Vebreltinib (APL-101): A Comprehensive Monograph on a Novel c-Met Inhibitor for MET-Altered Malignancies

Executive Summary

Vebreltinib is an investigational, orally bioavailable, small molecule inhibitor of the c-Met receptor tyrosine kinase, emerging as a potentially best-in-class therapeutic for cancers driven by mesenchymal-epithelial transition (MET) gene alterations. Its mechanism of action is characterized by potent, selective, and ATP-competitive inhibition of c-Met, leading to the disruption of oncogenic signaling and induction of apoptosis in tumor cells dependent on this pathway. The drug's development has been marked by a highly efficient, biomarker-driven clinical strategy, culminating in significant achievements in difficult-to-treat patient populations.

Clinically, Vebreltinib has demonstrated compelling efficacy in non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations, with the pivotal KUNPENG trial reporting an objective response rate of 75.0% and a median overall survival of 20.3 months. A key differentiating feature of Vebreltinib is its superior central nervous system (CNS) penetration, a preclinical property that has been validated by a 100% response rate in NSCLC patients with brain metastases and, most notably, a statistically significant overall survival benefit in the landmark FUGEN trial for patients with PTPRZ1−MET fusion-positive glioblastoma. This establishes Vebreltinib as a premier agent for MET-driven malignancies involving the CNS.

The drug's safety profile is considered manageable, characterized primarily by a high incidence of low-grade peripheral edema, a known class effect of MET inhibitors. Treatment-related adverse events are generally tolerable and rarely lead to discontinuation. Vebreltinib's development has followed a "China-first" regulatory and commercialization strategy, with its partner Avistone Biotechnology securing conditional approvals from China's National Medical Products Administration (NMPA) for both NSCLC and glioma. In the United States, Vebreltinib holds an Orphan Drug Designation, and its developer, Apollomics Inc., is advancing a global registration program with the Food and Drug Administration (FDA). Vebreltinib is poised to address critical unmet needs in MET-altered cancers, with its unique CNS activity providing a distinct and durable competitive advantage in the targeted therapy landscape.

I. Drug Profile and Chemical Characteristics

1.1. Nomenclature and Identifiers

Vebreltinib is a small molecule drug that has been assigned multiple names and codes throughout its development cycle, reflecting a complex, multi-partner history that has shaped its global clinical and commercial strategy.[1] The clarification of this nomenclature is essential for accurately tracking its progress across different regions and regulatory jurisdictions.

The officially recognized nonproprietary names are:

• International Nonproprietary Name (INN): Vebreltinib [1]
• United States Adopted Name (USAN): Vebreltinib [1]

In addition to its formal names, the compound is widely known by several synonyms and development codes. The most prominent of these are directly linked to the specific companies leading its development in distinct geographical territories. This naming convention is a direct result of an early-stage regional licensing strategy. Avistone Biotechnology and its subsidiary Beijing Pearl Biotechnology refer to the drug as PLB-1001 or Bozitinib in their development and regulatory filings within Greater China.[1] Concurrently, Apollomics Inc. uses the code

APL-101 for its development programs covering the rest of the world, including the United States and Europe.[9] Other historical codes include

CBT-101 and CBI-3103.[1] This bifurcated development structure, while allowing for shared risks and costs, necessitates careful coordination to present a unified clinical data package to global regulators, as is being done for the U.S. FDA submission which leverages data from both Chinese and global trials.[9]

For unambiguous identification in scientific literature and databases, Vebreltinib is cataloged under the following key identifiers:

• DrugBank ID: DB16823 [1]
• CAS Registry Number: 1440964-89-5 [1]
• PubChem Compound ID (CID): 72202701 [1]
• FDA Unique Ingredient Identifier (UNII): 2WZP8A9VFN [1]

1.2. Chemical Structure and Physicochemical Properties

Vebreltinib is classified as a synthetic organic small molecule belonging to the antineoplastic class.[1] Its complex heterocyclic structure is the basis for its high-affinity binding to the c-Met kinase.

• IUPAC Name: 6-(1-cyclopropylpyrazol-4-yl)-3-[difluoro-(6-fluoro-2-methylindazol-5-yl)methyl]-triazolo[4,3-b]pyridazine [1]
• Molecular Formula: C20​H15​F3​N8​ [1]
• Molecular Weight: Approximately 424.39 g/mol [1]

The two-dimensional structure of the molecule can be unambiguously represented by standard chemical notations:

• SMILES: CN1C=C2C=C(C(=CC2=N1)F)C(C3=NN=C4N3N=C(C=C4)C5=CN(N=C5)C6CC6)(F)F [1]
• InChIKey: QHXLXUIZUCJRKV-UHFFFAOYSA-N [1]

Computed physicochemical properties provide insight into the molecule's "drug-likeness" and potential pharmacokinetic behavior. These properties are generally consistent with those of an orally administered therapeutic agent, although some parameters fall outside the typical Lipinski Rule-of-Five guidelines, which is not uncommon for kinase inhibitors.

• Hydrogen Bond Acceptors: 5 to 8 [1]
• Hydrogen Bond Donors: 0 [3]
• Rotatable Bonds: 4 [1]
• Topological Polar Surface Area (TPSA): 78.7 Ų [1]
• Calculated LogP (XLogP): 5.93 [3]

II. Preclinical Pharmacology and Mechanism of Action

2.1. Primary Target: The c-Met Signaling Pathway in Oncogenesis

The therapeutic rationale for Vebreltinib is firmly rooted in its ability to inhibit the proto-oncogene c-Met, also known as the hepatocyte growth factor receptor (HGFR).[1] The c-Met signaling pathway is a critical regulator of essential cellular processes, including proliferation, survival, differentiation, motility, invasion, and angiogenesis.[16] While vital for normal embryonic development and adult tissue regeneration, aberrant activation of this pathway is a well-established driver of oncogenesis and metastasis in a wide array of human cancers.[15]

Dysregulation of c-Met signaling in tumor cells can occur through several distinct genomic mechanisms, making it a versatile therapeutic target. These mechanisms include:

