Nevertheless, if as anticipated, lorlatinib is going to be the new standard of care in ALK-and ROS1-positive NSCLC, the development of neurological symptoms should deserve peculiar attention. Prescribing physicians will need to be aware of the neurocognitive and mood effects triggered by the drug, as they can be managed by drug dose interruption and reduction.

Regarding lorlatinib activity, two meaningful elements emerged in the study. First, lorlatinib maintained its clinical activity regardless of the number of previous TKI administered (including after acquired resistance to previous generations). Among the 41 ALK-positive cases, confirmed complete and partial responses were achieved in 3 (7%) and 16 (39%) patients. Focusing on the 11 (27%) patients experiencing disease progression, three had received insufficient lorlatinib dose (35 mg twice daily). Most of the patients (n= 23) had previously received a sequence of crizotinib followed by a second-generation inhibitor. Importantly, the 9.2 months of estimated median progression-free survival (PFS) for the 26 patients who had previously received two or more ALK TKI, increased to 13.5 months in patients pretreated with one inhibitor. Importantly, the three patients who had previously received the sequence of crizotinib, ceritinib and alectinib achieved tumor shrinkage, with one complete and one partial response documented. Albeit the lack of systematic prelorlatinib biopsies does not allow definite conclusions, the molecular study of 12 samples obtained after the progression to a second-generation TKI sustains what was anticipated by preclinical findings: a divergent lorlatinib efficacy in tumors harboring wild-type rearranged ALK compared to ALK-mutated ones (6, 8). The presence of mutations in the ALK kinase domain (whose occurrence is more frequent after second-generation compounds rather than after crizotinib) does not impair lorlatinib activity. This involves the G1202R mutation, the most challenging to overcome (7). On the other hand, if resistance to previous inhibitors is mediated by off-target mechanisms, providing lorlatinib does not translate into clinical benefit, as the signal directly depending on ALK is already fully compensated by activation of alternative kinases (8). If we dare a molecular parallelism, the actions of the respective EGFR and ALK third-generation TKIs can be simplified as being similar: both osimertinib and lorlatinib are effective in 50–60% of patients in which on-target mutations explaining resistance to previous inhibitors are detected. However, we cannot conclude yet that lorlatinib should be given only to patients with ALK secondary mutations.