*October 2025*
Zipalertinib demonstrated preliminary efficacy and was associated with low rates of treatment-related dose reductions and discontinuations in patients with non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertions or other uncommon single or compound uncommon mutations and active central nervous system (CNS) metastases and/or leptomeningeal disease, according to preliminary data from cohort C of the REZILENT2 trial (NCT05967689) presented at the 2025 ESMO Congress .1
The intracranial objective response rate (ORR) in RANO-BM–evaluable patients (n = 16) was 31.3% (n = 5), which included 1 intracranial complete response. Notably, 2 of 5 intracranial responders also had leptomeningeal disease at baseline, and 4 of the 5 did not receive prior CNS radiotherapy. The intracranial disease control rate (DCR) was 68.8%, and the median intracranial duration of response (DOR) was 8.1 months (95% CI, 3.1-not evaluable).
The systemic ORR in RECIST 1.1–evaluable patients (n = 29) was 27.6% (n = 8) and the DCR was 58.6%. The median DOR was 7.6 months (95% CI, 2.07-9.07).
“Zipalertinib demonstrated clinically meaningful intracranial antitumor activity…in patients with NSCLC harboring EGFR exon 20 insertions or other uncommon single or compound uncommon mutations,” Helena A. Yu, MD, attending physician at Memorial Sloan Kettering Cancer Center in New York, New York, stated in the presentation. “The intracranial response rate was similar to the systemic response rate in the reported population,” Yu added.
What Led to Zipalertinib’s Evaluation in the REZILENT2 Trial?
Poor prognosis is associated with the presence of CNS metastases in patients with EGFR-mutant NSCLC, reflecting a clinical need for more effective treatment options.
Zipalertinib is an oral, highly selective, irreversible EGFR TKI that has proven active in advanced or metastatic NSCLC with EGFR exon 20 insertion mutations in the phase 1/2 REZILIENT1 trial (NCT04036682), including in patients with CNS metastases.2
To be eligible for enrollment in the subsequent REZILIENT2 trial, patients had to be at least 18 years of age and have received a diagnosis of locally advanced or metastatic NSCLC with documented exon 20 insertions or other uncommon single or compound non–EGFR exon 20 insertion mutations. Measurable disease per RECIST 1.1/CNS per RANO-BM criteria was also required, as was an ECOG performance status of 0 or 1.
Patients with active brain metastases had to be newly diagnosed and/or have progressing brain lesions without CNS targeted therapy and/or leptomeningeal disease. There was no limit on the number of prior therapies patients could have received in the advanced or metastatic setting.
Patients received 100 mg of oral zipalertinib twice daily until progressive disease or other discontinuation criteria were met. A total of 32 patients were enrolled, 16 of whom were evaluable by RANO-BM.
The data cutoff was February 17, 2025, and the study remains ongoing.
The primary end point was ORR per RECIST 1.1 criteria. Secondary end points included intracranial ORR, intracranial DOR, intracranial DCR per RANO-BM, and safety. Read more.
