Telisotuzumab Vedotin (Emrelis® / ABBV 399 / ABBV-399 / ABT 399) Drug Description

On May 15, 2025 the US Food and Drug Administration (FDA) granted accelerated approval to telisotuzumab vedotin-tllv (Emrelis®, AbbVie; see ADC Drugmap).

Telisotuzumab vedotin, previously known as ABBV 399 (ABBV-399; ABT 399), is a novel, first-in-class, antibody-drug conjugate developed by AbbVie comprised of the anti-c-Met antibody, ABT-700, directed against the cell surface glycoprotein mesothelia, conjugated to monomethyl auristatin E (MMAE) for the treatment of patients with solid tumors.

Although prior efforts at targeting c-Met over-expression have met with limited clinical success, an ADC directed against c-Met represents a unique strategy to deliver a potent cytotoxin directly to c-Met+ tumor cells.

ABBV-399 inhibits growth of xenograft tumors refractory to other c-Met inhibitors and provides significant therapeutic benefit in combination with standard of care chemotherapy.

Telisotuzumab vedotin represents a novel therapeutic strategy to deliver a potent cytotoxin to c-Met over-expressing tumor cells enabling cell killing regardless of reliance on MET signaling.[1]

ABBV-399 has progressed to a Phase I study  (ongoing in the United States) where it has been well tolerated and has produced objective responses in c-Met expressing non small cell lung cancer (NSCLC) patients.

Description MOA
c-Met receptor tyrosine kinase (c-MET) (MET) (HGFR) (c-Met proto-oncogene) inhibitor.

ABT-700
The targeting moiety in telisotuzumab vedotin (ABBV-399), ABT-700, is a is a humanized immunoglobulin G1 kappa (IgG1κ) monoclonal antibody directed against human hepatocyte growth factor receptor (HGFR or c-Met), with potential antineoplastic activity.

Anti-c-Met monoclonal antibody ABT-700 binds to c-Met, thereby preventing c-Met binding to its ligand, HGF and the subsequent activation of the HGF/c-Met signaling pathway. This may cause cell death in c-Met-expressing tumor cells. c-Met, a receptor tyrosine kinase over-expressed or mutated in many tumor cell types, plays a key role in cancer cell growth, survival, angiogenesis, invasion, and metastasis.

The small molecule, monomethyl auristatin E (MMAE), a small molecule microtubule-disrupting agent, attached to the antibody via a via a protease-cleavable valinecitrulline (vc) linker. Following binding to c-Met-expressing cells, telisotuzumab vedotin undergoes internalization and intracellular cleavage of MMAE. MMAE disrupts the microtubule network of actively dividing cells, subsequently inducing cell cycle arrest and apoptotic cell death. Telisotuzumab vedotin exhibited antitumor activity in xenograft models of NSCLC.

The antibody is produced in a mammalian cell line (Chinese hamster ovary) and the drug-linker is produced by chemical synthesis. Each monoclonal antibody molecule carries an average of 3 MMAE molecules.

Telisotuzumab vedotin has an approximate molecular weight of 152 kDa.

Treatment related information

Indication
Telisotuzumab vedotin is indicated for the treatment of adult patients with 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, who have received a prior systemic therapy.

This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Dosage and Administration
Patient Selection Select patients for treatment with telisotuzumab vedotin is based on the presence of high c-Met protein over-expression [≥50% of tumor cells with strong (3+) staining] in patients with non-squamous NSCLC  based on the outcome of the VENTANA MET (SP44) RxDx Assay (Ventana Medical Systems/Roche Diagnostics) companion diagnostic test.

Recommended Dosage
The recommended dosage of telisotuzumab vedotin is 1.9 mg/kg (up to a maximum of 190 mg for patients greater than or equal to 100 kg) administered as an intravenous infusion over 30 minutes every 2 weeks until disease progression or unacceptable toxicity.

Clinical development

LUMINOSITY-study
The efficacy of telisotuzumab vedotin was evaluated in the LUMINOSITY study (NCT03539536), a multicenter, open-label, single-arm, multi-cohort clinical trial.[2]

This study included two-stages, In the first stage, the researchers aimed to identify the c-Met over-expressing NSCLC population that would best respond to telisotuzumab vedotin. In the second stage, they expanded selected groups to further evaluate efficacy. 

