Complete Longitudinal Analyses of the Randomized, Placebo-controlled, Phase III Trial of Sunitinib in Patients with Gastrointestinal Stromal Tumor Following Imatinib Failure
Identifieur interne : 002177 ( Pmc/Corpus ); précédent : 002176; suivant : 002178Complete Longitudinal Analyses of the Randomized, Placebo-controlled, Phase III Trial of Sunitinib in Patients with Gastrointestinal Stromal Tumor Following Imatinib Failure
Auteurs : George D. Demetri ; Christopher R. Garrett ; Patrick Schöffski ; Manisha H. Shah ; Jaap Verweij ; Serge Leyvraz ; Herbert I. Hurwitz ; Antonio Lopez Pousa ; Axel Le Cesne ; David Goldstein ; Luis Paz-Ares ; Jean-Yves Blay ; Grant A. Mcarthur ; Qiang Casey Xu ; Xin Huang ; Charles S. Harmon ; Vanessa Tassell ; Darrel P. Cohen ; Paolo G. CasaliSource :
- Clinical cancer research : an official journal of the American Association for Cancer Research [ 1078-0432 ] ; 2012.
Abstract
To analyze final long-term survival and clinical outcomes from the randomized phase III study of sunitinib in gastrointestinal stromal tumor (GIST) patients after imatinib failure; to assess correlative angiogenesis biomarkers with patient outcomes.
Blinded sunitinib or placebo was given daily on a 4-week-on/2-week-off treatment schedule. Placebo-assigned patients could cross over to sunitinib at disease progression/study unblinding. Overall survival (OS) was analyzed using conventional statistical methods and the rank-preserving structural failure time (RPSFT) method to explore crossover impact. Circulating levels of angiogenesis biomarkers were analyzed.
In total, 243 patients were randomized to receive sunitinib and 118 to placebo, 103 of whom crossed over to open-label sunitinib. Conventional statistical analysis showed that OS converged in the sunitinib and placebo arms (median 72.7 versus 64.9 weeks; hazard ratio [HR], 0.876;
The crossover design provided evidence of sunitinib clinical benefit based on prolonged time to tumor progression during the double-blind phase of this trial. As expected, following crossover there was no statistical difference in OS. RPSFT analysis modeled the absence of crossover, estimating a substantial sunitinib OS benefit relative to placebo. Long-term sunitinib treatment was tolerated without new adverse events.
Url:
DOI: 10.1158/1078-0432.CCR-11-3005
PubMed: 22661587
PubMed Central: 4030710
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PMC:4030710Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Complete Longitudinal Analyses of the Randomized, Placebo-controlled, Phase III Trial of Sunitinib in Patients with Gastrointestinal Stromal Tumor Following Imatinib Failure</title><author><name sortKey="Demetri, George D" sort="Demetri, George D" uniqKey="Demetri G" first="George D." last="Demetri">George D. Demetri</name><affiliation><nlm:aff id="A1">Dana-Farber Cancer Institute, Boston, MA, USA</nlm:aff></affiliation></author><author><name sortKey="Garrett, Christopher R" sort="Garrett, Christopher R" uniqKey="Garrett C" first="Christopher R." last="Garrett">Christopher R. Garrett</name><affiliation><nlm:aff id="A2">H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA</nlm:aff></affiliation></author><author><name sortKey="Schoffski, Patrick" sort="Schoffski, Patrick" uniqKey="Schoffski P" first="Patrick" last="Schöffski">Patrick Schöffski</name><affiliation><nlm:aff id="A3">University Hospitals Leuven, Leuven Cancer Institute, Catholic University Leuven, Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Shah, Manisha H" sort="Shah, Manisha H" uniqKey="Shah M" first="Manisha H." last="Shah">Manisha H. Shah</name><affiliation><nlm:aff id="A4">Ohio State University Comprehensive Cancer Center, Columbus, OH, USA</nlm:aff></affiliation></author><author><name sortKey="Verweij, Jaap" sort="Verweij, Jaap" uniqKey="Verweij