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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Characterization of Tumor Size Changes Over Time From the Phase 3 Study of Lenvatinib in Thyroid Cancer</title><author><name sortKey="Robinson, Bruce" sort="Robinson, Bruce" uniqKey="Robinson B" first="Bruce" last="Robinson">Bruce Robinson</name></author><author><name sortKey="Schlumberger, Martin" sort="Schlumberger, Martin" uniqKey="Schlumberger M" first="Martin" last="Schlumberger">Martin Schlumberger</name></author><author><name sortKey="Wirth, Lori J" sort="Wirth, Lori J" uniqKey="Wirth L" first="Lori J." last="Wirth">Lori J. Wirth</name></author><author><name sortKey="Dutcus, Corina E" sort="Dutcus, Corina E" uniqKey="Dutcus C" first="Corina E." last="Dutcus">Corina E. Dutcus</name></author><author><name sortKey="Song, James" sort="Song, James" uniqKey="Song J" first="James" last="Song">James Song</name></author><author><name sortKey="Taylor, Matthew H" sort="Taylor, Matthew H" uniqKey="Taylor M" first="Matthew H." last="Taylor">Matthew H. Taylor</name></author><author><name sortKey="Kim, Sung Bae" sort="Kim, Sung Bae" uniqKey="Kim S" first="Sung-Bae" last="Kim">Sung-Bae Kim</name></author><author><name sortKey="Krzyzanowska, Monika K" sort="Krzyzanowska, Monika K" uniqKey="Krzyzanowska M" first="Monika K." last="Krzyzanowska">Monika K. Krzyzanowska</name></author><author><name sortKey="Capdevila, Jaume" sort="Capdevila, Jaume" uniqKey="Capdevila J" first="Jaume" last="Capdevila">Jaume Capdevila</name></author><author><name sortKey="Sherman, Steven I" sort="Sherman, Steven I" uniqKey="Sherman S" first="Steven I." last="Sherman">Steven I. Sherman</name></author><author><name sortKey="Tahara, Makoto" sort="Tahara, Makoto" uniqKey="Tahara M" first="Makoto" last="Tahara">Makoto Tahara</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27548104</idno><idno type="pmc">5095235</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095235</idno><idno type="RBID">PMC:5095235</idno><idno type="doi">10.1210/jc.2015-3989</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">002642</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002642</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Characterization of Tumor Size Changes Over Time From the Phase 3 Study of Lenvatinib in Thyroid Cancer</title><author><name sortKey="Robinson, Bruce" sort="Robinson, Bruce" uniqKey="Robinson B" first="Bruce" last="Robinson">Bruce Robinson</name></author><author><name sortKey="Schlumberger, Martin" sort="Schlumberger, Martin" uniqKey="Schlumberger M" first="Martin" last="Schlumberger">Martin Schlumberger</name></author><author><name sortKey="Wirth, Lori J" sort="Wirth, Lori J" uniqKey="Wirth L" first="Lori J." last="Wirth">Lori J. Wirth</name></author><author><name sortKey="Dutcus, Corina E" sort="Dutcus, Corina E" uniqKey="Dutcus C" first="Corina E." last="Dutcus">Corina E. Dutcus</name></author><author><name sortKey="Song, James" sort="Song, James" uniqKey="Song J" first="James" last="Song">James Song</name></author><author><name sortKey="Taylor, Matthew H" sort="Taylor, Matthew H" uniqKey="Taylor M" first="Matthew H." last="Taylor">Matthew H. Taylor</name></author><author><name sortKey="Kim, Sung Bae" sort="Kim, Sung Bae" uniqKey="Kim S" first="Sung-Bae" last="Kim">Sung-Bae Kim</name></author><author><name sortKey="Krzyzanowska, Monika K" sort="Krzyzanowska, Monika K" uniqKey="Krzyzanowska M" first="Monika K." last="Krzyzanowska">Monika K. Krzyzanowska</name></author><author><name sortKey="Capdevila, Jaume" sort="Capdevila, Jaume" uniqKey="Capdevila J" first="Jaume" last="Capdevila">Jaume Capdevila</name></author><author><name sortKey="Sherman, Steven I" sort="Sherman, Steven I" uniqKey="Sherman S" first="Steven I." last="Sherman">Steven I. Sherman</name></author><author><name sortKey="Tahara, Makoto" sort="Tahara, Makoto" uniqKey="Tahara M" first="Makoto" last="Tahara">Makoto Tahara</name></author></analytic><series><title level="j">The Journal of Clinical Endocrinology and Metabolism</title><idno type="ISSN">0021-972X</idno><idno type="eISSN">1945-7197</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Context:</title><p>Lenvatinib improved the progression-free survival (PFS) and overall response rate of patients with radioiodine-refractory differentiated thyroid cancer vs placebo in the Phase 3 <italic>S</italic>tudy of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT).</p></sec><sec><title>Objective:</title><p>The objective of the study was to characterize tumor size changes with lenvatinib treatment.</p></sec><sec><title>Design:</title><p>SELECT was a phase 3, randomized, double-blind, multicenter study.</p></sec><sec><title>Setting:</title><p>In this clinical trial, tumor assessments of lenvatinib (n = 261) and placebo-treated (n = 131) patients were performed by independent radiological review per Response Evaluation Criteria in Solid Tumors version, 1.1 at 8-week intervals.</p></sec><sec><title>Patients:</title><p>Patients with complete or partial response were defined as responders to lenvatinib (n = 169). Of the 92 nonresponders, 76 had at least one postbaseline tumor assessment and were included in this analysis.</p></sec><sec><title>Interventions:</title><p>Lenvatinib (24 mg once daily) or placebo in 28-day cycles until unacceptable toxicity, disease progression, or death.</p></sec><sec><title>Main Outcome Measures:</title><p>This was an exploratory analysis of key end points from SELECT, including PFS, overall response rate, and tumor reduction.