Lung toxicity is a potential fatal effect involving non-small-cell lung cancer 
(NSCLC) patients exposed to tyrosine kinase inhibitors (TKIs). Moving from our 
experience regarding a patient who developed lung toxicity while receiving 2 
different anaplastic lymphoma kinase (ALK)-TKIs, we performed a systematic 
review to assess the epidemiologic magnitude and the clinical significance of 
such toxicity in NSCLC patients treated with ALK-TKIs. Studies were identified 
using MEDLINE and additional sources (European Society for Medical Oncology, 
American Society of Clinical Oncology, and World Conference on Lung Cancer 
abstracts) in agreement with Preferred Reporting Items for Systematic Reviews 
and Meta-Analyses and Cochrane guidelines. Lung toxicity was reported in 105 of 
4943 NSCLC patients (2.1%). Crizotinib was responsible for pulmonary adverse 
events (AEs) in 1.8% of exposed patients (49 of 2706). With the limit of a lower 
number of treated patients (n = 359), brigatinib resulted as the most frequently 
involved in lung toxicity (7%; n = 25). Pulmonary AEs during therapy with 
ceritinib, alectinib, and lorlatinib occurred in 1.1%, 2.6%, and 1.8% of the 
patients, respectively. Sixty-five percent of cases accounted for Grade 3 or 4 
events, with a mortality rate of 9%. Radiological patterns of pneumonia were 
reported in 25 patients, whereas imaging evocative of interstitial lung disease 
in 37. Overall, 26 of 105 patients (25%) permanently discontinued treatment 
because of lung toxicity. Lung toxicity is a rare albeit potentially severe side 
effect in NSCLC patients receiving ALK-TKIs, apparently more frequent with 
brigatinib. Its early recognition and treatment are crucial for the best outcome 
of this subgroup of patients, whose overall prognosis is being improved by the 
availability of several targeted agents.