• MET Gene Mutations: Specific point mutations can lead to constitutive activation of the kinase. A clinically important example is the mutation that causes aberrant splicing and subsequent skipping of exon 14 in the MET mRNA, resulting in a more stable and active receptor.[16]
• MET Gene Amplification: An increased copy number of the MET gene leads to overexpression of the c-Met protein on the cell surface, resulting in ligand-independent signaling.[16]
• MET Gene Fusions/Rearrangements: Chromosomal rearrangements can create fusion proteins (e.g., PTPRZ1−MET) that contain the c-Met kinase domain, leading to its constitutive activation.[16]
• Protein Overexpression: Increased expression of the c-Met receptor and/or its ligand, HGF, can also drive oncogenic signaling.[16]

The diversity of these activation mechanisms underscores the potential for c-Met inhibitors like Vebreltinib to be effective in a "tumor-agnostic" manner, where treatment is guided by the presence of a specific biomarker (MET alteration) rather than the anatomical origin of the tumor.[16]

2.2. Molecular Mechanism of Vebreltinib Inhibition

Vebreltinib is a novel, potent, and selective small molecule inhibitor designed for oral administration.[1] Its antineoplastic activity is achieved through direct and specific interference with the c-Met kinase function.

At the molecular level, Vebreltinib functions as an ATP-competitive inhibitor.[3] It binds reversibly to the ATP-binding pocket within the intracellular kinase domain of the c-Met receptor. This physical occupation of the active site prevents the binding of endogenous ATP, which is the necessary phosphate donor for kinase activity.[3] By blocking ATP binding, Vebreltinib directly inhibits the autophosphorylation of tyrosine residues on the c-Met receptor, which is the initial and critical step in signal transduction upon ligand binding or constitutive activation.[1]

The inhibition of c-Met phosphorylation effectively shuts down the entire downstream signaling cascade. This disrupts key pro-cancer pathways, including the RAS-RAF-MEK-ERK pathway (involved in proliferation) and the PI3K-AKT-mTOR pathway (critical for cell survival).[21] The ultimate consequence of this signaling blockade in MET-dependent tumor cells is the induction of apoptosis, or programmed cell death, leading to tumor growth inhibition and regression.[1] The high potency of Vebreltinib is quantified by a preclinical inhibition constant (

Ki​) of approximately 2.2 nM, indicating very high affinity for its target.[19]

2.3. Kinome Selectivity and Off-Target Activity

A critical attribute of any targeted therapy is its selectivity for the intended target over other related proteins, as this largely determines the therapeutic window. The available evidence overwhelmingly characterizes Vebreltinib as a highly selective Type 1b class c-Met inhibitor.[16] This exquisite kinome selectivity means it has a much higher affinity for c-Met than for other kinases in the human genome, which is expected to minimize off-target toxicities.[19]

One source described a broader, multi-targeted profile for Vebreltinib, suggesting inhibitory activity against other receptor tyrosine kinases such as EGFR, ALK, and ROS1.[21] However, this assertion is inconsistent with the vast majority of preclinical and clinical data. The entire clinical development program has been narrowly focused on patient populations with specific

MET gene alterations, and a key strategic area of investigation is the combination of Vebreltinib with EGFR inhibitors to overcome resistance.[23] This combination strategy would be irrational if Vebreltinib were already a potent EGFR inhibitor. Therefore, the preponderance of evidence supports the classification of Vebreltinib as a highly selective c-Met inhibitor.

2.4. Preclinical Pharmacodynamics and Anti-Tumor Activity

Prior to human trials, Vebreltinib underwent extensive preclinical evaluation that provided strong proof-of-concept for its anti-tumor activity. It demonstrated significant tumor growth inhibition in a variety of in vivo models, including cell line-derived xenografts and more clinically relevant patient-derived xenograft (PDX) models of human gastric, hepatic, pancreatic, and lung cancers harboring MET-driver alterations.[16]

In the MET-amplified MKN45 gastric cancer xenograft model, Vebreltinib showed a dose-dependent anti-tumor effect, with an effective dose for 90% tumor growth inhibition (ED90​) of 6.1 mg/kg administered orally once daily.[19] Pharmacodynamic studies in this model confirmed a direct link between drug exposure and target engagement. Doses associated with anti-tumor efficacy achieved a plasma concentration that resulted in 50% inhibition of c-Met phosphorylation (

EC50​) of 886 ng/mL and sustained this target inhibition (≥50%) for at least 16 hours post-administration.[19]

Significantly, preclinical models also suggested that Vebreltinib may be active against tumors that have developed resistance to other MET tyrosine kinase inhibitors (TKIs). It retained activity against cell lines engineered with secondary kinase domain mutations known to confer resistance to both type I MET TKIs (such as capmatinib, tepotinib, and crizotinib) and type II MET TKIs (such as cabozantinib).[19] This finding is of high strategic importance, as it implies a potential clinical role for Vebreltinib in treating patients who have progressed on earlier-generation MET inhibitors, addressing a significant and growing unmet medical need.

2.5. Preclinical Pharmacokinetics and CNS Penetration

Vebreltinib was designed for convenient oral administration and is characterized as being orally bioavailable.[1] However, its most compelling and differentiating pharmacokinetic property identified in preclinical studies is its ability to cross the blood-brain barrier (BBB).[3]

Preclinical cell models demonstrated that Vebreltinib possesses superior BBB permeability when compared to other c-Met inhibitors.[16] This property is of immense clinical significance, as the brain is a frequent site of metastasis for many solid tumors, and primary brain tumors like glioblastoma are notoriously difficult to treat due to the inability of most systemic therapies to achieve therapeutic concentrations in the CNS. This strong preclinical signal for CNS penetration was not merely an ancillary finding but became a central pillar of Vebreltinib's clinical development strategy. It provided a strong scientific rationale and significantly de-risked the decision to investigate the drug in patients with primary CNS tumors and those with brain metastases, a strategy that has since yielded impressive clinical results.