</p></sec><sec><title>Results:</title><p>The median maximum percentage change in tumor size was −42.9% for patients receiving lenvatinib (responders, −51.9%; nonresponders, −20.2%). Tumor size reduction was most pronounced at first assessment (median, −24.7% at 8 wk after randomization); thereafter, the rate of change was slower but continuous (−1.3% per mo). In a multivariate model, percentage change in tumor size at the first assessment was a marginally significant positive predictor for PFS (<italic>P</italic> = .06).</p></sec><sec><title>Conclusions:</title><p>The change in tumor size conferred by lenvatinib was characterized by two phases: an initial, rapid decline, followed by slower, continuous shrinkage.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Matsui, J" uniqKey="Matsui J">J Matsui</name></author><author><name sortKey="Yamamoto, Y" uniqKey="Yamamoto Y">Y Yamamoto</name></author><author><name sortKey="Funahashi, Y" uniqKey="Funahashi Y">Y Funahashi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Matsui, J" uniqKey="Matsui J">J Matsui</name></author><author><name sortKey="Funahashi, Y" uniqKey="Funahashi Y">Y Funahashi</name></author><author><name sortKey="Uenaka, T" uniqKey="Uenaka T">T Uenaka</name></author><author><name sortKey="Watanabe, T" uniqKey="Watanabe T">T Watanabe</name></author><author><name sortKey="Tsuruoka, A" uniqKey="Tsuruoka A">A Tsuruoka</name></author><author><name sortKey="Asada, M" uniqKey="Asada M">M Asada</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Okamoto, K" uniqKey="Okamoto K">K Okamoto</name></author><author><name sortKey="Kodama, K" uniqKey="Kodama K">K Kodama</name></author><author><name sortKey="Takase, K" uniqKey="Takase K">K Takase</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schlumberger, M" uniqKey="Schlumberger M">M Schlumberger</name></author><author><name sortKey="Tahara, M" uniqKey="Tahara M">M Tahara</name></author><author><name sortKey="Wirth, Lj" uniqKey="Wirth L">LJ Wirth</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bruzzi, P" uniqKey="Bruzzi P">P Bruzzi</name></author><author><name sortKey="Del Mastro, L" uniqKey="Del Mastro L">L Del Mastro</name></author><author><name sortKey="Sormani, Mp" uniqKey="Sormani M">MP Sormani</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jain, Rk" uniqKey="Jain R">RK Jain</name></author><author><name sortKey="Lee, Jj" uniqKey="Lee J">JJ Lee</name></author><author><name sortKey="Ng, C" uniqKey="Ng C">C Ng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Blumenthal, Gm" uniqKey="Blumenthal G">GM Blumenthal</name></author><author><name sortKey="Karuri, Sw" uniqKey="Karuri S">SW Karuri</name></author><author><name sortKey="Zhang, H" uniqKey="Zhang H">H Zhang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bergers, G" uniqKey="Bergers G">G Bergers</name></author><author><name sortKey="Hanahan, D" uniqKey="Hanahan D">D Hanahan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="St Bernard, R" uniqKey="St Bernard R">R St Bernard</name></author><author><name sortKey="Zheng, L" uniqKey="Zheng L">L Zheng</name></author><author><name sortKey="Liu, W" uniqKey="Liu W">W Liu</name></author><author><name sortKey="Winer, D" uniqKey="Winer D">D Winer</name></author><author><name sortKey="Asa, Sl" uniqKey="Asa S">SL Asa</name></author><author><name sortKey="Ezzat, S" uniqKey="Ezzat S">S Ezzat</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nikiforov, Ye" uniqKey="Nikiforov Y">YE Nikiforov</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Okamoto, K" uniqKey="Okamoto K">K Okamoto</name></author><author><name sortKey="Ikemori Kawada, M" uniqKey="Ikemori Kawada M">M Ikemori-Kawada</name></author><author><name sortKey="Jestel, A" uniqKey="Jestel A">A Jestel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dadu, R" uniqKey="Dadu R">R Dadu</name></author><author><name sortKey="Waguespack, Sg" uniqKey="Waguespack S">SG Waguespack</name></author><author><name sortKey="Sherman, Si" uniqKey="Sherman S">SI Sherman</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Clin Endocrinol Metab</journal-id><journal-id journal-id-type="iso-abbrev">J. Clin. Endocrinol. Metab</journal-id><journal-id journal-id-type="hwp">jcem</journal-id><journal-id journal-id-type="publisher-id">jceme</journal-id><journal-id journal-id-type="pmc">jcem</journal-id><journal-title-group><journal-title>The Journal of Clinical Endocrinology and Metabolism</journal-title></journal-title-group><issn pub-type="ppub">0021-972X</issn><issn pub-type="epub">1945-7197</issn><publisher><publisher-name>Endocrine Society</publisher-name><publisher-loc>Washington, DC</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27548104</article-id><article-id pub-id-type="pmc">5095235</article-id><article-id pub-id-type="publisher-id">15-3989</article-id><article-id pub-id-type="doi">10.1210/jc.2015-3989</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Articles</subject></subj-group></article-categories><title-group><article-title>Characterization of Tumor Size Changes Over Time From the Phase 3 Study of Lenvatinib in Thyroid Cancer</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Robinson</surname><given-names>Bruce</given-names></name></contrib><contrib contrib-type="author"><name><surname>Schlumberger</surname><given-names>Martin</given-names></name></contrib><contrib contrib-type="author"><name><surname>Wirth</surname><given-names>Lori J.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Dutcus</surname><given-names>Corina E.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Song</surname><given-names>James</given-names></name></contrib><contrib contrib-type="author"><name><surname>Taylor</surname><given-names>Matthew H.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Sung-Bae</given-names></name></contrib><contrib contrib-type="author"><name><surname>Krzyzanowska</surname><given-names>Monika K.