A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck†
Identifieur interne : 000302 ( Pmc/Corpus ); précédent : 000301; suivant : 000303A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck†
Auteurs : T. Y. Seiwert ; J. Fayette ; D. Cupissol ; J. M. Del Campo ; P. M. Clement ; R. Hitt ; M. Degardin ; W. Zhang ; A. Blackman ; E. Ehrnrooth ; E. E. W. CohenSource :
- Annals of Oncology [ 0923-7534 ] ; 2014.
Abstract
Afatinib, an oral irreversible ErbB family blocker, showed comparable activity to cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma in this phase II trial. Further, sequential EGFR/ErbB treatment provided sustained clinical benefit in some patients, suggesting a lack of cross-resistance.
Url:
DOI: 10.1093/annonc/mdu216
PubMed: 24928832
PubMed Central: 4143093
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PMC:4143093Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck<sup><xref ref-type="author-notes" rid="mdu216_AN1">†</xref></sup></title><author><name sortKey="Seiwert, T Y" sort="Seiwert, T Y" uniqKey="Seiwert T" first="T. Y." last="Seiwert">T. Y. Seiwert</name><affiliation><nlm:aff id="mdu216_af1"><addr-line>Department of Medicine</addr-line>,<institution>University of Chicago Medical Centre</institution>,<addr-line>Chicago</addr-line>,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Fayette, J" sort="Fayette, J" uniqKey="Fayette J" first="J." last="Fayette">J. Fayette</name><affiliation><nlm:aff id="mdu216_af2"><addr-line>Department of Medicine</addr-line>,<institution>Université de Lyon</institution>,<addr-line>Lyon</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cupissol, D" sort="Cupissol, D" uniqKey="Cupissol D" first="D." last="Cupissol">D. Cupissol</name><affiliation><nlm:aff id="mdu216_af3"><institution>Institut du Cancer de Montpellier Val d'Aurelle</institution>,<addr-line>Montpellier</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Del Campo, J M" sort="Del Campo, J M" uniqKey="Del Campo J" first="J. M." last="Del Campo">J. M. Del Campo</name><affiliation><nlm:aff id="mdu216_af4"><addr-line>Department of Medical Oncology</addr-line>,<institution>Hospital Universitario Vall d'Hebron</institution>,<addr-line>Barcelona</addr-line>,<country>Spain</country></nlm:aff></affiliation></author><author><name sortKey="Clement, P M" sort="Clement, P M" uniqKey="Clement P" first="P. M." last="Clement">P. M. Clement</name><affiliation><nlm:aff id="mdu216_af5"><addr-line>Division of Oncology</addr-line>,<institution>KU Leuven</institution>,<addr-line>Leuven</addr-line>,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Hitt, R" sort="Hitt, R" uniqKey="Hitt R" first="R." last="Hitt">R. Hitt</name><affiliation><nlm:aff id="mdu216_af6"><addr-line>Centro Integral Oncológico Clara Campal (CIOCC), Madrid</addr-line>,<country>Spain</country></nlm:aff></affiliation></author><author><name sortKey="Degardin, M" sort="Degardin, M" uniqKey="Degardin M" first="M." last="Degardin">M. Degardin</name><affiliation><nlm:aff id="mdu216_af7"><institution>Centre Oscar Lambret</institution>,<addr-line>Lille</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Zhang, W" sort="Zhang, W" uniqKey="Zhang W" first="W." last="Zhang">W. Zhang</name><affiliation><nlm:aff id="mdu216_af8"><institution>Boehringer Ingelheim Shanghai Pharmaceuticals Co., Ltd</institution>,<addr-line>Shanghai</addr-line>,<country>China</country></nlm:aff></affiliation></author><author><name sortKey="Blackman, A" sort="Blackman, A" uniqKey="Blackman A" first="A." last="Blackman">A. Blackman</name><affiliation><nlm:aff id="mdu216_af9"><institution>Boehringer Ingelheim Pharmaceuticals, Inc.</institution>,<addr-line>Ridgefield</addr-line>,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Ehrnrooth, E" sort="Ehrnrooth, E" uniqKey="Ehrnrooth E" first="E." last="Ehrnrooth">E. Ehrnrooth</name><affiliation><nlm:aff id="mdu216_af10"><institution>Boehringer Ingelheim</institution><addr-line>Danmark A/S</addr-line>,<country>Copenhagen, Denmark</country></nlm:aff></affiliation></author><author><name sortKey="Cohen, E E W" sort="Cohen, E E W" uniqKey="Cohen E" first="E. E. W." last="Cohen">E. E. W. Cohen</name><affiliation><nlm:aff id="mdu216_af11"><addr-line>Department of Medicine</addr-line>,<institution>University of California San Diego Moores Cancer Center</institution>,<addr-line>La Jolla</addr-line>,<country>USA</country></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24928832</idno><idno type="pmc">4143093</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143093</idno><idno type="RBID">PMC:4143093</idno><idno type="doi">10.1093/annonc/mdu216</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000302</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000302</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck<sup><xref ref-type="author-notes" rid="mdu216_AN1">†</xref></sup></title><author><name sortKey="Seiwert, T Y" sort="Seiwert, T Y" uniqKey="Seiwert T" first="T. Y." last="Seiwert">T. Y. Seiwert</name><affiliation><nlm:aff id="mdu216_af1"><addr-line>Department of Medicine</addr-line>,<institution>University of Chicago Medical Centre</institution>,<addr-line>Chicago</addr-line>,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Fayette, J" sort="Fayette, J" uniqKey="Fayette J" first="J." last="Fayette">J. Fayette</name><affiliation><nlm:aff id="mdu216_af2"><addr-line>Department of Medicine</addr-line>,<institution>Université de Lyon</institution>,<addr-line>Lyon</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cupissol, D" sort="Cupissol, D" uniqKey="Cupissol D" first="D." last="Cupissol">D. Cupissol</name><affiliation><nlm:aff id="mdu216_af3"><institution>Institut du Cancer de Montpellier Val d'Aurelle</institution>,<addr-line>Montpellier</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Del Campo, J M" sort="Del Campo, J M" uniqKey="Del Campo J" first="J. M." last="Del Campo">J. M. Del Campo</name><affiliation><nlm:aff id="mdu216_af4"><addr-line>Department of Medical Oncology</addr-line>,<institution>Hospital Universitario Vall d'Hebron</institution>,<addr-line>Barcelona</addr-line>,<country>Spain</country></nlm:aff></affiliation></author><author><name sortKey="Clement, P M" sort="Clement, P M" uniqKey="Clement P" first="P. M." last="Clement">P. M. Clement</name><affiliation><nlm:aff id="mdu216_af5"><addr-line>Division of Oncology</addr-line>,<institution>KU Leuven</institution>,<addr-line>Leuven</addr-line>,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Hitt, R" sort="Hitt, R" uniqKey="Hitt R" first="R." last="Hitt">R. Hitt</name><affiliation><nlm:aff id="mdu216_af6"><addr-line>Centro Integral Oncológico Clara Campal (CIOCC), Madrid</addr-line>,<country>Spain</country></nlm:aff></affiliation></author><author><name sortKey="Degardin, M" sort="Degardin, M" uniqKey="Degardin M" first="M." last="Degardin">M. Degardin</name><affiliation><nlm:aff id="mdu216_af7"><institution>Centre Oscar Lambret</institution>,<addr-line>Lille</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Zhang, W" sort="Zhang, W" uniqKey="Zhang W" first="W." last="Zhang">W. Zhang</name><affiliation><nlm:aff id="mdu216_af8"><institution>Boehringer Ingelheim Shanghai Pharmaceuticals Co., Ltd</institution>,<addr-line>Shanghai</addr-line>,<country>China</country></nlm:aff></affiliation></author><author><name sortKey="Blackman, A" sort="Blackman, A" uniqKey="Blackman A" first="A." last="Blackman">A. Blackman</name><affiliation><nlm:aff id="mdu216_af9"><institution>Boehringer Ingelheim Pharmaceuticals, Inc.