Development of a Clincial Diagnostic Assay for ALK Inhibitor Mutations

尽管在ALK驱动的肿瘤中观察到对Xalkori的显著抗肿瘤应答，但大多数患者最终由于对ALK抑制剂的耐药性而经历疾病进展。为了应对Xalkori耐药性问题，许多制药和生物技术公司目前正在开发第二代ALK小分子抑制剂。然而，目前没有可用于抗性测试的诊断标准。满足这一未满足的临床需求的强大伴随诊断将具有三个主要能力：1）临床试验入组的实用性，2）从头突变筛查能力，以及3）整个疾病过程中可靠和有效的耐药突变谱分析。在我们的I期开发过程中，Insight ALK Resistance的可行性被证明是一组检测试剂盒，这些检测试剂盒将共同识别对Xalkori耐药的ALK阳性癌症患者中报告的所有ALK耐药突变。分析设计在患者FFPE癌症标本中得到了证实，表明灵敏度足以提供一种稳健的检测方法来分析异质性肿瘤细胞群。Insight ALK Resistance现在已经准备好进入更大规模的临床前试验，以确定是否可以在临床相关的FFPE标本中重现灵敏度和特异性，从而准备进入最终开发以获得FDA的全面批准。

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.