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  • In the antivascular endothelial growth


    In 2009 the antivascular endothelial growth factor (anti-VEGF) antibody (Ab) bevacizumab was approved as the first angiogenesis inhibitor (AI) for the treatment of non-squamous NSCLC. The second AI, ramucirumab (anti-VEGFR2 Ab), was approved in 2016 [7], [8]. In 2012 the first anaplastic lymphoma kinase (ALK) TKI (crizotinib) was approved for the treatment of NSCLC patients with the ALK fusion gene [9], [10]. Two additional ALK-TKIs (alectinib and ceritinib) were approved in 2014 and 2016, respectively. More recently, the use of immune checkpoint inhibitors (ICIs), including anti-programmed cell death 1 (PD-1) Ab, for the treatment of NSCLC has been widespread. In 2015, nivolumab—a fully human IgG4 anti-PD-1 Ab—was approved as the first ICI against NSCLC [11], [12].
    Patients and methods
    Discussion During the previous two decades a major shift has occurred in the pharmacological agents used for the treatment of patients with advanced NSCLC (Fig. 1). These patients are able to undergo treatment using their preferred drug among numerous anticancer agents. As demonstrated in pivotal studies, these new KX2-391 of drugs significantly extend progression-free survival. However, the use of these agents did not result in a marked difference in patient survival [7], [10], [13], [14], [15], [16], [17]. In those pivotal studies treatment crossover was permitted (i.e., patients received various drugs). Demonstrating the extent of improvement in survival outcomes induced by one of these drugs is therefore challenging. The present study revealed superior outcomes in patients with EGFR mutation treated with gefitinib and ALK-positive patients treated with crizotinib compared with those observed before the approval of these drugs. This finding is consistent with those of previous reports [18], [19]. In contrast, no significant improvement in the survival of patients with EGFR mutation was observed from 2005. This lack of improvement was observed despite the approval of erlotinib and afatinib (after the approval of gefitinib) in Japan in 2002. Previously, prospective randomized trials compared the efficacy of erlotinib or afatinib with that of gefitinib. However, they failed to show a significant benefit in survival over gefitinib [17], [20], [21]. The present findings are consistent with those of the previous randomized trials and suggest that the approval of multiple EGFR-TKIs was not responsible for the observed improvement in the survival of patients with EGFR mutation. Although the median OS of patients with EGFR mutation in period E was not reached at the data cut-off, we hypothesize that the use of new agents (i.e., osimertinib) may prolong the survival of patients with EGFR mutation. This hypothesis is based on the significantly greater efficacy of osimertinib compared with that of platinum-doublet chemotherapy demonstrated in patients with EGFR Thr790Met (T790M) point mutation—the most frequently reported mechanism of acquired resistance to first-line treatment with EGFR-TKI [22]. Furthermore, the EML4-ALK fusion oncogene, which was described in 2007, represents one of the molecular targets in NSCLC. In 2012 crizotinib was the first ALK-TKI to be approved for the treatment of ALK-positive patients with advanced NSCLC [9]. Subsequently, alectinib and ceritinib were approved in Japan. Currently, ALK-TKIs are considered the standard first-line treatment for ALK-positive patients. In our study, the proportion of patients treated with ALK-TKIs increased after period C. However, the number of patients was insufficient to demonstrate the superiority of alectinib or ceritinib versus crizotinib in terms of survival. In prospective analyses, alectinib, ceritinib, brigatinib, and lorlatinib demonstrated clinical efficacy in ALK-positive patients with disease progression while receiving treatment with crizotinib [16], [23], [24], [25]. The development of next-generation ALK-TKIs may overcome the resistance mechanisms in these patients. Consequently, this may lead to an improvement in the survival of ALK-positive patients.