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.

 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.

 The approval was supported by prior data from LUMINOSITY.

“Telisotuzumab vedotin is an exciting compound,” Sabari said in an interview with 

®. “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).

: 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 

 wild-type, advanced NSCLC. We know that in the 

-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 

 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 

 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 

-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.

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 

-wildtype advanced NSCLC: efficacy outcomes by prior therapy. 

. 2025;43(suppl 16):8618. doi:10.1200/JCO.2025.43.16_suppl.8618

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

Articles

Joshua K. Sabari, MD, discusses the role of telisotuzumab vedotin in patients with locally advanced/metastatic NSCLC with c-MET overexpression.

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

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.

 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.

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).

, Goldman presented findings from a subgroup analysis of LUMINOSITY that further evaluated telisotuzumab vedotin in terms of outcomes by prior therapy.

 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 

®. “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.

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

: [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 

 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] 

-mutant and squamous cell [cohorts]. Both of those populations didn’t meet the criteria for expanding study as a single agent. However, the nonsquamous, 

 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 

-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.

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

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 

Jonathan Goldman, MD, discusses the role of telisotuzumab vedotin in c-MET–overexpressing, nonsquamous, EGFR wild-type advanced NSCLC.

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

Telisotuzumab vedotin-tllv (Emrelis) demonstrated durable responses in patients with c-MET–overexpressing, nonsquamous, EGFR-wildtype non–small cell lung cancer (NSCLC), regardless of whether they received prior treatment with a platinum-based therapy, immune checkpoint inhibitor (ICI), or both, according to an analysis of the phase 2 LUMINOSITY trial (NCT03539536) presented at the 

Results showed that objective response rates (ORRs) were similar across prior therapy arms. The ORR was 29.3% (95% CI, 22.4%-36.9%) if treated with prior platinum-based therapy, 28.9% (95% CI, 21.4%-37.3%) for prior ICI treatment, and 28.8% (95% CI, 21.2%-37.3%).

“Efficacy outcomes in the prior therapy groups were consistent with those in the overall patient population,” lead study author Jonathan W. Goldman, MD, professor of medicine in the Division of Hematology/Oncology, UCLA Director of Clinical Trials in Thoracic Oncology, associate director of Early Drug Development, and chair of University of California Lung Cancer Consortium, at the David Geffen School of Medicine at UCLA in Los Angeles, CA, and coinvestigators, wrote in the poster presented at the meeting. “The safety profile was generally manageable in each prior therapy group and consistent with observations in the overall population.”

 for the treatment of adult patients with locally advanced or metastatic, nonsquamous NSCLC harboring high c-MET protein overexpression who have received a prior systemic treatment.

 The decision was based on the preliminary LUMINOSITY findings.

Nearly 25% of patients with nonsquamous, EGFR-wildtype NSCLC express c-MET, which is known to be a negative prognostic survival marker. Current treatment includes immunotherapy and platinum-based chemotherapy, either in combination or sequentially, but options are limited following disease progression on these therapies. Telisotuzumab vedotin is a c-MET protein–targeted antibody-drug conjugate consisting of telisotuzumab, a monoclonal antibody, and the microtubule polymerization inhibitor monomethyl auristatin E.

In the 2-stage trial, investigators evaluated efficacy and safety outcomes based on prior therapy for this patient population treated with telisotuzumab vedotin. Patients at least 18 years old were treated with telisotuzumab vedotin at 1.9 mg/kg every 2 weeks.

In stage 1 (n = ~150), approximately 60 patients with nonsquamous EGFR-wildtype disease were c-MET high (n = ~30) and c-MET intermediate (n = ~30); another 60 patients had nonsquamous 

-mutant disease with the same amount of patients labeled as c-MET high and c-MET intermediate. Thirty patients had squamous histology.