III. Clinical Development Program

3.1. Overview of Phase 1 Studies: Safety, Tolerability, and Recommended Phase 2 Dose (RP2D)

The clinical development of Vebreltinib began with Phase 1 studies designed to assess its safety, tolerability, and pharmacokinetic profile in human subjects, and to determine the optimal dose for further investigation. These early-phase trials successfully established a generally well-tolerated safety profile and identified a Recommended Phase 2 Dose (RP2D) of 200 mg administered orally twice daily (BID).[16] This dose has been consistently used in all subsequent pivotal Phase 2 and 3 studies, providing a uniform basis for evaluating efficacy across different patient populations.[22]

Beyond establishing safety and dosage, these initial trials also provided the first crucial signals of Vebreltinib's anti-tumor activity in its target populations. Preliminary evidence of clinical activity was observed in patients with NSCLC harboring MET exon 14 skipping mutations and in patients with secondary glioblastoma multiforme (sGBM) harboring MET fusions.[16] These early efficacy signals were instrumental in building confidence in the drug's mechanism and guiding the design of the later-stage, registration-enabling trials. Furthermore, a dedicated Phase 1 bioequivalence study (NCT05367388) was conducted to formally compare the APL-101 and PLB-1001 capsule formulations, a necessary step to bridge the clinical data generated in the global and Chinese development programs for regulatory submissions.[28]

3.2. Pivotal Trials in MET-Altered Cancers: KUNPENG, SPARTA, and FUGEN

The clinical evidence supporting Vebreltinib rests on a foundation of three key pivotal trials, each designed to address a specific patient population and regulatory goal. This program demonstrates a highly efficient, biomarker-driven strategy that simultaneously pursues both broad, tumor-agnostic signals and specific, indication-based approvals in areas of high unmet need.

• KUNPENG (NCT04258033): This was a pivotal Phase 2, single-arm, multicenter study conducted exclusively in China. It was designed to evaluate the efficacy and safety of Vebreltinib (as PLB-1001) in patients with locally advanced or metastatic NSCLC harboring MET exon 14 skipping mutations.[14] The robustly positive results from this trial formed the primary basis for the drug's first conditional approval from China's NMPA.[7]
• SPARTA (NCT03175224): This is an ongoing global Phase 1/2, single-arm, multi-cohort "basket" trial that serves as the cornerstone of the global (ex-China) development program. The trial's innovative design allows for the simultaneous evaluation of Vebreltinib (as APL-101) across a range of solid tumors defined by specific MET alterations.[25] Its key cohorts include patients with:
• NSCLC with MET exon 14 skipping (both MET inhibitor-naïve and experienced)
• Solid tumors with MET amplification (a pan-cancer cohort)
• Solid tumors with MET fusions (a pan-cancer cohort)
• Primary CNS tumors with MET alterations.[17]

This master protocol design enables rapid signal-seeking across multiple populations and is intended to support regulatory submissions in the U.S. and other regions.17

• FUGEN: This was a randomized, multicenter, open-label, Phase 2/3 trial conducted in China. It was the first study of its kind, comparing the efficacy and safety of Vebreltinib against standard-of-care chemotherapy in patients with previously treated, secondary glioblastoma or IDH-mutant glioblastoma that harbors the specific PTPRZ1−MET fusion gene.[23] The trial's success in demonstrating a statistically significant survival benefit led to Vebreltinib's second NMPA approval, establishing it as a new standard of care for this rare and aggressive brain tumor.[10]

3.3. Rationale and Status of Combination Therapy Trials

A key component of Vebreltinib's long-term strategy involves its use in combination with other anticancer agents to enhance efficacy, overcome resistance, and expand its therapeutic reach.

• Combination with EGFR Inhibitors: The most advanced combination strategy is with EGFR tyrosine kinase inhibitors (TKIs) for the treatment of EGFR-mutant NSCLC. The scientific rationale is compelling: amplification of the MET gene is a primary mechanism of acquired resistance to EGFR TKIs.[23] By co-administering a MET inhibitor like Vebreltinib with an EGFR TKI, it is hypothesized that this resistance mechanism can be overcome or delayed, leading to improved patient outcomes. Several clinical trials are actively exploring this approach, including studies combining Vebreltinib with the third-generation EGFR TKI osimertinib (NCT06827145) and with another EGFR TKI, andamertinib (PLB1004), in the KYLIN-1 study (NCT06343064).[23]
• Combination with Immune Checkpoint Inhibitors (ICIs): Preclinical data suggested potential synergy between MET inhibition and immunotherapy.[16] This led to the initiation of the APOLLO trial (NCT03655613), which investigated Vebreltinib in combination with the anti-PD-1 antibody nivolumab in patients with renal cell carcinoma and with another anti-PD-1 agent (APL-501) in hepatocellular carcinoma.[16]
• Neoadjuvant Setting: Vebreltinib is also being explored in earlier stages of disease. The initiation of a Phase 2 trial (NCT06644313) to evaluate Vebreltinib as a neoadjuvant (pre-surgical) therapy for patients with resectable Stage IIIA-IIIB MET-altered NSCLC represents a significant strategic move.[23] The goal of neoadjuvant therapy is to shrink the tumor prior to surgery, thereby increasing the likelihood of a complete (R0) resection and improving long-term, potentially curative outcomes like event-free survival.[35] Success in this setting would position Vebreltinib much earlier in the treatment paradigm and significantly expand its potential market beyond the advanced/metastatic setting.

IV. Clinical Efficacy Analysis

The clinical efficacy of Vebreltinib has been rigorously evaluated across multiple trials, demonstrating robust and consistent anti-tumor activity in patient populations defined by specific MET gene alterations. The data are particularly strong in NSCLC with MET exon 14 skipping and in MET-fusion positive gliomas, with emerging evidence supporting its utility in a broader pan-cancer context.

Table 1: Summary of Key Clinical Trials for Vebreltinib
Trial Name (Identifier)	Phase	Design	Patient Population (Indication & Biomarker)	N	Key Efficacy Results	Status/Source
KUNPENG	II	Single-Arm	NSCLC with MET exon 14 skipping	52	ORR: 75.0%; mPFS: 14.3 months; mOS: 20.3 months	Completed 22
FUGEN	II/III	Randomized vs. Chemo	Glioblastoma with PTPRZ1−MET fusion	81	mOS: 6.31 vs 3.38 months (HR=0.52, p=0.009)	Completed 22
SPARTA (MET Fusion Cohort)	II	Single-Arm	Pan-Cancer Solid Tumors with MET fusion	14	ORR: 43%; mOS: 12.4 months; mPFS: 4.5 months	Ongoing (Prelim. data) 25
KYLIN-1	Ib/II	Single-Arm	EGFRm+ NSCLC w/ MET amp after TKI failure	56	ORR: 50.0%; mPFS: 9.9 months	Ongoing 34

Abbreviations: ORR, Objective Response Rate; mPFS, median Progression-Free Survival; mOS, median Overall Survival; HR, Hazard Ratio; NSCLC, Non-Small Cell Lung Cancer; TKI, Tyrosine Kinase Inhibitor.