</institution>,<addr-line>Ridgefield</addr-line>,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Ehrnrooth, E" sort="Ehrnrooth, E" uniqKey="Ehrnrooth E" first="E." last="Ehrnrooth">E. Ehrnrooth</name><affiliation><nlm:aff id="mdu216_af10"><institution>Boehringer Ingelheim</institution><addr-line>Danmark A/S</addr-line>,<country>Copenhagen, Denmark</country></nlm:aff></affiliation></author><author><name sortKey="Cohen, E E W" sort="Cohen, E E W" uniqKey="Cohen E" first="E. E. W." last="Cohen">E. E. W. Cohen</name><affiliation><nlm:aff id="mdu216_af11"><addr-line>Department of Medicine</addr-line>,<institution>University of California San Diego Moores Cancer Center</institution>,<addr-line>La Jolla</addr-line>,<country>USA</country></nlm:aff></affiliation></author></analytic><series><title level="j">Annals of Oncology</title><idno type="ISSN">0923-7534</idno><idno type="eISSN">1569-8041</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Afatinib, an oral irreversible ErbB family blocker, showed comparable activity to cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma in this phase II trial. Further, sequential EGFR/ErbB treatment provided sustained clinical benefit in some patients, suggesting a lack of cross-resistance.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Ferlay, J" uniqKey="Ferlay J">J Ferlay</name></author><author><name sortKey="Shin, Hr" uniqKey="Shin H">HR Shin</name></author><author><name sortKey="Bray, F" uniqKey="Bray F">F Bray</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Seiwert, Ty" uniqKey="Seiwert T">TY Seiwert</name></author><author><name sortKey="Salama, Jk" uniqKey="Salama J">JK Salama</name></author><author><name sortKey="Vokes, Ee" uniqKey="Vokes E">EE Vokes</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gold, Ka" uniqKey="Gold K">KA Gold</name></author><author><name sortKey="Lee, Hy" uniqKey="Lee H">HY Lee</name></author><author><name sortKey="Kim, Es" uniqKey="Kim E">ES 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Ann Oncol</journal-id><journal-id journal-id-type="iso-abbrev">Ann. Oncol</journal-id><journal-id journal-id-type="publisher-id">annonc</journal-id><journal-id journal-id-type="hwp">annonc</journal-id><journal-title-group><journal-title>Annals of Oncology</journal-title></journal-title-group><issn pub-type="ppub">0923-7534</issn><issn pub-type="epub">1569-8041</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24928832</article-id><article-id pub-id-type="pmc">4143093</article-id><article-id pub-id-type="doi">10.1093/annonc/mdu216</article-id><article-id pub-id-type="publisher-id">mdu216</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Articles</subject><subj-group subj-group-type="overline"><subject>Head and Neck Tumors</subject></subj-group></subj-group><series-title>Editor's choice</series-title></article-categories><title-group><article-title>A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck<sup><xref ref-type="author-notes" rid="mdu216_AN1">†</xref></sup></article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Seiwert</surname><given-names>T. Y.</given-names></name><xref ref-type="aff" rid="mdu216_af1">1</xref><xref ref-type="corresp" rid="mdu216_cor1">*</xref></contrib><contrib contrib-type="author"><name><surname>Fayette</surname><given-names>J.</given-names></name><xref ref-type="aff" rid="mdu216_af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Cupissol</surname><given-names>D.</given-names></name><xref ref-type="aff" rid="mdu216_af3">3</xref></contrib><contrib contrib-type="author"><name><surname>del Campo</surname><given-names>J. M.</given-names></name><xref ref-type="aff" rid="mdu216_af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Clement</surname><given-names>P. M.</given-names></name><xref ref-type="aff" rid="mdu216_af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Hitt</surname><given-names>R.</given-names></name><xref ref-type="aff" rid="mdu216_af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Degardin</surname><given-names>M.</given-names></name><xref ref-type="aff" rid="mdu216_af7">7</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>W.</given-names></name><xref ref-type="aff" rid="mdu216_af8">8</xref></contrib><contrib contrib-type="author"><name><surname>Blackman</surname><given-names>A.</given-names></name><xref ref-type="aff" rid="mdu216_af9">9</xref></contrib><contrib contrib-type="author"><name><surname>Ehrnrooth</surname><given-names>E.</given-names></name><xref ref-type="aff" rid="mdu216_af10">10</xref></contrib><contrib contrib-type="author"><name><surname>Cohen</surname><given-names>E. E. W.</given-names></name><xref ref-type="aff" rid="mdu216_af11">11</xref></contrib><aff id="mdu216_af1"><label>1</label><addr-line>Department of Medicine</addr-line>,<institution>University of Chicago Medical Centre</institution>,<addr-line>Chicago</addr-line>,<country>USA</country></aff><aff id="mdu216_af2"><label>2</label><addr-line>Department of Medicine</addr-line>,<institution>Université de Lyon</institution>,<addr-line>Lyon</addr-line></aff><aff id="mdu216_af3"><label>3</label><institution>Institut du Cancer de Montpellier Val d'Aurelle</institution>,<addr-line>Montpellier</addr-line>,<country>France</country></aff><aff id="mdu216_af4"><label>4</label><addr-line>Department of Medical Oncology</addr-line>,<institution>Hospital Universitario Vall d'Hebron</institution>,<addr-line>Barcelona</addr-line>,<country>Spain</country></aff><aff id="mdu216_af5"><label>5</label><addr-line>Division of Oncology</addr-line>,<institution>KU Leuven</institution>,<addr-line>Leuven</addr-line>,<country>Belgium</country></aff><aff id="mdu216_af6"><label>6</label><addr-line>Centro Integral Oncológico Clara Campal (CIOCC), Madrid</addr-line>,<country>Spain</country></aff><aff id="mdu216_af7"><label>7</label><institution>Centre Oscar Lambret</institution>,<addr-line>Lille</addr-line>,<country>France</country></aff><aff id="mdu216_af8"><label>8</label><institution>Boehringer Ingelheim Shanghai Pharmaceuticals Co., Ltd</institution>,<addr-line>Shanghai</addr-line>,<country>China</country></aff><aff id="mdu216_af9"><label>9</label><institution>Boehringer Ingelheim Pharmaceuticals, Inc.</institution>,<addr-line>Ridgefield</addr-line>,<country>USA</country></aff><aff id="mdu216_af10"><label>10</label><institution>Boehringer Ingelheim</institution><addr-line>Danmark A/S</addr-line>,<country>Copenhagen, Denmark</country></aff><aff id="mdu216_af11"><label>11</label><addr-line>Department of Medicine</addr-line>,<institution>University of California San Diego Moores Cancer Center</institution>,<addr-line>La Jolla</addr-line>,<country>USA</country></aff></contrib-group><author-notes><corresp id="mdu216_cor1"><label>*</label><italic>Correspondence to:</italic> Dr Tanguy Y. Seiwert, Section of Hematology/Oncology, University of Chicago Medical Center, 5841 South Maryland Avenue, MC2115, Chicago, IL 60637, USA. Tel: +1-773-702-2452; Fax: +<fax>1-773-702-3002</fax>; E-mail: <email>tseiwert@medicine.bsd.uchicago.edu</email></corresp><fn id="mdu216_AN1"><label>†</label><p>List of where and when the study has been presented in part elsewhere: Previously presented at the 46th Annual Meeting of American Society of Clinical Oncology, 4–8 June 2010, Chicago, IL, USA; the 3rd Trends in Head & Neck Oncology (THNO), 3–5 November 2011, Rome, Italy; the Multidisciplinary Head and Neck Cancer Symposium, 26–28 January 2012, Phoenix, Arizona, USA; the European Conference on Head and Neck Oncology (EHNS), 18–21 April 2012, Poznan, Poland; the 10th Annual Meeting of the Japanese Society of Medical Oncology, 26–28 July 2012, Osaka, Japan and the 49th American Society of Clinical Oncology, May 31–June 4 2013, Chicago, IL, USA.