All 3 groups went onto a waiting period before they went onto stage 2, which was based on the Bayesian posterior probability of success. The stage 2 portion was a single-arm expansion phase comprised of patients with nonsquamous EGFR-wildtype disease, with a planned maximum 160 patients enrolled by the end of this stage.

c-MET high was defined as having at least 50% of tumor cells with 3+ staining intensity; c-MET intermediate was defined as having between 25% and 50% of tumor cells with 3+ staining intensity.

The primary end point was ORR by independent central review via RECIST v1.1 criteria; secondary end points were duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

Initial findings showed that the agent elicited a 29.2% ORR in the overall patient population; in patients with c-MET high, the ORR was 34.5% and was 23.8% in those with c-MET intermediate disease.

At the 2025 ASCO Annual Meeting, investigators presented an analysis of efficacy and safety outcomes stratified by prior therapy (platinum- or ICI–based treatment) of patients enrolled on LUMINOSITY.

A total 168 patients with c-MET protein–overexpressing nonsquamous EGFR-wildtype NSCLC received at least 1 dose of telisotuzumab vedotin as of February 21, 2024, and were included in the exploratory analyses. Eighty-four patients each had c-MET high or c-MET intermediate disease.

The median age was 64.5 years (range, 33-83) and most patients were male (70%), with 65% of patients being White. Sixty-three percent of patients were former smokers, 21% had brain metastasis, and 71% had an ECOG performance status of 1 at baseline. The median number of prior systemic therapies was 1 (range, 1-3) with a median duration of 9.9 months (range, 0.03-53.4) of treatment. Patients received either platinum-based therapy alone (98%), immunotherapy alone (80%), or a combination of both (79%).

Additional data showed that, when stratified based on c-MET status, the ORR was 34.6% (95% CI, 24.3%-46.0%) if treated with prior platinum-based therapy, 33.3% (95% CI, 22.4%-45.4%) for prior ICI treatment, and 32.8% (95% CI, 21.8%-45.4%) for the c-MET group. For those with c-MET intermediate status, the ORRs were 24.1% (95% CI, 15.4%-34.7%), 24.2% (95% CI, 14.5%-36.4%), and 24.6% (95% CI, 14.8%-36.9%), respectively.

Investigators noted that within the overall c-MET–overexpressing population, the ORRs were 26.2% (95% CI, 18.1%-35.6%) and 34.4% (95% CI, 22.7%-47.7%) for patients who received 1 and 2 or more prior lines of systemic therapy, respectively.

In the prior platinum therapy group, the median DOR was 7.2 months (95% CI, 5.5-11.3) overall; this was 9.0 months (95% CI, 3.8-12.0) and 7.2 months (95% CI, 4.7-11.5) for those who were c-MET high and c-MET intermediate, respectively. Responses were at least 6 months in 54.2%, 60.7%, and 45.0%, respectively. The median PFS was 5.6 months (95% CI, 4.6-6.8), 5.5 months (95% CI, 4.1-8.3), and 5.9 months (95% CI, 4.5-8.1), respectively; the median OS was 14.3 months (95% CI, 9.9-16.5), 14.6 months (95% CI, 9.2-25.6), and 14.2 months (95% CI, 9.6-16.5), respectively.

Results were comparable in the prior ICI group. The median DOR was 7.2 months (95% CI, 5.5-11.0) overall; this was 8.0 months (95% CI, 3.8-11.2) and 7.2 months (95% CI, 5.3-11.5) for those who were c-MET high and c-MET intermediate, respectively. Responses were at least 6 months in 53.8%, 56.5%, and 50.0%, respectively. The median PFS was 5.9 months (95% CI, 5.2-8.0), 5.5 months (95% CI, 4.1-8.3), and 6.5 months (95% CI, 5.2-8.3), respectively; the median OS was 14.3 months (95% CI, 9.8-16.5), 16.3 months (95% CI, 9.5-25.6), and 12.6 months (95% CI, 8.0-15.9), respectively.

