A subsequent study showed that genetically modified mice with lung-specific expression of develop lung adenocarcinoma demonstrating that fusion gene is a potent cancer driver gene, and since then it has been the subject of global attention in the field of oncology (4). progression-free survival (PFS) of 9.7 months (10). The results of a subsequent phase II clinical trial provided comparable ORR and PFS outcomes (PROFILE1005) (11). Based on these favorable clinical outcomes, crizotinib was granted an accelerated approval by the Food and Drug Administration (FDA) in 2011 for clinical use, just 4 years after its initial report. Ginsenoside Rg2 Crizotinib has been shown to be significantly effective for the treatment of patients with fusion gene-positive lung cancer and it is presently one of the Ginsenoside Rg2 first-line treatments for this type of cancer. However, therapeutic problems such as progressive disease, relapse due to acquired resistance and brain metastases have emerged (12-14). Later, a phase III trial (PROFILE1007) was conducted in 347 fusion gene-positive non-small cell lung cancer patients who had previously undergone platinum-based chemotherapy (15). Patients were randomized to a crizotinib group or chemotherapy group (pemetrexed or docetaxel). Both PFS (7.7 3.0 months; HR =0.49, P 0.001) and ORR (65% 20%; P 0.001) were superior in the crizotinib group. The median survival time (MST) was not significantly different (20.3 22.8 months; HR =1.02, P=0.54) between the two groups, but this lacks of survival benefit was interpreted as being due to the confounding effects of crossover (15). Alectinib is usually a second generation inhibitor with broader selectivity than crizotinib. Alectinib exhibits anti-tumor activity in the crizotinib-resistant L1196M mutation (16). A randomized, open-label, phase III trial (J-ALEX study) that directly compared alectinib and crizotinib in inhibitor-naive patients was conducted in Japan. In February 2016, an independent data monitoring committee reviewed the clinical outcomes of a pre-planned interim analysis and recommended the early termination of the J-ALEX clinical trial because a statistically significant extension of PFS was observed in the alectinib monotherapy group (HR =0.34, P 0.0001). Based on these results, alectinib was granted the breakthrough therapy designation from FDA in September 2016, and considered as the first-line treatment for patients with inhibitor-naive and chemotherapy-naive or had previously received only one chemotherapy regimen (17). The hazard ratio of PFS in the alectinib monotherapy group in relation to the crizotinib monotherapy group was 0.34, indicating a statistically significant extension (P 0.0001) of PFS in the alectinib monotherapy group (17). The median PFS was 10.2 months in the crizotinib monotherapy group [95% confidence interval (CI): 8.2C12.0] but that of the alectinib monotherapy group (95% CI: 20.3C not estimated) had not been as yet reached at the time of the interim analysis (17). Currently, a global phase III trial (ALEX study) to directly compare the efficacy and safety of alectinib and crizotinib as Ginsenoside Rg2 first-line treatment is usually ongoing. A report at an academic conference showed that, according to an independent review committee, the disease progression or death risk decreased 50% in the alectinib group compared to the crizotinib group (HR =0.50, 95% CI: 0.36C0.70) and that the median PFS was 25.7 months in the alectinib group (95% CI: 19.9C not estimated) and NEK3 10.4 months in the crizotinib group (95% CI: 7.7C14.6). Like alectinib, ceritinib is usually a second generation inhibitor. Ceritinib exhibits broader selectivity and is a more potent inhibitor than crizotinib (18). It crosses the blood brain barrier (BBB) (18). An open-label phase I trial (ASCEND1) was conducted in fusion gene-positive patients with locally advanced or metastatic cancer and with progressive disease despite standard therapy (19). The results showed a ORR of.