The most frequent grade 3 or 4 4 adverse events were increased alanine aminotransferase (ALT, 21%), increased aspartate aminotransferase (AST, 11%), diarrhea (7%), and elevated lipase (7%); these toxicities were reversible after ceritinib was stopped. most common sites of relapse in patients with ALK-positive NSCLC, and CNS disease can prove refractory to standard therapies.10 In light of these limitations with crizotinib, many novel ALK inhibitors that have greater potency and different kinase selectivity compared with crizotinib are currently in development (Table 1). Additionally, heat shock protein 90 (Hsp90) inhibitors have emerged as potentially active agents in the treatment of ALK-positive lung cancers, Cyantraniliprole D3 and these are being tested alone and in combination with ALK TKIs. This review provides an update on each of the TKIs and Hsp90 inhibitors in clinical development for ALK-positive NSCLC (Table 2), focusing on drug potency, selectivity, Cyantraniliprole D3 and side effects (Table 3). Table 1 ALK Inhibitors in Clinical Development rearrangement or mutation is a dominant oncogenic driver in several tumor types other than NSCLC, and crizotinib appears to be active in these cancers as well. Roughly 50% of inflammatory myofibroblastic tumors (IMTs) harbor rearrangements,13 and several patients with tyrosine kinase domain have been detected in approximately 10% of cases of neuroblastoma; the most commonly described amino acid substitutions are R1275Q and F1174L.18 Both in preclinical models and in phase 1 clinical trials of neuroblastoma, crizotinib has been shown to be an effective inhibitor in cases with the R1275Q mutation, but not the F1174L mutation15,19; this finding is consistent with the fact that F1174L has also been described as an acquired mutation that confers resistance to crizotinib in have also been described in other cancer types, including renal cell carcinoma,21 rhabdomyosarcoma,22 thyroid carcinoma,23 colorectal cancer,24 spitzoid melanomas,25 and others, but the use of ALK Cyantraniliprole D3 inhibitors in these patient populations has not been described. Efficacy of Crizotinib in NonCSmall Cell Lung Cancer With MET or ROS1 Abnormalities In addition to being an inhibitor of ALK, crizotinib is a potent inhibitor of the tyrosine kinases MET26 and ROS1,27 and these findings have translated into clinical benefit for patients who have NSCLC with genomic aberrations in these kinases. In patients who have lung cancer with de novo genomic amplification and no rearrangements, crizotinib has resulted in rapid and durable responses.28,29 Short-term responses to crizotinib in locus as a mechanism of acquired resistance.32,33 In preclinical models of kinase domain were identified.38 Limitations of Crizotinib Central Nervous System Relapse Although there Cyantraniliprole D3 are individual case reports of patients with ALK-positive NSCLC and brain metastases having a CNS response to crizotinib,39 a significant limitation of crizotinib appears to be poor activity in the CNS. Numerous reports have highlighted the ineffectiveness of crizotinib at controlling disease in the CNS.40,41 In a retrospective analysis of pooled data from the PROFILE 1005 and PROFILE 1007 studies, the intracranial ORR to crizotinib in patients with ALK-positive NSCLC and previously treated or untreated brain metastases was only 7%, although the 12-week intracranial disease control rate (percentage of complete responses + partial responses + stable disease) was approximately 60%.42 Further, among the 146 patients with ALK-positive NSCLC from the crizotinib phase 1 and phase 2 trials (PROFILE 1001 and PROFILE 1005) in whom progressive disease developed while they were taking crizotinib, the brain was the most common site of cancer recurrence in a single organ. In many of these patients with brain-only recurrence, it was possible to maintain systemic cancer control with continued administration of crizotinib once their CNS disease had been treated with radiation or surgery.10 The high rate of CNS relapse in patients treated with crizotinib is likely due to poor blood-brain barrier penetration of crizotinib; in one patient with ALK-positive NSCLC on crizotinib who had a relapse only in the CNS, the ratio of the cerebrospinal fluid concentration of crizotinib to the plasma concentration was found to be Cyantraniliprole D3 just 0.0026, a very low value.43 Resistance to Crizotinib For patients who have ALK-positive NSCLC, the median PFS with MKI67 crizotinib is 8 to 10 months.9 Multiple mechanisms of crizotinib resistance have been described in ALK-positive NSCLC (Table 4). To.