J" first="Jaap" last="Verweij">Jaap Verweij</name><affiliation><nlm:aff id="A5">Erasmus University Medical Centre, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Leyvraz, Serge" sort="Leyvraz, Serge" uniqKey="Leyvraz S" first="Serge" last="Leyvraz">Serge Leyvraz</name><affiliation><nlm:aff id="A6">Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Hurwitz, Herbert I" sort="Hurwitz, Herbert I" uniqKey="Hurwitz H" first="Herbert I." last="Hurwitz">Herbert I. Hurwitz</name><affiliation><nlm:aff id="A7">Duke University Medical Center, Durham, NC, USA</nlm:aff></affiliation></author><author><name sortKey="Pousa, Antonio Lopez" sort="Pousa, Antonio Lopez" uniqKey="Pousa A" first="Antonio Lopez" last="Pousa">Antonio Lopez Pousa</name><affiliation><nlm:aff id="A8">Hospital de la Santa Creu i Sant Pau, Barcelona, Spain</nlm:aff></affiliation></author><author><name sortKey="Le Cesne, Axel" sort="Le Cesne, Axel" uniqKey="Le Cesne A" first="Axel" last="Le Cesne">Axel Le Cesne</name><affiliation><nlm:aff id="A9">Institut Gustave-Roussy, Villejuif, France</nlm:aff></affiliation></author><author><name sortKey="Goldstein, David" sort="Goldstein, David" uniqKey="Goldstein D" first="David" last="Goldstein">David Goldstein</name><affiliation><nlm:aff id="A10">UNSW Prince of Wales Clinical School, Randwick, Australia</nlm:aff></affiliation></author><author><name sortKey="Paz Ares, Luis" sort="Paz Ares, Luis" uniqKey="Paz Ares L" first="Luis" last="Paz-Ares">Luis Paz-Ares</name><affiliation><nlm:aff id="A11">Instituto de Biomedicina de Sevilla (IBIS), Seville and Hospital Universitario Doce de Octubre, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Blay, Jean Yves" sort="Blay, Jean Yves" uniqKey="Blay J" first="Jean-Yves" last="Blay">Jean-Yves Blay</name><affiliation><nlm:aff id="A12">University Claude Bernard Lyon I, Centre Léon Bérard, Lyon, France</nlm:aff></affiliation></author><author><name sortKey="Mcarthur, Grant A" sort="Mcarthur, Grant A" uniqKey="Mcarthur G" first="Grant A." last="Mcarthur">Grant A. Mcarthur</name><affiliation><nlm:aff id="A13">Peter MacCallum Cancer Centre, Melbourne, Australia</nlm:aff></affiliation></author><author><name sortKey="Xu, Qiang Casey" sort="Xu, Qiang Casey" uniqKey="Xu Q" first="Qiang Casey" last="Xu">Qiang Casey Xu</name><affiliation><nlm:aff id="A14">Columbia University, New York, NY, USA</nlm:aff></affiliation></author><author><name sortKey="Huang, Xin" sort="Huang, Xin" uniqKey="Huang X" first="Xin" last="Huang">Xin Huang</name><affiliation><nlm:aff id="A15">Pfizer Oncology, La Jolla, CA, USA</nlm:aff></affiliation></author><author><name sortKey="Harmon, Charles S" sort="Harmon, Charles S" uniqKey="Harmon C" first="Charles S." last="Harmon">Charles S. Harmon</name><affiliation><nlm:aff id="A15">Pfizer Oncology, La Jolla, CA, USA</nlm:aff></affiliation></author><author><name sortKey="Tassell, Vanessa" sort="Tassell, Vanessa" uniqKey="Tassell V" first="Vanessa" last="Tassell">Vanessa Tassell</name><affiliation><nlm:aff id="A15">Pfizer Oncology, La Jolla, CA, USA</nlm:aff></affiliation></author><author><name sortKey="Cohen, Darrel P" sort="Cohen, Darrel P" uniqKey="Cohen D" first="Darrel P." last="Cohen">Darrel P. Cohen</name><affiliation><nlm:aff id="A15">Pfizer Oncology, La Jolla, CA, USA</nlm:aff></affiliation></author><author><name sortKey="Casali, Paolo G" sort="Casali, Paolo G" uniqKey="Casali P" first="Paolo G." last="Casali">Paolo G. Casali</name><affiliation><nlm:aff id="A16">Istituto Nazionale Tumori, Milan, Italy</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22661587</idno><idno type="pmc">4030710</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030710</idno><idno type="RBID">PMC:4030710</idno><idno