Finally, in the prior platinum plus ICI group, the median DOR was 7.2 months (95% CI, 5.5-11.0) overall; this was 9.0 months (95% CI, 3.8-11.3) and 7.2 months (95% CI, 5.3-11.5) for those who were c-MET high and c-MET intermediate, respectively. Responses were at least 6 months in 55.3%, 59.1%, and 50.0%, respectively. The median PFS was 6.0 months (95% CI, 5.2-8.0), 5.5 months (95% CI, 4.1-8.9), and 6.5 months (95% CI, 5.2-8.3), respectively; the median OS was 14.3 months (95% CI, 9.8-16.6), 16.3 months (95% CI, 9.5-25.6), and 12.6 months (95% CI, 8.0-16.4), respectively.

Regarding safety, investigators tested the most common treatment-related adverse events (TRAEs) by prior platinum-based therapy (n = 164), prior ICI (n = 135), and (n = 132). Any-grade TRAEs occurred in 81%, 82%, and 82%, respectively; grade 3 or higher events occurred in 28%, 32%, and 31%, respectively. Any-grade and grade 3 or higher TRAEs across the 3 groups were comprised of peripheral sensory neuropathy (32%, 82%, and 82%; 7%, 8%, and 8%), peripheral edema (16%, 20%, and 20%; 2% for each), fatigue (14%, 16%, and 17%; 2%, 3%, and 3%), decreased appetite (12%, 11%, and 11%; 1% for each), increased alanine aminotransferase (12% for each; 4%, 3%, 3%), hypoalbuminemia (10%, 11%, and 11%; 0% for each), pneumonitis (10%, 12%, and 11%; 2%, 4%, 3%), blurred vision (10%, 9%, and 9%; 1%, 1%, and 2%), increased aspartate aminotransferase (10%, 10%, 11%; 0% for each), nausea (10%, 13%, 12%; 0% for each), and asthenia (8%, 10%, 10%; 1% for each).

TRAEs of special interest for the prior platinum-based, ICI, and combination groups, respectively, consisted of peripheral neuropathy narrow (standardized MedDRA Query [SMQ], any-grade: 41%, 43%, and 43; grade ≥3, 10%, 11%, and 11%), corneal epitheliopathy customized MedDRA query (20%, 19%, and 20%; 1%, 1%, and 2%), adjudicated interstitial lung disease (ILD; 10%, 11%, and 11%; 5% for each), and hematopoietic erythropenia SMQ (broad; 5%, 6%, and 6%; 1% for each).

The most common TRAEs that led to treatment discontinuation were peripheral neuropathy SMQ (20%) and ILD (9%). The peripheral neuropathy SMQ events that led to discontinuation occurred at a median of 238.5 days (range, 57-519) after treatment initiation; it was a median 48.0 days (range, 7-344) for the ILD SMQ events to occur until discontinuation. TRAEs led to death in 2 patients; 1 was ILD and 1 was respiratory failure.

“Safety and efficacy outcomes in the analyzed prior therapy groups were consistent with outcomes observed in the overall population,” the authors concluded.

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. 

. 2025;43(suppl 16; abstr 8618). doi:10.1200/JCO.2025.43.16_suppl.8618

Camidge DR, Bar J, Horinouchi H, et al. Telisotuzumab vedotin monotherapy in patients with previously treated c-met protein–overexpressing advanced nonsquamous 

-Wildtype non–small cell lung cancer in the phase II LUMINOSITY trial. 

. 2024;42(supp; 25):3000-3011. doi:10.1200/JCO.24.00720

Telisotuzumab vedotin showed durable responses in c-MET–overexpressing, nonsquamous, EGFR-wildtype NSCLC, regardless of prior platinum or ICI therapy.