</p></fn></author-notes><pub-date pub-type="ppub"><month>9</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>13</day><month>6</month><year>2014</year></pub-date><pub-date pub-type="pmc-release"><day>13</day><month>6</month><year>2014</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>25</volume><issue>9</issue><fpage>1813</fpage><lpage>1820</lpage><history><date date-type="received"><day>3</day><month>4</month><year>2014</year></date><date date-type="rev-recd"><day>1</day><month>6</month><year>2014</year></date><date date-type="accepted"><day>4</day><month>6</month><year>2014</year></date></history><permissions><copyright-statement>© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology.</copyright-statement><copyright-year>2014</copyright-year><license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (<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>), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com</license-p></license></permissions><self-uri content-type="pdf" xlink:type="simple" xlink:href="mdu216.pdf"></self-uri><abstract abstract-type="precis"><p>Afatinib, an oral irreversible ErbB family blocker, showed comparable activity to cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma in this phase II trial. Further, sequential EGFR/ErbB treatment provided sustained clinical benefit in some patients, suggesting a lack of cross-resistance.</p></abstract><abstract><sec><title>Background</title><p>Afatinib is an oral, irreversible ErbB family blocker that has shown activity in epidermal growth factor receptor (EGFR)-mutated lung cancer. We hypothesized that the agent would have greater antitumor activity compared with cetuximab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients, whose disease has progressed after platinum-containing therapy.</p></sec><sec><title>Patients and methods</title><p>An open-label, randomized, phase II trial was conducted in 43 centers; 124 patients were randomized (1 : 1) to either afatinib (50 mg/day) or cetuximab (250 mg/m<sup>2</sup>/week) until disease progression or intolerable adverse events (AEs) (stage I), with optional crossover (stage II). The primary end point was tumor shrinkage before crossover assessed by investigator (IR) and independent central review (ICR).</p></sec><sec><title>Results</title><p>A total of 121 patients were treated (61 afatinib, 60 cetuximab) and 68 crossed over to stage II (32 and 36 respectively). In stage I, mean tumor shrinkage by IR/ICR was 10.4%/16.6% with afatinib and 5.4%/10.1% with cetuximab (<italic>P</italic> = 0.46/0.30). Objective response rate was 16.1%/8.1% with afatinib and 6.5%/9.7% with cetuximab (IR/ICR). Comparable disease control rates were observed with afatinib (50%) and cetuximab (56.5%) by IR; similar results were seen by ICR. Most common grade ≥3 drug-related AEs (DRAEs) were rash/acne (18% versus 8.3%), diarrhea (14.8% versus 0%), and stomatitis/mucositis (11.5% versus 0%) with afatinib and cetuximab, respectively. Patients with DRAEs leading to treatment discontinuation were 23% with afatinib and 5% with cetuximab. In stage II, disease control rate (IR/ICR) was 38.9%/33.3% with afatinib and 18.8%/18.8% with cetuximab.</p></sec><sec><title>Conclusion</title><p>Afatinib showed antitumor activity comparable to cetuximab in R/M HNSCC in this exploratory phase II trial, although more patients on afatinib discontinued treatment due to AEs. Sequential EGFR/ErbB treatment with afatinib and cetuximab provided sustained clinical benefit in patients after crossover, suggesting a lack of cross-resistance.</p></sec></abstract><kwd-group><kwd>afatinib</kwd><kwd>cetuximab</kwd><kwd>recurrent HNSCC</kwd><kwd>metastatic HNSCC</kwd><kwd>EGFR inhibitor therapy</kwd></kwd-group></article-meta></front><body><sec sec-type="intro" id="mdu216_s1"><title>introduction</title><p>Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide [<xref rid="MDU216C1" ref-type="bibr">1</xref>]. Patients diagnosed with recurrent or metastatic (R/M) disease have a poor prognosis [<xref rid="MDU216C2" ref-type="bibr">2</xref>]. The majority of HNSCC tumors overexpress the epidermal growth factor receptor (EGFR/ErbB1), which correlates with poor clinical outcomes [<xref rid="MDU216C3" ref-type="bibr">3</xref>]; human epidermal growth factor receptor 2 (HER2/ErbB2) amplification also occurs [<xref rid="MDU216C4" ref-type="bibr">4</xref>].</p><p>Cetuximab (EGFR monoclonal antibody) is indicated for locoregionally advanced and R/M HNSCC patients [<xref rid="MDU216C5" ref-type="bibr">5</xref>–<xref rid="MDU216C7" ref-type="bibr">7</xref>]. However, the objective response (OR) to cetuximab monotherapy is modest (∼13%) [<xref rid="MDU216C5" ref-type="bibr">5</xref>], and predictive biomarkers of efficacy are lacking. Somatic EGFR mutations in HNSCC are rare [<xref rid="MDU216C4" ref-type="bibr">4</xref>], and while earlier reports documented EGFR deletion mutation (EGFRvIII) in ∼40% of HNSCC tumors [<xref rid="MDU216C8" ref-type="bibr">8</xref>], more recently, EGFRvIII mutations were only identified in <0.5% of 279 HNSCC samples from the Cancer Genome Atlas (TCGA) project [<xref rid="MDU216C4" ref-type="bibr">4</xref>].</p><p>Afatinib, an oral, irreversible ErbB family blocker [<xref rid="MDU216C9" ref-type="bibr">9</xref>, <xref rid="MDU216C10" ref-type="bibr">10</xref>] has potent preclinical activity against wild-type and mutant EGFR (including EGFRvIII) and HER2, and is used in the treatment of patients with EGFR mutation-positive non-small-cell lung cancer [<xref rid="MDU216C9" ref-type="bibr">9</xref>, <xref rid="MDU216C11" ref-type="bibr">11</xref>, <xref rid="MDU216C12" ref-type="bibr">12</xref>]. In HNSCC, EGFR tyrosine kinase inhibitor therapy has been associated with low response rates [<xref rid="MDU216C13" ref-type="bibr">13</xref>–<xref rid="MDU216C16" ref-type="bibr">16</xref>] and has not been directly compared with cetuximab. We hypothesized that irreversible ErbB family blockade with afatinib would have greater antitumor activity compared with cetuximab, and that cross-resistance between them would not be universal, with some patients potentially benefitting from sequential treatment.</p></sec><sec sec-type="methods" id="mdu216_s2"><title>patients and methods</title><sec id="mdu216_s2a"><title>study design and patients</title><p>The study was conducted in 43 centers in Belgium, France, Spain and the United States. Eligible patients (aged ≥18 years) had pathologically confirmed R/M HNSCC, progression following any line of prior platinum-based therapy, measurable disease [Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0], an Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤1, adequate end-organ function, and provided written informed consent. Key exclusion criteria included: receiving more than two chemotherapeutic regimens for R/M disease and progressive disease (PD) within 3 months of completion of intended curative treatment of localized/locoregional advanced disease.