Data from a phase II study investigating the efficacy of the ALK and ROS1 tyrosine-kinase inhibitor (TKI) lorlatinib reveal encouraging response rates in patients with ALK-rearranged and/or ROS1-rearranged non-small-cell lung cancer (NSCLC) in multiple settings. The majority (90%) of patients with treatment-naive disease had a response to lorlatinib. Objective responses were observed in 69.5% of those who previously received crizotinib and in 32.1–47% of patients who received at least one previous other ALK-TKI with or without chemotherapy. Similar intracranial response rates were observed in patients with brain metastases, thus confirming the brain penetrance of this agent. Hyperchlolesterolaemia and hypertryglyceridaemia were the most common grade ≥3 adverse events (both in 16% of patients). These data suggest that lorlatinib could be effective in both the first-line and later-line treatment settings. Extended follow-up data from this trial are eagerly awaited.