4.1. Efficacy in Non-Small Cell Lung Cancer with MET Exon 14 Skipping

The most mature and compelling efficacy data for Vebreltinib comes from the pivotal Phase 2 KUNPENG study in patients with locally advanced or metastatic NSCLC harboring MET exon 14 skipping mutations. The results from this trial, which enrolled both treatment-naïve and previously treated patients, have established Vebreltinib as a highly active agent in this setting.[7]

In the primary efficacy analysis of 52 patients, the key outcomes assessed by a blinded independent review committee (BIRC) were:

• Objective Response Rate (ORR): 75.0% (95% CI, 61.1% to 86.0%), indicating that three-quarters of patients experienced significant tumor shrinkage.[19]
• Disease Control Rate (DCR): 96.2% (95% CI, 86.8% to 99.5%), demonstrating that nearly all patients derived at least stable disease from the treatment.[22]
• Median Duration of Response (mDoR): 16.5 months, highlighting the durability of the responses.[22]
• Median Progression-Free Survival (mPFS): 14.3 months, a substantial improvement over historical outcomes with chemotherapy.[22]
• Median Overall Survival (mOS): 20.3 months, showing a meaningful survival benefit.[22]

The efficacy of Vebreltinib was consistently high across various clinically important subgroups. Notably, in the particularly difficult-to-treat population of patients with baseline brain metastases (N=5), the ORR was 100%.[22] This remarkable result provides strong clinical validation of the drug's excellent CNS penetration. High activity was also maintained in patients with baseline liver metastases (ORR 66.7%) and in those with co-occurring

MET gene amplification (ORR 100%).[22]

4.2. Efficacy in Primary Central Nervous System Tumors with MET Alterations

Vebreltinib's superior CNS activity, first suggested in preclinical models, has been definitively confirmed in the clinical setting, most notably in the randomized Phase 2/3 FUGEN trial. This study evaluated Vebreltinib in patients with PTPRZ1−MET fusion-positive, recurrent glioblastoma, a patient population with a dismal prognosis and no effective targeted therapies.[10]

The FUGEN trial met its primary and key secondary endpoints, demonstrating a statistically significant and clinically meaningful improvement in survival compared to standard chemotherapy:

• Median Overall Survival (mOS): Patients treated with Vebreltinib had a median OS of 6.31 months, nearly double that of the 3.38 months observed in the chemotherapy arm. This represented a 48% reduction in the risk of death (Hazard Ratio = 0.52; p=0.009).[10]
• Median Progression-Free Survival (mPFS): Vebreltinib also significantly extended mPFS to 1.87 months compared to 1.05 months with chemotherapy (HR = 0.54; p=0.014).[22]

Interestingly, the profound survival benefit was observed despite a non-significant difference in the ORR between the two arms (9.5% for Vebreltinib vs. 2.6% for chemotherapy).[31] This disconnect between response rate and survival is not uncommon for targeted agents in glioblastoma and suggests that Vebreltinib's primary clinical benefit in this context may be cytostatic (inhibiting tumor growth and stabilizing disease) rather than overtly cytotoxic (causing rapid tumor shrinkage). This sustained disease control translates directly into longer survival, a highly meaningful outcome in this devastating disease. The collective evidence from the FUGEN trial and the NSCLC brain metastasis cohort solidifies Vebreltinib's position as a premier therapeutic agent for MET-driven cancers involving the CNS.

4.3. Efficacy in Pan-Cancer Cohorts with MET Fusions and Amplifications

The SPARTA trial is exploring the potential of Vebreltinib beyond its initial indications in a tumor-agnostic manner. Preliminary data from the cohort of patients with solid tumors harboring MET fusions (excluding primary CNS tumors) shows promising and broad anti-tumor activity.[25]

As of a July 2024 data cutoff for 14 evaluable patients with diverse cancer types (including NSCLC, pancreatic cancer, colon cancer, and bile duct cancer), the results were:

• ORR: 43%, which included one complete response and five partial responses.[25]
• mOS: 12.4 months.[25]
• mPFS: 4.5 months.[25]

These early data suggest that MET fusions are actionable targets across multiple histologies and that Vebreltinib has the potential for a broad, biomarker-defined label. In a further indication of its expanding utility, Avistone has submitted a new drug application to China's CDE for the treatment of NSCLC with MET amplification, which has been granted priority review, signaling the existence of a positive dataset for this patient population as well.[37]

4.4. Emerging Efficacy of Combination Regimens

Initial results from studies combining Vebreltinib with EGFR TKIs are validating the strategy of dual pathway inhibition to overcome resistance. The Phase 1b/2 KYLIN-1 study is evaluating Vebreltinib plus the EGFR TKI andamertinib (PLB1004) in 56 patients with EGFR-mutant NSCLC who had progressed on prior EGFR TKI therapy due to MET amplification.[34]

The combination therapy demonstrated significant clinical activity:

• ORR: 50.0%.[34]
• mPFS: 9.9 months.[34]
• CNS Efficacy: Consistent with Vebreltinib's known properties, the combination showed robust activity in 19 patients with brain metastases, achieving an ORR of 42.1% and an mPFS of 9.5 months.[34]

These results provide strong clinical proof-of-concept for this combination approach and have led to the initiation of a randomized Phase 3 trial (KYLIN-3) to confirm these findings.[37]

V. Safety and Tolerability Profile

The safety of Vebreltinib has been evaluated in over 500 patients and 170 healthy volunteers across its clinical development program.[27] The overall safety profile is considered acceptable and generally manageable, with most adverse events being low-grade and rarely leading to treatment discontinuation.[21]