</p><p>The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines, and approved by relevant regulatory and independent ethics committees.</p></sec><sec id="mdu216_s2b"><title>randomization and masking</title><p>Patients were randomized in a 1 : 1 ratio to afatinib or cetuximab in stage I, stratified by number of prior chemotherapies for R/M HNSCC (0 versus ≥1). In stage I, patients received afatinib (50 mg once daily) or cetuximab (loading dose of 400 mg/m<sup>2</sup> followed by weekly doses of 250 mg/m<sup>2</sup>) treatment until progression or intolerable adverse events (AEs). In stage II, patients who failed or experienced intolerable AEs on afatinib or cetuximab were able to cross over to the opposite treatment, cetuximab or afatinib (<ext-link ext-link-type="uri" xlink:href="http://annonc.oxfordjournals.org/lookup/suppl/doi:10.1093/annonc/mdu216/-/DC1">supplementary Figure S1, available at <italic>Annals of Oncology</italic> online</ext-link>).</p></sec><sec id="mdu216_s2c"><title>procedures</title><p>Patients experiencing grade ≥3 drug-related AEs (DRAEs) according to the National Cancer Institute Common Terminology Criteria for AEs (NCI-CTCAE) version 3.0 or grade ≥2 diarrhea, nausea, or vomiting for ≥7 consecutive days despite optimal supportive care, paused treatment (maximum 14 days). Following this and recovery to a grade ≤1 AE, afatinib was restarted with the dose reduced by 10 mg; this reduction could be repeated twice. Afatinib was discontinued after a third occurrence of AEs as specified above. Patients who did not recover within 14 days could cross over to afatinib or cetuximab in stage I, or be discontinued, if in stage II. Safety was assessed every 2 weeks during the first cycle and then every 4 weeks.</p></sec><sec id="mdu216_s2d"><title>end points and assessments</title><p>Primary end point was tumor shrinkage (mm) before crossover, defined as the change from baseline in the smallest postrandomization sum of the longest diameters (SLDs) of the target lesions. Secondary end points included the best RECIST assessment, duration of OR, progression-free survival (PFS), overall survival (OS), safety, pharmacokinetic assessments (PK) and patient-reported outcomes (PRO).</p><p>Computed tomography (CT) scans or magnetic resonance imaging (MRI) were carried out at baseline and thereafter at 8-week intervals (stage I). The last image before crossover was taken as baseline for stage II and tumor assessments were carried out at weeks 4 and 8, and every 8 weeks following stage II treatment start. Tumor evaluation was conducted at investigational sites [investigator review (IR)] and by an independent central review (ICR).</p><p>Blood samples for PK analyses were collected from all patients who received afatinib in stage I and patients who crossed over from cetuximab to afatinib treatment in stage II. Plasma concentrations of afatinib were analyzed by a validated high-performance liquid chromatography tandem mass spectrometry method using [D<sub>6</sub>]afatinib as an internal standard.</p><p>PRO were assessed using the self-administered European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ)-C30 and its head and neck-specific module (QLQ-HN35) [<xref rid="MDU216C17" ref-type="bibr">17</xref>, <xref rid="MDU216C18" ref-type="bibr">18</xref>]. Prespecified assessments included time to deterioration in global health status as well as head and neck-specific symptoms of pain and swallowing.</p><p>Immunohistochemistry (IHC) established p16 expression and EGFRvIII mutation status; the latter was also determined using quantitative reverse transcription polymerase chain reaction as previously described [<xref rid="MDU216C19" ref-type="bibr">19</xref>].</p></sec><sec id="mdu216_s2e"><title>statistical analysis</title><p>Tumor shrinkage based on the continuous variable, SLD of target lesions, was chosen because it was expected to be more sensitive in detecting differences between treatment groups, compared with a binary variable, such as response rate [<xref rid="MDU216C20" ref-type="bibr">20</xref>]. In determining sample size, 40 patients per treatment group with at least one postrandomization tumor assessment were expected to provide ∼80% power to detect a difference of 0.38 standard deviation in the true mean tumor shrinkage between groups, using a one-sided <italic>α</italic> level of 0.20. This could provide ∼80% power to detect a difference of 18% in the objective response rate (ORR).</p><p>Comparisons between afatinib and cetuximab were made via analysis of covariance for tumor shrinkage, Cochran's statistics for best RECIST assessment, log-rank test and Cox proportional hazards regression for PFS and OS. PRO analysis focused on time to deterioration (defined as a 10-point change towards worsening from baseline score on a 0–100 point scale) for: global health status (Q29 and Q30 in C30), pain (Q9 and Q19 in C30) and swallowing (Q35 to Q38 in H&N35). Safety end points were analyzed descriptively.</p><p>For stage I, efficacy analyses included all randomized patients, and safety analyses comprised the treated population. Efficacy and safety analyses in stage II included all treated patients.</p></sec></sec><sec sec-type="results" id="mdu216_s3"><title>results</title><sec id="mdu216_s3a"><title>patient population</title><p>Between October 2007 and June 2011, 124 patients were randomized to receive afatinib (62 patients) or cetuximab (62 patients) during stage I (Figure <xref ref-type="fig" rid="MDU216F1">1</xref>). Baseline characteristics were balanced (Table <xref ref-type="table" rid="MDU216TB1">1</xref>); although, there were more patients with ECOG PS 0 in the afatinib group [23 (37.1%)] versus cetuximab [11 (17.7%)].<table-wrap id="MDU216TB1" position="float"><label>Table 1.</label><caption><p>Demographics, baseline disease characteristics and treatment history for randomized patients</p></caption><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="char" char=" " span="1"></col><col align="char" char=" " span="1"></col></colgroup><thead><tr><th rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1">Afatinib (<italic>N</italic> = 62)</th><th align="left" rowspan="1" colspan="1">Cetuximab (<italic>N</italic> = 62)</th></tr></thead><tbody><tr><td colspan="3" rowspan="1">Gender, <italic>n</italic> (%)</td></tr><tr><td rowspan="1" colspan="1"> Female</td><td rowspan="1" colspan="1">7 (11.3)</td><td rowspan="1" colspan="1">10 (16.1)</td></tr><tr><td rowspan="1" colspan="1"> Male</td><td rowspan="1" colspan="1">55 (88.7)</td><td rowspan="1" colspan="1">52 (83.9)</td></tr><tr><td colspan="3" rowspan="1">Race, <italic>n</italic> (%)</td></tr><tr><td rowspan="1" colspan="1"> Black</td><td rowspan="1" colspan="1">1 (1.6)</td><td rowspan="1" colspan="1">4 (6.5)</td></tr><tr><td rowspan="1" colspan="1"> White</td><td rowspan="1" colspan="1">45 (72.6)</td><td rowspan="1" colspan="1">41 (66.1)</td></tr><tr><td rowspan="1" colspan="1"> American Indian/Alaska Natives</td><td