ECB-ART-50028
Ther Adv Med Oncol
2015 Sep 01;75:274-90. doi: 10.1177/1758834015590593.
Show Gene links
Show Anatomy links
Treating patients with ALK-positive non-small cell lung cancer: latest evidence and management strategy.
Liao BC
,
Lin CC
,
Shih JY
,
Yang JC
.
Abstract
Rearrangements in anaplastic lymphoma kinase (ALK) gene and echinoderm microtubule-associated protein-like 4 (EML4) gene were first described in a small portion of patients with non-small cell lung cancer (NSCLC) in 2007. Fluorescence in situ hybridization is used as the diagnostic test for detecting an EML4-ALK rearrangement. Crizotinib, an ALK inhibitor, is effective in treating advanced ALK-positive NSCLC, and the US Food and Drug Administration approved it for treating ALK-positive NSCLC in 2011. Several mechanisms of acquired resistance to crizotinib have recently been reported. Second-generation ALK inhibitors were designed to overcome these resistance mechanisms. Two of them, ceritinib and alectinib, were approved in 2014 for advanced ALK-positive NSCLC in the US and Japan, respectively. Heat shock protein 90 (Hsp90) inhibitors also showed activity against ALK-positive NSCLC. Here we review the recent development of crizotinib, ceritinib, alectinib and other second-generation ALK inhibitors as well as Hsp90 inhibitors. We also discuss management strategies for advanced ALK-positive NSCLC.
PubMed ID: 26327925
PMC ID: PMC4543853
Article link: Ther Adv Med Oncol
References [+] :
Acquaviva,
Targeting KRAS-mutant non-small cell lung cancer with the Hsp90 inhibitor ganetespib.
2012, Pubmed
Acquaviva, Targeting KRAS-mutant non-small cell lung cancer with the Hsp90 inhibitor ganetespib. 2012, Pubmed
Bergethon, ROS1 rearrangements define a unique molecular class of lung cancers. 2012, Pubmed
Camidge, Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. 2012, Pubmed
Camidge, Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. 2011, Pubmed
Cheng, CEP-28122, a highly potent and selective orally active inhibitor of anaplastic lymphoma kinase with antitumor activity in experimental models of human cancers. 2012, Pubmed
Choi, EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. 2010, Pubmed , Echinobase
Conklin, Immunohistochemistry is a reliable screening tool for identification of ALK rearrangement in non-small-cell lung carcinoma and is antibody dependent. 2013, Pubmed
Costa, Acquired resistance to the ALK inhibitor crizotinib in the absence of an ALK mutation. 2012, Pubmed
Costa, Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases. 2015, Pubmed
Cui, Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). 2011, Pubmed
Doebele, Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. 2012, Pubmed
Eccles, NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. 2008, Pubmed
Friboulet, The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. 2014, Pubmed
Gadgeel, Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. 2014, Pubmed
Gainor, The central nervous system as a sanctuary site in ALK-positive non-small-cell lung cancer. 2013, Pubmed
Gainor, Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer. 2013, Pubmed
Gainor, ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. 2013, Pubmed
Galkin, Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. 2007, Pubmed
Gandhi, High-dose pemetrexed in combination with high-dose crizotinib for the treatment of refractory CNS metastases in ALK-rearranged non-small-cell lung cancer. 2013, Pubmed
Garon, The HSP90 inhibitor NVP-AUY922 potently inhibits non-small cell lung cancer growth. 2013, Pubmed
Graham, The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non-small cell lung cancer. 2012, Pubmed
Hanna, Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. 2004, Pubmed
Huang, Multiplexed deep sequencing analysis of ALK kinase domain identifies resistance mutations in relapsed patients following crizotinib treatment. 2013, Pubmed
Ignatius Ou, Next-generation sequencing reveals a Novel NSCLC ALK F1174V mutation and confirms ALK G1202R mutation confers high-level resistance to alectinib (CH5424802/RO5424802) in ALK-rearranged NSCLC patients who progressed on crizotinib. 2014, Pubmed
