Vebreltinib Receives NMPA Approval in China for MET Fusion+ Glioma

China’s National Medical Products Administration (NMPA) has approved vebreltinib (APL-101; PLB-1001) for the treatment of patients with IDH-mutant, World Health Organization grade 4 astrocytoma or glioblastoma who harbor PTPRZ1-MET (ZM) fusions, have a history of low-grade disease, and have progressed on prior treatments.¹

Positive results from the phase 2/3 FUGEN study (NCT06105619) supported this approval, demonstrating a 48% reduction in the risk of death with vebreltinib monotherapy vs temozolomide or etoposide plus cisplatin. The median overall survival (OS) was 6.31 months in the vebreltinib monotherapy arm compared with 3.38 months in the control arm, significantly improving survival outcomes in patients with relapsed/recurrent ZM fusion–positive glioma. The agent also demonstrated an acceptable safety profile.

This regulatory decision marks the first global approval of a c-Met inhibitor for central nervous system (CNS) tumors expressing c-Met alterations. Vebreltinib was previously granted conditional marketing approval by the NMPA for the treatment of patients with non–small cell lung cancer (NSCLC) who displayed MET exon 14 skipping mutations in November 2023.²

As a highly selective, potent, and orally bioavailable c-Met inhibitor, vebreltinib was designed to counteract the aberrant activation of the HGF/c-Met pathway implicated in tumor growth, proliferation, and resistance to specific targeted therapies. Through this mechanism, vebreltinib offers potential therapeutic benefits for patients within this targeted population as well as those with other cancers characterized by c-MET alterations.

“The NMPA’s approval of vebreltinib in gliomas is an important, first-in-class approval as it demonstrates vebreltinib’s CNS penetration ability and c-Met inhibitory activity in the tumors there,” Guo-Liang Yu, PhD, chairman and chief executive officer of Apollomics, stated in a press release.¹ “Our collaboration with Avistone, which includes data-sharing, and our ongoing global [phase 2] SPARTA trial [NCT03175224] with vebreltinib underscores our commitment and the potential to develop vebreltinib for treating patients with solid tumors with c-Met alterations globally, outside of China.”

FUGEN is a randomized, two-arm, multicenter study compared safety and efficacy outcomes with vebreltinib vs either temozolomide or etoposide and cisplatin in patients with IDH-mutant glioblastoma expressing a ZM fusion.^1,3 From December 2018 to March 2023, the trial recruited 84 patients across 19 centers in China.

Patients were required to be at least 18 years of age and younger than 65 years, have histologically confirmed secondary glioblastoma or IDH-mutant glioblastoma, have confirmed expression of the ZM fusion gene in their latest surgical sample, and a life expectancy of 3 months or more. Those who experienced recurrence with prior radiotherapy and temozolomide treatment, had received temozolomide but were not suitable for radiotherapy, or had received radiotherapy but were intolerant to temozolomide, were also allowed to enroll.

Prior exposure to c-Met inhibitors or HGF-targeted agents, treatment with antibody-based agents within 30 days prior to enrollment, treatment with carmustine extended-release implants or intralesional radiotherapy, and an inability to undergo a brain MRI scan excluded patients from the study.

Patients were stratified according to whether they had a Karnofsky Performance Status between 60% and 80% vs 80% or higher, and randomly assigned 1:1 to the vebreltinib arm vs control arm.

In the experimental arm, patients receive a twice-daily 300 mg dose of oral vebreltinib every 28 days. Those in the control arm received a daily 100 to 150 mg/m2 dose of temozolomide for 7 days, followed by a 7-day interval every 28 days; or intravenous administration of an 80 to 100 mg/m2 dose of cisplatin along with a 100 mg/m2 dose of etoposide for 3 days every 28 days. Safety and efficacy were evaluated at the end of cycles 1 through 4, as well as cycles 6, 9 and 12.

The study’s primary efficacy end point is OS, with secondary end points of progression-free survival and objective response rate.

In addition to its ongoing evaluation in FUGEN, vebreltinib is currently being assessed in patients with METexon 14 skipping–positive NSCLC in the phase 2 study SPARTA trial (NCT03175224).1,4 This ongoing, multi-cohort study is being conducted across more than 90 centers in 12 countries and is currently recruiting patients.

Cohort A-1 comprises patients with MET exon 14 skipping–positive NSCLC in the first-line setting; cohort A-2 includes patients with this tumor type exposed to no more than 3 prior lines of therapy and naive to MET inhibitors. Cohort B consists of patients who received no more than 3 prior lines of therapy and has completed enrollment. Cohort C is evaluating patients with histology agnostic MET-amplified cancers, excluding primary CNS tumors; and cohort C-1 includes patients with c-Met–amplified NSCLC expressing wild-type EGFR.

Preliminary findings from SPARTA showed that patients with relapsed/recurrent c-Met altered CNS tumors treated with vebreltinib (n = 25) achieved a median OS of 6.5 months.¹ Of these patients, 8 had centrally confirmed ZM fusion–positive glioma; this subgroup also experienced a median OS of 6.5 months, indicating cross-region similarity of patient responses with vebreltinib.

References

1. Apollomics announces approval of vebreltinib in China as a first-in-class treatment for gliomas with MET fusion gene. News release. Apollomics Inc. April 25, 2024. Accessed April 25, 2024. https://ir.apollomicsinc.com/news-releases/news-release-details/apollomics-announces-approval-vebreltinib-china-first-class
2. Apollomics announces the first approval of vebreltinib for MET exon 14 skip non-small cell lung cancer. News release. Apollomics Inc. November 16, 2023. Accessed April 25, 2024. https://ir.apollomicsinc.com/news-releases/news-release-details/apollomics-announces-first-approval-vebreltinib-met-exon-14-skip
3. Bao Z, Li S, Wang L, et al. PTPRZ1-METFUsion GENe (ZM-FUGEN) trial: study protocol for a multicentric, randomized, open-label phase II/III trial. Chin Neurosurg J. 2023;9(1):21. doi:10.1186/s41016-023-00329-0
4. APL-101 study of subjects with NSCLC with c-MET exon 14 skip mutations and c-MET dysregulation advanced solid tumors (SPARTA). ClinicalTrials.gov. Updated October 23, 2023. Accessed April 25, 2024. https://clinicaltrials.gov/ct2/show/NCT03175224