Table 2: Summary of Common Treatment-Related Adverse Events (TRAEs) with Vebreltinib (KUNPENG Study, N=52)
Adverse Event	Any Grade Frequency (%)	Grade ≥3 Frequency (%)
Peripheral Edema	82.7%	13.5%
QT Prolongation	30.8%	1.9%
Elevated Serum Creatinine	28.8%	1.9%
Hypoalbuminemia	26.9%	0.0%
Anemia	25.0%	3.8%
Hypoproteinemia	25.0%	0.0%
Elevated Alanine Aminotransferase (ALT)	23.1%	7.7%
Pruritus	23.1%	0.0%
Weight Gain	23.1%	0.0%
Elevated Lipase	21.2%	5.8%
Abnormal Liver Function	15.4%	9.6%
Elevated Aspartate Aminotransferase (AST)	15.4%	5.8%

Data compiled from [41] and.[38]

5.1. Summary of Treatment-Emergent Adverse Events

Across the clinical program, the vast majority of patients experience at least one treatment-related adverse event (TRAE). In a pooled analysis of 135 patients from the KUNPENG study, the most frequently reported TRAEs (≥20% incidence) were peripheral edema (56.3%), hypoalbuminemia (27.4%), hypoproteinemia (25.9%), and anemia (20.7%).[36] Data from a 52-patient cohort also highlighted QT prolongation (30.8%) and elevated serum creatinine (28.8%) as common events.[38]

5.2. Analysis of Common and Clinically Significant Toxicities

The majority of TRAEs associated with Vebreltinib are mild to moderate (Grade 1 or 2) in severity.[36] The high incidence of peripheral edema is a known class effect of MET inhibitors. While a very common event with Vebreltinib (any-grade incidence of 56-83%), the rate of severe (Grade ≥3) edema is substantially lower, reported at 13.5%.[38] This profile, while requiring clinical vigilance and management (e.g., with diuretics or dose modification), appears to be within the expected range for this drug class and is generally considered manageable.

The overall rate of Grade 3 or higher TRAEs in the KUNPENG NSCLC study was 48.1%.[38] Besides peripheral edema, the most common Grade ≥3 events were related to liver function, including abnormal liver function (9.6%) and elevated ALT (7.7%).[27] In the FUGEN trial for glioblastoma, Vebreltinib demonstrated a more favorable safety profile compared to chemotherapy, with a markedly lower rate of Grade 3-4 TRAEs (7% vs. 12.2%).[31] Importantly, no treatment-related deaths have been reported in the pivotal KUNPENG or FUGEN studies.[31]

5.3. Dose Modifications and Management of Adverse Events

The clinical trial protocols for Vebreltinib include clear guidelines for managing adverse events through dose modifications. To manage intolerable toxicity, the standard 200 mg BID dose can be reduced sequentially to 150 mg BID and then to a minimum of 100 mg BID.[38] This structured approach to dose reduction allows most patients to continue treatment, and despite the high frequency of low-grade AEs, treatment discontinuations due to toxicity have been reported to be rare.[23]

5.4. Potential Drug-Drug Interactions and Contraindications

While specific drug-drug interaction studies for Vebreltinib are not detailed in the provided materials, its metabolism and potential for interactions can be inferred from its class as an oral small-molecule kinase inhibitor.[42]

• Drug Interactions: Like many oral oncolytics, Vebreltinib is likely a substrate for the cytochrome P450 3A4 (CYP3A4) enzyme system in the liver.[42] This creates a high potential for pharmacokinetic interactions:
• CYP3A4 Inhibitors: Co-administration with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, voriconazole) is expected to increase Vebreltinib plasma concentrations, potentially leading to increased toxicity. Dose reduction of Vebreltinib may be required.[42]
• CYP3A4 Inducers: Co-administration with strong CYP3A4 inducers (e.g., rifampin, carbamazepine, St. John's Wort) is expected to decrease Vebreltinib plasma concentrations, potentially reducing its efficacy. This combination should generally be avoided.[42]
• Acid-Reducing Agents: Drugs that increase gastric pH, such as proton pump inhibitors and H2-receptor antagonists, can decrease the absorption of some oral kinase inhibitors. It is often recommended to space the administration of these medications apart from Vebreltinib.[43]
• Contraindications and Precautions:
• Vebreltinib is contraindicated in patients with a known hypersensitivity to the active substance or any of its excipients.[43]
• Due to the potential for harm to a developing fetus, it is contraindicated in pregnant and breastfeeding women.[43]
• Caution is advised in patients with pre-existing cardiac conditions, given the observed risk of QT interval prolongation, or in those with significant hepatic impairment.[43]
• Clinical trial exclusion criteria further delineate populations at higher risk, including patients with a history of interstitial lung disease, uncontrolled systemic diseases, or other recent malignancies.[35]

VI. Regulatory and Commercial Landscape

6.1. Global Regulatory Status and Approvals

Vebreltinib's regulatory journey is a prime example of a modern, "China-first" global drug development strategy. By achieving initial approvals in a major market, the program has been significantly de-risked both clinically and financially, creating a stronger foundation for subsequent submissions to Western regulatory agencies like the FDA.

• China (National Medical Products Administration - NMPA): Vebreltinib has secured two conditional approvals in China, making it a commercial-stage product in that territory.

