Intracranial efficacy of crizotinib versus chemotherapy in PROFILE 1014: shining a light on central nervous system endpoints in clinical trials

PROFILE 1014 is the first phase III, randomized controlled trial that has prospectively studied the CNS efficacy of crizotinib compared to platinum-pemetrexed chemotherapy in ALK positive NSCLC, including among those with stable, treated CNS disease. Overall, PROFILE 1014 has given us valuable information to inform our optimal first line treatment decision for those with CNS disease at baseline, reassuring us about the efficacy of local treatment and use of crizotinib in these patients. It also highlights some of the design aspects that still need to be addressed for future clinical trials if we are to most informatively assess the activity of drugs in the CNS. Many next generation ALK inhibitors have been associated with significantly increased CNS activity compared to crizotinib and are now entering the clinic. Their CNS activity is so significant that their initial use could potentially allow the use of local CNS therapies, such as radiotherapy, to be deferred for those with CNS disease at baseline. Capturing robust CNS endpoints and learning the lessons from PROFILE 1014 will be vital if we are to determine the optimal use of these new drugs, among those both with and without CNS disease at baseline, in the future.