Redefining Biomarker-Driven Care: Telisotuzumab Vedotin-tllv for Advanced Non-Squamous NSCLC

In NSCLC there has been a therapeutic revolution in the management of patients with advanced stage disease, by identifying the genomic alterations that are driving the growth of the cancer in each individual patient. The major classes of cancer therapeutics, such as targeted therapies and immunotherapies, have been designed to specifically kill cancer cells harboring particular alterations. So while there has been significant progress in the management of patients with NSCLC that harbor particular alterations, there remains a large proportion of patients with advanced stage NSCLC for which there are few therapeutic options available. Non-squamous NSCLC patients that are EGFR wild-type are typically treated with a platinum-based chemotherapeutic agent in combination with a second chemotherapeutic agent as first line of therapy. Non-squamous NSCLC patients that are EGFR mutant are typically treated with a tyrosine kinase inhibitor as first line of therapy, and patients that have progressed on prior therapy can be treated with a variety of different agents, such as additional tyrosine kinase inhibitors or chemotherapy.

The FDA granted accelerated approval to telisotuzumab vedotin-tllv (Emrelis), a c-Met targeted antibody-drug conjugate, for the treatment of adult patients with locally advanced or metastatic, non-squamous NSCLC with high c-Met protein overexpression who have previously received systemic therapy for their disease.

2026 ASCO Annual Meeting

The 2026 ASCO Annual Meeting session New Medications for the Treatment of Cancer: Clinical Applications will review several recently approved medications and their safe use in clinical practice.

telisotuzumab vedotin-tllv is the first and only targeted therapeutic to be approved for the treatment of cancer based on c-Met overexpression alone, irrespective of any genomics data.

Why It Matters

Overcoming a Major Onco-Driver and Resistance Mechanism

c-Met or MET is a component of normal and abnormal signaling pathways that regulate growth, survival, motility, remodeling, and angiogenesis. c-Met can become a potent oncogene or cancer causing gene when it becomes overactive. In such situations, c-Met can promote the growth of cancer and the cancer’s ability to metastasize.

The Biomechanics of Telisotuzumab Vedotin:

1. Precision Homing: Monoclonal antibody binds with high affinity to cell-surface c-Met receptors overexpressed on non-squamous NSCLC cellls.
2. Receptor-Mediated Internalization: The ADC complex is engulfed via endocytosis into the tumor cell.
3. Lysosomal Cleavage: Intracellular proteases cleave the valine-citrulline linker.
4. Cytotoxic Payload Release: Monomethyl auristatin E (MMAE) is liberated directly into cytoplasm.
5. Mitotic Arrest & Apoptosis: MMAE binds to tubulin, disrupting microtubule networks, causing cell-cycle arrest and targeted tumor cell death.

The majority of NSCLC are of EGFR wild-type genotype and have been traditionally treated with cytotoxic chemotherapy. Although there have been therapeutic strategies targeting the MET pathway for these patients, most of them are small-molecule tyrosine kinase inhibitors (TKIs) that are active in patients with tumors that have mutations in MET exon 14 or high-level amplification of the MET gene. These drugs have shown very promising clinical activity in these patient populations. However, the majority of NSCLC patients do not have tumors with these specific alterations, and therefore, there has been a large unmet need for therapeutic strategies targeting c-Met in these patients. c-Met protein overexpression is a negative prognostic marker in many cancers and is associated with aggressive tumor biology, early disease progression, and resistance to cytotoxic chemotherapy as well as to many forms of immunotherapy.

Telisotuzumab vedotin-tllv is an antibody-drug conjugate (ADC) which is comprised of a humanized monoclonal antibody and a drug linkered to the antibody. The antibody selectively targets c-Met overexpressing cancer cells. Once attached to c-Met expressing cancer cells, the drug is released and induces cell death.

The Mechanism of Action

1. Targeted Delivery: The antibody component binds with high affinity to the extracellular domain of the overexpressed cell-surface c-Met receptor.
2. Internalization: Upon binding, the ADC undergoes rapid receptor-mediated internalization into the endosomal-lysosomal compartment of the cancer cell.
3. Payload Release: Intracellular lysosomal enzymes cleave the valine-citrulline linker, liberating the cytotoxic payload: monomethyl auristatin E (MMAE).
4. Cytotoxic Destruction: MMAE binds directly to intracellular tubulin, disrupting the microtubule network required for mitotic spindle formation. This induces cell-cycle arrest at the G2/M phase, culminating in target-directed apoptosis of the tumor cell while minimizing off-target exposure to surrounding healthy parenchyma.

Targeting an overexpressed protein on a cancer cell with a drug that enters the cancer cell through that protein and then kills the cancer cell is a new mechanism of action in lung cancer and can be a future target in other types of cancer as well.

Who It Affects

Defining the Patient Population

This new drug will have a focused impact in lung cancer. It will be used to treat a subset of patients with non-squamous NSCLC, approximately 25% of advanced EGFR wild-type, non-squamous NSCLC patients.