1. November 2023: Conditional approval was granted for the treatment of adult patients with locally advanced or metastatic NSCLC harboring a MET exon 14 skipping mutation. This was based on the positive results of the pivotal KUNPENG study.[7]
2. April 2024: The label was expanded to include the treatment of adult patients with recurrent, isocitrate dehydrogenase (IDH)-mutant astrocytoma with a PTPRZ1−MET fusion gene, or glioblastoma with a history of lower-grade disease. This first-in-class approval was based on the FUGEN trial's demonstration of a significant survival benefit.[10]

Furthermore, in December 2024, a New Drug Application (NDA) for a third indication—the treatment of NSCLC with MET amplification—was accepted by the Center for Drug Evaluation (CDE) and granted priority review status, signaling a high likelihood of another label expansion.37

• United States (Food and Drug Administration - FDA): Vebreltinib is currently an investigational drug in the U.S. but is on a clear path toward a regulatory submission.
• August 2022: The FDA granted Vebreltinib an Orphan Drug Designation for the "Treatment of Non-Small Cell Lung Cancer with MET Genomic Tumor Aberrations".[17] This designation provides significant development incentives, including potential market exclusivity for seven years post-approval, tax credits, and exemption from PDUFA fees.[17]
• NDA Pathway: Apollomics is engaged in active discussions with the FDA regarding an NDA submission. The company plans to leverage the totality of clinical data from both the global SPARTA trial and the Chinese KUNPENG trial to support its application for the METex14 NSCLC indication.[9] Following a meeting with the FDA in February 2024, Apollomics will continue to enroll patients in the SPARTA trial into 2025. This may lead to a potential NDA submission in 2026, initially seeking accelerated approval for Vebreltinib as a second-line treatment for NSCLC patients with MET amplification.[46]
• Europe (European Medicines Agency - EMA): There is no specific information available regarding regulatory filings or status with the EMA at this time.[9]

6.2. Corporate Development, Partnerships, and Commercial Rights

The development and commercialization of Vebreltinib are managed through a network of strategic partnerships that divide global rights and responsibilities.

• Originator: The molecule was originally developed by Crown Bioscience.[2]
• Key Developers and Partnership Structure: The primary development is led by Apollomics Inc. and Avistone Biotechnology Co., Ltd. (which acquired Beijing Pearl Biotechnology).[2] The partnership agreement establishes a clear geographical division of the asset:
• Avistone Biotechnology: Holds the exclusive rights to develop and commercialize Vebreltinib in Greater China (mainland China, Hong Kong, and Macau). They are responsible for all clinical development and commercial activities within this territory.[7]
• Apollomics Inc.: Retains the exclusive rights to Vebreltinib for the rest of the world, including the key markets of the United States and Europe. They are responsible for the global SPARTA trial and all regulatory and commercial activities outside of Greater China.[9]

A crucial component of this partnership is a data-sharing agreement, which allows both companies to access each other's clinical trial data.9 This synergy is vital, as it enables Apollomics to use the robust data from the Chinese KUNPENG and FUGEN trials to strengthen its regulatory submissions to the FDA and other global health authorities.

• Additional Partnerships: In March 2025, Apollomics further expanded its partnership network by entering into an agreement with LaunXP Biomedical. This agreement grants LaunXP the rights to develop and commercialize Vebreltinib in combination with an EGFR inhibitor for NSCLC in Asia (excluding Greater China).[24]

VII. Strategic Analysis and Future Outlook

7.1. Synthesis of Vebreltinib's Therapeutic Profile: Strengths and Limitations

Vebreltinib has cultivated a distinct and compelling therapeutic profile that positions it for success in the competitive oncology market.

• Strengths:
• Potent and Selective MET Inhibition: The drug has demonstrated robust and durable clinical responses in cancers that are genomically defined as being dependent on the MET pathway.
• Clinically Validated CNS Activity: This is arguably Vebreltinib's most significant strength and key differentiator. The combination of a 100% ORR in NSCLC brain metastases, a statistically significant survival benefit in primary glioblastoma, and strong combination therapy activity in the CNS provides an unparalleled level of clinical evidence for its ability to treat MET-driven cancers in the brain.
• Broad Pan-Cancer Potential: With activity demonstrated against MET exon 14 skipping, MET fusions, and MET amplification across diverse tumor types, Vebreltinib has the potential for a broad, tumor-agnostic label.
• Favorable Safety Profile: While adverse events are common, they are predominantly low-grade and manageable. The safety profile appears favorable when compared directly to chemotherapy in the glioma setting.[31]
• Limitations and Challenges:
• High Incidence of Low-Grade Edema: Peripheral edema is a very common side effect that, while rarely severe, can impact patient quality of life and requires proactive clinical management.
• Competitive Landscape: The therapeutic space for MET inhibitors is maturing, with several approved agents (e.g., capmatinib, tepotinib) and others in late-stage development. Vebreltinib will need to differentiate itself clearly to capture market share.
• Dependence on Biomarker Testing: As a targeted therapy, Vebreltinib's use is entirely dependent on the availability and adoption of high-quality, comprehensive genomic testing to identify patients with the requisite MET alterations.

7.2. Positioning in the MET Inhibitor Landscape

Vebreltinib is strategically positioned as a potential best-in-class MET inhibitor. While it will compete with existing agents in the METex14 NSCLC market, its future commercial success will likely be defined by its dominance in the "MET + CNS" niche. Its approval in China for glioblastoma is a first-in-class achievement for any MET inhibitor, carving out a unique market where competitors have not demonstrated similar efficacy. The powerful clinical data in both primary brain tumors and brain metastases provides a compelling and defensible advantage. For any patient with a MET-altered cancer that involves the CNS, Vebreltinib presents itself as the essential and evidence-backed therapeutic choice. Furthermore, preclinical data suggesting activity against mutations that confer resistance to other MET TKIs could position it as a valuable second-line therapy in a sequential treatment paradigm.[19]

7.3. Future Development Trajectories and Unmet Needs

The future development of Vebreltinib is focused on expanding its global reach, moving into earlier lines of therapy, and solidifying its role in combination regimens.

• Global Regulatory Approvals: The most critical near-term objective for Apollomics is to secure FDA approval for MET-altered NSCLC, which will validate the drug in a major Western market and unlock significant commercial value.
• Combination Therapies: The combination of Vebreltinib with EGFR inhibitors represents a major growth opportunity. If the ongoing Phase 3 KYLIN-3 trial is successful, this combination could become a new standard of care for a large population of EGFR-mutant NSCLC patients who develop MET-mediated resistance.
• Earlier Lines of Therapy: The neoadjuvant NSCLC trial is a key component of the drug's life cycle management. Success in this earlier, potentially curative setting would establish Vebreltinib as a foundational therapy and dramatically expand its eligible patient population.
• Tumor-Agnostic Expansion: Continued positive data from the pan-cancer cohorts of the SPARTA trial could support a broad, tumor-agnostic approval based on the presence of a MET fusion or amplification, regardless of the cancer's tissue of origin. This remains one of the most valuable and sought-after regulatory outcomes in modern oncology.