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Capdevila</surname><given-names>Jaume</given-names></name></contrib><contrib contrib-type="author"><name><surname>Sherman</surname><given-names>Steven I.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Tahara</surname><given-names>Makoto</given-names></name></contrib><aff>Kolling Institute of Medical Research (B.R.), University of Sydney, New South Wales 2006, Australia; Department of Nuclear Medicine and Endocrine Oncology (M.S.), Gustave Roussy and University Paris-Sud, 94805 Villejuif, France; Department of Medicine (L.J.W.), Massachusetts General Hospital, Boston, Massachusetts 02114; Eisai Inc (C.E.D., J.S.), Woodcliff Lake, New Jersey 07677; Knight Cancer Institute (M.H.T.), Oregon Health and Science University, Portland, Oregon 97239; Department of Oncology (S.-B.K.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Republic of South Korea; Division of Medical Oncology and Hematology (M.K.K.), Princess Margaret Cancer Centre, Toronto, Ontario, Canada M5G 2M9; Department of Medical Oncology (J.C.), Vall d'Hebron University Hospital, Vall Hebron Institute of Oncology, 08035 Barcelona, Spain; Department of Endocrine Neoplasia and Hormonal Disorders (S.I.S.), Division of Internal Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; and Department of Head and Neck Medical Oncology (M.T.), National Cancer Center Hospital East, Kashiwa 277-8577, Japan</aff></contrib-group><author-notes><corresp>Address all correspondence and requests for reprints to: Bruce G. Robinson, MD, Kolling Institute of Medical Research and Department of Endocrinology, Royal North Shore Hospital, St Leonards University of Sydney, Room 201, Edward Ford Building A27, New South Wales 2006, Australia. E-mail: <email>bruce.robinson@sydney.edu.au</email>.</corresp></author-notes><pub-date pub-type="ppub"><month>11</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>17</day><month>10</month><year>2016</year></pub-date><pub-date pub-type="pmc-release"><day>17</day><month>10</month><year>2016</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>101</volume><issue>11</issue><fpage>4103</fpage><lpage>4109</lpage><history><date date-type="received"><day>17</day><month>11</month><year>2015</year></date><date date-type="accepted"><day>16</day><month>8</month><year>2016</year></date></history><permissions><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/"><license-p>This article is published under the terms of the Creative Commons Attribution-Non Commercial License (CC-BY-NC; <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/">http://creativecommons.org/licenses/by-nc/4.0/</ext-link>).</license-p></license></permissions><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="zeg01116004103.pdf"></self-uri><abstract><sec><title>Context:</title><p>Lenvatinib improved the progression-free survival (PFS) and overall response rate of patients with radioiodine-refractory differentiated thyroid cancer vs placebo in the Phase 3 <italic>S</italic>tudy of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT).</p></sec><sec><title>Objective:</title><p>The objective of the study was to characterize tumor size changes with lenvatinib treatment.</p></sec><sec><title>Design:</title><p>SELECT was a phase 3, randomized, double-blind, multicenter study.</p></sec><sec><title>Setting:</title><p>In this clinical trial, tumor assessments of lenvatinib (n = 261) and placebo-treated (n = 131) patients were performed by independent radiological review per Response Evaluation Criteria in Solid Tumors version, 1.1 at 8-week intervals.</p></sec><sec><title>Patients:</title><p>Patients with complete or partial response were defined as responders to lenvatinib (n = 169). Of the 92 nonresponders, 76 had at least one postbaseline tumor assessment and were included in this analysis.</p></sec><sec><title>Interventions:</title><p>Lenvatinib (24 mg once daily) or placebo in 28-day cycles until unacceptable toxicity, disease progression, or death.</p></sec><sec><title>Main Outcome Measures:</title><p>This was an exploratory analysis of key end points from SELECT, including PFS, overall response rate, and tumor reduction.</p></sec><sec><title>Results:</title><p>The median maximum percentage change in tumor size was −42.9% for patients receiving lenvatinib (responders, −51.9%; nonresponders, −20.2%). Tumor size reduction was most pronounced at first assessment (median, −24.7% at 8 wk after randomization); thereafter, the rate of change was slower but continuous (−1.3% per mo). In a multivariate model, percentage change in tumor size at the first assessment was a marginally significant positive predictor for PFS (<italic>P</italic> = .06).</p></sec><sec><title>Conclusions:</title><p>The change in tumor size conferred by lenvatinib was characterized by two phases: an initial, rapid decline, followed by slower, continuous shrinkage.</p></sec></abstract><abstract abstract-type="precis"><p>In the phase 3 SELECT study, change in tumor size mediated by lenvatinib treatment occurred in 2 phases, with an initial rapid decline followed by slower continuous shrinkage.</p></abstract></article-meta></front><body><p>Lenvatinib is an oral multikinase inhibitor of vascular endothelial growth factor (VEGF) receptor 1–3, fibroblast growth factor receptor 1–4, platelet-derived growth factor receptor-α, ret protooncogene (RET), and stem cell factor receptor (KIT) (<xref rid="B1" ref-type="bibr">1</xref><xref ref-type="bibr" rid="B2">–</xref><xref rid="B3" ref-type="bibr">3</xref>). In the Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT), a phase 3, randomized, double-blind, multicenter study of 392 patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC), treatment with lenvatinib significantly prolonged progression-free survival (PFS; hazard ratio [HR] 0.21; 99% confidence interval [CI] 0.14–0.31; <italic>P</italic> < .001) by 14.7 months (lenvatinib median PFS, 18.3 mo) compared with placebo (median PFS, 3.6 mo) (<xref rid="B4" ref-type="bibr">4</xref>).