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Telisotuzumab vedotin showed durable responses in c-MET–overexpressing, nonsquamous, EGFR-wildtype NSCLC, regardless of prior platinum or ICI therapy.
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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 2025 ASCO Annual Meeting.1
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.”
In May 2025, the FDA granted accelerated approval to telisotuzumab vedotin 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.2 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 EGFR-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.2
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.
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