Zipalertinib

In a genomic-profiling series of 14,483 NSCLC cases, 263 (1.8%) had EGFR exon 20 insertions, representing 12% of EGFR-mutated cases. These are case-series frequencies, not population incidence rates. A retrospective comparison reported median real-world overall survival of 16.2 months with exon 20 insertions versus 25.5 months with common EGFR mutations. A separate analysis projected that PCR-based assays would miss approximately 50% of variants identified by NGS.

REZILIENT1 included 176 participants in its pivotal efficacy population and 244 in its safety population. Among 125 participants with prior platinum-based chemotherapy only, ORR was 40% and median DOR was 8.8 months. Two treatment-related deaths were reported in the safety population. In REZILIENT3, 279 participants were randomized. Median PFS was 14.5 months with Zipalertinib plus chemotherapy versus 8.5 months with chemotherapy, with a hazard ratio of 0.50. Grade ≥3 adverse events occurred in 87.1% versus 54.4%, respectively.

Zipalertinib remains investigational. The NDA concerns treatment after platinum-based chemotherapy, with or without amivantamab; the stated FDA target action date is February 27, 2027. The first-line REZILIENT3 combination results address a different treatment setting. At its interim OS analysis, event maturity was 30% and the hazard ratio was 0.72 with a 95% CI of 0.42 to 1.23, so an OS benefit is not established by that analysis.