Cullinan Therapeutics, Inc., Taiho Pharmaceutical Co., Ltd., and Taiho Oncology, announced new positive results from the pivotal Phase 2b cohorts of the REZILIENT1 trial, a Phase 1/2 clinical trial of zipalertinib monotherapy in patients with advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations (ex20ins) who have received prior therapy. These data will be presented on Sunday, June 1 at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting as an oral presentation during the “Lung Cancer – Non-Small Cell Metastatic” session from 9:00 AM-9:12 AM CDT.

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“People living with EGFR ex20ins NSCLC urgently need well-tolerated targeted therapies with durable clinical benefit,” said Helena A. Yu, MD, Thoracic Medical Oncologist & Early Drug Development Specialist, Memorial Sloan Kettering Cancer Center. “It is encouraging to see a program that can potentially offer a meaningful option for some of the sickest patients with lung cancer. The findings from the REZILIENT1 trial may support zipalertinib as a potential new oral treatment option for patients whose disease progressed after prior therapies.”

Summary of Efficacy Results

As of the December 2024 data cutoff, 244 patients were enrolled in REZILIENT1 and received at least one dose of 100 mg zipalertinib. The overall efficacy population (n=176) consisted of all patients who received at least one dose of 100 mg zipalertinib and had approximately 8 months of minimum follow-up at data cutoff. Patients had received a median of 2 prior therapies, and 39% of patients had a history of brain metastases.

With median follow-up of 9.3 months, zipalertinib demonstrated:

  • In the overall efficacy population (n=176), confirmed overall objective response rate (ORR) was 35% with median duration of response (mDOR) of 8.8 months
  • In patients with prior platinum-based chemotherapy only (n=125), ORR was 40% with mDOR of 8.8 months, consistent with REZILIENT1 Phase 1/2a results
  • In patients with prior chemo and amivantamab (without the addition of other prior ex20ins-targeted therapy) (n=30), ORR was 30% with mDOR of 14.7 months
    • In patients with prior chemo and amivantamab (with or without other ex20ins-targeted therapy) (n=51), ORR was 24% with mDOR of 8.5 months
  • In patients with brain metastases (n=68), the ORR was 31% with mDOR of 8.3 months


Summary of Safety and Tolerability Results

The safety analysis population included all REZILIENT1 patients who received at least one dose of 100 mg zipalertinib (n=244). The results showed that zipalertinib demonstrated a manageable safety profile in this heavily pre-treated patient population, consistent with previously reported data. The most common treatment-related adverse events (TRAEs, all-grade) were paronychia (38.5%), rash (30.3%), dermatitis acneiform (24.6%), dry skin (24.6%), diarrhea (21.7%), and stomatitis (20.1%). The majority of TRAEs were grade 1 or 2.

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The most common grade ≥3 TRAEs were anemia (7%), pneumonitis and rash (2.5% each), increased alanine aminotransferase, diarrhea, and decreased platelet count (2.0% each).

About REZILIENT1

REZILIENT1 (Researching Zipalertinib In EGFR Non-Small Cell Lung Cancer Tumors) is a Phase 1/2 clinical trial to evaluate efficacy and safety of zipalertinib in adult patients with advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations who have received prior therapy. Patients were treated with oral zipalertinib 100 mg twice daily. The primary endpoints were ORR and DOR as assessed by blinded independent central review (ICR) per RECIST v1.1. Adverse events were characterized and graded according to Common Terminology Criteria for Adverse Events (CTCAE v5.0).

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, 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.

About the EGFR Exon 20 Insertion Mutations

NSCLC is a common form of lung cancer and up to 4% of all cases have EGFR exon 20 insertions, which makes them the third most common EGFR mutation subtype.2 In the United States, approximately 16% of patients with NSCLC harbor EGFR mutations,3 with insertions at exon 20 accounting for up to 12% of these mutations.

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Source – GlobeNewswire