Telisotuzumab vedotin — Drug Monograph

Telisotuzumab Vedotin (Emrelis) — c-Met ADC for NSCLC

Telisotuzumab vedotin (Emrelis) is a c-Met-directed antibody-drug conjugate (ADC) for non-small cell lung cancer (NSCLC) with high c-Met protein overexpression. Its anti-c-MET antibody delivers the microtubule inhibitor MMAE, causing cell-cycle arrest and apoptosis. It targets c-Met protein overexpression (≥50% of tumor cells with strong 3+ staining by IHC) rather than a MET gene mutation or amplification, confirmed with the VENTANA MET (SP44) companion diagnostic before starting. This monograph covers telisotuzumab vedotin dosing, c-Met protein overexpression and the ADC mechanism, non-squamous NSCLC indications, IHC screening requirements, and management of peripheral neuropathy and ocular toxicities.

Indications (FDA / NCCN)

• Locally advanced or metastatic non-squamous NSCLC with high c-Met protein overexpression (≥50% cells at 3+) after prior systemic therapy (LUMINOSITY)
• Accelerated approval (May 2025) based on ORR and duration of response
• First-in-class c-Met protein-directed ADC (distinct from MET exon 14 / MET amplification)

Dosing

• Standard dose: 1.9 mg/kg (actual body weight) IV once every 2 weeks
• Confirm high c-Met overexpression with the VENTANA MET (SP44) RxDx assay before starting
• Continue until progression or unacceptable toxicity
• Manage toxicity with dose interruption, reduction, or discontinuation

Monitoring

• Neurologic assessment for peripheral neuropathy at baseline and periodically (cumulative MMAE effect)
• Ophthalmologic assessment if ocular symptoms occur
• Pulmonary monitoring for pneumonitis / ILD
• c-Met protein overexpression status by an FDA-approved test

Brand names: Emrelis

Drug class: Antibody-Drug Conjugate

Mechanism of Action

Telisotuzumab vedotin is a c-MET-directed antibody-drug conjugate. It comprises a humanized c-MET-targeting monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. The ADC binds c-MET on the surface of tumor cells, is internalized, and undergoes proteolytic cleavage to release MMAE, which binds tubulin, inhibiting microtubule polymerization and causing cell-cycle arrest and apoptosis. It targets the c-MET protein (overexpression) rather than a MET gene mutation or amplification.

FDA Indications

• Locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) with high c-Met protein overexpression (≥50% of tumor cells with strong [3+] staining as determined by an FDA-approved test) in adults who have received a prior systemic therapy. Accelerated approval (May 2025) based on overall response rate and duration of response; continued approval may be contingent on confirmatory trials.

Common Side Effects

• Peripheral neuropathy
• Fatigue
• Decreased appetite
• Peripheral edema
• Nausea
• Decreased lymphocytes
• Increased glucose
• Increased ALT
• Increased gamma-glutamyl transferase (GGT)
• Decreased hemoglobin

Clinical Pearl

First-in-class c-Met-directed ADC and the first therapy approved specifically for the 'c-Met protein-high' non-squamous NSCLC population (≥50% of tumor cells 3+ by IHC), identified with the companion VENTANA MET (SP44) assay — a protein-overexpression biomarker distinct from MET exon 14 skipping or MET amplification. Accelerated approval rests on the LUMINOSITY trial (NCT03539536; n=84 EGFR wild-type, non-squamous), where confirmed ORR was 35% (95% CI 24–46) with median DOR 7.2 months (95% CI…

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