Telisotuzumab Vedotin Maintains Efficacy Across Key Subgroups in Pretreated NSCLC With c-MET Overexpression

Joshua K. Sabari, MD

Data from an analysis of the phase 2 LUMINOSITY trial (NCT03539536) demonstrated that telisotuzumab vedotin-tllv (Emrelis) was active in patients with c-MET protein–overexpressing non–small cell lung cancer (NSCLC) regardless of prior therapy, further supporting the agent’s role in the second-line setting, according to Joshua K. Sabari, MD.1

Findings shared during the 2025 ASCO Annual Meeting indicated that response-evaluable patients with c-MET–high (≥50% of tumor cells with immunohistochemistry [IHC] 3+) disease who received prior platinum-based therapy (n = 81), an immune checkpoint inhibitor (ICI; n = 69), or prior platinum-based therapy plus an ICI (n = 67) achieved overall response rates (ORRs) of 34.6%, 33.3%, and 32.8%, respectively. Among patients with intermediate c-MET overexpression (25% to <50% of tumor cells with IHC 3+), these respective rates were 24.1% (n = 20/83), 24.2% (n = 16/66), and 24.6% (n = 16/65). In the overall c-MET–overexpressing population, the ORR was 26.2% (95% CI, 18.1%-35.6%) among patients who received at least 1 prior line of therapy (n = 107) and 34.4% (95% CI, 22.7%-47.7%) in those who received at least 2 prior lines (n = 61).

In May 2025, the FDA granted accelerated approval to telisotuzumab vedotin for the treatment of adult patients with previously treated locally advanced or metastatic, nonsquamous NSCLC with high c-MET protein overexpression (≥50% of tumor cells with strong 3+ staining) as determined by an FDA-approved test.2 The approval was supported by prior data from LUMINOSITY.

“Telisotuzumab vedotin is an exciting compound,” Sabari said in an interview with OncLive®. “It’s an antibody-drug conjugate [ADC] with a monomethyl auristatin E [MMAE] payload conjugated to a c-MET antibody that targets [the] MET antigen. We just saw an FDA approval in [patients with NSCLC with] c-MET 3+ overexpression following disease progression on standard frontline chemotherapy and immunotherapy. We also saw it [added to] the National Comprehensive Cancer Network guidelines for [patients with IHC] 2+ and 3+ [disease]. It’s an exciting agent that is differentiated from how other agents, such as TKIs or chemotherapeutics, bind [to a target].”

Sabari is the director of High Reliability Organization Initiatives at the Perlmutter Cancer Center and an assistant professor in the Department of Medicine at the NYU Grossman School of Medicine, both in New York, New York.

In the interview, Sabari discussed data from LUMINOSITY, how the FDA approval of telisotuzumab vedotin has changed his clinical practice, and the ongoing phase 2 TeliMET NSCLC-04 trial (NCT06568939).

OncLive: What was the rationale for LUMINOSITY?

Sabari: LUMINOSITY was a phase 2 study of telisotuzumab vedotin in patients with C-MET protein overexpression, which we look at as a biomarker for patients who may benefit from this therapeutic [agent]. If a patient expresses high levels of c-MET on the cell surface, they can have increased binding and potentially activity of that MMAE payload. [Telisotuzumab vedotin] was evaluated in patients with nonsquamous EGFR wild-type, advanced NSCLC. We know that in the EGFR-mutated population, c-MET expression is a common resistance mechanism, both [in terms of] protein expression and amplification.

What were some of the notable efficacy findings from LUMINOSITY that were presented at ASCO?

It was interesting to see the proportions of patients with c-MET–high [disease], which was 84 patients, vs c-MET–intermediate disease, which was also 84 patients. In all-comers, [approximately] 25% of patients will have c-MET–high [disease]. In the total c-MET–expressing population, 98% of these patients received prior platinum and 79% received prior platinum and an ICI.

