What was the REZILIENT 3 safety profile?
Treatment-related adverse events (TRAEs) occurred in 98.6% of patients receiving zipalertinib plus chemotherapy vs 88.2% receiving chemotherapy alone, with grade 3 or higher TRAEs in 80.7% vs 40.4%, respectively. Serious adverse events occurred in 50.7% vs 33.1% of patients. The investigators reported that although the combination resulted in more grade 3 AEs, these were largely related to cytopenias and associated sequelae, particularly during the first 4 cycles of combination with the platinum doublet, and were managed with patient selection, dose modifications, and supportive care.
AEs with an outcome of death occurred in 9.3% of patients in the combination arm vs 2.9% in the chemotherapy arm, including treatment-related deaths in 2.1% (all due to sepsis or septic shock) in the combination arm.
What is the REZILIENT 3 trial design?
REZILIENT 3 is a randomized phase 3 trial that enrolled patients with previously untreated, locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations and an ECOG performance status of 0 or 1; stable brain metastases were permitted. Following a safety lead-in, 280 patients were randomly assigned to zipalertinib at 100 mg twice daily plus pemetrexed and platinum (carboplatin or cisplatin) or to pemetrexed and platinum alone, with optional crossover to zipalertinib. The primary end point was PFS by BICR assessment; secondary end points included overall survival, investigator-assessed PFS, ORR, DOR, safety, and patient-reported outcomes. The trial was conducted at 122 clinical sites globally.
What is zipalertinib’s regulatory status?
Zipalertinib is an investigational, orally available, next-generation irreversible EGFR inhibitor designed to manage EGFR exon 20 insertion mutations. The agent holds FDA breakthrough therapy designation for patients with locally advanced or metastatic EGFR exon 20 insertion mutation–positive NSCLC who have previously received platinum-based chemotherapy. A separate NDA seeking accelerated approval for zipalertinib monotherapy in that previously treated population remains under FDA review, with a Prescription Drug User Fee Act target action date of February 27, 2027.
References
- 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, Inc. October 1, 2026. Accessed October 5, 2026. https://tinyurl.com/3hryejjd
- Tan DSW, Danchaivijitr P, Shinno Y, et al. Zipalertinib plus chemotherapy for 1st line mNSCLC with EGFR exon 20 insertions: results from the phase 3 trial (REZILIENT 3). Presented at: 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Abstract PL03.04.
