On October 12, 2025 Taiho Oncology, Inc., and Cullinan Therapeutics, Inc., reported new data from the central nervous system (CNS) involvement cohort of the REZILIENT2 study of zipalertinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations (ex20ins) or uncommon non-ex20ins EGFR mutations and CNS involvement (Press release, Taiho, OCT 12, 2025, View Source [SID1234656562]). Data will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2025, as a mini oral presentation on October 19 during the "NSCLC metastatic" session from 8:30 to 10 a.m. CEST.
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The mini oral presentation will highlight preliminary efficacy and safety data from the CNS involvement cohort of the ongoing parallel cohort Phase 2b REZILIENT2 trial of zipalertinib.1
Patients with locally advanced or metastatic NSCLC harboring EGFR ex20ins mutations represent a significant unmet medical need. An incidence of baseline brain metastases in EGFR ex20ins NSCLC patients ranging from 23% to 39% has been reported.² Patients with lung cancer with CNS involvement have a worse prognosis and require more aggressive therapy, including surgery and radiotherapy.
"Treatment options are limited for patients with NSCLC with EGFR mutations and active brain metastases," said Helena A. Yu, MD, Thoracic Medical Oncologist, Memorial Sloan Kettering Cancer. "We are pleased to see that in approximately one-third of patients exposed to zipalertinib, a decrease in CNS lesions was observed. These preliminary results suggest the potential for zipalertinib to treat these patients, warranting future investigation."
Authors will report results from the REZILIENT2 study of zipalertinib against active CNS metastases in patients with NSCLC harboring EGFR ex20ins or other uncommon mutations1:
Summary of Preliminary Efficacy – by Investigator
As of the February 2025 data cutoff, 32 patients were enrolled in the CNS involvement cohort of the ongoing parallel cohort Phase 2b REZILIENT2 trial and received zipalertinib 100 mg orally twice daily. Patients received a median of 2 prior lines of therapy, and of all patients enrolled, 21 patients had ex20ins mutations and 13 patients had other uncommon mutations.
As of the data cutoff, zipalertinib demonstrated:
In the Response Assessment in Neuro-Oncology for Brain Metastases (RANO-BM) criteria evaluable population with measurable CNS disease (n=16, including 3 patients with leptomeningeal disease (LMD), intracranial objective response rate was 31.3% including 1 intracranial complete response.
In the same population, the intracranial disease control rate (iDCR) was 68.8% and the median intracranial duration of response (DOR) was 8.1 months.
Measured in 29 of the cohort’s patients, preliminary systemic objective response rate (ORR) was 27.6% and median DOR was 7.6 months.
Intracranial antitumor activity was found to be similar to its overall systemic anticancer activity in this cohort of patients.
Summary of Preliminary Safety and Tolerability
Administered at 100 mg orally twice daily, zipalertinib was found to be well tolerated, with no new safety signals observed.
Treatment-related adverse events of grade 3 or higher occurred in 8 patients (25%) and included anemia (n=3) and interstitial lung disease (n=2). There was one death due to interstitial lung disease.
About REZILIENT2
REZILIENT2 is a Phase 2b clinical trial (NCT05967689), evaluating the safety and efficacy of zipalertinib in patients with locally advanced or metastatic NSCLC harboring ex20ins mutations or other uncommon/single or compound EGFR mutations. Patients are enrolled into one of four cohorts: Cohort A ("prior ex20ins treatment"), Cohort B ("first-line"), Cohort C ("active brain metastases"), and Cohort D ("other uncommon EGFR mutations"). Cohort C includes patients harboring EFGR ex20ins or other uncommon/single or compound EGFR mutations and CNS involvement. In this cohort, patients may or may not have had prior treatment for advanced disease. Patients are treated with oral zipalertinib 100 mg twice daily. The primary endpoint is ORR and confirmed per investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and the secondary endpoints include DOR, DCR, PFS, OS, intracranial efficacy by RANO-BM criteria, PK and safety.
About Zipalertinib
Zipalertinib (development code: CLN-081/TAS6417) is an orally available small molecule designed to target activating mutations in EGFR. The molecule was selected because of its ability to inhibit EGFR variants with ex20ins mutations, while sparing wild-type EGFR. Zipalertinib is designed as a next generation, irreversible EGFR inhibitor for the treatment of a genetically defined subset of patients with non-small cell lung cancer. Zipalertinib has received Breakthrough Therapy Designation from the FDA. Zipalertinib is investigational and has not been approved by any health authority.
Zipalertinib is being developed by Taiho Oncology, Inc., its parent company, Taiho Pharmaceutical Co., Ltd., and in collaboration with Cullinan Therapeutics, Inc. in the U.S.