</p><p>Notably, lenvatinib treatment also resulted in an overall response rate (ORR) of 64.8%, which included four patients who achieved complete responses (CR), compared with an ORR of 1.5% in placebo-treated patients (all partial responses) (<xref rid="B4" ref-type="bibr">4</xref>). ORR is a key end point in oncology clinical trials and has been correlated with improved overall survival in several studies, including metastatic breast cancer (<xref rid="B5" ref-type="bibr">5</xref>) and a meta-analysis of mixed tumor types, but not yet in RR-DTC (<xref rid="B6" ref-type="bibr">6</xref>). In a recent meta-analysis of metastatic nonsmall cell lung cancer clinical trials submitted to the US Food and Drug Administration, ORR was found to be strongly associated with PFS. An association between ORR or PFS with overall survival, however, was not established, possibly because of the crossover study designs and post-study interventions (<xref rid="B7" ref-type="bibr">7</xref>). Because the change in tumor volume is central to measuring patient response to therapy, this exploratory analysis examines the rate, magnitude, and duration of tumor size changes in SELECT.</p><sec sec-type="subjects|methods"><title>Patients and Methods</title><sec><title>The SELECT trial</title><p>This phase 3, randomized, double-blind, multicenter study enrolled male or female patients with RR-DTC, measurable disease, and independently reviewed radiological evidence of progression (by computed tomography or magnetic resonance imaging scans per Response Evaluation Criteria in Solid Tumors, version 1.1) within the prior 13 months. All patients provided written informed consent, and the study was conducted in accordance with the principles of the Declaration of Helsinki. Patients could have previously been treated with up to one prior VEGF or VEGF receptor-targeted therapy. Further details of the SELECT study design, including relevant protocol approvals, have been previously published (<xref rid="B4" ref-type="bibr">4</xref>). Briefly, patients with RR-DTC were randomized 2:1 to receive oral lenvatinib (24 mg once daily) or placebo in 28-day cycles until unacceptable toxicity, independently reviewed radiological-confirmed disease progression, unacceptable toxicity, or death. Blinded, central radiological tumor assessments were performed using Response Evaluation Criteria in Solid Tumors version, 1.1 criteria every 8 weeks. Dose interruptions and incremental, sequential reductions due to adverse events were permitted (from 24 mg/d to 20, 14, and 10 mg/d).</p><p>Blood samples were collected at baseline, cycle 1/day 15, day 1 of subsequent cycles, and at the end of randomized study treatment. Serum was isolated from blood samples using standard techniques and frozen at −20°C and then shipped overnight on dry ice from the clinical site to the analytical laboratory and stored at −80°C. Thyroglobulin (Tg) levels were analyzed using the Elecsys 2010 kit by Cobas (Roche Diagnostics).</p></sec><sec><title>Statistical analysis</title><p>Patients who responded to lenvatinib treatment (responders) were defined as those patients who had a CR or partial response as their best overall response. Patients were considered responders at 24 mg if their earliest responses occurred within 30 days of receiving 24 mg/d; otherwise, patients were considered responders at less than 24 mg lenvatinib. The rate of change in tumor size over time was analyzed using a two-segment linear regression model, in which the first segment was from baseline to the first radiological tumor assessment at 8 weeks, and the second segment was from the first radiological tumor assessment onward. The associations between PFS and variables of interest were analyzed by univariate analyses; variables with a univariate <italic>P</italic> < .2 were then included in a multivariate Cox regression model.</p></sec></sec><sec sec-type="results"><title>Results</title><sec><title>Patient characteristics</title><p>SELECT randomized 392 (male, n = 200; female, n = 192) patients to receive lenvatinib (n = 261) or placebo (n = 131). Baseline demographics and patient characteristics are summarized in <ext-link ext-link-type="uri" xlink:href="http://press.endocrine.org/doi/suppl/10.1210/jc.2015-3989/suppl_file/jc-15-3989.pdf">Supplemental Table 1</ext-link>. The primary analysis of SELECT, including an examination of the safety of lenvatinib, has already been published. At baseline, the median tumor size as measured by the sum of diameters of target lesions for all patients receiving lenvatinib was 59.1 mm (range, 15.1–331.2). Of the 261 patients who received lenvatinib, 169 were responders and 92 were nonresponders (defined above). Of the nonresponders, 60 had stable disease, 16 had progressive disease, and 16 were not included in the analysis.