type="doi">10.1158/1078-0432.CCR-11-3005</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">002177</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002177</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Complete Longitudinal Analyses of the Randomized, Placebo-controlled, Phase III Trial of Sunitinib in Patients with Gastrointestinal Stromal Tumor Following Imatinib Failure</title><author><name sortKey="Demetri, George D" sort="Demetri, George D" uniqKey="Demetri G" first="George D." last="Demetri">George D. Demetri</name><affiliation><nlm:aff id="A1">Dana-Farber Cancer Institute, Boston, MA, USA</nlm:aff></affiliation></author><author><name sortKey="Garrett, Christopher R" sort="Garrett, Christopher R" uniqKey="Garrett C" first="Christopher R." last="Garrett">Christopher R. Garrett</name><affiliation><nlm:aff id="A2">H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA</nlm:aff></affiliation></author><author><name sortKey="Schoffski, Patrick" sort="Schoffski, Patrick" uniqKey="Schoffski P" first="Patrick" last="Schöffski">Patrick Schöffski</name><affiliation><nlm:aff id="A3">University Hospitals Leuven, Leuven Cancer Institute, Catholic University Leuven, Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Shah, Manisha H" sort="Shah, Manisha H" uniqKey="Shah M" first="Manisha H." last="Shah">Manisha H. Shah</name><affiliation><nlm:aff id="A4">Ohio State University Comprehensive Cancer Center, Columbus, OH, USA</nlm:aff></affiliation></author><author><name sortKey="Verweij, Jaap" sort="Verweij, Jaap" uniqKey="Verweij J" first="Jaap" last="Verweij">Jaap Verweij</name><affiliation><nlm:aff id="A5">Erasmus University Medical Centre, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Leyvraz, Serge" sort="Leyvraz, Serge" uniqKey="Leyvraz S" first="Serge" last="Leyvraz">Serge Leyvraz</name><affiliation><nlm:aff id="A6">Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Hurwitz, Herbert I" sort="Hurwitz, Herbert I" uniqKey="Hurwitz H" first="Herbert I." last="Hurwitz">Herbert I. Hurwitz</name><affiliation><nlm:aff id="A7">Duke University Medical Center, Durham, NC, USA</nlm:aff></affiliation></author><author><name sortKey="Pousa, Antonio Lopez" sort="Pousa, Antonio Lopez" uniqKey="Pousa A" first="Antonio Lopez" last="Pousa">Antonio Lopez Pousa</name><affiliation><nlm:aff id="A8">Hospital de la Santa Creu i Sant Pau, Barcelona, Spain</nlm:aff></affiliation></author><author><name sortKey="Le Cesne, Axel" sort="Le Cesne, Axel" uniqKey="Le Cesne A" first="Axel" last="Le Cesne">Axel Le Cesne</name><affiliation><nlm:aff id="A9">Institut Gustave-Roussy, Villejuif, France</nlm:aff></affiliation></author><author><name sortKey="Goldstein, David" sort="Goldstein, David" uniqKey="Goldstein D" first="David" last="Goldstein">David Goldstein</name><affiliation><nlm:aff id="A10">UNSW Prince of Wales Clinical School, Randwick, Australia</nlm:aff></affiliation></author><author><name sortKey="Paz Ares, Luis" sort="Paz Ares, Luis" uniqKey="Paz Ares L" first="Luis" last="Paz-Ares">Luis Paz-Ares</name><affiliation><nlm:aff id="A11">Instituto de Biomedicina de Sevilla (IBIS), Seville and Hospital Universitario Doce de Octubre, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Blay, Jean Yves" sort="Blay, Jean Yves" uniqKey="Blay J" first="Jean-Yves" last="Blay">Jean-Yves Blay</name><affiliation><nlm:aff id="A12">University Claude Bernard Lyon I, Centre Léon Bérard, Lyon, France</nlm:aff></affiliation></author><author><name sortKey="Mcarthur, Grant A" sort="Mcarthur, Grant A" uniqKey="Mcarthur G" first="Grant A." last="Mcarthur">Grant A. Mcarthur</name><affiliation><nlm:aff id="A13">Peter MacCallum Cancer Centre, Melbourne, Australia</nlm:aff></affiliation></author><author><name sortKey="Xu, Qiang Casey" sort="Xu, Qiang Casey" uniqKey="Xu Q" first="Qiang Casey" last="Xu">Qiang Casey Xu</name><affiliation><nlm:aff id="A14">Columbia University, New