REZILIENT3: First-Line Zipalertinib Plus Chemotherapy in EGFR Exon 20 NSCLC

In "REZILIENT3: First-Line Zipalertinib Plus Chemotherapy in EGFR Exon 20 NSCLC," our expert turns to the phase 3 data presented at the World Conference on Lung Cancer this fall.

Dr. Yu first places the trial in context. Zipalertinib monotherapy has already shown a good overall response rate and progression-free survival in the second-line setting after platinum-based chemotherapy. A new drug application for that indication has been submitted to the FDA, with a decision expected within the next couple of months.

REZILIENT3 evaluated zipalertinib plus chemotherapy in patients with untreated metastatic exon 20 insertion-positive disease. Its design parallels the established approach of adding a targeted agent to chemotherapy. Nearly 300 patients were randomized 1:1 to the combination or to chemotherapy alone. Patients with untreated brain metastases up to 2 cm were eligible. Patients progressing on chemotherapy were permitted to cross over to zipalertinib monotherapy.

The primary endpoint, progression-free survival, favored the combination at 14.5 months versus 8.5 months, a hazard ratio of 0.5. Response rates were 65% versus 40%, and duration of response was 14.2 versus 9.9 months. Overall survival data remain immature. Dr. Yu notes that 64% of patients crossed over after progressing on chemotherapy, a rate she considers good. She concludes that the trial supports the combination as a potential new first-line regimen.

On safety, Dr. Yu describes zipalertinib alone as relatively well tolerated. Its effects include occasional cytopenias, lower-extremity cramping, looser stools, and mild rash, which only partially overlap with chemotherapy. In combination, the most frequent adverse events were anemia and thrombocytopenia, many of them grade 3 or higher. These cytopenias clustered in the first 4 cycles, when patients received carboplatin, pemetrexed, and zipalertinib together. EGFR-directed effects such as rash, paronychia, and mild stomatitis also occurred. Pneumonitis, a class effect of targeted therapies, appeared in 5.7% of treated patients.

The next episode in this series, "First-Line Options and PAPILLON Survival Data in EGFR Exon 20 NSCLC," features Dr. Yu comparing the emerging first-line options and reviewing newly reported long-term survival data.