</p></sec><sec><title>Tumor reduction with lenvatinib treatment</title><p>At the time of primary data cutoff (November 15, 2013), the median maximum percentage change in tumor size was −42.9% for all patients receiving lenvatinib (range, −100.0 to 65.6), and the median time to first objective response was 2.0 months (95% CI 1.9, 3.5). Among the responders to lenvatinib treatment (patients with CR or partial response, n = 169), 75% had an objective response duration that was longer than 9.4 months; however, the median duration of objective response was not yet reached at the time of analysis. Overall, responders had a median target lesion reduction of −51.9% (range, −100 to −30.3). Target lesion size reduction was also experienced by nonresponders to lenvatinib treatment (n = 92; <xref ref-type="fig" rid="F1">Figure 1</xref>). Of the 92 nonresponders, 76 patients had at least one postbaseline target lesion measurement and were included in this analysis, with a median target lesion reduction of −20.2% (range, −37.8 to 65.6). Median target lesion reduction was −20.3% (range, −37.4 to −2.9) and −15.7% (range, −37.8 to 65.6) for patients with stable disease (n = 60) and progressive disease (n = 16) receiving lenvatinib, respectively. Among the 16 remaining patients who were not included in the analysis, seven discontinued treatment due to an adverse event, five experienced unconfirmed disease progression prior to discontinuing treatment, and four discontinued by choice.</p><fig id="F1" position="float"><label>Figure 1.</label><caption><p>Maximum percentage change in sum of target lesion diameters from baseline in patients with RR-DTC who were randomized to receive lenvatinib in SELECT. Patients with best overall response of partial or complete response were considered responders. Patients whose earliest responses occurred within 30 days of receiving 24 mg/d lenvatinib were defined as responders at 24-mg lenvatinib; otherwise, patients were considered responders at less than 24-mg lenvatinib. Nonresponders shown include the 76 patients who had at least one postbaseline target lesion measurement.</p></caption><graphic xlink:href="zeg0101628000001"></graphic></fig><p>Tumor reduction was significantly greater in patients receiving lenvatinib compared with those receiving placebo in all specific target lesion metastasis sites examined. Mean percentage change from baseline was −45.9% for lenvatinib vs 2.7% for placebo (<italic>P</italic> < .0001) in lung, −35.6% vs 5.1% (<italic>P</italic> < .0001) in liver, −47.5% vs −2.9% (<italic>P</italic> < .0001) for lymph node, and −10.7% vs 6.5% (<italic>P</italic> < .01) for bone metastases (<xref ref-type="table" rid="T1">Table 1</xref>).</p><table-wrap id="T1" position="float"><label>Table 1.</label><caption><p>Percentage Change From Baseline in Sum of Target Lesion Diameter by Metastasis Site</p></caption><table frame="hsides" rules="groups"><thead valign="bottom"><tr><th align="left" rowspan="2" colspan="1">Metastasis Site</th><th align="left" colspan="2" rowspan="1">Lenvatinib<hr></hr></th><th align="left" colspan="2" rowspan="1">Placebo<hr></hr></th><th align="left" rowspan="2" colspan="1"><italic>P</italic> Value</th></tr><tr><th align="left" rowspan="1" colspan="1">n</th><th align="left" rowspan="1" colspan="1">Mean Maximum Change, %</th><th align="left" rowspan="1" colspan="1">n</th><th align="left" rowspan="1" colspan="1">Mean Maximum Change, %</th></tr></thead><tbody valign="top"><tr><td align="left" rowspan="1" colspan="1">Lung</td><td align="left" rowspan="1" colspan="1">189</td><td align="left" rowspan="1" colspan="1">−45.9</td><td align="left" rowspan="1" colspan="1">103</td><td align="left" rowspan="1" colspan="1">2.7</td><td align="left" rowspan="1" colspan="1"><.0001</td></tr><tr><td align="left" rowspan="1" colspan="1">Liver</td><td align="left" rowspan="1" colspan="1">14</td><td align="left" rowspan="1" colspan="1">−35.6</td><td align="left" rowspan="1" colspan="1">12</td><td align="left" rowspan="1" colspan="1">5.1</td><td align="left" rowspan="1" colspan="1"><.0001</td></tr><tr><td align="left" rowspan="1" colspan="1">Lymph node</td><td align="left" rowspan="1" colspan="1">119</td><td align="left" rowspan="1" colspan="1">−47.5</td><td align="left" rowspan="1" colspan="1">55</td><td align="left" rowspan="1" colspan="1">−2.9</td><td align="left" rowspan="1" colspan="1"><.0001</td></tr><tr><td align="left" rowspan="1" colspan="1">Bone</td><td align="left" rowspan="1" colspan="1">34</td><td align="left" rowspan="1" colspan="1">−10.7</td><td align="left" rowspan="1" colspan="1">16</td><td align="left" rowspan="1" colspan="1">6.5</td><td align="left" rowspan="1" colspan="1">.0021</td></tr></tbody></table></table-wrap><p>Notably, lenvatinib-induced tumor size reduction appeared to occur in two phases (<xref ref-type="fig" rid="F2">Figure 2</xref>A). First, a rapid initial decline in average tumor size (−25.2%; median −25.0%) was observed by 8 weeks, which was the time of the first radiological tumor assessment. Thereafter, a slower, continuous decrease in tumor size was observed at an average rate of −1.3% per month. As demonstrated by the proportion of patients who reached nadir tumor size, tumor regression continued throughout the course of the treatment period, even after the rapid decline at the first tumor assessment (<xref ref-type="fig" rid="F2">Figure 2</xref>B). Median percentage change from baseline in tumor size decreased 22.1% at week 8, 28.9% at week 16, and greater than 50% by week 88 (<xref ref-type="fig" rid="F2">Figure 2</xref>A). This reduction in tumor size occurred concurrently with a decrease in Tg levels that was also observed with lenvatinib treatment. The maximum decrease in Tg levels occurred at 88 weeks (median 92.3%), with a corresponding median percentage change from baseline in tumor size of 57.0% (<xref ref-type="fig" rid="F2">Figure 2</xref>, A and C).</p><fig id="F2" position="float"><label>Figure 2.