rowspan="1" colspan="1">1 (1.6)</td><td rowspan="1" colspan="1">0</td></tr><tr><td rowspan="1" colspan="1"> Missing</td><td rowspan="1" colspan="1">15 (24.2)</td><td rowspan="1" colspan="1">17 (27.4)</td></tr><tr><td colspan="3" rowspan="1">Age (years)</td></tr><tr><td rowspan="1" colspan="1"> Median (range)</td><td rowspan="1" colspan="1">58.0 (23–78)</td><td rowspan="1" colspan="1">58.0 (29–83)</td></tr><tr><td colspan="3" rowspan="1">Weight (kg)</td></tr><tr><td rowspan="1" colspan="1"> Median (range)</td><td rowspan="1" colspan="1">70.0 (43–114)</td><td rowspan="1" colspan="1">61.3 (37–109)</td></tr><tr><td colspan="3" rowspan="1">ECOG performance status</td></tr><tr><td rowspan="1" colspan="1"> 0</td><td rowspan="1" colspan="1">23 (37.1)</td><td rowspan="1" colspan="1">11 (17.7)</td></tr><tr><td rowspan="1" colspan="1"> 1</td><td rowspan="1" colspan="1">38 (61.3)</td><td rowspan="1" colspan="1">48 (77.4)</td></tr><tr><td rowspan="1" colspan="1"> 2<sup>a</sup></td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">1 (1.6)</td></tr><tr><td rowspan="1" colspan="1"> Missing</td><td rowspan="1" colspan="1">1 (2.6)</td><td rowspan="1" colspan="1">2 (3.2)</td></tr><tr><td colspan="3" rowspan="1">Primary tumor site, <italic>n</italic> (%)</td></tr><tr><td rowspan="1" colspan="1"> Oral cavity</td><td rowspan="1" colspan="1">13 (21.0)</td><td rowspan="1" colspan="1">16 (25.8)</td></tr><tr><td rowspan="1" colspan="1"> Oropharynx</td><td rowspan="1" colspan="1">22 (35.5)</td><td rowspan="1" colspan="1">16 (25.8)</td></tr><tr><td rowspan="1" colspan="1"> Hypopharynx</td><td rowspan="1" colspan="1">10 (16.1)</td><td rowspan="1" colspan="1">9 (14.5)</td></tr><tr><td rowspan="1" colspan="1"> Larynx</td><td rowspan="1" colspan="1">8 (12.9)</td><td rowspan="1" colspan="1">12 (19.4)</td></tr><tr><td rowspan="1" colspan="1"> Nasopharynx</td><td rowspan="1" colspan="1">1 (1.6)</td><td rowspan="1" colspan="1">0</td></tr><tr><td rowspan="1" colspan="1"> Pharynx</td><td rowspan="1" colspan="1">1 (1.6)</td><td rowspan="1" colspan="1">1 (1.6)</td></tr><tr><td rowspan="1" colspan="1"> Sinus</td><td rowspan="1" colspan="1">3 (4.8)</td><td rowspan="1" colspan="1">2 (3.2)</td></tr><tr><td rowspan="1" colspan="1"> Unknown primary</td><td rowspan="1" colspan="1">3 (4.8)</td><td rowspan="1" colspan="1">6 (9.7)</td></tr><tr><td rowspan="1" colspan="1"> Missing</td><td rowspan="1" colspan="1">1 (1.6)</td><td rowspan="1" colspan="1">0</td></tr><tr><td colspan="3" rowspan="1">Clinical stage at diagnosis, <italic>n</italic> (%)</td></tr><tr><td rowspan="1" colspan="1"> I</td><td rowspan="1" colspan="1">3 (4.8)</td><td rowspan="1" colspan="1">4 (6.5)</td></tr><tr><td rowspan="1" colspan="1"> II</td><td rowspan="1" colspan="1">3 (4.8)</td><td rowspan="1" colspan="1">6 (9.7)</td></tr><tr><td rowspan="1" colspan="1"> III</td><td rowspan="1" colspan="1">9 (14.5)</td><td rowspan="1" colspan="1">15 (24.2)</td></tr><tr><td rowspan="1" colspan="1"> IVa</td><td rowspan="1" colspan="1">28 (45.2)</td><td rowspan="1" colspan="1">23 (37.1)</td></tr><tr><td rowspan="1" colspan="1"> IVb</td><td rowspan="1" colspan="1">10 (16.1)</td><td rowspan="1" colspan="1">12 (19.4)</td></tr><tr><td rowspan="1" colspan="1"> IVc</td><td rowspan="1" colspan="1">8 (12.9)</td><td rowspan="1" colspan="1">2 (3.2)</td></tr><tr><td rowspan="1" colspan="1"> Missing</td><td rowspan="1" colspan="1">1 (1.6)</td><td rowspan="1" colspan="1">0</td></tr><tr><td colspan="3" rowspan="1">Metastasis and recurrence</td></tr><tr><td rowspan="1" colspan="1"> Local only</td><td rowspan="1" colspan="1">17 (27.4)</td><td rowspan="1" colspan="1">19 (30.6)</td></tr><tr><td rowspan="1" colspan="1"> Distant only</td><td rowspan="1" colspan="1">19 (30.6)</td><td rowspan="1" colspan="1">18 (29.0)</td></tr><tr><td rowspan="1" colspan="1"> Both</td><td rowspan="1" colspan="1">24 (38.7)</td><td rowspan="1" colspan="1">24 (38.7)</td></tr><tr><td rowspan="1" colspan="1"> Missing</td><td rowspan="1" colspan="1">2 (3.2)</td><td rowspan="1" colspan="1">1 (1.6)</td></tr><tr><td colspan="3" rowspan="1">Number of prior chemotherapies,<sup>b</sup><italic>n</italic> (%)</td></tr><tr><td rowspan="1" colspan="1"> 1</td><td rowspan="1" colspan="1">28 (45.2)</td><td rowspan="1" colspan="1">33 (53.2)</td></tr><tr><td rowspan="1" colspan="1"> 2</td><td rowspan="1" colspan="1">29 (46.8)</td><td rowspan="1" colspan="1">22 (35.5)</td></tr><tr><td rowspan="1" colspan="1"> 3</td><td rowspan="1" colspan="1">3 (4.8)</td><td rowspan="1" colspan="1">5 (8.1)</td></tr><tr><td rowspan="1" colspan="1"> 4</td><td rowspan="1" colspan="1">1 (1.6)</td><td rowspan="1" colspan="1">2 (3.2)</td></tr><tr><td rowspan="1" colspan="1"> Missing</td><td rowspan="1" colspan="1">1 (1.6)</td><td rowspan="1" colspan="1">0</td></tr><tr><td colspan="3" rowspan="1">Prior chemotherapy for R/M disease, <italic>n</italic> (%)</td></tr><tr><td rowspan="1" colspan="1"> Yes</td><td rowspan="1" colspan="1">42 (67.7)</td><td rowspan="1" colspan="1">41 (66.1)</td></tr><tr><td rowspan="1" colspan="1"> No</td><td rowspan="1" colspan="1">20 (32.3)</td><td rowspan="1" colspan="1">21 (33.9)</td></tr><tr><td colspan="3" rowspan="1">Other prior anticancer therapies, <italic>n</italic> (%)</td></tr><tr><td rowspan="1" colspan="1"> Surgery</td><td rowspan="1" colspan="1">48 (77.4)</td><td rowspan="1" colspan="1">45 (72.6)</td></tr><tr><td rowspan="1" colspan="1"> Radiotherapy</td><td rowspan="1" colspan="1">56 (90.3)</td><td rowspan="1" colspan="1">60 (96.8)</td></tr><tr><td rowspan="1" colspan="1"> Missing</td><td rowspan="1" colspan="1">1 (1.6)</td><td rowspan="1" colspan="1">0</td></tr><tr><td colspan="3" rowspan="1">EGFRvIII mutation status, <italic>n</italic> (%)</td></tr><tr><td rowspan="1" colspan="1"> Positive</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">0</td></tr><tr><td rowspan="1" colspan="1"> Negative</td><td rowspan="1" colspan="1">25 (40.3)</td><td rowspan="1" colspan="1">28 (45.2)</td></tr><tr><td rowspan="1" colspan="1"> Unknown</td><td rowspan="1" colspan="1">37 (59.7)</td><td rowspan="1" colspan="1">34 (54.8)</td></tr><tr><td colspan="3" rowspan="1">p16 status, <italic>n</italic> (%)</td></tr><tr><td rowspan="1" colspan="1"> Positive</td><td rowspan="1" colspan="1">9 (14.5)</td><td rowspan="1" colspan="1">8 (12.9)</td></tr><tr><td rowspan="1" colspan="1"> Negative</td><td rowspan="1" colspan="1">25 (40.3)</td><td rowspan="1" colspan="1">23 (37.1)</td></tr><tr><td rowspan="1" colspan="1"> Unknown</td><td rowspan="1" colspan="1">28 (45.2)</td><td rowspan="1" colspan="1">31 (50.0)</td></tr></tbody></table><table-wrap-foot><fn id="tbnfn1"><p><sup>a</sup>Patient with ECOG performance status 2 was recorded as a protocol violation.</p></fn><fn id="tbnfn2"><p><sup>b</sup>Any chemotherapy received since diagnosis. Note: Percentage calculated from the total population; some factors total <100% due to missing data.</p></fn><fn id="tbnfn3"><p>ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor.</p></fn></table-wrap-foot></table-wrap><fig id="MDU216F1" position="float"><label>Figure 1.</label><caption><p>Participant flow diagram. AE, adverse event.