Telisotuzumab Vedotin Elicits Responses in c-MET–Overexpressing NSCLC, Regardless of Prior Therapy

Dr Sabari on c-MET as a Potential Biomarker of Response in EGFR Wild-Type NSCLC

"We want to look at [c-MET] as a biomarker for patients who may benefit from [telisotuzumab vedotin]. If a patient expresses high levels of 

 on the surface of the cell, they can have increased binding and potentially activity of the MMAE payload. We looked at this [agent] specifically in patients with nonsquamous, 

Joshua K. Sabari, MD, an associate professor in the Department of Medicine at New York University (NYU) Grossman School of Medicine and medical director of Thoracic Medical Oncology at NYU Langone Health’s Perlmutter Cancer Center, discussed the prevalence of and rationale behind targeting c-MET in nonsquamous, 

There has been increasing interest in exploring the role of c-MET as a biomarker in 

 wild-type advanced NSCLC to identify patients who may benefit from targeted therapies, Sabari began. Expression of high levels of c-MET on the cell surface can lead to increased binding and potentially enhanced activity of the monomethyl auristatin E chemotherapeutic payload, Sabari explained. In the 

 expression is a common potential resistance mechanism, Sabari noted. However, this approach may also be relevant for patients with nonsquamous 

 wild-type advanced NSCLC, where c-MET overexpression may predict therapeutic response, Sabari detailed.

The phase 2 LUMINOSITY trial (NCT03539536) evaluated the efficacy and safety of telisotuzumab vedotin-tllv (Emrelis) in patients with nonsquamous, 

 wild-type advanced NSCLC with c-MET overexpression, Sabari noted. This population did not include patients with known driver mutations, focusing on patients without actionable mutations, Sabari detailed.

 showed that among patients with high c-MET protein overexpression who had previously received platinum-based chemotherapy alone (n = 81), the objective response rate (ORR) was 34.6% (95% CI, 24.3%-46.0%). Conversely, patients with high c-MET protein overexpression who had received both platinum chemotherapy and an immune checkpoint inhibitor (n = 67) achieved an ORR of 32.8% (95% CI, 21.8%-45.4%).

Notably, patients with intermediate c-MET protein overexpression demonstrated similar response outcomes regardless of prior therapy exposure, suggesting that c-MET expression level, rather than prior treatment regimen, may be the more relevant predictor of therapeutic response in this subgroup, Sabari concluded.

Videos

Joshua Sabari, MD, explains the rationale behind targeting c-MET in nonsquamous EGFR wild-type advanced NSCLC.

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we spoke with Jonathan W. Goldman, MD, about the phase 2 LUMINOSITY study (NCT03539536) evaluating telisotuzumab vedotin-tllv (Emrelis) in patients with 

wild-type advanced non–small cell lung cancer (NSCLC). On May 14, 2025, the 

FDA granted accelerated approval to telisotuzumab vedotin

for the treatment of adult patients with locally advanced or metastatic, nonsquamous NSCLC harboring high 

 protein overexpression who have received a prior systemic therapy. This decision was based on data from LUMINOSITY. Dr Goldman is a professor of medicine in the Division of Hematology/Oncology at UCLA, as well as director of Clinical Trials in Thoracic Oncology, associate director of Early Drug Development, and chair of the University of California Lung Cancer Consortium.

In our exclusive interview, Dr Goldman discussed the evolving role of c-MET as a therapeutic target in NSCLC, the mechanism and rationale behind using telisotuzumab vedotin in 

-overexpressing tumors, and key efficacy outcomes from the nonsquamous, 

 wild-type cohort of the LUMINOSITY trial. He reviewed how high 

 expression, identified through immunohistochemistry, was associated with confirmed objective responses and how this drug compares with existing second-line therapies. Dr Goldman also highlighted telisotuzumab vedotin's safety profile, as well as the agent’s clinical application in patients who have progressed on chemoimmunotherapy.

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Jonathan W. Goldman, MD, discusses the role of telisotuzumab vedotin in c-MET protein–overexpressing, nonsquamous, EGFR wild-type NSCLC. 

