LUMINOSITY Data Continue to Highlight Utility of Telisotuzumab Vedotin in c-MET–Overexpressing NSCLC

Jonathan Goldman, MD

By leveraging a unique mechanism of action to target c-MET, telisotuzumab vedotin-tllv (Emrelis) represents an additional therapeutic option for patients with c-MET–overexpressing, nonsquamous advanced non–small cell lung cancer (NSCLC), according to Jonathan Goldman, MD.

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 by immunohistochemistry [IHC]), as determined by an FDA-approved test.1

The regulatory decision was supported by data from the phase 2 LUMINOSITY trial (NCT03539536), which demonstrated that patients who received the agent (n = 84) achieved an overall response rate (ORR) of 35% (95% CI, 24%-46%) per RECIST 1.1 criteria. The median duration of response (DOR) was 7.2 months (95% CI, 4.2-12).

During the 2025 ASCO Annual Meeting, Goldman presented findings from a subgroup analysis of LUMINOSITY that further evaluated telisotuzumab vedotin in terms of outcomes by prior therapy.2 Patients with high c-MET overexpression who received prior platinum-based therapy (n = 81) achieved an ORR of 34.6% (95% CI, 24.3%-46.0%); those who received a prior immune checkpoint inhibitor (ICI; n = 69) experienced an ORR of 33.3% (95% CI, 22.4%-45.7%), and those who received both a platinum-based regimen and an ICI (n = 67) had an ORR of 32.8% (95% CI, 21.8%-45.4%). In the c-MET–intermediate overexpression group, the ORR among patients who received prior platinum-based therapy (n = 83) was 24.1% (95% CI, 15.4%-34.7%); the ORRs were 24.3% (95% CI, 14.5%-36.4%) and 24.6% (95% CI, 14.8%-36.9%) among patients with intermediate c-MET overexpression who received a prior ICI (n = 66) or an ICI and platinum-based therapy (n = 65), respectively.

“The primary end point of LUMINOSITY was ORR in the C-Met–high group, which was 34.6%; this is meaningfully superior [compared with] other approved agents in the second-line [setting],” Goldman said in an interview with OncLive®. “In the c-MET–intermediate group, the ORR was 24.1%.”

Goldman is the UCLA Director of Clinical Trials in Thoracic Oncology, the associate director of Early Drug Development, and a professor in medicine in the Hematology/Oncology Division at UCLA. He is also the chair of the University of California Lung Cancer Consortium.

In the interview, Goldman discussed the design of LUMINOSITY and the mechanism of action of telisotuzumab vedotin; the clinical implications of the data from the study; and the next steps for the development of the agent.

OncLive: How does the mechanism of action of telisotuzumab vedotin differ from prior approaches to target c-MET?

Goldman: [The development of] c-Met–[directed] therapy has gone through many phases and has become more sophisticated. Initially, we had some simple, naked antibodies that had some early signals [of efficacy] but [showed] little benefit in phase 3 trials.

The next real success was the identification of MET exon 14 skipping mutations, and those are well targeted with oral drugs. Initially, [it was with] crizotinib [Xalkori], and now [we have] some newer TKIs.

However, we are talking about something very different [with telisotuzumab vedotin, which] targets the overexpression of MET on the cell surface. TKIs would be expected to have little or no benefit here. Instead, this antibody-drug conjugate [ADC] is using MET as a target to bring a cytotoxic payload to the tumor cell. This has recently been successfully used in [patients with] lung cancer, but these are [still] early and exciting days for this class of medicines.

What was the rationale for examining telisotuzumab vedotin in the patient population enrolled in LUMINOSITY?

MET is a target that is quite prevalent in [patients with] lung cancer. When we’re talking about targeted therapies, often we’re talking about [approximately] 10% of patients, or even 1% to 5% [of patients, expressing the target]. MET overexpression is much more common. Even if you look at the high degree of MET expression, it’s [approximately] 12% to 25% [of patients], depending on how you identify it.

MET is prevalent at initial diagnosis, but it also becomes more prevalent as tumors become resistant to first-line therapy. [In this setting], we see an increase of approximately 10% in [MET] positivity on testing, and that overexpression is likely part of the explanation for resistance to first-line therapy. That’s why coming in [with telisotuzumab vedotin] at that point is appealing. We may be able to move MET targeting to earlier lines of therapy, but at this point, [this setting] is a good entry into clinical use for these drugs.