</label><caption><p>A, Change in tumor size over time (median and interquartile range of the percentage change in the sum of target lesion diameters) for patients with RR-DTC who were randomized to receive lenvatinib in SELECT. B, Percentage of lenvatinib-treated patients with observed nadir in tumor size over time. C, Change from baseline in Tg levels (median and SE) for lenvatinib-treated patients from SELECT. A straight dotted line is used to connect time points between 0 and 8 weeks because the real curve during this period is actually unknown. The connected lines are intended to highlight the general tumor shrinkage pattern over 88 weeks. The data are based on patients with both baseline and postbaseline tumor assessments. SE, standard error.</p></caption><graphic xlink:href="zeg0101628000002"></graphic></fig></sec><sec><title>Tumor size reduction, lenvatinib exposure, and PFS</title><p>Increased lenvatinib exposure (area under the curve) was correlated with greater tumor size reduction during the first 8 weeks (R<sup>2</sup> = 0.355; <xref ref-type="fig" rid="F3">Figure 3</xref>A). Tumor size reduction was also correlated with treatment duration (<xref ref-type="fig" rid="F3">Figure 3</xref>B). Based on the first radiological tumor assessment on treatment, the initial mean tumor size reduction for patients who had received 1 or more years of lenvatinib treatment compared with those who had received less than 1 year of treatment was 27.4% and 21.9%, respectively. The rates of change in tumor size after subsequent assessments were similar for all patients. For patients with smaller lesions at baseline (less than median baseline tumor size), the percentage change in tumor size from baseline at week 8 was −30.3% (range, −57.9 to 4.3) compared with a change of −20.8% (range, −49.2 to 65.6) for patients with larger lesions at baseline (median baseline tumor size or greater).</p><fig id="F3" position="float"><label>Figure 3.</label><caption><p>A, Percentage change in tumor size at first postdose assessment and lenvatinib exposure during the first 8 weeks of treatment (at time of first tumor assessment). B, The relationship between lenvatinib treatment duration and maximum percentage tumor size change from baseline. AUC, area under the curve.</p></caption><graphic xlink:href="zeg0101628000003"></graphic></fig><p>Patients with greater tumor size reduction during the first 8 weeks (defined as greater than the median of −24.7%) had significantly prolonged PFS compared with patients whose tumor size reduction was less than the median (HR 0.61; 95% CI 0.41–0.91; log rank <italic>P</italic> = .014; <xref ref-type="fig" rid="F4">Figure 4</xref>). Because many variables may influence PFS, a multivariate Cox regression analysis was planned to further evaluate the possible relationship between tumor size reduction during the first 8 weeks of lenvatinib treatment and PFS (<xref ref-type="table" rid="T2">Table 2</xref>). Of the tested variables, baseline body weight, histology, baseline Eastern Cooperative Oncology Group (ECOG) performance status, baseline tumor size, and percentage change in tumor size at the first radiological tumor assessment (all <italic>P</italic> < .05) were found to be associated with PFS in univariate analyses. When these variables were included in the multivariate Cox regression model, several factors remained significantly associated with PFS, including baseline body weight, baseline ECOG performance status, and baseline tumor size. Percentage tumor size reduction at the first radiological tumor assessment was determined to be a marginally significant positive predictor for PFS in the multivariate model (<italic>P</italic> = .06; <xref ref-type="table" rid="T2">Table 2</xref>). Median PFS for patients with smaller tumors (less than the median baseline tumor size) at baseline was not estimable (95% CI 16.7 to not estimable), but patients with larger tumors (median baseline tumor size or greater) at baseline had a median PFS of 13.9 months (95% CI 9.3–18.3).</p><fig id="F4" position="float"><label>Figure 4.</label><caption><p>Kaplan-Meier estimate of PFS of lenvatinib-treated patients with RR-DTC stratified by tumor size reduction (above vs below the median at wk 8, −24.7%).</p></caption><graphic xlink:href="zeg0101628000004"></graphic></fig><table-wrap id="T2" position="float"><label>Table 2.</label><caption><p>Univariate and Multivariate Analyses of Potential Factors Associated With PFS</p></caption><table frame="hsides" rules="groups"><thead valign="bottom"><tr><th align="left" rowspan="2" colspan="1">Parameter</th><th align="left" colspan="3" rowspan="1">Univariate Analysis<hr></hr></th><th align="left" colspan="3" rowspan="1">Multivariate Analysis<sup><xref ref-type="table-fn" rid="TF2-1">a</xref></sup><hr></hr></th></tr><tr><th align="left" rowspan="1" colspan="1">HR<sup><xref ref-type="table-fn" rid="TF2-2">b</xref></sup></th><th align="left" rowspan="1" colspan="1">95% CI</th><th align="left" rowspan="1" colspan="1"><italic>P</italic> Value<sup><xref ref-type="table-fn" rid="TF2-2">b</xref></sup></th><th align="left" rowspan="1" colspan="1">HR</th><th align="left" rowspan="1" colspan="1">95% CI</th><th align="left" rowspan="1" colspan="1"><italic>P</italic> Value<sup><xref ref-type="table-fn" rid="TF2-1">a</xref>,<xref ref-type="table-fn" rid="TF2-2">b</xref></sup></th></tr></thead><tbody valign="top"><tr><td align="left" rowspan="1" colspan="1">Age (≤ vs > 65 y)</td><td align="left" rowspan="1" colspan="1">0.79</td><td align="left" rowspan="1" colspan="1">0.54–1.17</td><td align="left" rowspan="1" colspan="1">.24</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Sex (male vs female)</td><td align="left" rowspan="1" colspan="1">1.26</td><td align="left" rowspan="1" colspan="1">0.86–1.84</td><td align="left" rowspan="1" colspan="1">.24</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Baseline