Clinical Summary:

• Design/Population: The phase 3 REZILIENT 3 trial compared zipalertinib plus platinum-pemetrexed chemotherapy with chemotherapy alone in patients with previously untreated advanced non-small cell lung cancer harboring EGFR exon 20 insertion mutations. The primary end point was progression-free survival (PFS). 
• Key Outcomes: Zipalertinib plus chemotherapy significantly improved median PFS and reduced the risk of disease progression or death by 50% compared with chemotherapy alone. The combination also significantly improved objective response and prolonged duration of response, with PFS benefit observed across subgroups, including patients with brain metastases. 
• Clinical Relevance: These findings support combining EGFR-targeted therapy with platinum-based chemotherapy as a potential new first-line option. Overall survival data remain immature and grade ≥3 adverse events were more frequent with the combination. 

Interim results from the phase 3 REZILIENT 3 trial demonstrated that adding zipalertinib to platinum-pemetrexed chemotherapy significantly improved progression-free survival (PFS)  compared with chemotherapy alone as first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations.

These results were presented in a plenary session at the World Conference on Lung Cancer by Daniel Tan, MBBS, PhD, National Cancer Centre Singapore. 

In this open-label trial, researchers enrolled 279 patients who had not received prior systemic treatment for advanced disease, including patients with previously untreated, asymptomatic brain metastases measuring 2 cm or less. Patients were randomized 1:1 to receive platinum-pemetrexed chemotherapy either alone (n = 139) or in combination with 100 mg of twice daily zipalertinib (n = 140). Patients assigned to chemotherapy alone were permitted to cross over to zipalertinib following disease progression.

The primary end point was PFS, assessed via blinded independent central review. Key secondary end points included objective response rate (ORR), duration of response, overall survival (OS), and safety. 

At the prespecified efficacy interim analysis, median PFS was 14.5 months in the zipalertinib arm and 8.5 months in the chemotherapy arm. The combination reduced the risk of disease progression or death by 50% (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.34 to 0.73; P = .00015).

 The PFS benefit was consistent across all subgroups, including patients with brain metastases, among whom the HR for disease progression or death was 0.38. 

The ORR was 65% in the zipalertinib arm and 40.3% in the chemotherapy arm (P < .0001). Median duration of response was 14.2 months and 9.9 months, respectively. 

At the interim OS analysis, which had reached 30% maturity, the HR for death with zipalertinib plus chemotherapy compared with chemotherapy alone was 0.72. Continued follow-up is required to further characterize the OS effect. 

Grade ≥3 adverse events occurred in 87.1% of patients in the zipalertinib arm and 54.4% of patietns in the chemotherapy arm. These events were primarily hematologic, with grade ≥3 hematologic adverse events occurring in 58.6% and 28.7% of patients, respectively. 

Grade ≥3 EGFR-related toxicities were uncommon and occurred only in the zipalertinib arm. The most frequently reported events included rash (10.7%) and diarrhea (1.4%). 

No new safety signals were identified, and the overall adverse event profile of the combination was generally consistent with the known safety profiles of the individual agents. 

Adding zipalertinib to platinum-based chemotherapy produced a statistically significant and clinically meaningful improvement in PFS as first-line treatment for advanced EGFR exon 20 insertion-mutated NSCLC. Follow-up of REZILIENT 3 is ongoing to further characterize OS.

Source:

Tan DS, Danchaivijitr P, Shinno Y, et al. Zipalertinib plus chemotherapy for 1st Line NSCLC with EGFR exon 20 insertions: Results from the phase 3 trial (REZILIENT 3). Presented at the World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Abstract PL03.04.