SUMMARY: The FDA on May 14, 2025, granted accelerated approval to Telisotuzumab vedotin-tllv (EMRELIS®), a c-Met-directed antibody and microtubule inhibitor conjugate, for adults 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. FDA also approved the VENTANA MET (SP44) RxDx Assay as a companion diagnostic test to aid in detecting c-Met protein overexpression in patients with non-squamous NSCLC who may be eligible for treatment with Telisotuzumab vedotin.
The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma is now the most frequent histologic subtype of lung cancer.
The MET proto-oncogene encodes c-Met, a receptor tyrosine kinase also known as the Hepatocyte Growth Factor (HGF) receptor, that plays a central role in regulating cellular processes such as proliferation, survival, and angiogenesis. Aberrations in the MET pathway, including gene amplification or exon 14 skipping mutations, are implicated in a subset of non–small cell lung cancer (NSCLC) cases. Approximately 5% of patients harbor MET amplification and 2-4% carry MET mutations, making this an increasingly relevant therapeutic target. While MET tyrosine kinase inhibitors (TKIs) are approved for MET exon 14 skipping mutations and are under investigation for amplification, no targeted therapies are currently available for MET protein overexpression, a phenomenon observed in roughly 25-39% of NSCLCs and associated with poor prognosis.
Telisotuzumab vedotin is a first-in-class Antibody-Drug Conjugate directed against c-Met. It combines a monoclonal antibody targeting c-Met with the cytotoxic agent MonoMethyl Auristatin E (MMAE). Telisotuzumab uses c-Met protein overexpression as a biomarker to deliver its cytotoxic payload selectively to tumor cells, distinguishing it from therapies that rely on genomic alterations alone. In early-phase studies, it demonstrated encouraging antitumor activity and manageable toxicity in c-Met–overexpressing NSCLC.
LUMINOSITY Trial Design
The Phase II LUMINOSITY trial evaluated Telisotuzumab in patients with locally advanced or metastatic c-Met–overexpressing NSCLC who had received ≤2 prior lines of systemic therapy. Stage I of this study enrolled three cohorts based on tumor histology and EGFR status:
- Nonsquamous EGFR-wildtype
- Nonsquamous EGFR-mutant
- Squamous NSCLC
Stage II of this trial focused on the nonsquamous EGFR-wildtype cohort, which showed the most promise in Stage I part of the study. c-Met overexpression was determined by immunohistochemistry (IHC), with high expression defined as ≥50% of tumor cells showing 3+ membrane staining, and intermediate expression as ≥25% to <50%. Telisotuzumab was administered at a dose of 1.9 mg/kg IV every two weeks. The Primary endpoint was Overall Response Rate (ORR) as assessed by Independent Central Review using RECIST v1.1 criteria. Secondary endpoints included Duration of Response (DOR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Overall Survival (OS).
Efficacy Outcomes
Among 172 patients with nonsquamous EGFR wild-type NSCLC treated at the 1.9 mg/kg dose, 161 were evaluable for efficacy. This group included 84 patients with high c-Met expression and 84 with intermediate expression. The ORR in the total c-Met overexpression group was 28.6% (95% CI, 21.7–36.2). When stratified, ORRs were higher in the c-Met high group at 34.6% (95% CI, 24.2–46.2) compared to 22.9% (95% CI, 14.4–33.4) in the intermediate group.
The median time to response was 1.41 months. Duration of response was also encouraging, with medians of 9.0 months in the high-expression group and 7.2 months in the intermediate group. Median PFS across all c-Met–overexpressing patients was 5.7 months, with similar figures for the high and intermediate groups. Median OS was 14.5 months overall and nearly identical across subgroups.
Safety Profile
Telisotuzumab was generally well tolerated. The most common treatment-related Adverse Events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%). Grade ≥3 AEs were infrequent, with peripheral sensory neuropathy being the most common (7%).
Conclusion
Telisotuzumab demonstrated durable antitumor activity and manageable toxicity in patients with c-Met protein–overexpressing, nonsquamous EGFR-wildtype NSCLC, especially those with high c-Met expression. Although the LUMINOSITY trial lacked a comparator arm, the results support further evaluation of Telisotuzumab in this population. A randomized phase III trial is ongoing and will compare Telisotuzumab monotherapy with Docetaxel in previously treated patients. Given the unmet need and lack of approved therapies targeting c-Met protein overexpression, Telisotuzumab represents a promising therapeutic advance in NSCLC.
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. Camidge DR, Bar J, Horinouchi H, et al. J Clin Oncol 42:3000-3011, 2024