Rolling NDA Submission Completed for Zipalertinib in EGFR+ NSCLC

Developers at Cullinan Therapeutics have completed a rolling new drug application (NDA) submission to the FDA for the accelerated approval of zipalertinib as a treatment for those with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations previously managed with platinum-containing chemotherapy, according to a press release from the developers.¹

The release noted that developers completed the rolling submission in February 2026. The rolling submission of the NDA for zipalertinib in this NSCLC population was originally initiated in November 2025.² Supporting data for the application came from the phase 1/2 REZILIENT1 trial (NCT04036682) assessing zipalertinib among previously treated patients with locally advanced or metastatic EGFR exon 20 insertion mutation-positive NSCLC. Investigators previously presented data from the REZILIENT1 trial at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.³

Across the overall efficacy population (n = 176), zipalertinib produced a confirmed objective response (ORR) of 35% (95% CI, 28%-43%), a disease control rate (DCR) of 89% (95% CI, 84%-93%), and a median duration of response of 8.8 months (95% CI, 8.3-12.7). Among patients with prior platinum-based chemotherapy without EGFR exon 20 insertion mutation-targeted therapy (n = 125), these respective values were 40% (95% CI, 31%-49%), 89% (95% CI, 82%-94%), and 8.8 months (95% CI, 8.3-12.7). Additionally, among those with prior amivantamab-vmjw (Rybrevant) with or without other EGFR exon 20 insertion mutation-targeted therapy (n = 51), these values were 24% (95% CI, 13%-38%), 90% (95% CI, 79%-97%), and 8.5 months (95% CI, 4.2-14.8).

Data showed a median progression-free survival (PFS) of 9.4 months (95% CI, 7.4-10.0) across the overall population, 9.5 months (95% CI, 7.7-11.5) in those with prior platinum-based chemotherapy alone, and 7.3 months (95% CI, 5.3-9.7) among those with prior amivantamab with or without other targeted agents. The 12-month overall survival (OS) rates in each respective population were 69.3%, 73.4%, and 59.8%.

Treatment-emergent adverse effects (TEAEs) of any grade occurred in 99.2% of patients, and 56.1% experienced grade 3 or higher TEAEs. Treatment-related AEs (TRAEs) associated with dose reduction, dose interruption, and treatment discontinuation were noted in 14.3%, 39.3%, and 8.2% of patients, respectively. The most common TRAEs of any grade included rash (30.3%), diarrhea (21.7%), and anemia (19.7%).

In the open-label, multicenter phase 1/2 REZILIENT1 trial, 244 patients across the safety population received at least 1 dose of zipalertinib at 100 mg twice daily. The trial’s primary end points were ORR and DOR per blinded independent central review using RECIST v1.1 criteria. Secondary end points included DCR, clinical benefit rate, PFS, OS, and safety.

Patients 18 years and older with locally advanced or metastatic NSCLC, documented EGFR exon 20 insertion mutations, and an ECOG performance status of 0 or 1 were eligible for enrollment on the trial. Having stable or asymptomatic central nervous system (CNS) metastases was permissible for study entry.

Across the safety population, the median age was 65 years (range, 31-86), and most patients were female (64%) and Asian (50%). Most of the study population had stage IV disease (96%), adenocarcinoma (97%), an ECOG performance status of 1 (68%), and no history of smoking (62%). Additionally, 42% of patients had CNS or brain metastases.

Among patients with brain metastases (n = 68), treatment with zipalertinib yielded a confirmed ORR of 31% (95% CI, 20%-43%), which included partial responses in 20 patients and a complete response in 1. The median DOR was 8.3 months (95% CI, 4.2-9.9) in this population.

References

1. Cullinan Therapeutics provides corporate update and reports fourth quarter and full year 2025 financial results. News release. Cullinan Therapeutics, Inc. March 10, 2026. Accessed March 10, 2026. https://tinyurl.com/4m5wekh8
2. 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, Inc., Taiho Pharmaceutical Co., Ltd., and Cullinan Therapeutics, Inc. November 20, 2025. Accessed March 10, 2025. https://tinyurl.com/333754eb
3. Yu H, Nguyen D, Ruiter G, et al. Efficacy of zipalertinib in NSCLC patients with EGFR exon 20 insertion mutations who received prior platinum-based chemotherapy with or without amivantamab. J Clin Oncol. 2025;43(suppl 16):8503. doi:10.1200/JCO.2025.43.16_suppl.8503