Zipalertinib Plus Chemotherapy Nearly Doubles Progression-Free Time in Lung Cancer Trial

Adding the experimental drug zipalertinib to standard platinum-pemetrexed chemotherapy significantly extended progression-free survival for patients with advanced non-small cell lung cancer (NSCLC) carrying EGFR (a growth-signaling protein) exon 20 insertion mutations, according to results from the international Phase 3 REZILIENT 3 trial presented at the 2026 World Conference on Lung Cancer.

The trial enrolled 279 patients with advanced NSCLC who had received no prior treatment for advanced disease, randomly assigning them 1:1 to chemotherapy plus zipalertinib (140 patients) or chemotherapy alone (139 patients). Patients with untreated, asymptomatic brain metastases up to 2 centimeters were eligible, and those on chemotherapy alone could switch to zipalertinib once their disease progressed.

Median progression-free survival, assessed by blinded independent central review, was 14.5 months with the combination versus 8.5 months with chemotherapy alone — a 50% reduction in the risk of disease progression or death (hazard ratio 0.50). The benefit held up even in patients with brain metastases (hazard ratio 0.38). The objective response rate was also higher with the combination, at 65.0% versus 40.3%, and the median duration of response was longer, at 14.2 months versus 9.9 months.

An early look at overall survival, based on 30% of the expected data, found a hazard ratio for death of 0.72 (95% CI 0.42-1.23); the trial's follow-up continues to further assess overall survival. Grade 3 or higher adverse events occurred more often with the combination, in 87.1% of patients versus 54.4% with chemotherapy alone, driven mainly by manageable blood-related side effects, and no new safety concerns emerged.

"REZILIENT 3 demonstrated that adding zipalertinib to platinum-based chemotherapy produced a statistically significant and clinically meaningful six-month improvement in progression-free survival for patients with advanced NSCLC and EGFR exon 20 insertion mutations," said Dr. Daniel Tan of the National Cancer Centre Singapore and Duke-NUS Medical School, who presented the findings.