Development of a Clincial Diagnostic Assay for ALK Inhibitor Mutations

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Despite the marked anti-tumor responses to Xalkori observed with ALK-driven tumors, most patients eventually experience disease progression as a consequence of resistance to the ALK inhibitor. In response to the issue of Xalkori resistance, a number of pharmaceutical and biotech companies currently have 2ndgeneration ALK small-molecule inhibitors in development. However, there are currently no diagnostic standards available for resistance testing. A robust companion diagnostic fulfilling this unmet clinical need will possess three main capabilities: 1) utility for clinical trial enrollment, 2) de novo mutation screening capability, and 3) reliable and efficient resistance mutation profiling over the entire disease course. During our Phase I development, the feasibility of Insight ALK Resistance was demonstrated as a panel of assays that will collectively identify all ALK inhibitor-resistance mutations reported in ALK-positive cancer patients resistant to Xalkori. The analytical design was proven in patient FFPE cancer specimens, indicating that the sensitivity was sufficient to provide a robust assay to profile heterogeneous tumor cell populations. Insight ALK Resistance is now ready to enter larger, pre-clinical trials to determine if the sensitivity and specificity can be recapitulated in clinically relevant FFPE specimens, and thus readied to proceed into final development for full FDA approval.