York, NY, USA</nlm:aff></affiliation></author><author><name sortKey="Huang, Xin" sort="Huang, Xin" uniqKey="Huang X" first="Xin" last="Huang">Xin Huang</name><affiliation><nlm:aff id="A15">Pfizer Oncology, La Jolla, CA, USA</nlm:aff></affiliation></author><author><name sortKey="Harmon, Charles S" sort="Harmon, Charles S" uniqKey="Harmon C" first="Charles S." last="Harmon">Charles S. Harmon</name><affiliation><nlm:aff id="A15">Pfizer Oncology, La Jolla, CA, USA</nlm:aff></affiliation></author><author><name sortKey="Tassell, Vanessa" sort="Tassell, Vanessa" uniqKey="Tassell V" first="Vanessa" last="Tassell">Vanessa Tassell</name><affiliation><nlm:aff id="A15">Pfizer Oncology, La Jolla, CA, USA</nlm:aff></affiliation></author><author><name sortKey="Cohen, Darrel P" sort="Cohen, Darrel P" uniqKey="Cohen D" first="Darrel P." last="Cohen">Darrel P. Cohen</name><affiliation><nlm:aff id="A15">Pfizer Oncology, La Jolla, CA, USA</nlm:aff></affiliation></author><author><name sortKey="Casali, Paolo G" sort="Casali, Paolo G" uniqKey="Casali P" first="Paolo G." last="Casali">Paolo G. Casali</name><affiliation><nlm:aff id="A16">Istituto Nazionale Tumori, Milan, Italy</nlm:aff></affiliation></author></analytic><series><title level="j">Clinical cancer research : an official journal of the American Association for Cancer Research</title><idno type="ISSN">1078-0432</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="S1"><title>Purpose</title><p id="P1">To analyze final long-term survival and clinical outcomes from the randomized phase III study of sunitinib in gastrointestinal stromal tumor (GIST) patients after imatinib failure; to assess correlative angiogenesis biomarkers with patient outcomes.</p></sec><sec id="S2"><title>Experimental Design</title><p id="P2">Blinded sunitinib or placebo was given daily on a 4-week-on/2-week-off treatment schedule. Placebo-assigned patients could cross over to sunitinib at disease progression/study unblinding. Overall survival (OS) was analyzed using conventional statistical methods and the rank-preserving structural failure time (RPSFT) method to explore crossover impact. Circulating levels of angiogenesis biomarkers were analyzed.</p></sec><sec id="S3"><title>Results</title><p id="P3">In total, 243 patients were randomized to receive sunitinib and 118 to placebo, 103 of whom crossed over to open-label sunitinib. Conventional statistical analysis showed that OS converged in the sunitinib and placebo arms (median 72.7 versus 64.9 weeks; hazard ratio [HR], 0.876; <italic>P</italic> = 0.306) as expected, given the crossover design. RPSFT analysis estimated median OS for placebo of 39.0 weeks (HR, 0.505, 95% CI, 0.262–1.134; <italic>P</italic> = 0.306). No new safety concerns emerged with extended sunitinib treatment. No consistent associations were found between the pharmacodynamics of angiogenesis-related plasma proteins during sunitinib treatment and clinical outcome.</p></sec><sec id="S4"><title>Conclusions</title><p id="P4">The crossover design provided evidence of sunitinib clinical benefit based on prolonged time to tumor progression during the double-blind phase of this trial. As expected, following crossover there was no statistical difference in OS. RPSFT analysis modeled the absence of crossover, estimating a substantial sunitinib OS benefit relative to placebo. Long-term sunitinib treatment was tolerated without new adverse events.</p></sec></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">9502500</journal-id><journal-id journal-id-type="pubmed-jr-id">8794</journal-id><journal-id journal-id-type="nlm-ta">Clin Cancer Res</journal-id><journal-id journal-id-type="iso-abbrev">Clin. Cancer Res.