Phase 1 / 2 Multicenter Study of the Safety, Pharmacokinetics, and Preliminary Efficacy of APL-101 in Subjects With Non-Small Cell Lung Cancer With c-Met EXON 14 Skip Mutations and c-Met Dysregulation Advanced Solid Tumors

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Overview

Vebreltinib, also known as APL-101, Bozitinib, CBT-101, and PLB1001, is an investigational small-molecule inhibitor targeting the c-MET tyrosine kinase receptor. It is being developed for the treatment of cancers characterized by MET alterations, including non-small cell lung cancer (NSCLC) with MET exon 14 skipping mutations.

Mechanism of Action

Vebreltinib selectively binds to the c-MET receptor, inhibiting its phosphorylation and subsequent activation. This disruption of the hepatocyte growth factor (HGF)/c-MET signaling pathway impedes tumor cell proliferation, migration, invasion, and survival, processes often dysregulated in cancers with MET alterations.

Efficacy

Clinical trials have demonstrated promising efficacy of vebreltinib in patients with MET exon 14 skipping NSCLC:

• KUNPENG Study (Phase II): In patients with advanced NSCLC harboring MET exon 14 skipping mutations, vebreltinib achieved an objective response rate (ORR) of 75% and a median progression-free survival (PFS) of 14.1 months. Notably, patients with brain metastases (n=5) exhibited an ORR and disease control rate (DCR) of 100%, while those with liver metastases (n=6) had an ORR of 66.7%. (businesswire.com)

• SPARTA Study (Phase I/II): Interim data indicated that in NSCLC patients without concurrent MET amplification (gene copy number <4, n=76), the ORR was 64.5%, with a median duration of response (DOR) of 15.9 months and a DCR of 88%. In patients with MET amplification (GCN ≥4, n=7), the ORR was 85.7%, with a DCR of 100%. (globenewswire.com)

Safety

Vebreltinib has demonstrated a generally well-tolerated safety profile:

• In the KUNPENG study, most treatment-related adverse events (TRAEs) were grade 1 or 2. (sigma.larvol.com)

• In the SPARTA study, grade 3 or higher TRAEs were reported in 42.2% of patients, with the most common being edema (13.3%) and elevated alanine aminotransferase (ALT) levels (7.2%). (globenewswire.com)

Regulatory Status

In November 2023, the National Medical Products Administration (NMPA) of China granted conditional approval for vebreltinib for the treatment of NSCLC patients with MET exon 14 skipping mutations. (businesswire.com)

Further Reading

• Avistone Announces the First Approval of Vebreltinib for MET Exon 14 Skipping Non-Small Cell Lung Cancer

• Apollomics Presents Interim Data from Two Ongoing Phase 2 Clinical Trials with Vebreltinib in NSCLC Patients with MetExon14 Skipping Mutation

• Apollomics Presents Vebreltinib Data at the 2024 American Association for Cancer Research (AACR) Annual Meeting

Last updated: Apr 2025

Reported Early Results and Safety Data

• According to a 2023 ASCO abstract presented by Apollomics, early data from NCT03175224 indicated that APL-101 was generally well tolerated in patients with NSCLC harboring c-MET exon 14 skipping mutations and in patients with advanced solid tumors with c-Met dysregulation. The majority of adverse events were reported to be Grade 1 or 2. No dose-limiting toxicities were observed in the dose escalation stages (Source: ASCO Abstract 2023).
• Company press releases report that preliminary efficacy signals were observed in patients with METex14 skipping NSCLC, including partial responses and stable disease in several participants. Source: Apollomics press release, October 2023.

Significance and Context in the Field

• Biopharma news coverage noted that this trial is part of ongoing efforts to address the unmet need in NSCLC patients harboring MET exon 14 skipping mutations, which are present in approximately 3-4% of NSCLC cases and are associated with poor prognosis and limited treatment options. Source: Endpoints News, August 2023.
• The trial was highlighted during the World Conference on Lung Cancer (2023) as contributing to the expanding landscape of targeted therapies for MET-altered cancers, and its results may inform future treatment options for both MET inhibitor-naïve and pre-treated patients. Source: WCLC 2023 Newsroom.

Referrals to Full Results

• As of June 2024, comprehensive peer-reviewed publications for this study’s outcomes are not available. Results cited are based on conference abstracts, company press releases, and conference presentations.