It was exciting to see that across both platinum and prior platinum/ICI [subgroups], the response rates were quite high. In the c-MET–high patient population who had received prior platinum we saw an ORR of 34.6%, which was similar to what we had seen in an earlier analysis. In the c-MET–intermediate group with prior platinum exposure, [the ORR] was 24.1%, with [essentially] no change depending on whether patients received a prior ICI or not.

Equally as exciting were the median duration of response [DOR] data. In those patients who were C-MET high, the median DOR was 7.2 months, irrespective of whether they received a prior ICI or not. This is in line with what we saw in the label from the FDA. All patients who are c-MET high [IHC 3+] should be offered this agent in the second-line setting, post progression on chemotherapy and immunotherapy.

Were there any notable safety concerns with telisotuzumab vedotin?

Since telisotuzumab vedotin is an ADC, there’s a toxicity profile related to the MMAE payload. We most commonly saw [any-grade] peripheral sensory neuropathy in 32% of patients who received prior platinum. We also saw peripheral or lower extremity edema in 16% of this population and fatigue in 14%. In terms of grade 3 or greater toxicity, the most common event was peripheral sensory neuropathy in 7% [of patients], so that’s something to discuss with your patients when utilizing this agent.

The schema of the ongoing TeliMET NSCLC-04 trial was also presented at the meeting. What is the rationale for this study?

TeliMET NSCLC-04 is an open-label, randomized global study of telisotuzumab vedotin at 2 dose levels. This study is evaluating [telisotuzumab vedotin] at 1.6 mg/kg every 2 weeks vs 1.9 mg/kg every 2 weeks. These are patients with previously treated, c-MET–overexpressing, metastatic NSCLC that is EGFR wild-type. This population [represents] a significant unmet need because they tend to do poorly with other therapeutics. We hope to see whether there are any efficacy or safety differences between these 2 dose levels. We’ve seen with other ADCs that you can potentially lower the dose and still see the same efficacy with less of a toxicity profile.

What is the significance of the May 2025 FDA approval oftelisotuzumab vedotin in patients with NSCLC?

The FDA approval in May of 2025 in patients who received prior treatment with chemotherapy and immunotherapy, are c-MET overexpressing 3+ by IHC, and are EGFR wild-type is extremely important. The standard of care prior to this approval was docetaxel, or docetaxel and ramucirumab [Cyramza], which had response rates of up to 20%. With telisotuzumab vedotin, we’re seeing response rates as high as 35% in patients that are c-MET 3+ by IHC and in the middle of the 20% range in patients who are 2+ by IHC.

This is a game changer for patients. We are seeing durable responses more so than we’re seeing with docetaxel and ramucirumab. Remember that this is an ADC with a unique toxicity profile, in particular peripheral neuropathy. This needs to be managed and monitored closely. Patients need to be educated on the potential toxicity profile of these [types of] agents, but it is an agent that I’ll be using in my clinical practice over docetaxel, which has been historically hard to displace in this setting.

What are some remaining questions regarding the role oftelisotuzumab vedotin in patients with NSCLC?

There’s always a question about the non-overexpressed patients, including those with 1+ or 2+ [disease] by IHC. What about EGFR-mutated subtypes? What about the frontline setting?

We are tackling these [questions] with a new compound, ABBV-400, which is currently in development in this setting, which switches out the MMAE payload for a topoisomerase 1 inhibitor payload. This type of payload has conventionally been used in other ADCs in patients with NSCLC. This is an exciting time for patients with NSCLC as we now have more therapeutic options for them in the later-line setting.

References

1. Goldman JW, Lu S, Bar J, et al. LUMINOSITY, a phase 2 study of telisotuzumab vedotin in patients with c-Met protein–overexpressing non-squamous EGFR-wildtype advanced NSCLC: efficacy outcomes by prior therapy. J Clin Oncol. 2025;43(suppl 16):8618. doi:10.1200/JCO.2025.43.16_suppl.8618
2. FDA grants accelerated approval to telisotuzumab vedotin-tllv for NSCLC with high c-Met protein overexpression. FDA. May 14, 2025. Accessed June 10, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-telisotuzumab-vedotin-tllv-nsclc-high-c-met-protein-overexpression