Results from a small phase 2b study of zipalertinib in non-small cell lung cancer (NSCLC) show promise for patients with EGFR exon 20 insertions who progressed on or after standard-of-care treatment. Module C of the REZILIENT1 study of locally advanced or metastatic NSCLC showed an overall response rate (ORR) of 31.5% and a mean duration of response (DOR) of 9.5 months for patients who had received only prior amivantamab.
“Zipalertinib is an irreversible and selective EGFR exon 20 insertion tyrosine kinase inhibitor that has been granted breakthrough therapy designation by the US Food and Drug Administration (FDA) based on promising anti-tumor efficacy and a favorable safety profile,” said Zofia Piotrowska, MD, MHS, Assistant Professor at the Massachusetts General Research Center and Associate Professor at Harvard Medical School. “Module C investigates the efficacy and safety of zipalertinib specifically in patients who have progressed on or after amivantamab, which is reflective of our current clinical practice in many countries where patients receive amivantamab in the first-or second-line setting.”
Dr. Piotrowska presented data on the first 84 patients in the subgroup during a session titled Common and Uncommon EGFR Mutation: New Treatments on the Horizon at the 2025 World Conference on Lung Cancer. All patients had progressed on or after receiving amivantamab monotherapy or after receiving combination therapy that included amivantamab. All participants had a minimum of 9 months of follow-up.
The median age of the cohort was 62 years, and 59% were female. Patients had as many as seven prior systemic regimens, including 84% with prior amivantamab and 30% some other therapy targeting exon 20 insertions. Nearly half (46%) had a history of brain metastases.
A majority of patients, 54 (64.3%), had progressed on or after amivantamab only, and 30 (35.7%) had progressed on or after amivantamab plus other exon 20 insertion-targeted therapy.
The confirmed ORR for the entire cohort was 27.4%. The confirmed ORR was 20% for patients previously treated with amivantamab plus other exon 20 insertion-targeted therapy and 31.5% for those treated with prior amivantamab only. Patients with brain metastases who had only received prior amivantamab had a confirmed ORR of 29%.
Progression-free survival was 6.5 months for the entire cohort, ranging from 5.2 months for patients who had progressed after amivantamab plus other exon 20 insertion therapy to 7.4 months for those who had progressed after amivantamab alone.
The most common adverse events (AEs) were paronychia (41.7%), anemia (38.1%), rash (34.5%), nausea (28.6%), and diarrhea (22.6%). The most common grade ≥ 3 AEs were anemia (15.5%), pneumonia (10.7%), and dyspnea (6%). All had been observed in earlier trials, Dr. Piotrowska said.
“Zipalertinib demonstrated promising efficacy in the cohort of patients who had progressed on or after prior chemotherapy and amivantamab without other EGFR exon 20 insertion-directed therapy, reflective of the current patient population where we think about these exon 20 TKIs in our clinical practice,” she said. “Zipalertinib was overall well-tolerated and had a manageable safety profile, even for those patients who had received prior amivantamab. And there were no new safety signals identified.”