Inamura, EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset. 2009, Pubmed , Echinobase
Inamura, EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. 2008, Pubmed , Echinobase
Johnson, Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations. 2014, Pubmed
Jokoji, Combination of morphological feature analysis and immunohistochemistry is useful for screening of EML4-ALK-positive lung adenocarcinoma. 2010, Pubmed , Echinobase
Katayama, Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib. 2014, Pubmed
Katayama, Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. 2012, Pubmed
Kim, Epithelial-mesenchymal transition leads to crizotinib resistance in H2228 lung cancer cells with EML4-ALK translocation. 2013, Pubmed
Kim, Heterogeneity of genetic changes associated with acquired crizotinib resistance in ALK-rearranged lung cancer. 2013, Pubmed
Kim, High-dose crizotinib for brain metastases refractory to standard-dose crizotinib. 2013, Pubmed
Kinoshita, Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802). 2012, Pubmed
Kobayashi, Transformation to sarcomatoid carcinoma in ALK-rearranged adenocarcinoma, which developed acquired resistance to crizotinib and received subsequent chemotherapies. 2013, Pubmed
Kodama, Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases. 2014, Pubmed
Kodama, Selective ALK inhibitor alectinib with potent antitumor activity in models of crizotinib resistance. 2014, Pubmed
Koivunen, EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. 2008, Pubmed
Kwak, Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. 2010, Pubmed
Lee, Anaplastic lymphoma kinase translocation: a predictive biomarker of pemetrexed in patients with non-small cell lung cancer. 2011, Pubmed
Lin, Development of renal cysts after crizotinib treatment in advanced ALK-positive non-small-cell lung cancer. 2014, Pubmed
Lovly, Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors. 2011, Pubmed
Lovly, Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. 2014, Pubmed
Lovly, Escaping ALK inhibition: mechanisms of and strategies to overcome resistance. 2012, Pubmed
Maemondo, Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. 2010, Pubmed
Maillet, Ineffectiveness of crizotinib on brain metastases in two cases of lung adenocarcinoma with EML4-ALK rearrangement. 2013, Pubmed
Marsilje, Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. 2013, Pubmed
Mok, Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. 2009, Pubmed
Mori, The selective anaplastic lymphoma receptor tyrosine kinase inhibitor ASP3026 induces tumor regression and prolongs survival in non-small cell lung cancer model mice. 2014, Pubmed , Echinobase
Neckers, Hsp90 molecular chaperone inhibitors: are we there yet? 2012, Pubmed
Normant, The Hsp90 inhibitor IPI-504 rapidly lowers EML4-ALK levels and induces tumor regression in ALK-driven NSCLC models. 2011, Pubmed , Echinobase
Ou, Asymptomatic profound sinus bradycardia (heart rate ≤45) in non-small cell lung cancer patients treated with crizotinib. 2011, Pubmed
Ou, Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC. 2014, Pubmed
Ou, Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. 2011, Pubmed
Ou, Heart rate decrease during crizotinib treatment and potential correlation to clinical response. 2013, Pubmed
Park, Immunohistochemical screening for anaplastic lymphoma kinase (ALK) rearrangement in advanced non-small cell lung cancer patients. 2012, Pubmed
Pillai, Heat shock protein 90 inhibitors in non-small-cell lung cancer. 2014, Pubmed
Politi, Perfect ALKemy: optimizing the use of ALK-directed therapies in lung cancer. 2014, Pubmed
Proia, Synergistic activity of the Hsp90 inhibitor ganetespib with taxanes in non-small cell lung cancer models. 2012, Pubmed
Ramalingam, A randomized phase II study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel in second-line therapy of advanced non-small cell lung cancer (GALAXY-1). 2015, Pubmed
Rodig, Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. 2009, Pubmed
