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{\u0022basePath\u0022:\u0022\\\/\u0022,\u0022pathPrefix\u0022:\u0022\u0022,\u0022highwire\u0022:{\u0022markup\u0022:[{\u0022requested\u0022:\u0022full-text\u0022,\u0022variant\u0022:\u0022full-text\u0022,\u0022view\u0022:\u0022full\u0022,\u0022pisa\u0022:\u0022spmdc;14\\\/3\\\/24\u0022},{\u0022requested\u0022:\u0022long\u0022,\u0022variant\u0022:\u0022full-text\u0022,\u0022view\u0022:\u0022full\u0022,\u0022pisa\u0022:\u0022spmdc;14\\\/3\\\/24\u0022}],\u0022ac\u0022:{\u0022spmdc;14\\\/3\\\/24\u0022:{\u0022access\u0022:{\u0022reprint\u0022:true,\u0022full\u0022:true},\u0022pisa_id\u0022:\u0022spmdc;14\\\/3\\\/24\u0022,\u0022atom_uri\u0022:\u0022\u0022,\u0022jcode\u0022:\u0022spmdc\u0022}}},\u0022googleanalytics\u0022:{\u0022trackOutbound\u0022:1,\u0022trackMailto\u0022:1,\u0022trackDownload\u0022:1,\u0022trackDownloadExtensions\u0022:\u00227z|aac|arc|arj|asf|asx|avi|bin|csv|doc(x|m)?|dot(x|m)?|exe|flv|gif|gz|gzip|hqx|jar|jpe?g|js|mp(2|3|4|e?g)|mov(ie)?|msi|msp|pdf|phps|png|ppt(x|m)?|pot(x|m)?|pps(x|m)?|ppam|sld(x|m)?|thmx|qtm?|ra(m|r)?|sea|sit|tar|tgz|torrent|txt|wav|wma|wmv|wpd|xls(x|m|b)?|xlt(x|m)|xlam|xml|z|zip\u0022,\u0022trackUrlFragments\u0022:1},\u0022ajaxPageState\u0022:{\u0022js\u0022:{\u0022sites\\\/all\\\/libraries\\\/cluetip\\\/jquery.cluetip.js\u0022:1,\u0022sites\\\/all\\\/libraries\\\/cluetip\\\/lib\\\/jquery.hoverIntent.js\u0022:1,\u0022sites\\\/all\\\/libraries\\\/cluetip\\\/lib\\\/jquery.bgiframe.min.js\u0022:1,\u0022sites\\\/all\\\/modules\\\/highwire\\\/highwire\\\/plugins\\\/highwire_markup_process\\\/js\\\/highwire_at_symbol.js\u0022:1,\u0022sites\\\/all\\\/modules\\\/highwire\\\/highwire\\\/plugins\\\/highwire_markup_process\\\/js\\\/highwire_article_reference_popup.js\u0022:1,\u0022sites\\\/all\\\/modules\\\/contrib\\\/google_analytics\\\/googleanalytics.js\u0022:1,\u00220\u0022:1}}});\n\/\/--\u003E\u003C!]]\u003E\n\u003C\/script\u003E\n\u003Clink type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EIn some cases of non\u2014small cell lung cancer (NSCLC), mutations in oncogenes appear to be the underlying mechanism of lung cancer development. Specifically targeted therapies are promising in the treatment of NSCLC, but mutations in oncogenic drivers can result in drug resistance. This article discusses drug resistance to ALK and ROS1 inhibitors, as well as BRAF and HER2 mutations that result in drug resistance.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EOncology Genomics\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ERespiratory Cancers\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ECancer\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EOncology Genomics\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EOncology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ERespiratory Cancers\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ECancer\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EIn some cases of non-small cell lung cancer (NSCLC), mutations in oncogenes appear to be the underlying mechanism of lung cancer development. Specifically targeted therapies are promising in the treatment of NSCLC, but mutations in oncogenic drivers can result in drug resistance. Robert C. Doebele, MD, PhD, University of Colorado Cancer Center, Aurora, Colorado, USA, discussed drug resistance to ALK and ROS1 inhibitors. ALK and ROS1 gene fusions drive about 5% and 1% of lung cancers, respectively.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EThe ALK and ROS1 kinases have high homology, so some inhibitors are effective against both kinases \u003Cem\u003Ein vitro\u003C\/em\u003E, such as crizotinib and ceritinib [Davies KD et al. \u003Cem\u003EClin Can Res\u003C\/em\u003E 2012]. In addition, crizotinib treatment in patients with NSCLC with ALK or ROS1 gene fusions resulted in an objective response rate of 60.8% (95% CI, 52.3 to 68.9) and 56% (95% CI, 24.4 to 65.1), respectively, in 2 separate trials [Camidge DR et al. \u003Cem\u003ELancet Oncol\u003C\/em\u003E 2012; Ou SH et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2013. Abstract 8032]. Similarly, the 6-month progression-free survival was 87.9% and 71% in patients with NSCLC with ALK or ROS1 gene fusions (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E) [Camidge DR et al. \u003Cem\u003ELancet Oncol\u003C\/em\u003E 2012; Ou SH et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2013]. Crizotinib eventually fails in patients with ALK or ROS1 gene fusions, however, because of drug resistance.