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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\u003EThis article discusses targeted therapies in non\u2014small cell lung cancer (NSCLC), including the rise and partial fall in efficacy seen with tyrosine kinase inhibitors (TKIs) of the anaplastic lymphoma kinase (ALK) pathway. Other topics include a review of strategies to target the epidermal growth factor receptor (EGFR), as well as the challenge of targeting new pathways.\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\u003C\/li\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\u003Cp id=\u0022p-2\u0022\u003EThe initial speaker at the seminar on targeted therapies in non-small cell lung cancer (NSCLC) was Alice T. Shaw, MD, PhD, Massachusetts General Hospital, Boston, Massachusetts, USA. She detailed the rise and partial fall in efficacy seen with tyrosine kinase inhibitors (TKIs) of the anaplastic lymphoma kinase (ALK) pathway. Citing crizotinib as an example, she noted that crizotinib showed stunning results in patients with NSCLC who also had ALK rearrangement; the response rates were 65% (95% CI, 58 to 72) with crizotinib versus 20% (95% CI, 14 to 26) with chemotherapy (p\u0026lt;0.001) [Shaw et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2013] until the seemingly inevitable shadow of resistance fell. Targeted therapy is likely to become a continuum of developing novel agents as mutations conferring resistance arise.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EAt least 27 ALK fusion variants have been reported in lung cancer since the first was described in 2007 [Ou S-H et al. \u003Cem\u003EOncologist\u003C\/em\u003E 2012]. ALK fusion leads to constitutive kinase activation and represents a strong oncogenic driver in lung cancer; ALK-driven cancers are oncogene addicted. Crizotinib is a multitargeted TKI with activity against MET, ALK, and ROS1 [Cui et al. \u003Cem\u003EJ Med Chem\u003C\/em\u003E 2011]. The latter two drivers have similar domains with 77% identity in the ATP-binding site [Shaw et al. ASCO 2012 Abstract 7508].\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EIn terms of clinical features, both ALK and ROS rearrangement are found equally among men and women and in nonsmokers, and they are drivers of adenocarcinoma. The frequency of ALK and ROS rearrangement in NSCLC is 3% to 7% and 1%, respectively [Soda M et al. \u003Cem\u003ENature\u003C\/em\u003E 2007; Bergethon K et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2012].\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EFindings from a Phase 3 trial [Shaw AT et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2013] showed that patients with ALK-positive NSCLC receiving crizotinib achieved superior progression-free survival (PFS) of a median of 7.7 months compared to 3.0 months with chemotherapy (p\u0026lt;0.001). Crizotinib became and remains the standard first-line therapy in patients with ALK-positive or ROS-positive NSCLC. Acquired resistance to crizotinib has appeared, however, and this has been attributed to mutations in the ALK gene [Lovly C et al. \u003Cem\u003ESci Trans Med\u003C\/em\u003E 2012].\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003ESeveral next-generation ALK inhibitors are being investigated in Phase 1, 2, and 3 trials. They have the advantage of being uniformly effective in patients demonstrating crizotinib resistance, regardless of whether a resistance mutation has been identified in the tumor, said Dr. Shaw. Next-generation ALK inhibitors are likely to become standard in the treatment of crizotinib-resistant NSCLC, according to Dr. Shaw. Overall response rates (ORRs) have been confirmed so far only for ceritinib, however. The ORR with ceritinib in a Phase 1 study was 56% (range, 48% to 67%) in 80 patients versus 55% with alectinib in a Phase 1 study with 44 patients and 61% with AP26113 in 31 patients with ALK+ crizotinib-resistant NSCLC [Shaw et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2014; Ou \u003Cem\u003EEuropean Cancer Cong.\u003C\/em\u003E 2013]. A comparison of ceritinib and these other novel agents is summarized in \u003Ca id=\u0022xref-table-wrap-1-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003ETable 1\u003C\/a\u003E.\u003C\/p\u003E\u003Cdiv id=\u0022T1\u0022 class=\u0022table pos-float\u0022\u003E\u003Cdiv class=\u0022table-inline\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022\/\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/15810\/expansion?postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022 html=\u00221\u0022 fragment=\u0022#\u0022 external=\u00221\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/15810\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/15810\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\u003C\/div\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cspan class=\u0022table-label\u0022\u003ETable 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-7\u0022 class=\u0022first-child\u0022\u003EComparison of Second-Generation ALK TKIs in Crizotinib-Resistant ALK+ Non-Small Cell Lung Cancer\u003C\/p\u003E\n         \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-9\u0022\u003EDr. Shaw ended her talk by predicting that the next challenge in NSCLC will be to find strategies to counteract the resistance to next-generation inhibitors that will inevitably develop. She commented that combination therapy would likely be a promising approach, and she suggested that ALK and epidermal growth factor receptor (EGFR) inhibitor combinations or ALK inhibitors together with immunotherapy could provide benefit to patients with NSCLC who acquire resistance to crizotinib and next-generation ALK inhibitors.