Sym015, a mixture of two mAbs, is a differentiated MET inhibitor for the treatment of solid tumors across several indications. MET is a member of the receptor tyrosine kinase family.
Recent results suggest that MET amplification identifies a small but clinically important subgroup of cancer patients who are likely to benefit from MET targeting. Although MET amplification occurs in a relatively small percentage of patients, it is present in several highly prevalent cancers including gastric cancer, mCRC, NSCLC, and renal cell carcinoma. In addition to MET amplified tumors, preliminary data suggest activity in tumors with MET exon 14 skipping mutations in NSCLC. This may open an opportunity to identify another druggable target for patients with NSCLC. Which indications we will pursue with Sym015 is dependent on the clinical findings in the ongoing Phase 1b/2a expansion trial.
Mechanism of action
The two antibodies of Sym015 bind to non-overlapping epitopes on the SEMA-a domain of MET. This allows the antibodies to bind simultaneously to the receptor and effectively induce receptor internalization and degradation. Through this mechanism, Sym015 inhibits tumor cell growth and proliferation in vitro and tumor growth in vivo, in models where MET is constitutively activated. Sym015 blocks binding of the ligand HGF to the receptor and thereby inhibits ligand-induced MET activation.
PMID: 28679766 [PubMed - as supplied by publisher]
MET amplification in solid tumors
Sym015 has potential to treat patients with solid tumors showing alterations and/or amplification of the MET proto-oncogene including certain lung cancers and colorectal cancer. METexon 14 alterations for instance are detected in approximately 3–4% of lung adenocarcinomas and 20–30% of pulmonary sarcomatoid carcinomas. The prevalence of MET amplification in NSCLC ranges from 1% to 5%. In colorectal cancer the prevalence of MET amplification has been reported anywhere from 1% up to 23% depending on EGFR mutational status.