Key References

• ASCO 2023 Abstract: APL-101 Safety and Efficacy in c-Met Dysregulated Tumors
• Apollomics Press Release: Early Efficacy and Safety Data for APL-101
• Endpoints News: APL-101 and Targeted Therapy Progress
• WCLC 2023: Conference Spotlight on MET Inhibitors

If additional, more detailed efficacy and safety data or peer-reviewed publications become available, further updates should be incorporated.

Last updated: Apr 2025

Major Inclusion Criteria:

1. Men and women 18 years of age or older.

2. 9 cohorts will be enrolled:

* Cohort A1 / Exon 14 NSCLC MET inhibitor naive in first line: Histologically or cytologically confirmed NSCLC with Exon 14 skipping mutations; all histologies; unresectable or metastatic disease (Stage 3b/4); treatment-naive subjects in first line; not received any MET inhibitor and no known MET kinase inhibitor resistance mutations

* Cohort A2 / Exon 14 NSCLC - MET inhibitor naïve: Histologically or cytologically confirmed NSCLC with Exon 14 skipping mutations; all histologies; unresectable or metastatic disease (Stage 3b/4); pretreated subjects refractory to or intolerant of standard therapies with no more than three lines of prior therapy in the unresectable or metastatic setting; not received any MET inhibitor and no known MET kinase inhibitor resistance mutations

* Cohort B / Exon 14 NSCLC MET inhibitor experienced: ENROLLMENT COMPLETED

* Cohort C / MET amplification basket tumor types excluding primary CNS tumors: Any solid tumor type regardless of histology excluding primary CNS tumors, with MET amplification; unresectable or metastatic disease, refractory to or intolerant of standard therapies, or refused standard therapies, or if therapy was unavailable or unfeasible, with no more than 3 prior lines of therapy in the unresectable or metastatic setting; not received any MET inhibitor and no known MET kinase inhibitor resistance mutations

* Cohort C1 / MET amplification and wild-type EGFR NSCLC: NSCLC regardless of histology, harboring MET amplification and wild-type EGFR; unresectable or metastatic disease, previously untreated or treated with no more than 3 prior lines of therapy in the unresectable or metastatic setting; not received any MET inhibitor and no known MET kinase inhibitor resistance mutations

* Cohort C2 / EGFR positive NSCLC with acquired MET amplification (APL-101 Add-on Therapy): Unresectable or metastatic NSCLC regardless of histology, harboring EGFR activating mutations with acquired MET-Amplification as resistance mechanism to the EGFR-I; developed resistance to first-line EGFR-inhibitor therapy after an initial response (documented PR for at least 12 weeks); radiological documentation of disease progression per RECIST on first-line EGFR inhibitor therapy; currently on an EGFR-inhibitor therapy and agrees to receive APL-101 as an add-on therapy during the study; no history of interstitial lung disease (ILD)/pneumonitis, Grade ≥3 liver toxicity or QT prolongation with EGFR-I therapy; not received any MET inhibitor and no known MET kinase inhibitor resistance mutations

* Cohort D / MET fusion basket tumor types excluding primary CNS tumors: any solid tumor type regardless of histology excluding primary CNS tumors; unresectable or metastatic disease, refractory to or intolerant of standard therapies, or refused standard therapies, or if therapy was unavailable or unfeasible, with no more than 3 prior lines of therapy in the unresectable or metastatic setting; not received any MET inhibitor and no known MET kinase inhibitor resistance mutations

* Cohort E / Primary CNS tumors with MET alterations: subjects with primary CNS tumors who meet inclusion criteria of MET dysregulations defined as single or co-occurred MET fusion including PTPRZ1-MET (ZM) fusion, MET Exon 14 skipping mutations, or MET amplification; refractory to or intolerant of standard therapies, or refused standard therapies, or if therapy was unavailable or unfeasible, with no more than 3 prior lines of therapy in the unresectable or metastatic setting; not received any MET inhibitor and no known MET kinase inhibitor resistance mutations; neurological symptoms controlled on a stable/decreasing dose of steroids for at least 2 weeks before C1D1

* Cohort F / Basket tumor types harboring wild-type MET with over-expression of HGF and MET: any solid tumor type regardless of histology harboring wild-type MET with overexpression of HGF and MET; Unresectable or metastatic disease, refractory to or intolerant of standard therapies, or refused standard therapies, or if therapy was unavailable or unfeasible, with no more than 3 prior lines of therapy in the unresectable or metastatic setting; not received any MET inhibitor and no known MET kinase inhibitor resistance mutations