\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003ECaicun Zhou, MD, PhD, Shanghai Pulmonary Hospital, Tongi University, Shanghai, China, reviewed strategies to target the EGFR, which has been identified as the oncogenic driver in 54% of patients with NSCLC [Kris MG et al. ASCO 2011 CRA7501].\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003ENine Phase 3 trials of the approved EGFR-TKIs (quinazline, gefitinib, erlotinib, and afatinib) for first-line treatment have shown superior PFS, tumor response rate, quality of life, and safety compared with standard chemotherapy (CT) in 1957 patients with NSCLC [Haaland B et al. \u003Cem\u003EJ Thorac Oncol\u003C\/em\u003E 2014]. Overall survival (OS) was not improved, however. Based on these results, EGFR-TKIs have become standard first-line treatment for advanced NSCLC with positive EGFR mutation; 30% of patients, however, are nonresponders, PFS is 6 to 11 months, and relapses are unavoidable, according to these data.\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003EIn the LUX-Lung 6 and 3 trials, patients receiving afatinib achieved PFS of median 11.0 and 11.1 months versus PFS of 5.6 and 6.8 months seen with gemcitabine plus cisplatin or cisplatin plus pemetrexed (p\u0026lt;0.0001 and p=0.0004) in respective trials [Wu Y et al. \u003Cem\u003EASCO\u003C\/em\u003E 2013; Sequist LV et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2013].\u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003EAlthough there are several modalities for the sequence of CT and EGFR-TKI, it is not known which approach is best. However, in Dr. Zhou\u0027s opinion, first-line CT followed by EGFR-TKIs is not better than EGFR-TKI monotherapy.\u003C\/p\u003E\u003Cp id=\u0022p-14\u0022\u003ENext-generation EGFR-TKIs are CO-1686 and AZD 9291, which are active in T790M-mutation-positive patients with NSCLC. These drugs should be less toxic and more potent because they target the wild-type EGFR signaling pathway, said Dr. Zhou, in patients with acquired resistance to TKIs. In the Response Evaluation Criteria in Solid Tumors (RECIST) study, about 67% of patients with T790M-positive NSCLC had a durable tumor response with CO-1686 [Soria JC. WCLC 2013. Abstract 1354]. The toxicity profile was acceptable, with reports of low-grade adverse events (AEs) by only 22% of patients, and no cases of acneiform rash were reported.\u003C\/p\u003E\u003Cp id=\u0022p-15\u0022\u003EOther novel TKIs include dacomitinib, which targets 3 HER receptors and halts disease progression. A trial of dacomitinib versus erlotinib is planned in patients with advanced NSCLC who received no previous systemic therapy.\u003C\/p\u003E\u003Cp id=\u0022p-16\u0022\u003EDr. Zhou said that although EGFR-TKIs remain the standard first-line therapy in EGFR-mutated NSCLC, encouraging activity has been demonstrated by newer EGFR-TKIs in T790-mutated NSCLC. EGFR antibodies do not appear to be effective for non-squamous cell NSCLC. Dr. Zhou pointed out that afatinib is active in patients with less common mutations. Nevertheless, TKIs given in the second line yield inferior results to second-line chemotherapy across the board in terms of PFS and ORR in patients with wild-type EGFR.\u003C\/p\u003E\u003Cp id=\u0022p-17\u0022\u003EThe challenge of targeting new pathways was discussed by Alex A. Adjei, MD, of Roswell Park Cancer Institute, Buffalo, New York, USA. Areas of active research that look promising are the Wnt and Hedgehog pathways. Wnt signaling has been recognized as important in other cancers, especially colorectal cancer, and recently emerged as a pathway crucial to lung carcinogenesis [Stewart D et al. \u003Cem\u003EJ Nat Cancer Inst\u003C\/em\u003E 2014]. Wnt inhibition has been shown to reduce cell proliferation in NSCLC cell lines [Waaler et al. \u003Cem\u003ECancer Res\u003C\/em\u003E 2012].\u003C\/p\u003E\u003Cp id=\u0022p-18\u0022\u003EDr. Adjei pointed out that aberrant activation of the Hedgehog signaling pathway has been shown to be associated with malignancy, leading to its being considered a prognostic marker. Inhibition of this pathway has also been shown to increase the sensitivity of NSCLC tumors to treatment.\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\/22.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_openurl.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_tables.js?nzpb61\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}