The addition of zipalertinib to platinum/pemetrexed chemotherapy led to a significant improvement in progression-free survival in patients with advanced non–small cell lung cancer (NSCLC) harboring an EGFR exon 20 insertion mutation, according to phase III findings presented at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (WCLC; Abstract PL03.04).
“REZILIENT 3 demonstrated that adding zipalertinib to platinum-based chemotherapy produced a statistically significant and clinically meaningful 6-month improvement in progression-free survival for patients with advanced NSCLC and EGFR exon 20 insertion mutations,” said Daniel Tan, BSc (Hons), MBBS, MRCP, PhD, of National Cancer Centre Singapore and Duke-NUS Medical School, Singapore. “The combination also produced a substantially higher response rate, supporting its potential as a first-line treatment approach for this patient population.”
Background and Study Methods
Zipalertinib is an EGFR inhibitor that has demonstrated benefit in previously treated patients with advanced NSCLC who harbor an EGFR exon 20 insertion mutation. Research has also suggested that chemotherapy could be added to zipalertinib to extend the benefits of EGFR inhibition.
The international, randomized-controlled, open-label phase III REZILIENT 3 trial enrolled patients with advanced NSCLC with EGFR exon 20 insertion mutations and no prior treatment for advanced disease (n = 279). Patients were randomly assigned 1:1 to receive either platinum/pemetrexed chemotherapy plus zipalertinib at 100 mg twice-daily, or chemotherapy alone. Patients with small, untreated asymptomatic brain metastases were also eligible for enrollment.
The primary study endpoint was progression-free survival by blinded independent central review, and secondary endpoints included objective response rate, duration of response, safety, and overall survival.
Crossover to the zipalertinib arm was allowed after disease progression.
Key Findings
As of the preplanned efficacy analysis after 75% of target progression-free survival events, the combination of zipalertinib and chemotherapy led to a median progression-free survival of 14.5 months vs 8.5 months with chemotherapy alone (hazard ratio [HR] = 0.50; 95% confidence interval [CI] = 0.34–0.73; P = .00015).
Progression-free survival benefit was consistent across subgroups analyzed, including patients with brain metastases (HR = 0.38).
The objective response rate was 65% with the combination regimen vs 40.3% with chemotherapy alone (P < .0001) and the median duration of response was 14.2 months vs 9.9 months with zipalertinib plus chemotherapy and chemotherapy alone, respectively.
Overall survival only reached 30% maturity as of the interim analysis, and the HR for death was 0.72, favoring the combination regimen (95% CI = 0.42–1.23).
Grade 3 or higher adverse events were more common with the combination regimen at 87.1% of patients vs 54.4% (58.6% vs 28.7%); these were mostly hematologic events. EGFR-related toxicities of grade 3 or higher were rare and only seen in the combination arm, with rash observed in 10.7% of patients and diarrhea in 1.4%. The observed safety profile was considered consistent with known safety profiles for the agents.
DISCLOSURES: For full disclosures of the study authors, visit abstractsonline.com.
