May 11, 2026
Post-TTLC 2026: Dr. Doroshow transitions to MET-directed resistance and invites Dr. Patel to lead. He describes MET amplification or overexpression as a resistance pathway in roughly 15% of EGFR-mutated metastatic non-small cell lung cancer (NSCLC) patients. Amivantamab-based regimens, which target both EGFR and MET, may reduce MET-driven resistance though not eliminate it. Testing must distinguish DNA-level events (MET amplification, by copy number) from protein-level overexpression (by immunohistochemistry [IHC]). Telisotuzumab vedotin (Teliso-V), a MET-directed antibody-drug conjugate (ADC) with a monomethyl auristatin E (MMAE) payload, is an option for 3+ MET protein overexpression in more than 25% of cells. For genomic MET amplification, small molecule combinations — savolitinib (a CNS-penetrant third-generation MET inhibitor with peripheral edema and hepatotoxicity), capmatinib, or tepotinib paired with osimertinib or lazertinib — are standard.
Dr. Doroshow trusts MET amplification results from tissue more than liquid biopsy. Her institution performs MET-IHC alongside DNA and RNA next-generation sequencing (NGS). She stresses distinguishing overexpression from amplification, which are easy to conflate, including for ERBB2, and notes telisotuzumab vedotin is FDA-approved in EGFR wild-type, MET-overexpressing disease.
Both experts underscore precision: knowing whether MET status reflects amplification, overexpression, exon 14 skipping, or a kinase domain mutation matters because targeted therapies differ.
On toxicity, Dr. Doroshow describes difficulty managing peripheral edema and hypoalbuminemia, which can persist after stopping the drug. Dr. Patel recommends seeing patients within 1 to 2 weeks of starting therapy, using compression stockings with occupational therapy, attempting diuresis, and dose-reducing as the most reliable intervention. For hepatotoxicity, he reviews medications and herbals.
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