The regulatory agency has set a PDUFA action date of February 27, 2027, for zipalertinib in locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.
The FDA has accepted a new drug application (NDA) for zipalertinib for the treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy, with or without amivantamab-wmjw (Rybrevant).1
The Prescription Drug User Fee Act target action date is February 27, 2027.
The NDA is supported by data from the phase 2b portion of the phase 1/2 REZILIENT1 trial (NCT04036682), which met its primary end point of objective response rate (ORR) with zipalertinib monotherapy in patients with pretreated NSCLC harboring EGFR exon 20 insertion mutations.
Primary results shared during the 2025 American Society of Clinical Oncology Annual Meeting and published in the Journal of Clinical Oncology revealed that the confirmed ORR was 35.2% (95% CI, 28.2%-42.8%) in the primary efficacy population (n = 176), which included 51 patients who had received prior amivantamab.2 Moreover, the median duration of response (DOR) was 8.8 months (95% CI, 8.3-12.7).
“Zipalertinib was discovered at Taiho Pharmaceutical Co, Ltd, and has been developed with a focus on addressing the unmet needs of patients with EGFR exon 20 insertion–mutated NSCLC,” Harold Keer, MD, PhD, chief medical officer of Taiho Oncology, stated in a news release.1 “The FDA’s acceptance of the NDA for zipalertinib is an important milestone for this program, and we look forward to working with FDA during the review process.”
Zipalertinib is a next-generation, irreversible, oral small molecule inhibitor of activating EGFR mutations and EGFR variants that spares wild-type EGFR. The agent received prior breakthrough therapy designation from the FDA for the treatment of patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations who have previously received platinum-based systemic chemotherapy.
REZILIENT1 was designed to evaluate the efficacy and safety of zipalertinib in adult patients with pretreated locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations. Patients received 100 mg of oral zipalertinib twice daily.
The primary end points include ORR and DOR according to blinded independent central review per RECIST 1.1 criteria. Adverse effects were evaluated and graded according to v5.0 of the National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE v5.0).
“Zipalertinib is a compound created using Taiho Pharmaceutical’s proprietary drug discovery and development technologies, Cysteinomix, with the aim of delivering a new treatment option to address high unmet medical needs,” Takeshi Sagara, PhD, executive director and board member for medical affairs, translational development, clinical development, discovery and preclinical research at Taiho Pharmaceutical, added in the news release.1 “The FDA’s acceptance of the NDA represents an important milestone, reflecting the scientific and clinical data accumulated to date. We will continue to work closely with Taiho Oncology, Cullinan Therapeutics, and the FDA throughout the review process, with the shared goal of ultimately delivering a new treatment option to patients with NSCLC [and] EGFR exon 20 insertion mutations.”
The confirmed ORR was 40% (95% CI, 31.3%-49.1%) in patients who had only received prior platinum-based chemotherapy (n = 125), with a median DOR of 8.8 months (95% CI, 8.3-12.7).2
In an exploratory analysis of patients who had received amivantamab as their only EGFR exon 20 insertion mutation targeted therapy (n = 30), the confirmed ORR was 30% (95% CI, 14.7%-49.4%) and the median DOR was 14.7 months (95% CI, 4.2-not evaluable).
Zipalertinib’s safety profile proved manageable and mirrored previously reported data. The most common any-grade treatment-emergent adverse effects (TEAEs) were paronychia (38.5%), rash (30.3%), anemia (19.7%), dermatitis acneiform (24.6%), diarrhea (21.7%), dry skin (24.6%), nausea (14.3%) and stomatitis (20.1%). Most TEAEs were grade 1 or 2 per CTCAE v5.0.
“FDA acceptance of the zipalertinib NDA is an important step toward making zipalertinib available for people living with NSCLC with EGFR exon 20 insertion mutations, who continue to face limited treatment options,” Jeffrey Jones, MD, MBA, chief medical officer of Cullinan Therapeutics, stated in the news release.1 “We are deeply grateful to the patients and families who have participated in the REZILIENT program, and to the investigators, study teams, and advocates whose collaboration made achievement of this milestone possible. We believe zipalertinib has the potential to help address a significant unmet need, and we look forward to working with our partners at Taiho with the goal of bringing zipalertinib to patients waiting for new treatment options.”