</p></caption><graphic xlink:href="mdu21601"></graphic></fig></p></sec><sec id="mdu216_s3b"><title>tumor shrinkage</title><sec id="mdu216_s3b1"><title>stage I</title><p>Comparable tumor reduction was observed in both afatinib and cetuximab groups (<italic>P</italic> = 0.57 per ICR and 0.76 per IR, Figure <xref ref-type="fig" rid="MDU216F2">2</xref>A and B). Per ICR, 16 of 47 (34%) afatinib-treated patients experienced tumor size reduction of >30% versus 9 of 48 (18.7%) on cetuximab (Figure <xref ref-type="fig" rid="MDU216F3">3</xref>).<fig id="MDU216F2" position="float"><label>Figure 2.</label><caption><p>(A) Primary end point: mean tumor shrinkage<sup>a</sup> after treatment (stage I); (B) mean percentage change<sup>b</sup> in tumor shrinkage (stage I). <sup>a</sup>Tumor shrinkage was defined as the change from baseline in the smallest postrandomization sum of the longest diameters of the target lesions; adjusted mean change. Only patients with baseline and at least one postrandomization measurement are included in these analyses. Independent central review, <italic>n</italic> = 48 for afatinib and <italic>n</italic> = 48 for cetuximab; investigator review, <italic>n</italic> = 50 for afatinib and <italic>n</italic> = 55 for cetuximab. <sup>b</sup>Adjusted mean change. Only patients with baseline and at least one postrandomization measurement are included in these analyses. Independent central review, <italic>n</italic> = 47 for afatinib and <italic>n</italic> = 48 for cetuximab; investigator review, <italic>n</italic> = 50 for afatinib and <italic>n</italic> = 55 for cetuximab.</p></caption><graphic xlink:href="mdu21602"></graphic></fig><fig id="MDU216F3" position="float"><label>Figure 3.</label><caption><p>Waterfall plot of maximum percentage tumor shrinkage in stage I and stage II according to independent central review. Patients were required to have a baseline and postbaseline measurement for inclusion in the assessment of the tumor shrinkage (and Response Evaluation Criteria In Solid Tumors assessment). Factors contributing to missing data points included adverse events (AEs) leading to withdrawal, death before the first scan assessment at 8 weeks, patient withdrawal from the study, patient crossover to stage II due to an AE without a follow-up assessment being carried out in stage I and the removal of ineligible patients from the study.</p></caption><graphic xlink:href="mdu21603"></graphic></fig></p></sec><sec id="mdu216_s3b2"><title>stage II</title><p>Overall, 12/30 (40%) of afatinib- and 8/26 (30.8%) of cetuximab-treated assessable patients had a reduction in SLD by ICR (Figure <xref ref-type="fig" rid="MDU216F3">3</xref>). Waterfall plots show that one patient in each group experienced tumor size reduction of >30%.</p></sec><sec id="mdu216_s3b3"><title>RECIST-defined response</title><p>During stage I, confirmed ORR was 16.1% with afatinib and 6.5% with cetuximab (<italic>P</italic> = 0.09) by IR and 8.1% with afatinib and 9.7% with cetuximab (<italic>P</italic> = 0.78) by ICR (<ext-link ext-link-type="uri" xlink:href="http://annonc.oxfordjournals.org/lookup/suppl/doi:10.1093/annonc/mdu216/-/DC1">supplementary Table S1, available at <italic>Annals of Oncology</italic> online</ext-link>). There was disparity in agreement between IR and ICR, and in particular between reviewers within the ICR, where 49 of 106 cases (46%) required third-reader arbitration due to discrepancies between the first two readers. Disease control was achieved in 31 (50%) afatinib- and 35 (56.5%) cetuximab-treated patients by IR (<italic>P</italic> = 0.48) with similar findings using ICR in stage I (<ext-link ext-link-type="uri" xlink:href="http://annonc.oxfordjournals.org/lookup/suppl/doi:10.1093/annonc/mdu216/-/DC1">supplementary Table S1, available at <italic>Annals of Oncology</italic> online</ext-link>). ORRs in both groups were similar per ICR, regardless of prior chemotherapy in the R/M setting; per IR, afatinib showed higher ORR in patients with prior chemotherapy in the R/M setting (<ext-link ext-link-type="uri" xlink:href="http://annonc.oxfordjournals.org/lookup/suppl/doi:10.1093/annonc/mdu216/-/DC1">supplementary Table S2, available at <italic>Annals of Oncology</italic> online</ext-link>).</p><p>During stage II, the disease control rate (IR/ICR) for patients who switched from cetuximab to afatinib was 38.9%/33.3% compared with 18.8%/18.8% for those switched from afatinib to cetuximab (<ext-link ext-link-type="uri" xlink:href="http://annonc.oxfordjournals.org/lookup/suppl/doi:10.1093/annonc/mdu216/-/DC1">supplementary Table S1, available at <italic>Annals of Oncology</italic> online</ext-link>). Interestingly, several patients on both treatments appeared to maintain disease control after crossover (Figure <xref ref-type="fig" rid="MDU216F4">4</xref>).<fig id="MDU216F4" position="float"><label>Figure 4.</label><caption><p>Treatment duration and disease control in stages I and II. Each line denotes one patient and the blue portion is the treatment duration with afatinib and yellow corresponds to cetuximab. The solid dot associated with each line indicates the patient achieved disease control (DC) when treated with afatinib or cetuximab (again, differentiated by color) according to investigator review.</p></caption><graphic xlink:href="mdu21604"></graphic></fig></p></sec><sec id="mdu216_s3b4"><title>PFS and OS</title><p>In stage I, median PFS by ICR for afatinib- and cetuximab-treated patients was similar; 13.0 versus 15.0 weeks [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.62–1.38, <italic>P</italic> = 0.71, <ext-link ext-link-type="uri" xlink:href="http://annonc.oxfordjournals.org/lookup/suppl/doi:10.1093/annonc/mdu216/-/DC1">supplementary Figure S2A, available at <italic>Annals of Oncology</italic> online</ext-link>]. For stage II, median PFS for patients who crossed over to afatinib was 9.3 and 5.7 weeks for those crossing to cetuximab (HR 0.64, 95% CI 0.38–1.05, <italic>P</italic> = 0.08, <ext-link ext-link-type="uri" xlink:href="http://annonc.oxfordjournals.org/lookup/suppl/doi:10.1093/annonc/mdu216/-/DC1">supplementary Figure S2B, available at <italic>Annals of Oncology</italic> online</ext-link>).</p><p>Median OS was 35.9 weeks for afatinib- and 47.1 weeks for cetuximab-treated patients during stage I and II (HR 1.06, 95% CI 0.70–1.62, <italic>P</italic> = 0.78, <ext-link ext-link-type="uri" xlink:href="http://annonc.oxfordjournals.org/lookup/suppl/doi:10.1093/annonc/mdu216/-/DC1">supplementary Figure S3, available at <italic>Annals of Oncology</italic> online</ext-link>).</p></sec><sec id="mdu216_s3b5"><title>patient-reported outcomes</title><p>During both stages, PRO outcomes were comparable in both treatment groups for global health status, pain and swallowing (<ext-link ext-link-type="uri" xlink:href="http://annonc.oxfordjournals.org/lookup/suppl/doi:10.1093/annonc/mdu216/-/DC1">supplementary Figure S4, available at <italic>Annals of Oncology</italic> online</ext-link>).</p></sec><sec id="mdu216_s3b6"><title>PK assessments</title><p>Afatinib plasma levels reached steady state by day 15 and trough plasma concentrations were generally stable over the observation period (56 days), with no apparent differences between stages I and II (<ext-link ext-link-type="uri" xlink:href="http://annonc.oxfordjournals.org/lookup/suppl/doi:10.1093/annonc/mdu216/-/DC1">supplementary Figure S5A, available at <italic>Annals of Oncology</italic> online</ext-link>). Afatinib plasma concentrations were similar across different administration routes (oral tablet, gastric feeding tube and dispersion) (<ext-link ext-link-type="uri" xlink:href="http://annonc.oxfordjournals.org/lookup/suppl/doi:10.1093/annonc/mdu216/-/DC1">supplementary Figure S5B, available at <italic>Annals of Oncology</italic> online</ext-link>).