Telisotuzumab Vedotin Shakes Up Management of Pretreated, c-MET–Overexpressing NSCLC: With Jonathan W. Goldman, MD

Jonathan W. Goldman, MD, discusses the role of telisotuzumab vedotin for the treatment of locally advanced or metastatic NSCLC with c-MET overexpression.

Dr Goldman on the Telisotuzumab Vedotin Outcomes in Advanced NSCLC With c-MET Overexpression by Prior Therapy

“The primary end point of LUMINOSITY was the objective response rate in the c-MET–high group. It was 35%, so it was meaningfully superior to 2 other FDA-approved agents in the second-line setting.”

Jonathan W. Goldman, MD, a professor of medicine in the Hematology/Oncology Division, director of Clinical Trials in Thoracic Oncology, and associate director of Early Drug Development at UCLA Medical Center, discusses the efficacy of telisotuzumab vedotin-tllv (Emrelis) in the treatment of patients with nonsquamous, 

 wild-type, advanced non–small cell lung cancer (NSCLC) with c-MET overexpression, based on prior therapy, in the phase 2 LUMINOSITY trial (NCT03539536).

 for the treatment of adult patients with locally advanced or metastatic, nonsquamous NSCLC who harbor high c-MET protein overexpression and have previously received systemic therapy. The regulatory decision was based on data from the LUMINOSITY trial; findings supporting the approval revealed that patients with high c-MET protein overexpression treated with the agent (n = 84) experienced an overall response rate (ORR) of 35% (95% CI, 24%-46%), of which all responses were partial responses. Additionally, the median duration of response (DOR) was 7.2 months (95% CI, 4.2-12), with 6- and 12-month DOR rates of 59% and 21%, respectively.

The study’s primary end point was ORR, Goldman began. Among patients with high c-MET protein expression, the ORR was meaningfully superior vs historical data for other agents that have been FDA-approved in the second-line setting, he noted.

In an another analysis of data from LUMINOSITY presented at the 

, findings patients with high c-MET protein overexpression previously treated with platinum chemotherapy alone (n = 81) experienced an ORR of 34.6%, whereas those previously treated with platinum and an immune checkpoint inhibitor (n = 67) achieved an ORR of 32.8%. Patients with intermediate c-MET protein overexpression had similar response outcomes irrespective of prior therapy.

Regarding safety, the integration of antibody-drug conjugates with MMAE payloads into clinical practice has led to novel toxicities associated with this class of agents, Goldman said. Ocular toxicities represent 1 of these adverse effects (AEs), he continued. However, instances of these AEs have been low and generally mild with telisotuzumab vedotin, he noted. Peripheral neuropathy is another AE of concern, but Goldman explained that unlike taxane neuropathy, he has found peripheral neuropathy to be reversible with telisotuzumab vedotin. The emergence of neuropathy can also stem from a longer-term duration on treatment, Goldman added.

The open-label, single-arm study included patients 18 years of age or older with locally advanced or metastatic nonsquamous and 

 wild-type NSCLC, including high c-MET overexpression per immunohistochemistry testing. Those on the study were required to have experienced disease progression after or intolerance to systemic cytotoxic therapy, previously received an immune checkpoint inhibitor with or without chemotherapy, and targeted anticancer therapies if indicated. Specifically, no more than 2 prior lines of systemic therapy were allowed in the locally advanced or metastatic setting, which included 1 line of chemotherapy. Multiple prior lines of TKIs were allowed as 1 line of treatment. Of note, patients were also required to have an ECOG performance status of 0 or 1.

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Telisotuzumab Vedotin Elicits Responses in c-MET–Overexpressing NSCLC, Regardless of Prior Therapy

Dr Sabari on c-MET as a Potential Biomarker of Response in EGFR Wild-Type NSCLC

Telisotuzumab Vedotin Shakes Up Management of Pretreated, c-MET–Overexpressing NSCLC: With Jonathan W. Goldman, MD

Dr Goldman on the Efficacy of Telisotuzumab Vedotin in Advanced NSCLC With c-MET Overexpression