Works cited

1. Vebreltinib | C20H15F3N8 | CID 72202701 - PubChem, accessed August 22, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Bozitinib
2. Vebreltinib - Apollomics/Beijing Pearl Biotechnology - AdisInsight - Springer, accessed August 22, 2025, https://adisinsight.springer.com/drugs/800047623
3. vebreltinib | Ligand page - IUPHAR/BPS Guide to PHARMACOLOGY, accessed August 22, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=11677
4. Vebreltinib - Orphanet, accessed August 22, 2025, https://www.orpha.net/en/drug/substance/637226?name=&mode=pat®ion=&status=all
5. Drug Information | Therapeutic Target Database, accessed August 22, 2025, https://db.idrblab.net/ttd/data/drug/details/dv3y7f
6. STATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL USAN (HI-156) VEBRELTINIB PRONUNCIATION veb rel' ti nib THERAPE, accessed August 22, 2025, https://searchusan.ama-assn.org/usan/documentDownload?uri=/unstructured/binary/usan/vebreltinib-.pdf
7. Avistone Announces the First Approval of Vebreltinib for MET Exon 14 Skipping Non-Small Cell Lung Cancer Opening a New Chapter in MET-targeted Treatment of Lung Cancer - BioSpace, accessed August 22, 2025, https://www.biospace.com/avistone-announces-the-first-approval-of-vebreltinib-for-met-exon-14-skipping-non-small-cell-lung-cancer-opening-a-new-chapter-in-met-targeted-treatment-of-lung-cancer
8. Apollomics Presents Interim Data from Two Ongoing Phase 2 Clinical Trials with Vebreltinib in NSCLC Patients with MetExon14 Skipping Mutation - BioSpace, accessed August 22, 2025, https://www.biospace.com/apollomics-presents-interim-data-from-two-ongoing-phase-2-clinical-trials-with-vebreltinib-in-nsclc-patients-with-metexon14-skipping-mutation
9. Apollomics Announces the First Approval of Vebreltinib for MET Exon 14 Skip Non-Small Cell Lung Cancer - Investor Relations, accessed August 22, 2025, https://ir.apollomicsinc.com/news-releases/news-release-details/apollomics-announces-first-approval-vebreltinib-met-exon-14-skip/
10. Apollomics Announces Approval of Vebreltinib in China as a First-in-Class Treatment for Gliomas with MET Fusion Gene - GlobeNewswire, accessed August 22, 2025, https://www.globenewswire.com/news-release/2024/04/25/2869647/0/en/Apollomics-Announces-Approval-of-Vebreltinib-in-China-as-a-First-in-Class-Treatment-for-Gliomas-with-MET-Fusion-Gene.html
11. VEBRELTINIB - precisionFDA, accessed August 22, 2025, https://precision.fda.gov/ginas/app/ui/substances/2WZP8A9VFN
12. Vebreltinib - Wikipedia, accessed August 22, 2025, https://en.wikipedia.org/wiki/Vebreltinib
13. Vebreltinib | CAS No. 1440964-89-5 | Clearsynth, accessed August 22, 2025, https://clearsynth.com/product-details/vebreltinib
14. Vebreltinib - Drug Targets, Indications, Patents - Patsnap Synapse, accessed August 22, 2025, https://synapse.patsnap.com/drug/661efae12e8547c0abfd26772a21e41e
15. Definition of vebreltinib - NCI Drug Dictionary, accessed August 22, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/vebreltinib
16. Vebreltinib (APL-101) - Apollomics, Inc., accessed August 22, 2025, https://www.apollomicsinc.com/pipeline-drugs/apl-101/
17. Apollomics Inc. Receives FDA Orphan Drug Designation for Vebreltinib (APL-101) for Treatment of Non-Small Cell Lung Cancer with MET Genomic Tumor Aberrations, accessed August 22, 2025, https://www.apollomicsinc.com/investors/apollomics-inc-receives-fda-orphan-drug-designation-for-vebreltinib-apl-101-for-treatment-of-non-small-cell-lung-cancer-with-met-genomic-tumor-aberrations/
18. Antitumor Activity of Vebreltinib and Characterization of Clinicogenomic Features in Solid Tumors with MET Rearrangements - PubMed, accessed August 22, 2025, https://pubmed.ncbi.nlm.nih.gov/40202082/
19. Vebreltinib: A novel brain-penetrating MET kinase inhibitor ..., accessed August 22, 2025, https://ir.apollomicsinc.com/static-files/629cd964-a593-410a-9854-976ea3922722
20. www.apollomicsinc.com, accessed August 22, 2025, https://www.apollomicsinc.com/pipeline-drugs/apl-101/#:~:text=Vebreltinib%20is%20a%20novel%2C%20potent,mutated%20in%20several%20tumor%20types.
21. What is the mechanism of Vebreltinib? - Patsnap Synapse, accessed August 22, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-vebreltinib
22. Apollomics Announces Vebreltinib Data at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting - Investor Relations, accessed August 22, 2025, https://ir.apollomicsinc.com/news-releases/news-release-details/apollomics-announces-vebreltinib-data-2024-american-society/
23. What clinical trials have been conducted for Vebreltinib? - Patsnap Synapse, accessed August 22, 2025, https://synapse.patsnap.com/article/what-clinical-trials-have-been-conducted-for-vebreltinib
24. Apollomics and LaunXP Announce Development and Commercialization Agreement for Vebreltinib, accessed August 22, 2025, https://ir.apollomicsinc.com/news-releases/news-release-details/apollomics-and-launxp-announce-development-and-commercialization/
25. Apollomics Announces Positive Preliminary Data of Vebreltinib in ..., accessed August 22, 2025, https://ir.apollomicsinc.com/news-releases/news-release-details/apollomics-announces-positive-preliminary-data-vebreltinib/
26. Vebreltinib for Advanced Non–Small Cell Lung Cancer Harboring c-Met Exon 14 Skipping Mutation: A Multicenter, Single-Arm, Phase II KUNPENG Study - PMC - PubMed Central, accessed August 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11527384/