</p></sec><sec id="mdu216_s3b7"><title>EGFRvIII and p16 analysis</title><p>None of the 53 patients (25 afatinib, 28 cetuximab) with tumor samples for EGFRvIII mutation analysis harbored the EGFRvIII mutation. Of 65 patients (34 afatinib, 31 cetuximab) with samples for p16 analysis, 48 (74%) tested negative for p16 (25 afatinib, 23 cetuximab). Two responses were observed in p16-positive patients by ICR, one in each treatment group (<ext-link ext-link-type="uri" xlink:href="http://annonc.oxfordjournals.org/lookup/suppl/doi:10.1093/annonc/mdu216/-/DC1">supplementary Table S2, available at <italic>Annals of Oncology</italic> online</ext-link>).</p></sec><sec id="mdu216_s3b8"><title>AEs, dose reductions and treatment discontinuation</title><p>During stage I, 59/61 afatinib- and 51/60 cetuximab-treated patients had a DRAE, of which rash/acne and diarrhea were most common (Table <xref ref-type="table" rid="MDU216TB2">2</xref>). DRAEs led to dose reduction in 18 [29.5%; 9 (14.8%) rash/acne, 5 (8.2%) diarrhea, 3 (4.9%) mucosal inflammation and 1 (1.6%) fatigue] afatinib- and two (3.3%; one rash and one rash/skin fissures) cetuximab-treated patients. Discontinuation due to DRAEs occurred in 14 (23%) and 3 (5%) afatinib- and cetuximab-treated patients. Serious AEs that were possibly treatment-related occurred in 19 (31.1%) and 2 (3.3%) of afatinib- and cetuximab-treated patients, of which one was fatal (grade 5 pyrexia in the afatinib group). Similar AEs were reported during stages I and II; grade ≥3 rash/acne, diarrhea and dry skin occurred most often in stage II (Table <xref ref-type="table" rid="MDU216TB2">2</xref>).<table-wrap id="MDU216TB2" position="float"><label>Table 2.</label><caption><p>Treatment-related AEs in stages I and II for all grades and CTCAE grades 3–4 in ≥10% of patients in either treatment group</p></caption><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="char" char=" " span="1"></col><col align="char" char=" " span="1"></col><col align="char" char=" " span="1"></col><col align="char" char=" " span="1"></col><col align="char" char=" " span="1"></col><col align="char" char=" " span="1"></col><col align="char" char=" " span="1"></col><col align="char" char=" " span="1"></col></colgroup><thead><tr><th align="left" rowspan="3" colspan="1">CTCAE grades</th><th align="center" colspan="4" rowspan="1">Stage I<hr></hr></th><th align="center" colspan="4" rowspan="1">Stage II<hr></hr></th></tr><tr><th align="center" colspan="2" rowspan="1">Afatinib (<italic>N</italic> = 61)<hr></hr></th><th align="center" colspan="2" rowspan="1">Cetuximab (<italic>N</italic> = 60)<hr></hr></th><th align="center" colspan="2" rowspan="1">Cetuximab → afatinib (<italic>N</italic> = 36)<hr></hr></th><th align="center" colspan="2" rowspan="1">Afatinib → cetuximab (<italic>N</italic> = 32)<hr></hr></th></tr><tr><th align="left" rowspan="1" colspan="1">All</th><th align="left" rowspan="1" colspan="1">3–4</th><th align="left" rowspan="1" colspan="1">All</th><th align="left" rowspan="1" colspan="1">3–4</th><th align="left" rowspan="1" colspan="1">All</th><th align="left" rowspan="1" colspan="1">3–4</th><th align="left" rowspan="1" colspan="1">All</th><th align="left" rowspan="1" colspan="1">3–4</th></tr></thead><tbody><tr><td rowspan="1" colspan="1">Total, <italic>n</italic> (%)</td><td rowspan="1" colspan="1">59 (96.7)</td><td rowspan="1" colspan="1">32 (52.5)</td><td rowspan="1" colspan="1">51 (85.0)</td><td rowspan="1" colspan="1">11 (18.4)</td><td rowspan="1" colspan="1">31 (86.1)</td><td rowspan="1" colspan="1">17 (47.2)</td><td rowspan="1" colspan="1">22 (68.8)</td><td rowspan="1" colspan="1">5 (15.6)</td></tr><tr><td rowspan="1" colspan="1">Rash/acne<sup>a</sup></td><td rowspan="1" colspan="1">48 (78.7)</td><td rowspan="1" colspan="1">11 (18.0)</td><td rowspan="1" colspan="1">46 (76.7)</td><td rowspan="1" colspan="1">5 (8.3)</td><td rowspan="1" colspan="1">20 (55.6)</td><td rowspan="1" colspan="1">9 (25.0)</td><td rowspan="1" colspan="1">14 (43.8)</td><td rowspan="1" colspan="1">4 (12.5)</td></tr><tr><td rowspan="1" colspan="1">Diarrhea</td><td rowspan="1" colspan="1">48 (78.7)</td><td rowspan="1" colspan="1">9 (14.8)</td><td rowspan="1" colspan="1">12 (20.0)</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">19 (52.8)</td><td rowspan="1" colspan="1">4 (11.1)</td><td rowspan="1" colspan="1">1 (3.1)</td><td rowspan="1" colspan="1">0</td></tr><tr><td rowspan="1" colspan="1">Stomatitis<sup>a,b</sup></td><td rowspan="1" colspan="1">21 (34.4)</td><td rowspan="1" colspan="1">7 (11.5)</td><td rowspan="1" colspan="1">14 (23.3)</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">8 (22.2)</td><td rowspan="1" colspan="1">1 (2.8)</td><td rowspan="1" colspan="1">2 (6.3)</td><td rowspan="1" colspan="1">0</td></tr><tr><td rowspan="1" colspan="1">Fatigue<sup>a</sup></td><td rowspan="1" colspan="1">20 (32.8)</td><td rowspan="1" colspan="1">3 (4.9)</td><td rowspan="1" colspan="1">13 (21.7)</td><td rowspan="1" colspan="1">1 (1.7)</td><td rowspan="1" colspan="1">4 (11.1)</td><td rowspan="1" colspan="1">1 (2.8)</td><td rowspan="1" colspan="1">2 (6.3)</td><td rowspan="1" colspan="1">0</td></tr><tr><td rowspan="1" colspan="1">Nausea</td><td rowspan="1" colspan="1">17 (27.9)</td><td rowspan="1" colspan="1">1 (1.6)</td><td rowspan="1" colspan="1">12 (20.0)</td><td rowspan="1" colspan="1">1 (1.7)</td><td rowspan="1" colspan="1">5 (13.9)</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">1 (3.1)</td><td rowspan="1" colspan="1">0</td></tr><tr><td rowspan="1" colspan="1">Vomiting</td><td rowspan="1" colspan="1">10 (16.4)</td><td rowspan="1" colspan="1">1 (1.6)</td><td rowspan="1" colspan="1">8 (13.3)</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">3 (8.3)</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">1 (3.1)</td><td rowspan="1" colspan="1">0</td></tr><tr><td rowspan="1" colspan="1">Dry skin</td><td rowspan="1" colspan="1">9 (14.8)</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">15 (25.0)</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">4 (11.1)</td><td rowspan="1" colspan="1">2 (5.6)</td><td rowspan="1" colspan="1">3 (9.4)</td><td rowspan="1" colspan="1">1 (3.1)</td></tr><tr><td rowspan="1" colspan="1">Dehydration</td><td rowspan="1" colspan="1">8 (13.1)</td><td rowspan="1" colspan="1">5 (8.2)</td><td rowspan="1" colspan="1">1 (1.7)</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">0</td></tr><tr><td rowspan="1" colspan="1">Decreased appetite</td><td rowspan="1" colspan="1">5 (8.2)</td><td rowspan="1" colspan="1">3 (4.9)</td><td rowspan="1" colspan="1">8 (13.3)</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">6 (16.7)</td><td rowspan="1" colspan="1">1 (2.8)</td><td rowspan="1" colspan="1">2 (6.3)</td><td rowspan="1" colspan="1">0</td></tr><tr><td rowspan="1" colspan="1">Nail effects<sup>a,c</sup></td><td rowspan="1" colspan="1">4 (6.6)</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">6 (10.0)</td><td rowspan="1" colspan="1">1 (1.7)</td><td rowspan="1" colspan="1">2 (5.6)</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">3 (9.4)</td><td rowspan="1" colspan="1">0</td></tr><tr><td rowspan="1" colspan="1">Ocular effects<sup>a,d</sup></td><td rowspan="1" colspan="1">4 (6.6)</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">6 (10.0)</td><td rowspan="1" colspan="1">1 (1.7)</td><td rowspan="1" colspan="1">5 (13.9)</td><td rowspan="1" colspan="1">1 (2.8)</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">0</td></tr><tr><td rowspan="1" colspan="1">Constipation</td><td rowspan="1" colspan="1">2 (3.3)</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">7 (11.7)</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">0</td><td rowspan="1" colspan="1">1 (3.1)</td><td rowspan="1" colspan="1">0</td></tr></tbody></table><table-wrap-foot><fn id="tbnfn4"><p><sup>a</sup>Grouped terms of closely related AEs. Table sorted by afatinib ‘all grades’ in stage I.