Activating Point Mutations in the MET Kinase Domain Represent a Unique Molecular Subset of Lung Cancer and Other Malignancies Targetable with MET Inhibitors.

Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas. Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of ∼0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors. Significance: The identification of targetable genomic subsets of cancer has revolutionized precision oncology and offers patients treatments with more selective and effective agents. Here, we demonstrate that activating, oncogenic MET tyrosine kinase domain mutations are found across a diversity of cancer types and are responsive to MET tyrosine kinase inhibitors.

Safety of image guided research biopsies in patients with thoracic malignancies.

OBJECTIVE: A common opportunity to collect research samples is during image-guided percutaneous core needle biopsies (CNBs) performed when clinically indicated or for assessing clinical trial eligibility. The relative safety of extra CNBs collected for research is undefined. MATERIALS AND METHODS: Patients who underwent CNB for research purposes only [RO], as clinically indicated [CI], or as part of a clinical trial [CT] were identified. 30-day post-procedure adverse events (AEs) among the cohorts were examined and compared to the 2020 Society of Interventional Radiology QI guidelines. RESULTS: 236 patients with thoracic cancers (90 % NSCLC, 5 % SCLC, 4 % mesothelioma, and 1 % thymic) had 292 CNBs (63 RO, 229 CI + CT). AEs occurred in 13 % of both the RO and CI + CT groups. Compared to the CI + CT group, the RO group did not have a higher pneumothorax incidence (RO: 5/29 [17 %], CI + CT: 18/114 [16 %], p = 0.79); both were below the suggested QI threshold of 45 % for pneumothorax. There was a negative association between number of cores obtained and risk of AE (AE vs no AE mean cores = 3.5 vs 4.8). After adjusting for the number of cores and smoking history, RO vs CI + CT lung biopsies had a higher risk of AEs (adjusted relative risk [aRR] = 2.44, 1.08-5.55, p = 0.03 vs non-lung aRR = 0.86, 0.10-7.09, p = 0.89). CONCLUSION: CNBs performed for research purposes do not have a significantly increased risk of AEs when compared to those performed for clinical trials and/or when clinically indicated. However, AEs were most frequent in lung biopsies. When performing research biopsies, a target other than lung may be preferred when clinically appropriate.