Garrett Frampton¹, Siraj Ali², Ignatius Ou³, Garrett Frampton⁴ 

¹Research andDevelopment, Foundation Medicine, Inc, ²clinical development,Foundation Medicine, ³California, Universityof California Irvine, ⁴Inc, Foundation Medicine

Objective:Amplifications and activating mutations inthe c-MET proto-oncogene are known oncogenic drivers that have provenresponsive to targeted therapy. Mutations causing skipping of MET exon 14 arealso oncogenic, but less well characterized. Several recent case reports demonstrateresponse to targeted therapy in patients with these MET exon 14 alterations. Weundertook comprehensive genomic profiling (CGP) of a large series of advancedcancers to further characterize MET exon 14 alterations. 

Method: DNA wasextracted from 40 microns of FFPE sections from 38,028 advanced cancer cases.CGP was performed on hybridization-captured, adaptor ligation based librariesto a mean coverage depth of >500x. Base substitution, indel, copy numberalteration, and rearrangement variant calls were examined to identify thosenearby to the splice junctions of MET exon 14. These genomic alterations werethen manually inspected to identify those likely to affect splicing of exon 14,or delete the exon entirely. 

Result: 224 distinct MET exon 14 alterationswere identified, occurring in 221 specimens, with 126 different genomicsequence variants represented. The alterations were comprised basesubstitutions (n=2) and indels (33) at splice acceptor sites, basesubstitutions (102) and indels at splice donor sites, and base substitutions(2) and indels (49) in the ~25 bp intronic noncoding region immediatelyadjacent to the splice acceptor site and five whole exon deletions of MET exon14. Indels were predominantly deletions, but several insertions and complexindels were detected. MET exon 14 alterations were distributed among primarydisease site as; lung adenocarcinoma (3.0%, 131/4402), other lung neoplasms(2.3%, 62/2669), brain glioma (0.4%, 6/1708), tumors of unknown primary origin(0.4%, 15/3376), and other tumor types (<0.1%, 7/25873). MET exon 14alterations were not found in tumors of the female reproductive system(n=7436), colon and rectum (3714), pancreas (1424), or hematopoietic system(2113). Patients with MET exon 14 alterations had a median age of 70.5 years(range 15-88). with 97 males and 124 females. Identification of this alterationhas lead to treatment with MET inhibitors such as crizotinib, and to durablepartial responses or better exceeding 6 months in histiocytic sarcoma (1),sarcomatoid non small cell lung carcinoma (1), and NSCLC (3). Multiplepatients (10+) have initiated treatment on either crizotinib or MET inhibitorsin clinical development, and additional outcome data will be reported. Conclusion:MET exon 14 alterations define a hereto unrecognized population of advancedcancer cases. Multiple case reports demonstrate that these alterations confersensitivity to multiple small molecule MET inhibitors. This finding expands thepopulation of advanced cancer patients who can derive benefit from MET-targetedtherapies.

Key Words: met  crizotinib lung carcinoma