Rothenstein, Managing treatment-related adverse events associated with Alk inhibitors. 2014, Pubmed
Sakamoto, CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. 2011, Pubmed
Sang, Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK inhibitor resistance in non-small cell lung cancer. 2013, Pubmed
Sasaki, A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. 2011, Pubmed
Sasaki, The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers. 2010, Pubmed
Sequist, Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer. 2010, Pubmed
Sequist, Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. 2013, Pubmed
Seto, CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study. 2013, Pubmed
Shanthi, Focal adhesion kinase inhibitors in the treatment of metastatic cancer: a patent review. 2014, Pubmed
Shaw, Ceritinib in ALK-rearranged non-small-cell lung cancer. 2014, Pubmed
Shaw, Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. 2013, Pubmed
Shaw, Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. 2009, Pubmed
Shimamura, Ganetespib (STA-9090), a nongeldanamycin HSP90 inhibitor, has potent antitumor activity in in vitro and in vivo models of non-small cell lung cancer. 2012, Pubmed
Socinski, A multicenter phase II study of ganetespib monotherapy in patients with genotypically defined advanced non-small cell lung cancer. 2013, Pubmed
Soda, Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. 2007, Pubmed , Echinobase
Soda, A mouse model for EML4-ALK-positive lung cancer. 2008, Pubmed
Solomon, First-line crizotinib versus chemotherapy in ALK-positive lung cancer. 2014, Pubmed
Takeda, Clinical impact of continued crizotinib administration after isolated central nervous system progression in patients with lung cancer positive for ALK rearrangement. 2013, Pubmed
Takeuchi, KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. 2009, Pubmed
Tamiya, Severe acute interstitial lung disease after crizotinib therapy in a patient with EML4-ALK-positive non-small-cell lung cancer. 2013, Pubmed
Tanizaki, Activation of HER family signaling as a mechanism of acquired resistance to ALK inhibitors in EML4-ALK-positive non-small cell lung cancer. 2012, Pubmed
Togashi, KLC1-ALK: a novel fusion in lung cancer identified using a formalin-fixed paraffin-embedded tissue only. 2012, Pubmed
Trepel, Targeting the dynamic HSP90 complex in cancer. 2010, Pubmed
Vaishnavi, Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. 2013, Pubmed
Weickhardt, Symptomatic reduction in free testosterone levels secondary to crizotinib use in male cancer patients. 2013, Pubmed
Weickhardt, Rapid-onset hypogonadism secondary to crizotinib use in men with metastatic nonsmall cell lung cancer. 2012, Pubmed
Whitesell, HSP90 and the chaperoning of cancer. 2005, Pubmed
Wong, The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. 2009, Pubmed , Echinobase
Woodhead, Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design. 2010, Pubmed
Wu, EML4-ALK translocation predicts better outcome in lung adenocarcinoma patients with wild-type EGFR. 2012, Pubmed , Echinobase
Yamada, Paracrine receptor activation by microenvironment triggers bypass survival signals and ALK inhibitor resistance in EML4-ALK lung cancer cells. 2012, Pubmed
Yamaguchi, Dual ALK and EGFR inhibition targets a mechanism of acquired resistance to the tyrosine kinase inhibitor crizotinib in ALK rearranged lung cancer. 2014, Pubmed
Yang, A selective ALK inhibitor in ALK-rearranged patients. 2013, Pubmed
Yang, Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. 2013, Pubmed
Yasuda, Preclinical rationale for use of the clinically available multitargeted tyrosine kinase inhibitor crizotinib in ROS1-translocated lung cancer. 2012, Pubmed
Yi, Correlation of IHC and FISH for ALK gene rearrangement in non-small cell lung carcinoma: IHC score algorithm for FISH. 2011, Pubmed
Ying, Ganetespib, a unique triazolone-containing Hsp90 inhibitor, exhibits potent antitumor activity and a superior safety profile for cancer therapy. 2012, Pubmed
Zhang, Crizotinib-resistant mutants of EML4-ALK identified through an accelerated mutagenesis screen. 2011, Pubmed