</journal-id><journal-title-group><journal-title>Clinical cancer research : an official journal of the American Association for Cancer Research</journal-title></journal-title-group><issn pub-type="ppub">1078-0432</issn></journal-meta><article-meta><article-id pub-id-type="pmid">22661587</article-id><article-id pub-id-type="pmc">4030710</article-id><article-id pub-id-type="doi">10.1158/1078-0432.CCR-11-3005</article-id><article-id pub-id-type="manuscript">NIHMS579288</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Complete Longitudinal Analyses of the Randomized, Placebo-controlled, Phase III Trial of Sunitinib in Patients with Gastrointestinal Stromal Tumor Following Imatinib Failure</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Demetri</surname><given-names>George D.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Garrett</surname><given-names>Christopher R.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Schöffski</surname><given-names>Patrick</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Shah</surname><given-names>Manisha H.</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Verweij</surname><given-names>Jaap</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Leyvraz</surname><given-names>Serge</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Hurwitz</surname><given-names>Herbert I.</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Pousa</surname><given-names>Antonio Lopez</given-names></name><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>Le Cesne</surname><given-names>Axel</given-names></name><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Goldstein</surname><given-names>David</given-names></name><xref ref-type="aff" rid="A10">10</xref></contrib><contrib contrib-type="author"><name><surname>Paz-Ares</surname><given-names>Luis</given-names></name><xref ref-type="aff" rid="A11">11</xref></contrib><contrib contrib-type="author"><name><surname>Blay</surname><given-names>Jean-Yves</given-names></name><xref ref-type="aff" rid="A12">12</xref></contrib><contrib contrib-type="author"><name><surname>McArthur</surname><given-names>Grant A.</given-names></name><xref ref-type="aff" rid="A13">13</xref></contrib><contrib contrib-type="author"><name><surname>Xu</surname><given-names>Qiang (Casey)</given-names></name><xref ref-type="aff" rid="A14">14</xref></contrib><contrib contrib-type="author"><name><surname>Huang</surname><given-names>Xin</given-names></name><xref ref-type="aff" rid="A15">15</xref></contrib><contrib contrib-type="author"><name><surname>Harmon</surname><given-names>Charles S.</given-names></name><xref ref-type="aff" rid="A15">15</xref><xref rid="FN2" ref-type="author-notes">*</xref></contrib><contrib contrib-type="author"><name><surname>Tassell</surname><given-names>Vanessa</given-names></name><xref ref-type="aff" rid="A15">15</xref></contrib><contrib contrib-type="author"><name><surname>Cohen</surname><given-names>Darrel P.</given-names></name><xref ref-type="aff" rid="A15">15</xref></contrib><contrib contrib-type="author"><name><surname>Casali</surname><given-names>Paolo G.</given-names></name><xref ref-type="aff" rid="A16">16</xref></contrib></contrib-group><aff id="A1"><label>1</label>Dana-Farber Cancer Institute, Boston, MA, USA</aff><aff id="A2"><label>2</label>H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA</aff><aff id="A3"><label>3</label>University Hospitals Leuven, Leuven Cancer Institute, Catholic University Leuven, Leuven, Belgium</aff><aff id="A4"><label>4</label>Ohio State University Comprehensive Cancer Center, Columbus, OH, USA</aff><aff id="A5"><label>5</label>Erasmus University Medical Centre, Rotterdam, The Netherlands</aff><aff id="A6"><label>6</label>Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland</aff><aff id="A7"><label>7</label>Duke University Medical Center, Durham, NC, USA</aff><aff id="A8"><label>8</label>Hospital de la Santa Creu i Sant Pau, Barcelona, Spain</aff><aff