Strategies against Xalkori resistance

Two U.S. groups have uncovered multiple mechanisms in ALK-rearranged lung cancers that could drive resistance to Pfizer Inc.'s Xalkori crizotinib.1,2 The findings suggest Xalkori should be combined with drugs that target other oncogenic pathways such as the EGFR and KIT pathways, but future studies are needed to determine the frequencies of the identified resistance mechanisms and the best ways to overcome them.

Xalkori is a dual inhibitor of c-Met receptor tyrosine kinase (c-Met) and anaplastic lymphoma kinase (ALK), and their oncogenic variants. Last August, the FDA granted Xalkori accelerated approval to treat advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC).

Pfizer originally pursued Xalkori for its c-Met inhibition properties but ended up positioning the drug for ALK-positive lung cancers after two key developments suggested an ALK fusion gene was actually the oncogenic driver in a subset of patients with NSCLC.3,4

The fusion gene, which contains parts of echinoderm microtubule associated protein like 4 (EML4) and ALK, encodes a cytoplasmic protein with constitutive kinase activity.

In patients with ALK-positive NSCLC,

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