27. Apollomics Presents Interim Data from Two Ongoing Phase 2 Clinical Trials with Vebreltinib in NSCLC Patients with MetExon14 Skipping Mutation - Investor Relations, accessed August 22, 2025, https://ir.apollomicsinc.com/news-releases/news-release-details/apollomics-presents-interim-data-two-ongoing-phase-2-clinical/
28. Vebreltinib Unknown Status Phase 1 Trials for Bioequivalence Basic Science - DrugBank, accessed August 22, 2025, https://go.drugbank.com/drugs/DB16823/clinical_trials?conditions=DBCOND0039368&phase=1&purpose=basic_science&status=unknown_status
29. Vebreltinib Recruiting Phase 2 Trials for Renal Cancer / HGF / Lung Cancer / Gastric Cancer / Gastroesophageal Junction Adenocarcinoma / Solid Tumors / Non-Small Cell Lung Cancer (NSCLC) / Pancreatic Cancer / EGFR Gene Mutations / Brain Neoplasm / Glioblastoma Multiforme (GBM) / Thyroid Cancer / MET Alterations / Colon Cancer / Advanced Malignant Neoplasm Treatment - DrugBank, accessed August 22, 2025, https://go.drugbank.com/drugs/DB16823/clinical_trials?conditions=DBCOND0033490%2CDBCOND0028149%2CDBCOND0029029%2CDBCOND0086104%2CDBCOND0028483%2CDBCOND0038020%2CDBCOND0046976%2CDBCOND0161905%2CDBCOND0028388%2CDBCOND0144721%2CDBCOND0034130%2CDBCOND0028482%2CDBCOND0032584%2CDBCOND0029860%2CDBCOND0028144&phase=2&purpose=treatment&status=recruiting
30. APL-101 Study of Subjects With NSCLC With c ... - ClinicalTrials.gov, accessed August 22, 2025, https://clinicaltrials.gov/study/NCT03175224
31. Efficacy and safety of the vebreltinib in patients with previously treated, secondary glioblastoma/IDH mutant glioblastoma with PTPRZ1-METFUsion GENe (FUGEN): A randomised, multicentre, open-label, phase II/III trial. - ASCO, accessed August 22, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT446286
32. Vebreltinib | MedPath, accessed August 22, 2025, https://trial.medpath.com/drug/3b96f9d359548899/vebreltinib
33. Study Details | Vebreltinib Plus PLB1004 in EGFR-mutated, Advanced NSCLC With MET Amplification or MET Overexpression Following EGFR-TKI | ClinicalTrials.gov, accessed August 22, 2025, https://clinicaltrials.gov/study/NCT06343064?cond=(DEAFNESS,%20AUTOSOMAL%20RECESSIVE)%20OR%20(MET)&rank=10
34. Avistone's Dual-Target Therapy Shows 50% Response Rate in EGFR-Resistant Lung Cancer at ASCO 2025 - MedPath, accessed August 22, 2025, https://trial.medpath.com/news/808fd27cfb4c09b4/avistone-s-dual-target-therapy-shows-50-response-rate-in-egfr-resistant-lung-cancer-at-asco-2025
35. Vebreltinib for Neoadjuvant in MET-altered Stage IIIA-IIIB (N2) Non-small Cell Lung Cancer (NSCLC) | ClinicalTrials.gov, accessed August 22, 2025, https://clinicaltrials.gov/study/NCT06644313
36. Efficacy and safety of vebreltinib in patients with advanced NSCLC harboring MET exon 14-skipping: Results of 2.5-year follow-up in KUNPENG. - ASCO, accessed August 22, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT444082
37. Avistone Announces Encouraging Results for Vebreltinib plus Andamertinib (PLB1004) in EGFR-mutated NSCLC with MET Amplification or Overexpression at ASCO Annual Meeting 2025 - Business Wire, accessed August 22, 2025, https://www.businesswire.com/news/home/20250531731865/en/Avistone-Announces-Encouraging-Results-for-Vebreltinib-plus-Andamertinib-PLB1004-in-EGFR-mutated-NSCLC-with-MET-Amplification-or-Overexpression-at-ASCO-Annual-Meeting-2025
38. Vebreltinib for Advanced Non–Small Cell Lung Cancer Harboring c ..., accessed August 22, 2025, https://ascopubs.org/doi/10.1200/JCO.23.02363
39. Apollomics Announces Positive Preliminary Data of Vebreltinib in Patients with Non-CNS MET Fusion Solid Tumors from its Phase 2 SPARTA Trial - BioSpace, accessed August 22, 2025, https://www.biospace.com/apollomics-announces-positive-preliminary-data-of-vebreltinib-in-patients-with-non-cns-met-fusion-solid-tumors-from-its-phase-2-sparta-trial
40. News-Beijing Avistone Biotechnology Co., Ltd., accessed August 22, 2025, https://en.avistonebio.com/news_index.html
41. Vebreltinib for Advanced Non-Small Cell Lung Cancer Harboring c-Met Exon 14 Skipping Mutation: A Multicenter, Single-Arm, Phase II KUNPENG Study - PubMed, accessed August 22, 2025, https://pubmed.ncbi.nlm.nih.gov/39058972/
42. Managing Drug Interactions With Oral Anticancer Treatments - PMC, accessed August 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10414528/
43. What is Vebreltinib used for? - Patsnap Synapse, accessed August 22, 2025, https://synapse.patsnap.com/article/what-is-vebreltinib-used-for
44. Combination of Vebreltinib and Osimertinib in Patients with EGFR 21 L858R Mutation Advanced NSCLC | ClinicalTrials.gov, accessed August 22, 2025, https://clinicaltrials.gov/study/NCT06827145
45. Search Orphan Drug Designations and Approvals - FDA, accessed August 22, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=878722
46. Apollomics Highlights Clinical Progress and Reports Full Year 2023 Financial Results, accessed August 22, 2025, https://ir.apollomicsinc.com/news-releases/news-release-details/apollomics-highlights-clinical-progress-and-reports-full-year/
47. Continued cancer drug approvals in Japan and Europe after market withdrawal in the United States - PubMed Central, accessed August 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11236735/
48. Oncology (Cancer)/Hematologic Malignancies Approval ... - FDA, accessed August 22, 2025, https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancerhematologic-malignancies-approval-notifications