PROFILE 1014: lessons for the new era of lung cancer clinical research.

PROFILE 1014 compared crizotinib to up to six cycles of standard platinum-pemetrexed chemotherapy as the first line treatment of advanced anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC). Overall, PROFILE 1014 has taught us many valuable lessons about the natural history of ALK+ NSCLC, the effectiveness of key therapies and the positive ways in which clinical research in oncogene addicted subtypes of cancer continue to evolve. These lessons include (I) confirming the benefit of using personalized medicine approaches compared to chemotherapy that had already been established in EGFR mutant disease and in ALK+ disease in later lines of therapy; (II) demonstrating that molecular preselection can also affect outcomes from standard chemotherapy in addition to from targeted therapy. Specifically, the benefit of the control arm (platinum-pemetrexed), although inferior to that of crizotinib, was remarkable and expands the dataset on the increased sensitivity of ALK+ NSCLC to pemetrexed; (III) identifying the central nervous system (CNS) as a key battleground for metastatic NSCLC, especially for ALK+ disease. In PROFILE 1014 CNS time to progression (TTP) was included as a prominent secondary endpoint, which showed no difference between crizotinib and chemotherapy but all CNS lesions at baseline had to be both stable and treated, so any apparent stabilizing effect of the drug may be confounded. Ongoing studies with other ALK inhibitors vs. crizotinib that include untreated CNS diseases will provide greater clarity on the true effect of these drugs in the brain.