Eligible patients were required to have locally advanced or metastatic NSCLC with c-Met protein over-expression and treatment with prior systemic therapy (including no more than one line of prior chemotherapy) in the locally advanced or metastatic setting. The study excluded patients who had received radiation therapy to the lungs <6 months prior to enrollment and patients who had a history of ILD/pneumonitis requiring treatment with steroids or ILD/pneumonitis within 3 months of the first dose.

In this study, participating patients received telisotuzumab vedotin at 1.9 mg/kg intravenously every 2 weeks until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as assessed by a blinded independent central review (BICR). An additional efficacy outcome measure was duration of response (DOR) by BICR.

The efficacy population included 84 patients with non-squamous, EGFR wild-type NSCLC with high c-Met protein over-expression who had received prior systemic therapy. High c-Met protein over-expression was defined as ≥50% of tumor cells with strong (3+) membrane staining on archival or recent tissue samples by immunohistochemistry (IHC) and was determined by prospective testing at a central laboratory prior to enrollment using the MET (SP44) clinical trial assay (CTA).

Of the 84 participating patients with high c-Met protein over-expression identified by central testing using the CTA, tissue samples from 38/84 (45%) patients were tested retrospectively using the VENTANA MET (SP44) RxDx Assay (Ventana Medical Systems/Roche Diagnostics) companion diagnostic test. One sample was unevaluable.

Of the 37 samples retested and evaluable, 32 (87%) samples were confirmed to have high c-Met protein over-expression, defined as ≥50% of tumor cells with strong (3+) membrane and/or cytoplasmic staining.

The median age was 64 years (range: 38 to 83 years); 75% were male; 61% were White, 1.2% were Black or African American, 38% were Asian; none were of Hispanic or Latino ethnicity.

Twenty-five percent had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 and 74% had ECOG PS of 1; 19% were never smokers, 68% were former smokers, and 13% were current smokers; 99% had Stage IV disease; and 19% of patients had previously treated brain metastases.

The median number of lines of prior therapies was 1 (range 1 – 3); 73% of patients had one line, 24% had two lines, and 3.6% had three lines of prior systemic therapy; 96% of patients had prior platinum therapy, 82% had prior immunotherapy (anti-PD-1/PD-L1), 6% had prior targeted therapy, and 3.6% had prior MET tyrosine kinase inhibitor therapy.

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Clinical trials
A Study to Evaluate the Safety and Pharmacokinetics ABBV-399 in Japanese Participants With Solid Tumors – ClinicalTrials.gov ID NCT03311477
Lung-MAP S1400K: c-MET Positive – – ClinicalTrials.gov ID NCT03574753
A Study Evaluating the Safety, Pharmacokinetics (PK), and Preliminary Efficacy of ABBV-399 in Subjects With Advanced Solid Tumors – ClinicalTrials.gov ID NCT02099058
Study of Telisotuzumab Vedotin (ABBV-399) in Participants With Previously Treated c-Met+ Non-Small Cell Lung Cancer – ClinicalTrials.gov ID NCT03539536
A Study to Assess Disease Activity and Adverse Events of Intravenous (IV) Telisotuzumab Vedotin Compared to IV Docetaxel in Adult Participants With Previously Treated Non-Squamous Non-Small Cell Lung Cancer (NSCLC) ClinicalTrials.gov ID NCT04928846

Highlight of Prescribing Information
Telisotuzumab vedotin (Emrelis®, AbbVie Inc.)[Prescribing Information]

Reference
[1] Camidge DR, et al. Telisotuzumab Vedotin monotherapy in patients with previously treated c-Met protein-overexpressing advanced nonsquamous EGFR-wildtype non-small cell lung cancer in the Phase II LUMINOSITY trial. J Clin Oncol. 2024 Sep 1;42(25):3000-3011. doi: 10.1200/JCO.24.00720. Epub 2024 Jun 6. PMID: 38843488; PMCID: PMC11361350.
[2] Camidge DR, Bar J, Horinouchi H, Goldman JW, Vladimirovich Moiseenko F, Filippova E, Cicin I, Ciuleanu TE, Daaboul N, Liu C, Bradbury PA, Moskovitz M, Katgi N, Tomasini P, Zer A, Looman J, Ratajczak C, Li M, Xia S, Lu S. Telisotuzumab vedotin monotherapy in patients with previously treated c-Met over-expressing non-squamous EGFR wildtype advanced NSCLC: Primary analysis of the LUMINOSITY trial. JCO 42, 103-103(2024). DOI:10.1200/JCO.2024.42.16_suppl.103

Last Editorial Review: May 14, 2025