body weight (< vs ≥ median)</td><td align="left" rowspan="1" colspan="1">1.59</td><td align="left" rowspan="1" colspan="1">1.08–2.33</td><td align="left" rowspan="1" colspan="1">.02</td><td align="left" rowspan="1" colspan="1">1.55</td><td align="left" rowspan="1" colspan="1">1.03–2.32</td><td align="left" rowspan="1" colspan="1">004</td></tr><tr><td align="left" rowspan="1" colspan="1">Baseline ECOG performance status (< vs ≥ 1)</td><td align="left" rowspan="1" colspan="1">0.50</td><td align="left" rowspan="1" colspan="1">0.34–0.74</td><td align="left" rowspan="1" colspan="1"><.01</td><td align="left" rowspan="1" colspan="1">0.63</td><td align="left" rowspan="1" colspan="1">0.41–0.96</td><td align="left" rowspan="1" colspan="1">.03</td></tr><tr><td align="left" rowspan="1" colspan="1">Histology (follicular vs papillary)</td><td align="left" rowspan="1" colspan="1">0.64</td><td align="left" rowspan="1" colspan="1">0.43–0.97</td><td align="left" rowspan="1" colspan="1">.04</td><td align="left" rowspan="1" colspan="1">0.69</td><td align="left" rowspan="1" colspan="1">0.45–1.07</td><td align="left" rowspan="1" colspan="1">.10</td></tr><tr><td align="left" rowspan="1" colspan="1">Prior VEGF-targeted therapy (0 vs 1)</td><td align="left" rowspan="1" colspan="1">0.75</td><td align="left" rowspan="1" colspan="1">0.49–1.14</td><td align="left" rowspan="1" colspan="1">.18</td><td align="left" rowspan="1" colspan="1">0.86</td><td align="left" rowspan="1" colspan="1">0.55–1.34</td><td align="left" rowspan="1" colspan="1">.49</td></tr><tr><td align="left" rowspan="1" colspan="1">Baseline tumor size (< vs ≥ median)</td><td align="left" rowspan="1" colspan="1">0.49</td><td align="left" rowspan="1" colspan="1">0.33–0.72</td><td align="left" rowspan="1" colspan="1"><.01</td><td align="left" rowspan="1" colspan="1">0.61</td><td align="left" rowspan="1" colspan="1">0.40–0.94</td><td align="left" rowspan="1" colspan="1">.03</td></tr><tr><td align="left" rowspan="1" colspan="1">Percentage tumor reduction, wk 8 (< vs ≥ median)</td><td align="left" rowspan="1" colspan="1">1.67</td><td align="left" rowspan="1" colspan="1">1.11–2.50</td><td align="left" rowspan="1" colspan="1">.01</td><td align="left" rowspan="1" colspan="1">1.49</td><td align="left" rowspan="1" colspan="1">0.98–2.26</td><td align="left" rowspan="1" colspan="1">.06</td></tr></tbody></table><table-wrap-foot><fn id="TF2-1" fn-type="other"><label>a</label><p>Multivariate analysis includes only factors with <italic>P</italic> < .2 from univariate analyses.</p></fn><fn id="TF2-2" fn-type="other"><label>b</label><p>HRs and <italic>P</italic> values were estimated with Cox proportional hazard models.</p></fn></table-wrap-foot></table-wrap><p>A similar analysis to examine potential variables that may influence tumor size change with lenvatinib treatment was also performed (<xref ref-type="table" rid="T3">Table 3</xref>). In univariate linear regression analyses, age, baseline ECOG performance status, and baseline tumor size were associated with maximum percentage change in tumor size (all <italic>P</italic> < .05). In the multivariate model, factors that remained significantly associated with percentage tumor size reduction were those also associated with PFS, namely baseline body weight, baseline ECOG performance status, and baseline tumor size.</p><table-wrap id="T3" position="float"><label>Table 3.</label><caption><p>Univariate and Multivariate Analyses of Potential Factors Associated With Tumor Size Reduction</p></caption><table frame="hsides" rules="groups"><thead valign="bottom"><tr><th rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1">Univariate Analysis <italic>P</italic> Value</th><th align="left" rowspan="1" colspan="1">Multivariate Analysis <italic>P</italic> Value</th></tr></thead><tbody valign="top"><tr><td align="left" rowspan="1" colspan="1">Age (≤ vs > 65 y)</td><td align="left" rowspan="1" colspan="1">.027</td><td align="left" rowspan="1" colspan="1">.055</td></tr><tr><td align="left" rowspan="1" colspan="1">Sex (male vs female)</td><td align="left" rowspan="1" colspan="1">.432</td><td rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Baseline body weight (< vs ≥ median)</td><td align="left" rowspan="1" colspan="1">.075</td><td align="left" rowspan="1" colspan="1">.035</td></tr><tr><td align="left" rowspan="1" colspan="1">Baseline ECOG performance status (< vs ≥ 1)</td><td align="left" rowspan="1" colspan="1"><.001</td><td align="left" rowspan="1" colspan="1">.007</td></tr><tr><td align="left" rowspan="1" colspan="1">Histology (follicular vs papillary)</td><td align="left" rowspan="1" colspan="1">.359</td><td rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Prior VEGF-targeted therapy (0 vs 1)</td><td align="left" rowspan="1" colspan="1">.168</td><td align="left" rowspan="1" colspan="1">.459</td></tr><tr><td align="left" rowspan="1" colspan="1">Baseline tumor size (< vs ≥ median)</td><td align="left" rowspan="1" colspan="1"><.001</td><td align="left" rowspan="1" colspan="1"><.001</td></tr></tbody></table><table-wrap-foot><fn fn-type="other"><p><italic>P</italic> values were estimated with linear regression model. Factors with univariate <italic>P</italic> < .2 were included in the multivariate model.