Patient Eligibility Checklist for Teliso-V:

\[ \] Histology: Locally advanced or metastatic NON-SQUAMOUS NSCLC.

\[ \] Genomic Information: EGFR Wild-Type (or previously treated for EGFR TKI induced resistance).

\[ \] Prior Therapy for Non-Small Cell Lung Cancer: Patients with locally advanced or metastatic Non-Small Cell Lung Cancer who have experienced disease progression on/after prior systemic therapy for example a platinum-based doublet (chemo) and/or an anti–PD–L1 targeting mAb as single agent or in the advanced setting.

\[ \] The patient’s cancer was tested with the VENTANA MET (SP44) RxDx Assay and is VENTANA MET (SP

\[ \] Tumors contain ≥50% of tumor cells with strong (3+) membrane staining of c-Met protein as determined by the VENTANA MET (SP44) RxDx Assay.

Three criteria to help make decisions for the treatment of patients with Teliso-V are outlined below.

1) Histological and Genomic Subtype

Most of the studies of c-Met inhibition have focused on patients with NSCLC that are of non-squamous histology including adenocarcinoma, large cell carcinoma and other non-squamous types of NSCLC. The majority of studies have focused on patients with EGFR wild-type NSCLC. However, c-Met overexpression can also occur in EGFR-mutated NSCLC. In these cases, c-Met inhibition may also be effective in tumors that have become resistant to EGFR TKIs.

2) Treatment Setting

Disease must be advanced and have progressed on or after prior systemic therapy for non-squamous NSCLC, such as a platinum-based doublet chemotherapy in combination with an anti-PD-1/PD-L1 immune checkpoint inhibitor (for example, pemetrexed + cisplatin or carboplatin in combination with pembrolizumab, atezolizumab or nivolumab).

3) The Biomarker Imperative: High c-Met Overexpression

High c-Met overexpression defined as >= 50% of tumor cells demonstrating strong (3+) membrane staining as measured by the VENTANA MET (SP44) RxDx Assay, a companion diagnostic for Telisotuzumab vedotin-tllv.

“High c-Met protein overexpression” is defined by a strict pathological threshold:

• ≥ 50% of viable tumor cells must demonstrate strong (3+) membrane staining intensity via the approved IHC assay.

Patients with high c-Met expressing tumors have sufficient c-Met receptors on the surface of their cancer cells allowing for sufficient binding of the drug carryingadcmonomers to the cancer cell surface receptors. This allows for sufficient numbers ofadcmonomers to be internalized into the cancer cells where the vedotin is subsequently cleaved from the Met receptor by intracellular proteases releasing the attached cytotoxic MMA.

What Changes

Transforming the Clinical Practice Paradigm

Once in the Clinic: Changes in the Diagnostic and Therapeutic Workup of Patients with Non-Squamous Non-Small Cell Lung Cancer (NSCLC) due to the Introduction of telisotuzumab vedotin-tllv (telisotuzumab vedotin)

Diagnostic Workflows: Elevating IHC Alongside Sequencing

Historically, the work up of advanced non-squamous NSCLC would first diagnose the patient and then proceed to NGS to identify all of the potential targets for a patient’s cancer after they completed all of the initial chemotherapy. In some cases, FISH studies would also be performed to see if a particular gene, such as the MET gene, was amplified which would predict sensitivity to a particular drug.

For many patients with advanced non-squamous NSCLC who have received first-line therapy, c-Met IHC can now be part of the diagnostic work-up in conjunction with other genes for which NGS is performed. The testing for c-Met will no longer be reserved for NSCLC patients who are candidates for PD-L1 or other immune-checkpoint inhibitors or for patients with specific histologies. Instead, c-Met IHC will become a reflex test for patients with non-squamous NSCLC who have experienced disease progression on their first line of therapy for non-squamous NSCLC. Importantly, results from NGS or FISH testing will not identify a large proportion of patients with non-squamous NSCLC who would derive significant clinical benefit from this ADC.

The Treatment Algorithm: A More Effective Second-Line Strategy

Historically, for non-squamous NSCLC patients that have relapsed on front-line therapy and do not have any active mutations to be treated with targeted therapy, the standard-of-care second-line treatment has been salvage docetaxel (with or without ramucirumab) or to enroll on a clinical trial. The results with salvage docetaxel have been rather poor with an overall response rate of less than 15% (better with ramucirumab than without).

In addition, there are several aspects of current cancer treatment practice that will change as a result of the recently approved agent telisotuzumab vedotin-tllv. Most notably, this agent will serve as potentially more effective second-line treatment for patients with non-squamous NSCLC previously treated with chemotherapy, either as monotherapy or in combination with other targeted or immunotherapeutic agents, for whom no other targetable alterations have been identified by NGS. The FDA has granted an accelerated approval of this agent pending confirmation of results from an on-going Phase III clinical trial (TeliMET NSCLC-01). In this trial, patients with previously treated c-Met overexpressing non-squamous NSCLC will be randomized to receive either telisotuzumab vedotin-tllv as monotherapy or docetaxel.

