Taiho Oncology and Cullinan Therapeutics to Present Zipalertinib Data in EGFR-Mutated NSCLC with Active Brain Metastases at ESMO Congress 2025

PRINCETON, N.J. and CAMBRIDGE, Mass. – Taiho Oncology and Cullinan Therapeutics are making headlines at the European Society for Medical Oncology (ESMO) Congress 2025 with promising new data on zipalertinib, an oral EGFR tyrosine kinase inhibitor, for non-small cell lung cancer (NSCLC) patients. The spotlight is on the REZILIENT2 study cohort, specifically focusing on patients with advanced or metastatic NSCLC who harbor EGFR exon 20 insertion mutations (ex20ins) or uncommon non-ex20ins EGFR mutations, and critically, who also have central nervous system (CNS) involvement.

These findings, presented in a mini oral presentation today, offer a glimmer of hope for a patient population with historically limited treatment options. The REZILIENT2 study’s CNS involvement cohort has been closely watched by oncologists and investors alike, as brain metastases in EGFR-mutated NSCLC often lead to poorer prognoses and require aggressive interventions like surgery and radiotherapy.

The preliminary efficacy and safety data from this Phase 2b trial of zipalertinib has experts cautiously optimistic. “Treatment options are limited for patients with NSCLC with EGFR mutations and active brain metastases,” noted Dr. Helena A. Yu, a Thoracic Medical Oncologist at Memorial Sloan Kettering Cancer Center. “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.”

Key Preliminary Efficacy Data from REZILIENT2:

The February 2025 data cutoff revealed that 32 patients were enrolled in the CNS involvement cohort, receiving zipalertinib at 100 mg orally twice daily. A significant portion of these patients (median of 2) had already undergone prior lines of therapy. The cohort included 21 patients with notorious ex20ins mutations and 13 with other uncommon mutations.

• Intracranial Objective Response Rate (ORR): 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), zipalertinib achieved a 31.3% intracranial ORR, including one complete response.
• Intracranial Disease Control Rate (iDCR): The same population saw a strong intracranial disease control rate (iDCR) of 68.8%, showcasing zipalertinib’s ability to stabilize disease progression in the CNS.
• Intracranial Duration of Response (DOR): Patients experienced a median intracranial duration of response (DOR) of 8.1 months, indicating a sustained benefit in those who responded to the treatment.
• Systemic Activity: Measured in 29 patients, the preliminary systemic objective response rate (ORR) was 27.6% with a median DOR of 7.6 months. While the intracranial activity might be the main attraction, the drug’s systemic activity hints at a holistic approach to managing and treating the cancer.
• Correlated Activity: Intriguingly, intracranial antitumor activity presented as similar to its overall systemic anticancer activity in this cohort of patients.

Safety and Tolerability:

Administered at 100 mg orally twice daily, zipalertinib’s side effects were within manageable levels, showcasing a profile that offers balance between efficacy and treatment burden. Treatment-related adverse events of grade 3 or higher occurred in 8 patients (25%), including anemia (n=3) and interstitial lung disease (n=2), and one death due to interstitial lung disease.

The EGFR Exon 20 Insertion Mutation Landscape:

EGFR exon 20 insertion mutations represent a particular challenge in NSCLC treatment. These mutations, while less common than other EGFR mutations, often confer resistance to standard EGFR tyrosine kinase inhibitors. Analysis from early studies suggest that patients face a baseline brain metastases incidence ranging from 23% to 39%. The development of targeted therapies like zipalertinib is crucial in addressing this unmet need. Zipalertinib has received Breakthrough Therapy Designation from the FDA. However, Zipalertinib is investigational and has not been approved by any health authority.

The Bigger Picture: Market Implications and Future Prospects

The NSCLC market is a multi-billion dollar space, and the EGFR-mutated segment is rapidly evolving with the introduction of novel targeted therapies. Zipalertinib’s showing in the REZILIENT2 study positions it as a potential contender in this competitive landscape, particularly for patients with CNS involvement who currently have limited options. The financial community will be watching closely as zipalertinib progresses through further clinical development and regulatory review.

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 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 Taiho Oncology, Inc.
The mission of Taiho Oncology, Inc. is to improve the lives of patients with cancer, their families and their caregivers. The company specializes in the development and commercialization of orally administered anti-cancer agents for various tumor types. Taiho Oncology has a robust pipeline of small-molecule clinical candidates targeting solid-tumor and hematological malignancies, with additional candidates in pre-clinical development. Taiho Oncology is a subsidiary of Taiho Pharmaceutical Co., Ltd. which is part of Otsuka Holdings Co., Ltd. Taiho Oncology is headquartered in Princeton, New Jersey and oversees its parent company’s European and Canadian operations, which are located in Baar, Switzerland and Oakville, Ontario, Canada.

About Cullinan Therapeutics
Cullinan Therapeutics, Inc. (Nasdaq: CGEM) is a biopharmaceutical company dedicated to creating new standards of care for patients. Cullinan has strategically built a diversified portfolio of clinical-stage assets that inhibit key drivers of disease or harness the immune system to eliminate diseased cells in both autoimmune diseases and cancer. Cullinan’s portfolio encompasses a wide range of modalities, each with the potential to be best and/or first in class. Anchored in a deep understanding of oncology, immunology, and translational medicine, we create differentiated ideas, identify the most appropriate targets, and select the optimal modality to develop transformative therapeutics across a wide variety of autoimmune and cancer indications. We push conventional boundaries from candidate selection to differentiated therapeutic, applying rigorous go/no go criteria at each stage of development to fast-track only the most promising molecules to the clinic and, ultimately, commercialization. With deep scientific expertise, our teams exercise creativity and urgency to deliver on our promise to bring new therapeutic solutions to patients.

Forward Looking Statements
This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. These forward-looking statements include, but are not limited to, express or implied statements regarding the company’s beliefs and expectations regarding our plans regarding future data presentations, the clinical development and regulatory filing plan and timeline of zipalertinib, the safety and efficacy profile of zipalertinib and its potential to address unmet medical need, and other statements that are not historical facts. The words “believe,” “continue,” “could,” “estimate,” “expect,” “intends,” “may,” “plan,” “potential,” “project,” “pursue,” “will,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words.

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References

1. K. Ohashi et al. Activity of Zipalertinib Against Active Central Nervous System (CNS) Metastases in Patients With Non-Small Cell Lung Cancer (NSCLC) Harboring EGFR Exon 20 Insertion (Ex20ins)/Other Uncommon Mutations.
2. Remon J. et al. EGFR exon 20 insertions in advanced non-small cell lung cancer: A new history begins. Cancer Treatment Review. Volume 90, November 2020, 102105.