Dramatic Response to Crizotinib in a Patient With Lung Cancer Positive for an HLA-DRB1-MET Gene Fusion.

Non–small-cell lung cancer (NSCLC) is a disease in which tumor growth is commonly driven by alterations along the receptor tyrosine kinase–RAS-RAF–mitogen-activated protein kinase pathway. Consequently, activated kinases along this axis represent attractive therapeutic targets. Activation of kinases can occur via multiple mechanisms at the genetic level, including mutation, amplification, and rearrangement/fusion with other genes. The two best-characterized gene fusion classes in NSCLC are those that involve ALK and ROS1—accounting for approximately 5% and 2% of patients, respectively—and inhibition of these fusion proteins is now a standard of care. Gene fusions that involve RET, NTRK1/2/3, BRAF, FGFR1/2/3, EGFR, and NRG1 have also been identified in lung cancer samples—an approximately 2% frequency for RET, < 1% for others—and strategies to target these aberrations are in development.

Crizotinib, the first US Food and Drug Administration–approved drug for patients with NSCLC who harbor ALK rearrangements and currently the only approved drug for patients with NSCLC who harbor ROS1 rearrangements was originally designed to be an inhibitor of the MET gene product hepatocyte growth factor receptor (HGFR) (c-Met). Activation of HGFR-mediated signaling—most commonly via MET amplification and/or MET mutations that result in exon 14 skipping—is well described in NSCLC, and crizotinib is currently being investigated in these settings. Recently, gene fusions that involve MET have been described in various cancers, including NSCLC, and a pediatric patient with glioblastoma who harbored a MET fusion was reported to have achieved a partial response to crizotinib. In this study, we report the first case of a MET fusion in lung cancer identified and treated during course of clinical care and the dramatic response of the patient’s tumor to crizotinib treatment.

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