3 Things You Should Know About New Treatments for MET-Altered NSCLC

The authors

LEARNING OBJECTIVES

Upon successful completion of this activity, you should be better prepared to:

• Assess optimal molecular testing strategies for individual categories of MET alterations in patients with NSCLC

• Develop approaches to manage common and severe adverse events associated with c-Met–directed therapies

RELEASE DATE: September 1, 2025

EXPIRATION DATE: September 1, 2026

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c-Met was initially established as a therapeutic target with the approval of tyrosine kinase inhibitors (TKIs) for patients with non–small cell lung cancer (NSCLC) and a MET exon 14 skipping mutation. More recently, an antibody-drug conjugate (ADC) targeting c-Met has been approved, in this case for patients with previously treated NSCLC and high c-Met protein overexpression. These developments underscore the need for physicians to understand the different classes of MET aberrations, as well as which classes of c-Met–targeted agents are available for each aberration. Here are 3 things you should know about new treatments for MET-altered NSCLC.

1. Different MET alterations require different testing techniques.

c-Met is a receptor tyrosine kinase involved in several activities of relevance to NSCLC, including cell survival, proliferation, and invasion (Figure).^1,2 Alterations leading to dysregulation of signaling and pro-oncogenic behavior can occur in the MET gene as well as the c-Met protein. At the level of the MET gene, the exon 14 skipping mutation is detected through next-generation sequencing, and the TKIs capmatinib and tepotinib have been approved in this setting.^1-3 MET gene amplification is detected through fluorescence in situ hybridization; several agents are under investigation for patients with this genetic aberration.^1,2 Finally, overexpression of the c-Met protein is detected through immunohistochemistry, with telisotuzumab vedotin recently approved for treatment, as described below.^1,2

Figure. c-Met Signaling Pathways¹

2. Multiple new agents targeting c-Met are approved or being developed.

The first approval for patients with high c-Met protein overexpression was granted by the US FDA on May 14, 2025 to telisotuzumab vedotin based on data from the phase 2 LUMINOSITY trial.⁴ The indication defines high expression as at least 50% of tumor cells with a staining intensity of 3+ for c-Met, as determined by an FDA-approved test; additional criteria include previously treated advanced or metastatic, nonsquamous NSCLC.⁵

The LUMINOSITY trial was carried out in 2 stages: stage 1 identified the optimal population for further investigation, and stage 2 enrolled an expanded cohort of the identified population.⁴ Eligible patients had c-Met–overexpressing NSCLC and up to 2 lines of previous systemic therapy; stage 2 was restricted to patients with nonsquamous histology and EGFR wild-type disease.⁴ High c-Met expression was defined as a staining intensity of 3+ in at least 50% of tumor cells, and intermediate staining consisted of samples where at least 25%, but less than 50%, of tumor cells had 3+ staining.⁴

An updated analysis of patients with nonsquamous, EGFR wild-type disease treated with telisotuzumab vedotin 1.9 mg/kg, every 2 weeks, has been presented.⁶ In the overall cohort of 168 patients, the median age was 64.5 years, and the patients had a median of 1 prior line of therapy (range, 1-3). Within this cohort, 84 patients (50%) had high c-Met expression. In those 84 patients, the overall response rate (ORR) was 34.5%, with a median duration of response of 7.2 months.⁶ The median progression-free survival was 5.5 months, and the median overall survival was 14.3 months.

The circulating tumor DNA of patients in LUMINOSITY was collected and analyzed for genomic alterations.⁷ In patients who achieved at least a 50% reduction compared with baseline, there was a trend toward higher ORR compared with those who did not (35% vs 23%).

Adverse events of grade 3 or greater included peripheral sensory neuropathy (7%) and peripheral edema (2%).⁶ There were 7 cases of adjudicated interstitial lung disease (ILD) reported in the safety population of 172 patients. There were 2 deaths from treatment-related adverse events: 1 from ILD and 1 from respiratory failure.

The ongoing phase 3 TeliMET NSCLC-01 trial is comparing telisotuzumab vedotin with docetaxel as second-line therapy in patients with nonsquamous, EGFR wild-type NSCLC and c-Met overexpression.⁸

Together with the previous approval of amivantamab, which targets EGFR and c-Met, the approval of telisotuzumab vedotin illustrates the growing importance of c-Met as a therapeutic target in patients with NSCLC.

Several other agents targeting c-Met are either approved or under investigation, including c-Met ADCs, biparatopic c-Met antibodies, and EGFR/c-Met bispecific antibodies (Table 1).^9-15

Table 1. Approved and Investigational Agents Targeting c-Met^9-15

3. Physicians need to be aware of ADC-related toxicities and appropriate management.

Dosage modification guidelines are included in the prescribing information for adverse events.⁵ The decision to resume or permanently discontinue treatment with telisotuzumab vedotin depends on the adverse event and severity (Table 2).⁵

Table 2. Telisotuzumab Vedotin: Dosage Modifications for Peripheral Neuropathy and ILD/Pneumonitis⁵

For patients experiencing peripheral neuropathy, treatment can be withheld if grade 3 or less; treatment should be permanently discontinued if grade 4 in severity. In the event of grade 1 ILD/pneumonitis, treatment should be withheld with appropriate intervention (eg, corticosteroids) and potential resumption of therapy upon resolution. If the ILD/pneumonitis is grade 2 or greater in severity, however, treatment with telisotuzumab vedotin should be permanently discontinued.⁵

Key References

2. Michaels E, Bestvina CM. Meeting an un-MET need: targeting MET in non-small cell lung cancer. Front Oncol. 2022;12:1004198. doi:10.3389/fonc.2022.1004198

4. Camidge DR, Bar J, Horinouchi H, et al. 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.J Clin Oncol.2024;42(25):3000-3011. doi:10.1200/JCO.24.00720

8. A study to assess disease activity and adverse events of intravenous (IV) telisotuzumab vedotin compared to IV docetaxel in adult participants with previously treated non-squamous non-small cell lung cancer (NSCLC). ClinicalTrials.gov. Updated July 22, 2025. Accessed August 5, 2025. https://www.clinicaltrials.gov/study/NCT04928846

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CME Posttest Questions

1. Which of the following describes the optimal testing approach for the
corresponding dysregulation of MET?

A. Amplification – Reverse transcription polymerase chain reaction

B. Exon 14 mutation – Fluorescence in situ hybridization

C. Overexpression – Immunohistochemistry

2. A patient with c-MET–overexpressing NSCLC receiving telisotuzumab vedotin experiences grade 2 peripheral neuropathy after 8 weeks of therapy. What is the recommended next step in managing this adverse event?

A. Dose reduction at the next lower dosage level without treatment break

B. Withhold therapy until recovery to grade ≤1 and resume treatment at the next lower dosage level

C. Permanently discontinue telisotuzumab vedotin

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