China’s NMPA to Review NDA of Zorifertinib for EGFR-Mutated NSCLC With CNS Metastases


The phase 2/3 EVEREST study of zorifertinib for patients with advanced EGFR-mutated non–small cell lung cancer with central nervous system metastases elicited significant efficacy and comparable safety to other tyrosine kinase inhibitors in this indication.

A new drug application (NDA) for zorifertinib (AZD3759) has been accepted by the Center for Drug Evaluation of the National Medical Products Administration for patients with advanced EGFR-mutated non–small cell lung cancer (NSCLC) with central nervous system (CNS) metastases, according to Alpha Biopharma.1

Zorifertinib is a next-generation EGFR tyrosine kinase inhibitor (TKI) which works by targeting sensitive EGFR mutations, including exon 19 deletion and exon 21 L858R, and is designed for complete blood-brain barrier permeability. The agent is specially designed to treat this patient population of individuals with advanced NSCLC harboring an EGFR mutation who also have CNS metastases.

The basis of this NDA comes from findings from the phase 2/3 EVEREST study (NCT03653546) which evaluated the efficacy and safety of first-line zorifertinib when used in this patient population.

"Clinical results from this high-quality, controlled study demonstrated that zorifertinib provided consistent and statistically significant benefits to [patients with] EGFR-mutated NSCLC with different levels of CNS metastasis. It could provide a much-needed new treatment option for these difficult-to-treat patients,” said Yilong Wu, professor, president of the Chinese Thoracic Oncology Group and the leading principal investigator of the EVEREST study, in the press release. “The development of zorifertinib represents a great example of a patient-centric, targeted precision approach to address unmet medical needs.”

The multinational, multicenter, randomized, open-label, controlled phase 2/3 EVEREST trial evaluated zorifertinib in the first-line. Patients with advanced EGFR-mutated NSCLC with CNS metastases were enrolled across 55 study locations located in the Chinese mainland, Taiwan, South Korea, and Singapore.2

A total of 492 patients aged 18 years and older who have had no prior treatment with chemotherapy, EGFR-TKIs, or biological therapies considered first-line treatment for advanced NSCLC were enrolled in the trial. All patients must have a documented diagnosis of advanced NSCLC with CNS metastases, not be candidates for definitive surgical resection or radiation of all lesions in the opinion of the treating physician, be stable without any systemic (oral or parenteral) corticosteroid or anticonvulsant therapy for at least 2 weeks prior to study treatment and have an ECOG performance status 0 or 1.

Patients were administered AZD3759 at 200 mg twice a day or a standard of care TKI of either erlotinib (Tarceva) at 150 mg or gefitinib (Iressa) at 250 mg orally twice a day.

The primary end point of the study was progression-free survival (PFS) with secondary end points including intracranial and extracranial PFS, objective response rate, disease control rate, duration of response, and overall survival.

According to results from the EVEREST study, zorifertinib led to a reduced risk of disease progression and death in this targeted patient population. Treatment with zorifertinib showed significant efficacy in treating metastatic lesions in the CNS and the safety profile of zorifertinib was comparable with EGFR-TKIs which are already approved.

“After many years of dedicated research and development, we are very pleased to witness that all pre-clinical and clinical data have demonstrated that zorifertinib can achieve and maintain high CNS exposures, that it is safe, and it is advantageous in controlling CNS and overall disease progression in this difficult-to-treat population. We look forward to working closely with the regulatory agencies around the world to bring this innovative treatment option to patients in dire need,” added Eric Zhang, chief executive officer of Alpha Biopharma, in the press release.

1. Alpha biopharma submits new drug application for zorifertinib, a next-generation EGFR-TKI to treat EGFR-mutated NSCLC patients with CNS metastases. News release. Alpha Biopharma. January 29, 2023. Accessed January 30, 2023.
2. First line treatment in EGFR mutation positive advanced NSCLC patients with central nervous system (CNS) metastases (BM). Updated November 21, 2022. Accessed January 30, 2023.
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