For the subpopulation of c-Met overexpressing patients (Hypoc-Met-Exp > 0%), the treatment resulted in an ORR and DCR of 18.6% and 44.1% respectively.

• Overall Response Rate (ORR): Achieved 35% (with some analysis reporting a 34.6% confirmed ORR), which is a substantial improvement over historical salvage chemotherapy data.
• Duration of Response (DOR): Demonstrated sustained clinical efficacy, with a median DOR of 7.2 months (reaching up to 9.0 months in specific high-expressing subsets).
• Survival Signal: Provided a median Overall Survival (OS) of 14.6 months in the high c-Met population, confirming that this agent induces durable disease stabilization.

A global, randomized Phase III trial (TeliMET NSCLC-01) is currently enrolling patients with previously treated c-Met overexpressing NSCLC in a comparison of telisotuzumab vedotin as a monotherapy against docetaxel.

Dosing and Proactive Adverse Event Management

It is important for practicing oncologists to be familiar with this drug and its use in order to treat their patients optimally, maintain active doses of treatment, and protect their patients from potential toxicity.

• Administration Protocol: The drug is supplied as a white lyophilized powder in single-dose vials (20 mg or 100 mg). The standard recommended dose is 1.9 mg/kg, administered via a 30-minute intravenous infusion once every 2 weeks. The maximum dose is capped at 190 mg per infusion for patients weighing 100 kg or more.
• Toxicity Profile: In clinical evaluations, the most common treatment-emergent adverse events associated with the MMAE payload and c-Met targeting included peripheral neuropathy, peripheral edema, ocular surface disorders (such as dry eye, corneal changes, or blurred vision), interstitial lung disease (ILD)/pneumonitis, infusion-related reactions (IRRs), rash, paronychia, fatigue, and decreased appetite.
• Laboratory Abnormalities: Clinicians should watch for Grade 3 or 4 laboratory abnormalities ($\\ge$ 2%), including decreased lymphocytes, elevated alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), hyperglycemia, hypophosphatemia, hyponatemia, anemia, and hypocalcemia.

Another way of approaching the treatment is to take a proactive approach in managing the adverse effects of telisotuzumab vedotin-tllv. The agent must be held immediately for any sign of treatment-related ILD/pneumonitis and permanently discontinued for any severe cases of the condition. Ocular toxicity can be a challenge as well, and will require a collaborative approach with a patient’s optometry/ophthalmology as well as liberal use of preservative-free lubricating eye drops. Similarly, dose reductions or delays for peripheral neuropathy or for laboratory toxicities should be approached in a stepwise fashion as outlined in the CTCAE.

Conclusion: A Clear Step Forward for Precision Oncology

Advanced non-squamous NSCLC (nsNSCLC) patients now have another targeted treatment option available following FDA’s approval of telisotuzumab vedotin-tllv (telisotuzumab) for treatment of c-Met overexpressed/unmute advanced nsNSCLC after failure of prior therapies. This ADC fills a large unmet medical need in nsNSCLC management extending the precision oncology paradigm to c-Met protein overexpression (expression or activity).

Incorporating ADCs into cancer treatment will lead to the improvement of the survival of patients with non-squamous NSCLC who have relapsed after prior treatment. As ADCs target specific proteins in cancer cells, it is important for clinicians to know about the IHC assay to measure the expression of c-Met protein in order to use this drug for treating patients who could benefit from an alternative to chemotherapy. Furthermore, all side effects must be monitored and managed as aggressively as possible in order to allow patients to complete the intended course of treatment with this promising anticancer drug.

References

1. Khan MAH, Ahmad W, Ehsan H, Iqbal M, Rayyan SM, Mehrpoor AJ. Emrelis (telisotuzumab vedotin-tllv): targeting C-MET in non-small cell lung cancer. Ann Med Surg (Lond). 2025;87(12):7870-7871. Published 2025 Oct 14. doi:10.1097/MS9.0000000000004038
2. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-telisotuzumab-vedotin-tllv-nsclc-high-c-met-protein-overexpression
3. Hou, A. Y., Leone, R. D., et al. (2026). Emerging Immunotherapy and Antibody-Derived Therapeutics for the Treatment of Advanced Non-Small-Cell Lung Cancer: A Review. Cancers, 18(8), 1291. https://www.mdpi.com/2072-6694/18/8/1291
4. Fatima, S. H., et al. (2025). Evaluating the combined efficacy of Telisotuzumab Vedotin and artificial intelligence in the treatment of non-squamous non-small cell lung cancer: a narrative review focusing on pharmaceutical and technical insights. Frontiers in Oncology, 15(1), 1673586. https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1673586/full