Zorifertinib Receives NMPA Approval for EGFR+ NSCLC With CNS Metastases

China’s National Medical Products Administration (NMPA) has approved zorifertinib hydrochloride tablets (Zorifer; formerly AZD3759) for the first-line treatment of adult patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 19 deletion or exon 21 L858R substitution mutations and central nervous system (CNS) metastases.¹

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 3 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).² 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.¹ 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.³

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.^2,3

The primary end point was PFS by blinded independent central review (BICR)-assessed per RECIST 1.1 criteria. Secondary end points included investigator-assessed PFS; intracranial and extracranial PFS; overall, intracranial and extracranial overall response rate, disease control rate, duration of response, and time to response; OS; quality of life; and safety.³

Zhang Yong, chief executive officer of Alpha Biopharma, the drug’s developer, added in the news release that the company is dedicated to developing innovative drugs for use in clinical practice.¹ “We have collaborated with AstraZeneca to develop zorifertinib, aiming to address the unmet clinical needs of patients with lung cancer and CNS metastases. Zorifertinib has demonstrated its therapeutic value during the clinical stage and has received support from clinical experts and regulatory authorities. It has become the world's first approved new generation EGFR-TKI specifically targeting lung cancer with CNS metastases. The company anticipates that zorifertinib will significantly enhance patient care in the future, offering more effective treatments for individuals with lung cancer and brain metastases.”

References

1. Alpha Biopharma received NMPA approval for zorifertinib tablets (Zorifer), the world's first EGFR-TKI for lung cancer with brain metastases.News release. Alpha Biopharma. November 20, 2024. Accessed November 20, 2024. https://www.prnewswire.com/news-releases/alpha-biopharma-received-nmpa-approval-for-zorifertinib-tablets-zorifer-the-worlds-first-egfr-tki-for-lung-cancer-with-brain-metastases-302311486.html
2. Zhou 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 3 EVEREST trial. Med. Published online October 3, 2024. doi:10.1016/j.medj.2024.09.002
3. Wu YL, Zhou Q, Wang J, et al. Randomized phase 3 study of first-line AZD3759 (zorifertinib) versus gefitinib or erlotinib in EGFR-mutant (EGFRm+) non–small-cell lung cancer (NSCLC) with central nervous system (CNS) metastasis. J Clin Oncol. 2023;41(16):9001. doi:10.1200/JCO.2023.41.16_suppl.9001