Zipalertinib plus chemotherapy improves survival in advanced NSCLC harboring EGFR exon 20 insertion mutations

Adding zipalertinib to platinum-pemetrexed chemotherapy significantly improved progression-free survival in patients receiving first-line treatment for advanced non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, according to results presented at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (WCLC).

In the phase 3 REZILIENT 3 trial, an international, randomized, open-label study, median progression-free survival assessed by blinded independent central review was 14.5 months with zipalertinib plus chemotherapy compared with 8.5 months with chemotherapy alone, representing a 50% reduction in the risk of disease progression or death (HR 0.50; 95% CI, 0.34-0.73; P=0.00015). The progression-free survival benefit was consistent across subgroups, including patients with brain metastases (HR 0.38).

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. The combination also produced a substantially higher response rate, supporting its potential as a first-line treatment approach for this patient population.”

Professor Daniel Tan, National Cancer Center Singapore and Duke-NUS Medical School, Singapore

The trial enrolled 279 patients with advanced NSCLC harboring EGFR exon 20 insertion mutations who had received no prior treatment for advanced disease. Patients were randomly assigned 1:1 to platinum-pemetrexed chemotherapy with zipalertinib 100 mg twice daily (n=140) or chemotherapy alone (n=139). Patients with untreated, asymptomatic brain metastases up to 2 cm were eligible, and patients assigned to chemotherapy alone could cross over to zipalertinib after disease progression.

Objective response rate was significantly higher with zipalertinib plus chemotherapy than with chemotherapy alone, at 65.0% versus 40.3% (P<0.0001). Median duration of response was also longer with the combination, at 14.2 months compared with 9.9 months. At the interim overall survival analysis, which had reached 30% maturity, the hazard ratio for death with zipalertinib plus chemotherapy versus chemotherapy alone was 0.72 (95% CI, 0.42-1.23).

The adverse-event profile of the combination was generally consistent with the known safety profiles of the individual agents. Grade 3 or higher adverse events occurred in 87.1% of patients receiving zipalertinib plus chemotherapy and 54.4% receiving chemotherapy alone, driven primarily by manageable hematologic events. Grade 3 or higher EGFR-related toxicities were infrequent and occurred only in the combination arm, including rash in 10.7% of patients and diarrhea in 1.4%. No new safety signals were observed.

Investigators concluded that the addition of zipalertinib to platinum-based chemotherapy provided a statistically significant and clinically meaningful improvement in progression-free survival as first-line treatment for advanced NSCLC with EGFR exon 20 insertion mutations. Follow-up of REZILIENT 3 (NCT05973773) is ongoing to further characterize overall survival and exploratory endpoints.