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

The increasing appreciation of oncogenic driver alterations in non-small cell lung cancer (NSCLC) has resulted in a rapid expansion of therapeutic compounds. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) alterations are the prototypical examples and have driven the paradigm shift in NSCLC management. Early phase studies in previously treated ALK+ patients demonstrated activity and recently Solomon et al. confirmed the superiority of crizotinib over chemotherapy in first line treatment. The phase III PROFILE 1014 represents the culmination of the rapid development of crizotinib and provides lessons for future generation ALK inhibitors and other molecularly directed therapies in NSCLC. Important considerations for second and third generation inhibitors include the ability to overcome known resistance mechanisms, CNS activity, improvement in side effect profile, and safety in possible combination strategies.