Results from the phase 3 REZILIENT 3 trial, presented at the 2026 World Conference on Lung Cancer, show that adding zipalertinib to platinum-based chemotherapy significantly improved progression-free survival (PFS) as a first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations (ex20ins). The trial was an international, randomized, open-label study enrolling 279 patients with no prior treatment for advanced disease.

At a prespecified interim efficacy analysis, the combination of zipalertinib plus platinum-pemetrexed chemotherapy reduced the risk of disease progression or death by 50% compared with chemotherapy alone, with a median progression-free survival (PFS) of 14.5 months versus 8.5 months. Overall survival data remain immature, with only 30% maturity at the interim analysis, and continued follow-up is ongoing.

Key finding

In REZILIENT 3, zipalertinib plus platinum-pemetrexed chemotherapy reduced the risk of progression or death by 50% compared with chemotherapy alone in first-line EGFR exon 20 insertion NSCLC (HR, 0.50; 95% CI, 0.34–0.73; P=0.00015), though overall survival data remain immature at this interim analysis.

Study Design

TrialREZILIENT 3, international, randomized, open-label phase 3 trial
PopulationAdults with advanced NSCLC harboring EGFR exon 20 insertion mutations and no prior treatment for advanced disease; patients with untreated asymptomatic brain metastases ≤2 cm were eligible
TreatmentZipalertinib 100 mg twice daily plus platinum-pemetrexed chemotherapy (n=140) vs. platinum-pemetrexed chemotherapy alone (n=139), 1:1 randomization; crossover to zipalertinib was permitted upon progression in the chemotherapy-alone arm
Primary endpointProgression-free survival (PFS) by blinded independent central review (BICR)
Key secondary endpointsObjective response rate (ORR), duration of response (DoR), overall survival (OS), and safety

REZILIENT 3 enrolled 279 patients across its two arms, with baseline characteristics well balanced between groups, including median age (66.5 vs. 64 years), proportion of female patients (65.7% vs. 63.3%), and prevalence of brain metastases at baseline (31.4% vs. 31.7%). A prespecified interim efficacy analysis was planned after 75% of target PFS events, with 122 PFS events recorded at the time of analysis.

Results and Safety

At the prespecified interim analysis, BICR-assessed median PFS was 14.5 months (95% CI, 12.9–21.4 months) in the zipalertinib combination arm compared with 8.5 months (95% CI, 7.0–10.9 months) in the chemotherapy-alone arm, representing a statistically significant 6-month improvement (HR, 0.50; 95% CI, 0.34–0.73; P=0.00015). The PFS benefit was consistent across prespecified subgroups, including patients with brain metastases at baseline, among whom the hazard ratio was 0.38. ORR was significantly higher with the combination (65.0% vs. 40.3%; P<0.0001), and median duration of response was longer (14.2 vs. 9.9 months).

At the interim OS analysis, with 30% data maturity, the hazard ratio for death with zipalertinib plus chemotherapy compared with chemotherapy alone was 0.72 (95% CI, 0.42–1.23). The investigators noted that OS data remain immature and that follow-up is ongoing; no definitive OS conclusions can be drawn at this time.

The adverse event (AE) profile of the combination was described as broadly consistent with the known safety profiles of the individual agents. Grade ≥3 AEs were more frequent in the combination arm (87.1% vs. 54.4%), driven predominantly by hematologic events (58.6% vs. 28.7%), which were characterized as manageable. Grade ≥3 EGFR-related toxicities were observed only in the combination arm and were infrequent, including rash (10.7%) and diarrhea (1.4%). No new safety signals were identified.

Clinical Context

EGFR exon 20 insertion mutations represent a distinct molecular subset of NSCLC. Zipalertinib is a novel EGFR inhibitor that previously demonstrated activity in previously treated patients with EGFR ex20ins NSCLC. In REZILIENT 3, adding zipalertinib to platinum-pemetrexed chemotherapy significantly prolonged PFS in the first-line setting, with benefit observed across subgroups, including patients with brain metastases at baseline (HR, 0.38).

Key questions remain unanswered. Overall survival data are immature, and the crossover design, which permitted patients in the chemotherapy-alone arm to receive zipalertinib upon progression, should be considered when interpreting future OS results. Continued follow-up is needed to further characterize OS, long-term safety, and exploratory endpoints. Regulatory implications of these findings have not been disclosed.

Sources

AI disclosure: This article was prepared with assistance from generative AI using the source material cited above. It was reviewed and edited by Jason W. Oliver, MSN, APRN, FNP-C, before publication.