Telisotuzumab vedotin is an ADC [with an] antibody targeting an extracellular epitope of MET. Attached to the antibody is the toxic payload, monomethyl auristatin E [MMAE]. [The agent has] a cleavable linker and the drug-to-antibody ratio is 3:1. These are all important factors for the specificity of this drug.

What were the key design characteristics of LUMINOSITY?

LUMINOSITY had 3 subgroups that were examined, [including] EGFR-mutant and squamous cell [cohorts]. Both of those populations didn’t meet the criteria for expanding study as a single agent. However, the nonsquamous, EGFR wild-type group did [meet the expansion criteria]. LUMINOSITY used a Simon 2-stage design and met its first [ORR] end point. Therefore, it was expanded to include approximately 180 patients.

These patients received 1 or 2 prior lines [of therapy]. Immunotherapy was approved over the course of this trial, so that was allowed as 1 of the 2 prior lines. Nearly all of the patients received prior chemotherapy and immunotherapy, and a very small number received TKI therapy. Otherwise, the inclusion [criteria] were based on the biomarker, which was c-MET overexpression by IHC. Here, we identified as a biomarker the percentage of cells that were 3+ positive. High [c-MET] overexpression was 50% or more of the cells being 3+ positive, and intermediate overexpression was 25% to 50% of cells being 3+ positive.

In light of the efficacy observed with telisotuzumab vedotin across the subgroups in the analysis presented during the 2025 ASCO Annual Meeting, how do these data further contextualize the role of the ADC in the treatment paradigm?

When we’re looking at how this drug is going to be applied and be useful for our patients, the most important step is to identify the patients via MET testing, which can be done on the initial specimen or on a specimen obtained at the time of disease progression. Many labs are now bringing the antibody testing paradigm online to identify the biomarker. Over time, local labs may also start to develop this.

We focus on clinical trials, but in the absence of clinical trials, a patient in the second line who has experienced disease progression on chemoimmunotherapy—or chemotherapy [alone] if immunotherapy is contraindicated—would be a perfect patient to [consider for telisotuzumab vedotin]. We see that it is generally better tolerated than docetaxel, in my experience, with a higher ORR.

Were there any new safety signals seen in this data update?

ADCs are giving us a new set of toxicities to be aware of. With the MMAE payload, we have 2 primary toxicities. One is ocular toxicities, and those have been relatively rare and mild. Eye rewetting drops and an ophthalmology evaluation are sometimes needed, but [these toxicities] are rarely high grade, are reversible, and are rarely significantly problematic.

We saw any-grade peripheral [sensory] neuropathy in 32% of patients, and 7% had [grade 3 or] higher peripheral neuropathy. As opposed to taxane-[related] neuropathy, I have found [peripheral sensory neuropathy] to be reversible, so that is reassuring to me and patients. Sometimes we need to take a treatment break or dose reduce when we restart.

The other thing about neuropathy is that it is cumulative. Patients who have been on treatment for 3, 4, or even 8 months and are deriving benefit do experience some neuropathy and require attention. However, I found it to be manageable, and certainly, compared with docetaxel, which is also [associated with] neuropathy, it is not as treatment-limiting.

What are the next steps for the development of telisotuzumab vedotin?

The next step is the confirmatory phase 3 TeliMET NSCLC-01 trial [NCT04928846], which is well underway. I would love to see the benefit [with telisotuzumab vedotin] confirmed in a direct comparison vs docetaxel. I am also excited about some combination data where we showed benefit in the EGFR-mutated population when [telisotuzumab vedotin] was given with osimertinib [Tagrisso]. [However], that would require confirmation in a larger trial before being clinically applied.

What makes telisotuzumab vedotin stand out is its specificity and the ability to identify patients who are most likely to benefit. Those patients do have to be monitored, and management of the [peripheral sensory] neuropathy is necessary.

References

1. FDA grants accelerated approval to telisotuzumab vedotin-tllv for NSCLC with high c-Met protein overexpression. FDA. May 14, 2025. Accessed June 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-telisotuzumab-vedotin-tllv-nsclc-high-c-met-protein-overexpression
2. Goldman J, 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