\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/3\/24\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Effect of Crizotinib in Patients With ALK and ROS1 Gene Fusions\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1223614245\u0022 data-figure-caption=\u0022Effect of Crizotinib in Patients With ALK and ROS1 Gene Fusions\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/3\/24\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/3\/24\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/3\/24\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/15812\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-4\u0022 class=\u0022first-child\u0022\u003EEffect of Crizotinib in Patients With ALK and ROS1 Gene Fusions\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EPFS=progression-free survival; FISH+=fluorescence in situ hybridization-positive.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EReproduced from Camidge DR et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. \u003Cem\u003ELancet Oncology\u003C\/em\u003E 2012;13(10);1011\u20131019. With permission from Elsevier.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-5\u0022\u003EThe mechanisms of crizotinib resistance can be categorized as ALK-dominant mechanisms, such as resistance mutations or lack of adequate central nervous system (CNS) penetration, and ALK nondominant mechanisms, which are primarily a result of bypass signaling [Camidge DR, Doebele RC. \u003Cem\u003ENat Rev Clin Oncol\u003C\/em\u003E 2012]. Currently, multiple second-generation ALK and ROS1 inhibitors that can potentially overcome resistance are under development [Camidge DR et al. ESMO 2013 3.401]. Some ALK mutations may, however, be resistant to the second-generation ALK inhibitors [Doebele RC et al. \u003Cem\u003EJTO\u003C\/em\u003E 2014].\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003ESimilarly, next-generation ROS 1 inhibitors that may overcome resistance are under development. The agents PF-06463922 and foretinib demonstrated activity against ROS1 mutations \u003Cem\u003Ein vitro\u003C\/em\u003E [Zou HY et al. AACR 2013; Devare MA et al. \u003Cem\u003EProc Natl Acad Sci USA\u003C\/em\u003E 2013]. In crizotinib-na\u00efve and -resistant ALK+ patients, treatment with the agent LDK378 resulted in an overall response rate (ORR) of 60% and 57%, respectively [Shaw AT et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2013]. Similarly, in patients with NSLCL with ALK mutations, treatment with alectinib resulted in an ORR of 54.5% [Ou S et al. ESMO 2013. Abstract 44], and treatment with AP26113 resulted in an ORR of 61% [Camidge DR et al. ESMO 2013 3.401].\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EDr. Doebele pointed out that there appears to be a disconnect between the mechanisms believed to drive drug resistance and the response to second-generation ALK and ROS1 inhibitors. Considering that the approximately 30% of patients with NSCLC with ALK inhibitor-resistant mutations will not all respond to therapy, and some will have mutations that are expected to be resistant to the second-generation inhibitors, the response to these agents is far better than expected (\u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E) [Doebele RC. \u003Cem\u003EJ Thorac Oncol\u003C\/em\u003E 2014]. The reasons for this are unknown, but it maybe a result of having missed mutations in patient samples, resensitization, and targeting of bypass pathways by these new inhibitors.\u003C\/p\u003E\u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/3\/24\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Better Than Expected Response to Second-Generation ALK and ROS1 Inhibitors\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1223614245\u0022 data-figure-caption=\u0022Better Than Expected Response to Second-Generation ALK and ROS1 Inhibitors\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/3\/24\/F2.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/3\/24\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/3\/24\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/15814\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 2.