According to the phase 2b REZILIENT1 study, zipalertinib demonstrated efficacy and a manageable safety profile among patients with non-small cell lung cancer (NSCLC) with exon 20 insertion mutations who had received prior platinum-based chemotherapy and who had received prior amivantamab.

These data will first be presented by Helena Yu, MD, Memorial Sloan Kettering Cancer Center, New York, New York, at the 2025 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.

Previously, in a phase 1/2a study, the novel EGFR tyrosine kinase inhibitor zipalertinib showed promise among patients with NSCLC and exon 20 insertion mutations who had progressed on platinum-based chemotherapy. This phase 2b trial enrolled 176 patients with advanced or metastatic EGFR exon 20 insertion mutated NSCLC who had progressed after prior platinum-based chemotherapy, with or without amivantamab. Patients with brain metastases that were stable, asymptomatic, or treated were allowed. There were 51 patients included in the prior platinum-based chemotherapy and amivantamab cohort and 125 in the prior platinum-based chemotherapy. Patients received 100 mg zipalertinib twice daily.

With a median follow-up duration was 9.3 months, there was a confirmed overall response rate (ORR) of 35.2% among all patients treated with zipalertinib. The median duration of response (DOR) was 8.8 months, and the median progression-free survival (PFS) was 9.5 months. In the prior platinum-based chemotherapy without amivantamab cohort, the confirmed ORR was 40.0% (complete response [CR, n = 0; partial response [PR], n = 50; stable disease [SD], n = 55), the median DOR was 8.8 months, and the median PFS was 9.5 months.

In the prior platinum-based chemotherapy with amivantamab, the confirmed ORR was 23.5% (CR, n = 1; PR, n = 11; SD, n = 33), the median DOR was 8.5 months and the median PFS was 7.3 months. Of the 51 patients in this cohort, 30 had received no other exon 20 insertion mutation-based therapy, while 21 had received such therapy (including mobocertinib, sunvozertinib, BLU-451, or poziotinib). The confirmed ORR among these patients was 10.0% and 14.3%, respectively. Among all patients with brain metastases, the confirmed ORR was 10.9%.

A majority of reported treatment-emergent adverse events were grade 1/2. The most common all-grade treatment-emergent adverse events were paronychia, rash, anemia, diarrhea, dry skin, nausea, and stomatitis.

According to Dr Yu et al, “zipalertinib demonstrated a clinically meaningful efficacy with a manageable safety profile” among patients with NSCLC and exon 20 insertion mutations, who had received prior platinum-based chemotherapy or prior amivantamab, which is “a significant and growing unmet need.”

Source:

Yu H, Nguyen D, Ruiter G, et al. Efficacy of zipalertinib in NSCLC patient with EGFR exon 20 insertion mutations who received prior platinum-based chemotherapy with or without amivantamab. Presented at 2025 ASCO Annual Meeting. May 30-June 3, 2024; Chicago Illinois. Abstract 8503