can yield new drugs and diagnostics that have substantial benefits for human health.

THE DEVELOPMENT OF CRIZOTINIB FOR TREATMENT OF NON-SMALL-CELL LUNG CANCER

The drug crizotinib provides an excellent example of how a diagnostic test can be used to identify patients who will benefit from a treatment, said Steffan Ho of Pfizer Inc. Crizotinib, which was originally known as PF-02341066 and has the trade name XALKORI, is a small molecule that binds to the catalytic site of kinases and competes with ATP, thereby inhibiting kinase activity. Its primary targets are the receptor tyrosine kinases known as c-MET, ALK, and ROS. It was approved for use by the FDA on August 26, 2011.

As stated in the indications and usage notes for crizotinib, “XALKORI is a kinase inhibitor indicated for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.” The related diagnostic device, which was simultaneously approved for use with crizotinib, is the Abbott Vysis ALK Break Apart FISH Probe Kit, which is described in the package insert as “a qualitative test to detect rearrangements involving the ALK gene via fluorescence in situ hybridization (FISH) in formalin-fixed paraffin-embedded (FFPE) non-small-cell lung cancer tissue specimens to aid in identifying those patients eligible for treatment with XALKORI (crizotinib).” The device is a Class III diagnostic test, requiring the highest level of rigor and scrutiny, because of the risks associated with its use to inform physicians about how to treat or not treat a patient.

The approval of crizotinib was conditional, Ho noted, because it was based on the response rate. At the time of approval, no data were available that demonstrated improvement in patient-reported outcomes or survival with crizotinib. Additional Phase III clinical studies were under way at the time of the workshop to investigate the hypothesis that crizotinib both improves the response rate and provides a survival advantage.

From the treatment of the first patient deemed to be ALK-positive, approval took just 4 years—a “remarkable accomplishment,” Ho said (Figure 3-1). While uncommonly fast compared to most drugs, this timeframe has been fairly common in oncology with targeted therapeutic agents, he added. The development of vemurafenib, imatinib, and trastuzumab—other oncology drugs in which targeted patient populations are identified—also went quickly. “It supports the concept that once we can identify the right population, the clinical efficacy is very clear,” he said.

In oncology drug development, the datasets that provide the confidence to move into the clinic include not only the chemical and pharmaceutical



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