</p></fn></table-wrap-foot></table-wrap></sec></sec><sec sec-type="discussion"><title>Discussion</title><p>In the phase 3 SELECT study, lenvatinib treatment in patients with RR-DTC resulted in an early and pronounced reduction in tumor size in many patients, as assessed by the first post-treatment radiological evaluation at 8 weeks. Because 8 weeks was the earliest assessment time point, it is unclear whether the response might have been even more rapid. It is important that clinicians are aware of the important clinical value that can be attained due to this rapid response, especially because patients with advanced disease are likely to experience pain or other complications because of tumor bulk or burden; therefore, the substantial tumor debulking may delay or abrogate the need for surgical intervention in some patients or make surgery easier.</p><p>After the first radiological evaluation, the tumors of patients treated with lenvatinib demonstrated a slower but continuous decrease in size. A concern regarding most anticancer or antiangiogenic therapies is that tumors often circumvent treatment by up-regulating escape or resistance mechanisms, thus becoming refractory to therapy (<xref rid="B8" ref-type="bibr">8</xref>). The ongoing tumor reduction observed with lenvatinib treatment is, therefore, especially noteworthy. It may be because of the multitargeted nature of lenvatinib inhibition, specifically inhibition of the fibroblast growth factor receptor signaling network and RET, which have shown to play key roles in thyroid cancer development and progression (<xref rid="B9" ref-type="bibr">9</xref>, <xref rid="B10" ref-type="bibr">10</xref>). The unique binding mode of lenvatinib as a type V multikinase inhibitor could also explain the rapid and prolonged response observed with lenvatinib treatment (<xref rid="B11" ref-type="bibr">11</xref>).</p><p>The magnitude of lenvatinib-induced tumor reduction was correlated both to lenvatinib exposure during the first 8 weeks of treatment and treatment duration. Further, the tumor reduction observed was also associated with a decline in Tg levels, which is often used as a measure of successful thyroid tumor treatment. Although we do not know whether there is a causal relationship, this may provide supporting evidence that the starting dose of lenvatinib should not be lowered, contrary to the practice by some clinicians to try to limit drug-associated toxicities (<xref rid="B12" ref-type="bibr">12</xref>). Lenvatinib-induced tumor size reduction at 8 weeks was significantly correlated with PFS, although this correlation was diminished once other baseline patient characteristics were considered. This analysis had several limitations, including the lack of quality-of-life assessments and the collection of symptom data, which would provide additional context to the benefit of reducing tumor burden. The lack of data prior to the first 8-week radiological scan also limits the ability to more precisely determine when the reduction in tumor burden is truly occurring.</p><p>In conclusion, lenvatinib treatment in patients with RR-DTC in the phase 3 SELECT trial not only significantly prolonged PFS but also significantly reduced tumor burden, compared with placebo. Further investigation is warranted to confirm these findings.</p></sec></body><back><fn-group content-type="abbreviations"><fn fn-type="abbr"><p>Abbreviations:
<def-list><def-item><term id="G1">CI</term><def><p>confidence interval</p></def></def-item><def-item><term id="G2">CR</term><def><p>complete response</p></def></def-item><def-item><term id="G3">ECOG</term><def><p>Eastern Cooperative Oncology Group</p></def></def-item><def-item><term id="G4">HR</term><def><p>hazard ratio</p></def></def-item><def-item><term id="G5">ORR</term><def><p>overall response rate</p></def></def-item><def-item><term id="G6">PFS</term><def><p>progression-free survival</p></def></def-item><def-item><term id="G7">RET</term><def><p>ret protooncogene</p></def></def-item><def-item><term id="G8">RR-DTC</term><def><p>radioiodine-refractory differentiated thyroid cancer</p></def></def-item><def-item><term id="G9">SELECT</term><def><p>Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid</p></def></def-item><def-item><term id="G10">Tg</term><def><p>Thyroglobulin</p></def></def-item><def-item><term id="G11">VEGF</term><def><p>vascular endothelial growth factor.</p></def></def-item></def-list></p></fn></fn-group><ack><title>Acknowledgments</title><p>Editorial support was provided by Oxford PharmaGenesis Inc. We thank Junming Zhu, Xiaomin Yu, and Pallavi Sachdev, PhD, for their contributions to the analyses.</p><p>Current affiliation for James Song: Head of Biometry, BeiGene.</p><p>This study had a trial registration identification number NCT01321554 (<ext-link ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov">www.clinicaltrials.gov</ext-link>).</p><p content-type="financial-disclosure">This work was supported by <funding-source id="GS1">Eisai Inc</funding-source>.</p><p>Disclosure Summary: B.R. has served as an advisory board member for Eisai, Astra Zeneca, and Bayer and has served as a board member for MaynePharma. M.S. received grants and personal fees from Eisai Inc. L.J.W. has served as an advisory board member for Eisai and Loxo and has consulted for Eisai and Ashion. C.E.D. is employed by Eisai Inc. J.S. was employed by Eisai Inc at the time of this study. M.H.T. served as an advisory board consultant for Eisai and ONYX. M.K. has served as an advisory board member for Eisai and Bayer and has received research funding (site principal investigator for clinical trials) for Eisai, Astra Zeneca, Exelixis, and Novartis. J.C. has served as an advisory board member for Eisai, Bayer, and Astra Zeneca and received research funding for Eisai, Bayer, and Astra Zeneca. S.I.S. has served as an advisory board member for Eisai and Veracyte, has consulted for Exelixis and Rosetta Genomics, and has received research funding from Genzyme. S.-B.K. has nothing to disclose. 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