In today’s episode, we spoke with Lyudmila Bazhenova, MD, and Sandip Patel, MD. Dr Bazhenova is a thoracic medical oncologist and co-lead of the lung cancer team at University of California San Diego Moores Cancer Center, and Dr Patel is a professor of medical oncology at UC San Diego.

In our exclusive interview, Drs Bazhenova and Patel explained why describing a tumor as “MET positive” is no longer specific enough in non–small cell lung cancer (NSCLC). MET protein overexpression, MET exon 14 skipping mutations, and MET amplification are biologically distinct findings detected by different assays, and each carries its own treatment implications. Protein overexpression is identified by immunohistochemistry (IHC) on tumor tissue and defines eligibility for the antibody-drug conjugate (ADC) telisotuzumab vedotin-tllv (Emrelis), which is approved 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 therapy; c-MET protein overexpression is defined as at least 3+ staining in 50% or more of tumor cells per IHC testing. Dr Patel noted that roughly 1 in 5 patients may harbor this target. MET exon 14 skipping mutations, found in approximately 2% to 4% of patients, are genomic alterations detectable by next-generation sequencing (NGS) on tissue or liquid biopsy and are treated with the MET inhibitors capmatinib (Tabrecta) or tepotinib (Tepmetko). Dr Bazhenova cautioned that DNA-based NGS can miss MET exon 14 skipping mutations, making RNA-based testing a valuable complement. MET amplification, which can arise de novo or as a resistance mechanism after third-generation EGFR inhibition, lacks a specific FDA-approved therapy, although Dr Patel described combining an EGFR inhibitor such as osimertinib (Tagrisso) with a MET inhibitor in the acquired-resistance setting.

Because IHC and NGS measure different things, both experts order the 2 tests together rather than treating one as a substitute for the other. Dr Bazhenova likened NGS to examining a home’s blueprint and IHC to inspecting what was actually built, adding that high protein expression without a corresponding genomic alteration is not a discordant result. Dr Patel described sending liquid biopsy for genomic profiling alongside tissue so that limited tissue can be preserved for PD-L1, HER2, and MET IHC. When tissue is insufficient, he obtains a biopsy before second-line therapy, and he stressed documenting the exact aberration and score in the medical record so the finding can guide treatment years later. Dr Bazhenova also routinely repeats NGS and IHC at progression on EGFR-targeted therapy, since MET alterations are a common escape mechanism and acquired MET overexpression can emerge.

The experts also addressed borderline IHC results and assay variability. Dr Patel noted that interpretation tends to be more consistent at high-intensity, high-percentage staining with the SP44 assay, and he encouraged direct conversations with pathologists and multidisciplinary tumor boards for cases near the cutoff. Dr Bazhenova highlighted data from the phase 2 LUMINOSITY trial (NCT03539536) showing activity in MET-intermediate tumors, defined as IHC 3+ staining in 25% to 50% of cells, with an overall response rate of 23% and a median duration of response of about 7 months, although this population falls outside the current label. She pointed to the ongoing phase 3 TeliMET NSCLC-01 trial (NCT04928846) comparing telisotuzumab vedotin with docetaxel in both MET-high and -intermediate disease, and recommended considering a repeat biopsy for patients near the threshold given tumor heterogeneity.

On sequencing, Dr Patel described telisotuzumab vedotin as his standard of care for eligible patients after chemoimmunotherapy, citing a more favorable efficacy and toxicity profile than docetaxel, which yields a response rate of roughly 9%. He added that giving docetaxel first may blunt the benefit of a subsequent ADC with a similar mechanism. For patients with EGFR-mutant disease and acquired MET overexpression, Dr Bazhenova said she would favor datopotamab deruxtecan-dlnk (Datroway), noting that telisotuzumab vedotin produced a response rate of only about 16% in this group in LUMINOSITY. Looking ahead, she flagged payload-aware sequencing as a growing challenge, because many ADCs in development share a topoisomerase I inhibitor payload and trials often exclude patients previously exposed to that payload class, leaving little data to guide back-to-back use.

S19 Ep12: Order Both IHC and NGS: Defining MET Alterations and Positioning Telisotuzumab Vedotin in Non–Small Cell Lung Cancer

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S19 Ep12: Order Both IHC and NGS: Defining MET Alterations and Positioning Telisotuzumab Vedotin in Non–Small Cell Lung Cancer