\u003C\/span\u003E \n            \u003Cp id=\u0022p-8\u0022 class=\u0022first-child\u0022\u003EBetter Than Expected Response to Second-Generation ALK and ROS1 Inhibitors\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-3\u0022\u003ERECIST=response evaluation criteria in solid tumors; DCR=disease control rate; ORR=overall response rate; CNG=copy number gain.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-4\u0022\u003EReproduced with permission from RC Doebele, MD, PhD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-9\u0022\u003EBenjamin Besse, MD, PhD, Gustave Roussy Cancer Campus Grand Paris, Villejuif, France, discussed BRAF and HER2 mutations that result in drug resistance. The incidence of BRAF mutations is about 1.7%, with HER2 mutations even lower at 0.9% [Barlesi F et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2013]. It is not clear if BRAF mutations (specifically, the V600E mutation) are a negative prognostic factor. Two studies of patients with resected NSCLC, however, demonstrated that BRAF mutations resulted in lower overall survival compared with patients with wild-type BRAF [Kinno T et al. \u003Cem\u003EAnn Oncol\u003C\/em\u003E 2014; Marchetti A et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2011].\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EThe first BRAF inhibitor, vemurafenib, demonstrated promising results in melanoma with an improvement in progression-free survival (PFS) [Flaherty KT et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2010]. The second BRAF was dabrafenib, which also showed the promising results of an improvement in PFS in melanoma [Hauschild A et al. \u003Cem\u003ELancet\u003C\/em\u003E 2012]. In addition, a Phase 2, single-arm, open-label trial of dabrafenib in patients with BRAF V600E-mutation NSCLC is currently underway, with a primary objective of increasing the ORR [\u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT01336634\u0026amp;atom=%2Fspmdc%2F14%2F3%2F24.atom\u0022\u003ENCT01336634\u003C\/a\u003E]. Data from the first 20 patients indicate that the ORR is 40%, with a majority of the patients demonstrating partial response [Planchard D et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2013]. Although PFS is not available, the median duration of treatment was 84 days, with some patients receiving treatment for more than 1 year. Common adverse events included fatigue (40%), decreased appetite (32%), asthenia (24%), rash (24%), nausea (24%), diarrhea (20%), anemia (24%), and hypophosphatemia (12%). Importantly, patients must be followed closely for induction of other cancers, such as squamous cell carcinoma of the skin. The dabrafenib trial design was amended to allow recruitment of an additional cohort of patients who were treated with combination therapy of dabrafenib and the MEK inhibitor trametinib, and it demonstrated that PFS was improved with combination therapy versus monotherapy.\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003ENSCLC driven by HER2 mutations is rare, but it appears to occur mostly in women who were never smokers [Mazieres J et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2013]. These investigators also showed that in patients with stage IV lung cancer with HER2 mutations, the disease control rate was 93% with trastuzumab treatment and 100% with afatinib treatment. The results of Phase 2 trials that are underway are awaited, including a Phase 2 trial in patients with stage IV NSCLC with HER2 mutations who were pretreated and randomized to neratinib monotherapy or neratinib plus temsirolimus. The European Thoracic Oncology Platform trial will soon begin to recruit the same type of population for the evaluation of afatinib.\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003EIn conclusion, although drug resistance is a challenge with targeted therapies for treating NSCLC, the next-generation treatments that are being tested may potentially overcome resistance caused by many mutations.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/3\/24.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzpb61\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzpb61\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}