Non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase rearrangement (ALK) was first reported in 2007. ALK-rearranged NSCLC accounts for about 3–8% of NSCLC. The first-line therapy for ALK-rearranged advanced NSCLC is tyrosine kinase inhibitors (TKI) targeting ALK. Following the development of crizotinib, the first ALK-TKI, patient prognosis has been greatly improved. Currently, five TKIs are approved by the FDA. In addition, clinical trials of the novel TKI, ensartinib, and fourth-generation ALK-TKI for compound ALK mutation are ongoing. Treatment with angiogenesis inhibitors and immune checkpoint inhibitors is also being studied. However, as the disease progresses, cancers tend to develop resistance mechanisms. In addition to ALK mutations, other mechanisms, including the activation of bypass signaling pathways and histological transformation, cause resistance, and the identification of these mechanisms is important in selecting subsequent therapy. Studies on tissue and liquid biopsy have been reported and are expected to be useful tools for identifying resistance mechanisms. The purpose of this manuscript is to provide information on the recent clinical trials of ALK-TKIs, angiogenesis inhibitors, immune checkpoint inhibitors, and chemotherapy to describe tissue and liquid biopsy as a method to investigate the mechanisms of resistance against ALK-TKIs and suggest a proposed treatment algorithm.

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a common technique for sampling mediastinal and hilar lymph nodes. However, the optimal sedation for EBUS-TBNA remains unclear. We aimed to evaluate the efficacy of adding fentanyl to midazolam. We conducted a single-center, randomized, double-blind, phase III study. Patients who received midazolam with fentanyl (fentanyl group) were compared with those who received midazolam with placebo (placebo group) during EBUS-TBNA. The primary outcome was the proportion of patients meeting all three criteria: 1) adequate sedation (Modified Observer's Assessment of Alertness and Sedation scale ≤4 or bispectral index values ≤80), 2) minimal additional sedation requirement (no more than two additional sedative administrations within the first 30 min), and 3) successful procedure completion (at least three EBUS-TBNA punctures). A total of 84 patients (fentanyl group, 41; placebo group, 43) were enrolled. There were no significant differences in patient characteristics between the two groups. The primary outcome was significantly better in the fentanyl group than in the placebo group (46.3 % vs. 23.3 %, p = 0.038). A significantly lower rate of sedative-induced delirium, a lower number of additional sedative administrations, and a higher rate of ≥3 punctures were observed in the fentanyl group. There were no significant differences in complications. The operator visual analog scale questionnaire on cough, sputum, cooperation, and sedative effects was significantly better in the fentanyl group. Adding fentanyl to midazolam provided better sedation. Midazolam combined with fentanyl should be considered during EBUS-TBNA.