On October 19, 2026 Taiho Oncology, Inc. and Cullinan Therapeutics, Inc. (Nasdaq: CGEM) reported results from Cohort C of the Phase 2 REZILIENT2 trial evaluating zipalertinib monotherapy in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations or other uncommon EGFR mutations and active central nervous system (CNS) metastases. The data will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2026, October 23-27, in Madrid, Spain.
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Mature results from the first prospective study evaluating intracranial activity of an EGFR tyrosine kinase inhibitor in this patient population demonstrated clinically meaningful intracranial antitumor activity. Among 43 evaluable patients, zipalertinib achieved an intracranial objective response rate of 30% and an intracranial disease control rate of 72%, with a median intracranial duration of response of 9.7 months. Zipalertinib was well tolerated.
"Patients with NSCLC harboring EGFR exon 20 insertion mutations or other uncommon EGFR mutations and active CNS metastases have a significant need for therapies that can effectively address disease in the brain," said Helena A. Yu, MD, Thoracic Medical Oncologist at Memorial Sloan Kettering Cancer Center and study investigator. "The intracranial responses observed with zipalertinib in REZILIENT2 are encouraging and support continued evaluation of zipalertinib in this difficult-to-treat patient population."
"The REZILIENT2 results reflect a rigorous examination of the CNS activity of zipalertinib as monotherapy in patients with EGFR ex20ins or uncommon EGFR-mutated NSCLC and active CNS metastases," said Harold Keer, MD, PhD, Chief Medical Officer, Taiho Oncology. "The findings add to the growing clinical evidence supporting the continued evaluation of zipalertinib in patients with EGFR-mutated NSCLC and brain involvement."
"The REZILIENT program was designed to explore zipalertinib’s potential in clinically important settings where additional treatment options are needed," said Jeffrey Jones, MD, MBA, Chief Medical Officer, Cullinan Therapeutics. "Today’s REZILIENT2 update extends that commitment by providing evidence of intracranial activity in patients with active CNS metastases."
Summary of Results:
Cohort C of REZILIENT2 enrolled patients with NSCLC harboring EGFR ex20ins or other uncommon EGFR mutations and active CNS metastases, including leptomeningeal disease (LMD), irrespective of prior therapy. At the data cutoff, 59 patients were enrolled, with a median follow-up of 9.2 months. Intracranial efficacy was evaluated by Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM), and systemic response was measured by RECIST v1.1.
Among 43 RANO-BM-evaluable patients, including 9 with LMD, 29 (67.4%) had EGFR ex20ins mutations. The median number of prior lines of therapy was two (range 1-6), and 19 patients (44.2%) had received prior EGFR tyrosine kinase inhibitor therapy. In these 43 patients, zipalertinib achieved an intracranial objective response rate (iORR) of 30.2% (95% CI: 17.2, 46.1), an intracranial disease control rate (iDCR) of 72.1% (95% CI: 56.3, 84.7), and a median intracranial duration of response (iDoR) of 9.7 months (95% CI: 3.3, not estimable). Among 24 patients without prior EGFR tyrosine kinase inhibitor exposure, iORR was 37.5%. Systemic efficacy was consistent with intracranial outcomes.
Zipalertinib 100 mg twice daily was well tolerated. Common treatment-related adverse events (TRAEs) included paronychia (32.6%) and diarrhea (25.6%). Grade ≥3 TRAEs occurred in 9 patients (20.9%), including dermatitis acneiform in 4.7% of patients.
Session Information for the ESMO (Free ESMO Whitepaper) Presentation:
Title: 2621P – Central Nervous System (CNS) Activity of Zipalertinib in Non-Small Cell Lung Cancer (NSCLC) Patients with Uncommon EGFR Mutations (EGFRmt)
Presenting Author: Helena A. Yu, MD, Thoracic Medical Oncologist at Memorial Sloan Kettering Cancer Center and study investigator
Session Date: Monday, October 26, 2026
Session Time: 12:00 p.m.–12:45 p.m. CET
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 exon 20 insertion mutations. 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 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.
About the REZILIENT2 Trial
REZILIENT2 is a Phase 2b clinical trial (NCT05967689) evaluating zipalertinib in patients with locally advanced or metastatic NSCLC harboring EGFR ex20ins and uncommon single or compound EGFR mutations. Patients were treated with oral zipalertinib 100 mg twice daily. The primary endpoint was ORR and confirmed per investigator-assessed Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 and the secondary endpoints included duration of response (DOR), disease control rate (DCR) and safety.
About EGFR Exon 20 Insertion Mutations
NSCLC is a common form of lung cancer and up to 4% of all cases globally have EGFR ex20ins, which makes them the third most common EGFR mutation subtype.2 In the United States, approximately 16% of patients with NSCLC harbor EGFR mutations,2 with insertions at exon 20 accounting for up to 12% of these mutations.
(Press release, Taiho, OCT 19, 2026, View Source [SID1234673593])