The Phase III REZILIENT3 trial found that adding investigational EGFR inhibitor zipalertinib to platinum-based chemotherapy significantly improved progression-free survival in previously untreated patients with EGFR exon 20 insertion mutation-positive non-small cell lung cancer. Median PFS was 14.5 months with the combination versus 8.5 months with chemotherapy alone, a 6.0-month benefit. The combination also delivered higher objective response rates (65.0% vs 40.3%) and longer duration of response; an interim overall survival analysis showed a hazard ratio of 0.72 with additional follow-up ongoing.
Phase III REZILIENT3: Zipalertinib Plus Chemotherapy Extends PFS by 6 Months in EGFR Exon 20 Insertion NSCLC
The REZILIENT3 trial enrolled 285 adults with locally advanced or metastatic
Taiho Oncology, Taiho Pharmaceutical and Cullinan Therapeutics reported topline Phase III results from the REZILIENT3 trial showing that adding the investigational EGFR inhibitor zipalertinib to platinum-based chemotherapy significantly prolonged progression-free survival (PFS) in previously untreated, advanced non-small cell lung cancer (NSCLC) harbouring EGFR exon 20 insertion (ex20ins) mutations.
Study Design and Participants
REZILIENT3 was a multi-centre, randomised, open-label Phase III study that enrolled 285 adults with locally advanced or metastatic non-squamous NSCLC and confirmed EGFR ex20ins mutations. Patients were randomised to first-line zipalertinib plus platinum-based chemotherapy versus chemotherapy alone.
Key Efficacy Results
The trial met its primary endpoint of PFS: the combination arm achieved a median PFS of 14.5 months versus 8.5 months with chemotherapy alone, a 6.0-month benefit. The interim PFS analysis was conducted after 122 PFS events.
Objective response rate (ORR) was higher with the combination (65.0%) compared with chemotherapy alone (40.3%). Median duration of response was 14.2 months with zipalertinib plus chemotherapy versus 9.9 months with chemotherapy.
An interim overall survival (OS) analysis performed when ~30% of events had occurred showed a hazard ratio (HR) for death of 0.72 for the combination versus chemotherapy; follow-up is ongoing to mature survival data.
Safety
The safety profile of zipalertinib combined with chemotherapy was consistent with the known effects of the component agents. Grade ≥3 adverse events were more frequent in the combination arm (87.1% vs 54.4%), largely driven by haematological toxicities. Grade ≥3 EGFR‑related toxicities — chiefly rash (10.7%) and diarrhoea (1.4%) — were observed only in patients receiving the zipalertinib combination.
About Zipalertinib
Zipalertinib (CLN-081/TAS6417) is an oral, investigational inhibitor designed to target EGFR variants with exon 20 insertion mutations. It has not been approved by any regulatory authority.
"We believe these results mark a potentially important step forward in the treatment of EGFR exon 20 insertion mutation-positive non-small cell lung cancer," said Fabio Benedetti, Global Chief Medical Officer at Taiho Pharmaceutical. He added that Taiho, Taiho Oncology and Cullinan will continue efforts to make this therapy available to eligible patients.
The results were presented at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (WCLC) in Seoul, South Korea.
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