Moving molecularly directed therapies to the first-line in ALK -positive lung cancer: crizotinib is just the beginning

The concept of matching a drug to a specific cell surface receptor, initially referred to as “side-chain theory”, dates back to Paul Ehrlich in 1901 (1). Over one hundred years later anaplastic lymphoma kinase (ALK) rearrangement was identified as a transforming oncogenic driver and potential therapeutic target in lung cancer (2). The successes of the modern versions of side-chain theory are well known, imatinib, erlotinib, ibrutinib, vemurafenib, rituximab, trastuzumab, etc., but despite the improved recognition of possible driver alterations few targeted therapies improve survival, and none are curative. Tumor heterogeneity, the ability of coexistent genomic alterations to modify response, and the invariable development of resistance have limited the therapeutic efficacy of molecularly directed therapies