NMPA approves Zorifer (zorifertinib hydrochloride tablets) for NSCLC/EGFR+ Brain Metastases

Zorifertinib is currently the only available EGFR TKI specifically designed as a as non–blood-brain barrier efflux protein substrate that can fully penetrate the blood-brain barrier. The agent’s therapeutic advantages, including its ability to control intracranial lesions and prolong progression-free survival (PFS), were demonstrated in the phase III EVEREST trial (NCT03653546)..

In the phase III EVEREST trial (NCT03653546). Zorifertinib significantly reduced the risk of intracranial progression or death by 37% (P = .0018) vs a first-generation EGFR TKI and generated an intracranial PFS of 17.9 months. Consistent and significant benefits with zorifertinib were observed across patient subgroups, including those with intracranial symptoms, EGFR L858R mutations, and more than 3 intracranial lesions.

Additional results from EVEREST published in Med by CellPress in October 2024 showed that the median PFS with zorifertinib (n = 220) was 9.6 months vs 6.9 months with the control (n = 219; HR, 0.719; 95% CI, 0.580-0.893; P = .0024). Although overall survival (OS) data were immature at the time of analysis, a trend toward improved OS was observed among patients subsequently treated with third-generation TKI. In this patient subgroup, the estimated median OS was 37.3 months with zorifertinib vs 31.8 months with the control (HR, 0.833; 95% CI, 0.524-1.283). Regarding safety, the agent displayed a safety profile consistent with reported data.

In a news release, Yi-Long Wu, FACS, of Guangdong Provincial People’s Hospital in China, emphasized the lack of clinical head-to-head randomized trials addressing drug therapy for lung cancer with CNS metastases, despite the approval of multiple agents for EGFR-mutated NSCLC. Yilong, who is also the global lead principal investigator for the EVEREST study, added that these findings suggest that combining or sequencing zorifertinib with third-generation TKIs may lead to improved prognoses.

EVEREST is the world’s first large-scale, registered, international, multi-center, randomized controlled study evaluating zorifertinib in patients with advanced NSCLC and CNS metastases. The study enrolled patients with EGFR-sensitizing mutations, treatment-naive NSCLC, and at least 1 non-irradiated symptomatic or asymptomatic CNS metastasis. Documented MRI-confirmed CNS metastasis, no prior brain radiotherapy, no EGFR T790M, KRAS or cMET mutations, and an ECOG performance status of 0 or 1 was required. The study was conducted at 58 sites across mainland China, South Korea, Taiwan, and Singapore. Study enrollment began on February 1, 2019, and concluded on January 12, 2021. Upon enrollment, 439 patients were randomly assigned 1:1 to either 200 mg of zorifertinib twice-daily or a first-generation EGFR-TKI; the latter treatment included 250 mg of gefitinib (Iressa) or 150 mg of erlotinib (Tarceva) daily.

Citation:  WZhou Q, Yu Y, Xing L, et al. "First-line zorifertinib for EGFR-mutant non-small cell lung cancer with central nervous system metastases: The phase III EVEREST trial". Med. Published online October 3, 2024. doi:10.1016/j.medj.2024.09.002.