Cullinan Therapeutics and Taiho Highlight Promising Phase 2b Results of Zipalertinib in Advanced EGFR ex20ins NSCLC at ASCO 2025
Cullinan Therapeutics,in collaboration with Taiho Pharmaceutical Co., Ltd., and its U.S. affiliate Taiho Oncology, Inc., has announced encouraging new results from the pivotal Phase 2b cohorts of its ongoing REZILIENT1 trial. This study investigates zipalertinib, an investigational oral therapy, as a monotherapy for patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion mutations (ex20ins), a particularly aggressive subset of NSCLC. These patients had previously received systemic treatment, highlighting the urgent need for additional therapeutic options.
The data, which provide robust support for zipalertinib’s potential, will be formally presented at the 2025 Annual Meeting of the American Society of Clinical Oncology (ASCO). Scheduled for Sunday, June 1, the presentation will take place during the “Lung Cancer – Non-Small Cell Metastatic” oral session, from 9:00 AM to 9:12 AM CDT (Abstract #8503). These findings offer new hope for a group of patients with historically poor outcomes and limited targeted options.
Addressing an Unmet Need in EGFR ex20ins NSCLC
EGFR exon 20 insertion mutations occur in approximately 1–2% of patients with NSCLC, often conferring resistance to conventional EGFR inhibitors. These mutations lead to structural changes in the EGFR protein, making it difficult for standard tyrosine kinase inhibitors (TKIs) to bind effectively. Consequently, patients with EGFR ex20ins-mutant NSCLC typically face poorer prognoses and fewer treatment options compared to those with more common EGFR mutations.
Dr. Helena A. Yu, a thoracic medical oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center, emphasized the significance of the trial’s findings. “People living with EGFR ex20ins NSCLC urgently need well-tolerated targeted therapies with durable clinical benefit,” she stated. “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.”
A Closer Look at the REZILIENT1 Trial Design
The REZILIENT1 trial is a global, open-label, multi-cohort Phase 1/2 study evaluating the safety and efficacy of zipalertinib in patients with EGFR ex20ins NSCLC. The trial enrolled a total of 244 patients who had received at least one prior systemic therapy and were administered a 100 mg dose of zipalertinib.
The latest efficacy analysis focused on a subset of 176 patients who constituted the overall efficacy population. These patients had received at least one dose of zipalertinib and had a minimum follow-up of approximately 8 months as of the data cutoff in December 2024. Participants had received a median of two prior systemic therapies, and 39% had a documented history of brain metastases—an indicator of advanced disease.
Efficacy Outcomes: Promising Response Rates and Durability
With a median follow-up duration of 9.3 months, zipalertinib demonstrated clinically meaningful anti-tumor activity across multiple subgroups of patients. The confirmed overall objective response rate (ORR) in the efficacy population (n=176) was 35%, and the median duration of response (mDOR) was 8.8 months. These results mark a significant achievement in a patient population characterized by treatment resistance and high disease burden.
In subgroup analyses, efficacy was further delineated by prior treatment history:
- Patients previously treated with platinum-based chemotherapy only (n=125):
- ORR: 40%
- mDOR: 8.8 months
These results were consistent with outcomes previously observed in earlier phases of the REZILIENT1 trial.
- Patients who received both chemotherapy and amivantamab but no other ex20ins-targeted therapy (n=30):
- ORR: 30%
- mDOR: 14.7 months
Notably, this group demonstrated a longer duration of response, suggesting zipalertinib’s potential durability even after treatment with other targeted agents.
- Patients who received chemo, amivantamab, and possibly other ex20ins-targeted agents (n=51):
- ORR: 24%
- mDOR: 8.5 months
The modestly lower response rate in this more heavily pretreated group still reflects clinically meaningful activity.
- Patients with brain metastases (n=68):
- ORR: 31%
- mDOR: 8.3 months
Importantly, zipalertinib showed activity in patients with central nervous system involvement—a common and challenging complication in advanced NSCLC.
These data suggest that zipalertinib is effective across various subgroups of EGFR ex20ins NSCLC, including those who have exhausted multiple prior therapies and those with brain metastases, where therapeutic penetration and efficacy can be limited.
Safety and Tolerability Profile Supports Continued Development
The safety profile of zipalertinib remained consistent with previously reported findings, demonstrating manageable toxicity in this heavily pretreated population. All 244 patients who received at least one dose of zipalertinib were included in the safety analysis.
The most frequently reported treatment-related adverse events (TRAEs) were generally mild to moderate (Grade 1 or 2) and included:
- Paronychia (inflammation of the skin around the nails): 38.5%
- Rash: 30.3%
- Dermatitis acneiform: 24.6%
- Dry skin: 24.6%
- Diarrhea: 21.7%
- Stomatitis (inflammation of the mouth): 20.1%
Grade ≥3 TRAEs were relatively infrequent. The most common severe adverse events included:
- Anemia: 7%
- Pneumonitis: 2.5%
- Rash: 2.5%
- Increased alanine aminotransferase (ALT): 2.0%
- Diarrhea: 2.0%
- Decreased platelet count: 2.0%
No unexpected safety signals were observed, and the overall tolerability of the regimen supports continued clinical investigation and potential regulatory filing.
Positioning Zipalertinib in the Evolving NSCLC Treatment Landscape
The emergence of zipalertinib represents a significant advance for patients with EGFR exon 20 insertion mutations, a subgroup that has historically been difficult to treat. While existing therapies such as amivantamab and mobocertinib have provided some benefit, there remains an unmet need for effective, well-tolerated oral therapies that offer durable responses and activity in the brain.
Zipalertinib, developed by Cullinan Oncology in partnership with Taiho, is a novel oral EGFR inhibitor designed specifically to target exon 20 insertions with high selectivity. The REZILIENT1 trial data add to the growing body of evidence that this agent could offer a differentiated and valuable treatment option.
With a favorable balance of efficacy and safety demonstrated in a broad range of patients, including those with prior targeted therapy exposure and CNS metastases, zipalertinib is well-positioned for potential advancement into later-stage trials and regulatory discussions.
ASCO 2025 and Beyond
The presentation of the REZILIENT1 Phase 2b data at ASCO 2025 marks a critical milestone in the development of zipalertinib. As Cullinan Therapeutics and Taiho Oncology continue to work toward expanding treatment options for patients with hard-to-treat lung cancers, these findings may lay the groundwork for future Phase 3 studies and eventual submissions to regulatory agencies in the U.S., Europe, and Asia.
The companies have not yet disclosed timelines for next steps, but with robust efficacy and a manageable safety profile, zipalertinib is emerging as a promising contender in the targeted therapy space for EGFR ex20ins NSCLC. Continued data collection, further follow-up, and regulatory engagement will be essential to determine the drug’s future role in clinical practice.
For patients, advocates, and oncologists alike, the results from REZILIENT1 offer renewed optimism in the fight against one of the most challenging mutations in lung cancer.
