-application-to-us-food-and-drug-administration-for-zipalertinib-for-treatment-of-locally-advanced-or-metastatic-non-small-cell-lung-cancer-with-egfr-e/
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