id="A9"><label>9</label>Institut Gustave-Roussy, Villejuif, France</aff><aff id="A10"><label>10</label>UNSW Prince of Wales Clinical School, Randwick, Australia</aff><aff id="A11"><label>11</label>Instituto de Biomedicina de Sevilla (IBIS), Seville and Hospital Universitario Doce de Octubre, Madrid, Spain</aff><aff id="A12"><label>12</label>University Claude Bernard Lyon I, Centre Léon Bérard, Lyon, France</aff><aff id="A13"><label>13</label>Peter MacCallum Cancer Centre, Melbourne, Australia</aff><aff id="A14"><label>14</label>Columbia University, New York, NY, USA</aff><aff id="A15"><label>15</label>Pfizer Oncology, La Jolla, CA, USA</aff><aff id="A16"><label>16</label>Istituto Nazionale Tumori, Milan, Italy</aff><author-notes><corresp id="FN1">Corresponding Author: George D. Demetri, Center for Sarcoma and Bone Oncology, Ludwig Center at Dana-Farber/Harvard Cancer Center, Dana-Farber Cancer Institute, 450 Brookline Ave., Dana 1212, Boston, MA 02215. Phone: 617-632-3985; Fax: 617-632-3408; <email>gdemetri@partners.org</email></corresp><fn id="FN2"><label>*</label><p>Previous employee of Pfizer.</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>3</day><month>5</month><year>2014</year></pub-date><pub-date pub-type="ppub"><day>1</day><month>6</month><year>2012</year></pub-date><pub-date pub-type="pmc-release"><day>22</day><month>5</month><year>2014</year></pub-date><volume>18</volume><issue>11</issue><fpage>3170</fpage><lpage>3179</lpage><pmc-comment>elocation-id from pubmed: 10.1158/1078-0432.CCR-11-3005</pmc-comment>
<abstract><sec id="S1"><title>Purpose</title><p id="P1">To analyze final long-term survival and clinical outcomes from the randomized phase III study of sunitinib in gastrointestinal stromal tumor (GIST) patients after imatinib failure; to assess correlative angiogenesis biomarkers with patient outcomes.</p></sec><sec id="S2"><title>Experimental Design</title><p id="P2">Blinded sunitinib or placebo was given daily on a 4-week-on/2-week-off treatment schedule. Placebo-assigned patients could cross over to sunitinib at disease progression/study unblinding. Overall survival (OS) was analyzed using conventional statistical methods and the rank-preserving structural failure time (RPSFT) method to explore crossover impact. Circulating levels of angiogenesis biomarkers were analyzed.</p></sec><sec id="S3"><title>Results</title><p id="P3">In total, 243 patients were randomized to receive sunitinib and 118 to placebo, 103 of whom crossed over to open-label sunitinib. Conventional statistical analysis showed that OS converged in the sunitinib and placebo arms (median 72.7 versus 64.9 weeks; hazard ratio [HR], 0.876; <italic>P</italic> = 0.306) as expected, given the crossover design. RPSFT analysis estimated median OS for placebo of 39.0 weeks (HR, 0.505, 95% CI, 0.262–1.134; <italic>P</italic> = 0.306). No new safety concerns emerged with extended sunitinib treatment. No consistent associations were found between the pharmacodynamics of angiogenesis-related plasma proteins during sunitinib treatment and clinical outcome.</p></sec><sec id="S4"><title>Conclusions</title><p id="P4">The crossover design provided evidence of sunitinib clinical benefit based on prolonged time to tumor progression during the double-blind phase of this trial. As expected, following crossover there was no statistical difference in OS. RPSFT analysis modeled the absence of crossover, estimating a substantial sunitinib OS benefit relative to placebo. Long-term sunitinib treatment was tolerated without new adverse events.</p></sec></abstract><kwd-group><kwd>Phase III</kwd><kwd>GIST</kwd><kwd>sunitinib</kwd><kwd>antiangiogenic</kwd><kwd>tyrosine kinase inhibitor</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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