3. Treated or untreated asymptomatic parenchymal CNS disease or leptomeningeal disease is allowed.

4. Presence of ≥1 measurable lesion (scan done ≤28 days of C1D1) to serve as target lesion according to relevant criteria

5. ECOG performance status of 0-1. For subjects with primary CNS tumors, KPS score ≥70.

6. Acceptable organ function

7. For all prior anticancer treatment, a duration of 30 days or 5 half-lives of the agents used, whichever is shorter, must have elapsed, and any encountered toxicity must have resolved to levels meeting all the other eligibility criteria prior to the first dose of study treatment. Palliative radiotherapy to non-target lesions should be completed within 2 weeks prior to APL-101 administration.

8. Adequate cardiac function

9. Women of child-bearing potential must have a negative serum or Beta-hCG at screening or evidence of surgical sterility or evidence of post-menopausal status

10. No planned major surgery within 4 weeks of first dose of APL-101

11. Expected survival (life expectancy) ≥ 3 months from C1D1

12. Provision of sample; e.g. archival or a fresh tumor biopsy sample (if safe and feasible) either from the primary or a metastatic site) or liquid biopsy sample (if tumor tissue is insufficient or lacking, and approved by the sponsor) is required for prospective central lab confirmation for study entry (subjects with previously confirmed molecular status by the Sponsor designated central lab or FDA approved NGS based MET testing may be exempted, subjected to Sponsor approval.

Major Exclusion Criteria:

1. Hypersensitivity to APL-101, excipients of the drug product, or other components of the study treatment regimen.

2. Known actionable mutation/gene rearrangement of EGFR (except for NSCLC subjects in Cohort C and C-2), ALK, ROS1, RET, NTRK, KRAS, and BRAF.

3. Use or intended use of any other investigational product, including herbal medications, through Study Treatment Termination.

4. Active uncontrolled systemic bacterial, viral, or fungal infection or clinically significant, active disease process, which in the opinion of the investigator makes the risk: benefit unfavorable for the participation of the trial.

5. Life-threatening illness, significant organ system dysfunction or comorbid conditions, or other reasons that, in the investigator's opinion, could compromise the subject's safety or the integrity of the study outcomes, or interfere with the absorption or metabolism of APL-101.

6. Unstable angina or myocardial infarction within 1 year prior to first dose of APL-101, symptomatic or unstable arrhythmia requiring medical therapy, history of congenital prolonged QT syndrome, prolonged QT interval corrected by Fridericia formula (QTcF) at screening, or concurrent treatment with a medication that is a known risk for prolonging the QT interval. Chronic controlled atrial fibrillation is not excluded.

7. Historical seropositive results consistent with active infection for hepatitis C virus (HCV) or hepatitis B virus (HBV) with high viral loads not actively managed with antiviral therapy and human immunodeficiency virus (HIV) positive subjects who are not clinically stable or controlled on their medication (asymptomatic subjects with CD4+ T-cell (CD4+) counts ≥ 350 cells/μL and have not had an opportunistic infection within the past 12 months prior to first dose of APL-101 would be eligible for study entry. If history is unclear, relevant test(s) at Screening will be required to confirm eligibility.

8. Known significant mental illness or other conditions such as active alcohol or other substance abuse that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol treatment or assessments.

9. Unable to swallow orally administered medication whole.

10. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter drug absorption

11. Women who are breastfeeding

12. History of another malignancy within 3 years prior to C1D1. A subject with the following malignancies is allowed if considered cured or unlikely to recur within 3 years:

1. Carcinoma of the skin without melanomatous features.

2. Curatively treated cervical carcinoma in situ.

3. Bladder tumors considered superficial such as noninvasive (T1a) and carcinoma in situ (T1s), thyroid papillary cancer with prior treatment, prostate cancer which has been surgically or medically treated and not likely to recur within 3 years.

13. Subjects who are unable or unwilling to discontinue excluded medications (drugs with known QTc risk and known strong cytochrome P450 \[CYP\]3A4 inducer and/or strong inhibitors) for at least 5 half-lives prior to first dose of study drug. Subjects may qualify if such medication(s) can be safely replaced with alternate medications with less risk of drug-drug interaction.

14. Subjects with active COVID-19 infection.

15. Symptomatic and/or neurologically unstable CNS metastases, or who require an increase in steroid dose to control CNS disease. Subjects who have been receiving a stable steroid dose for at least 2 weeks prior to C1D1 may be allowed.