Molecular Analysis for Therapy Choice (MATCH)

RAS mutations result in upregulation of the mitogen-activated protein kinase (MAPK) pathway and are thought to be key driver mutations in many malignancies. . The importance of RAS mutations is underscored by its high prevalence in human malignancies. Data from the COSMIC database indicates that RAS, which has three highly homologous isoforms KRAS, N-RAS, and HRAS, is mutated in approximately 30% of human malignancies. Mutations in NRAS are found in approximately 8% of human cancers. While most frequently seen in melanomas, NRAS mutations are seen in many other solid malignancies including colorectal, gastric, thyroid, uterine endometrial, lung, among others. Despite enormous efforts from both academia and industry, successful targeting of RAS mutated malignancies has been an elusive goal. Clinical trials testing numerous strategies, including farnesyl transferase inhibitors and combined MEK/PI3K inhibition, have failed to produce widespread, clinically meaningful results. Interestingly, preclinical testing demonstrates that NRAS mutated cell lines are more sensitive to MEK inhibitor than KRAS mutated cell lines. For example, a study of lung cancer cell lines demonstrated that five of six NRAS mutant cell lines were sensitive to the MEK inhibitors. Consistent with in vitro observations, the most successful effort in targeting RAS mutations has been seen in NRAS mutated melanoma. In an open label phase 2 study, treatment of 117 patients with NRAS mutated melanoma with the MEK inhibitor binimetinib resulted in an overall response rate of 14.5% with PFS of 3.6 months and OS of 12.2 months14. In a smaller phase 2 trial of binimetinib, six (20%; 95% CI 8-39%) of 30 patients with NRAS-mutated melanoma had a partial response.

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