Prof Daniel Tan from Duke–NUS Medical School, Singapore, at WCLC 2026.In the phase III REZILIENT* 3 trial, adding zipalertinib to chemotherapy improves progression-free survival (PFS) in patients with treatment-naïve metastatic non-small cell lung cancer (NSCLC) harbouring EGFR exon 20 insertion mutations (ex20ins-mut).
The median PFS by blinded independent central review (BICR) was significantly longer with the combo regimen than with chemo alone (14.5 vs 8.5 months; hazard ratio [HR], 0.50; p=0.00015). [WCLC 2026, abstract PL03.04]
“Although the control group performed better than anticipated, the curves separated early and widened over time, with clear, durable separation up to the 15-month mark at this prespecified interim data cutoff,” said Prof Daniel Tan from Duke–NUS Medical School, Singapore, at WCLC 2026.
The PFS benefit was broadly consistent across subgroups, with the most pronounced effects observed among participants with brain metastases (HR, 0.38), those aged <65 years (HR, 0.38), and male patients (HR, 0.39).
Compared with chemo alone, the combo regimen was associated with a higher objective response rate (65 percent vs 40.3 percent; p<0.0001) and longer duration of response (median 14.2 vs 9.9 months).
There was a favourable overall survival (OS) trend with the combo regimen at a median follow-up of 10.9 months (HR, 0.72; p=0.11082). Of note, 64.2 percent of participants in the chemo group who had disease progression had crossed over to zipalertinib at the time of this analysis.
The combo regimen was associated with higher rates of grade ≥3 treatment-related adverse events (TRAEs; 80.7 percent vs 40.4 percent) and serious TRAEs (37.9 percent vs 12.5 percent) compared with chemo alone. The grade ≥3 AEs were primarily driven by haematologic events, including anaemia (48.6 percent vs 12.5 percent), neutropenia (33.6 percent vs 22.1 percent), and thrombocytopenia (30 percent vs 8.1 percent).
Of note, cytopenias in the combination group were more pronounced during the first four cycles of treatment, with a notably lower incidence during the maintenance pemetrexed phase, Tan noted. “These events were typically managed with dose interruptions and reductions, underscoring the need for judicious dose modification and supportive care, especially in the first four cycles.”
EGFR class effects were also observed, including rash, paronychia, stomatitis, and diarrhoea, but these were generally managed with interruptions and dose reductions, Tan added.
High selectivity for EGFR ex20ins
“EGFR ex20ins account for approximately 5–10 percent of all EGFR mutations, and this molecularly heterogeneous subgroup with more than 100 variants has historically responded poorly to conventional EGFR tyrosine kinase inhibitors,” Tan said. “Zipalertinib is a novel irreversible EGFR inhibitor with a unique pyrrolopyrimidine scaffold that forms a covalent bond with C797 and has high selectivity for EGFR ex20ins relative to wild-type EGFR.”
A total of 279 participants (median age 65 years, 64.5 percent women) were randomized 1:1 to platinum–pemetrexed chemo alone or with zipalertinib 100 mg BID. Participants in the chemo group may cross over to zipalertinib upon disease progression. Forty percent of participants were from Asia, 60 percent were never smokers, 31.5 percent had brain metastasis at baseline, and 97.1 percent had adenocarcinomas.
REZILIENT-3 met its primary endpoint, showing a statistically significant and clinically meaningful 6-month PFS improvement when zipalertinib was added to platinum-based chemo in patients with advanced NSCLC with EGFR ex20ins-mut.
“Despite the higher AE rates with the combo regimen, these were predominantly related to cytopenias and associated sequelae, which can be mitigated through patient selection, dose modification, and optimal supportive care,” Tan said.
“Taken together, zipalertinib plus platinum-based chemo represents a highly efficacious new frontline treatment option for this patient population,” Tan concluded. Follow-up is ongoing to further characterize the OS benefit and long-term safety profile of this combination.
Zipalertinib plus platinum-based chemo represents a highly efficacious new frontline treatment option for NSCLC harbouring EGFR exon 20 insertion mutations.