</p></fn><fn id="tbnfn5"><p><sup>b</sup>During stage I, the most frequently reported treatment-related AE within the grouped term ‘stomatitis’ was mucosal inflammation (afatinib 21.3% and cetuximab 13.3%).</p></fn><fn id="tbnfn6"><p><sup>c</sup>During stage I, the most frequently reported AE within the grouped term ‘nail effects’ was paronychia (afatinib 4.9% and cetuximab 6.7%).</p></fn><fn id="tbnfn7"><p><sup>d</sup>During stage I, the most frequently reported AEs within the grouped term ‘ocular effects’ were conjunctivitis (afatinib 3.3% and cetuximab 8.3%) and periorbital edema (afatinib 3.3% and cetuximab 0%).</p></fn><fn id="tbnfn8"><p>AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events.</p></fn></table-wrap-foot></table-wrap></p></sec></sec></sec><sec sec-type="discussion" id="mdu216_s4"><title>discussion</title><p>This is the only reported randomized trial to compare an irreversible, small molecule ErbB family blocker with cetuximab in patients with R/M HNSCC who progressed after platinum-based chemotherapy and investigate dual sequential treatment with these ErbB family-targeting agents. Afatinib showed comparable activity to cetuximab and the sequential treatment appeared to sustain clinical benefit, demonstrating a lack of cross-resistance between the two agents. In addition, afatinib levels were similar across different administration routes, suggesting that optimal doses of afatinib can be achieved in tube-feeding patients.</p><p>The primary outcome measure of tumor shrinkage as a continuous variable (assessed using RECIST) was chosen as it provides distinct power advantages compared with otherwise identical trial designs that use categorical outcomes [<xref rid="MDU216C21" ref-type="bibr">21</xref>]. Continuous outcome measures can enable smaller, more efficient randomized trials and randomized trials are generally more informative than single-arm studies with historical controls. Here, tumor shrinkage and response rate results were exactly concordant and demonstrate that the study design using the continuous outcome variable did not influence findings.</p><p>Evidence of disease control was visible in both crossover treatment arms with sequential EGFR/ErbB-targeting therapy using cetuximab followed by afatinib or vice versa. This finding may be clinically meaningful, especially as few approved therapies and no targeted agents are available in this treatment setting and non-cross-resistance with any other commonly used agents is likely (e.g. cytotoxic chemotherapy). This is the first report in HNSCC where PD under treatment with an EGFR-targeting monoclonal antibody does not necessarily induce resistance to a subsequent small molecule ErbB-targeted agent. However, it is unclear what precise mechanism of action of afatinib this relates to and further mechanistic insights and biomarker discovery are required to decipher this. It is interesting to note that HER2 is altered in 3%–5% of HNSCC tumors as recently reported by TCGA and this could be a potential mechanism by which afatinib acts after failure [<xref rid="MDU216C4" ref-type="bibr">4</xref>].</p><p>We were unable to identify EGFRvIII mutations in 53 samples tested, and taken together with a report of head and neck cancer exome sequencing that also could not identify EGFRvIII mutations at the DNA level in 74 samples [<xref rid="MDU216C22" ref-type="bibr">22</xref>], there is no clear evidence that EGFRvIII is present at a meaningful frequency in HNSCC populations [<xref rid="MDU216C4" ref-type="bibr">4</xref>]. While preclinical data showed that afatinib potently inhibits EGFRvIII(+) cells, this is unlikely to be the underlying mechanism of action in HNSCC or differential activity compared with cetuximab.</p><p>Frequency of grade ≥3 DRAEs was greater with afatinib than cetuximab, with grade ≥3 diarrhea and rash accounting for more dose reductions and discontinuations in the afatinib group, although this did not translate into efficacy differences. Despite the greater proportion of DRAEs observed with afatinib, significant deterioration in PRO end points was not noted compared with cetuximab. Proactive management of AEs associated with EGFR-targeted therapies is essential and frequently successful in allowing patients to continue treatment [<xref rid="MDU216C23" ref-type="bibr">23</xref>, <xref rid="MDU216C24" ref-type="bibr">24</xref>]. Of note, more recent studies with afatinib, including phase III trials in HNSCC, recommend a starting dose of 40 mg (instead of 50 mg) based on safety evaluations (e.g. NCT01345682, NCT01345669 and NCT01856478).</p><p>Our data suggest that afatinib has comparable activity to cetuximab in R/M HNSCC. Evidence of a lack of cross-resistance between these agents demonstrated by sustained clinical benefit of sequential EGFR/ErbB family therapy in a subgroup of patients is novel and potentially clinically meaningful, especially if biomarkers could be used to select patients.</p></sec><sec id="mdu216_s5"><title>funding</title><p>This work was supported by <funding-source>Boehringer Ingelheim</funding-source>. Medical writing assistance provided by Jamie Singer and Kay Roche of Ogilvy Healthworld, and editorial assistance provided by Katie McClendon of GeoMed, part of KnowledgePoint360, an Ashfield Company, was supported financially by Boehringer Ingelheim during the preparation of this manuscript.</p></sec><sec id="mdu216_s6"><title>disclosure</title><p>TS and EC have received consultancy fees and research funding from Boehringer Ingelheim. PC has received consultancy fees from Merck Serono. WZ and EE are employees of Boehringer Ingelheim. AB is a former employee of Boehringer Ingelheim. JF, DC, JdC, RH and MD have declared no conflicts of interest.</p></sec><sec sec-type="supplementary-material"><title>Supplementary Material</title><supplementary-material id="PMC_1" content-type="local-data"><caption><title>Supplementary Data</title></caption><media mimetype="text" mime-subtype="html" xlink:href="supp_25_9_1813__index.html"></media><media xlink:role="associated-file" mimetype="application" mime-subtype="msword" xlink:href="supp_mdu216_mdu216supp.docx"></media><media xlink:role="associated-file" mimetype="image" mime-subtype="tiff" xlink:href="supp_mdu216_mdu216supp_fig1.tif"></media><media xlink:role="associated-file" mimetype="image" mime-subtype="tiff" xlink:href="supp_mdu216_mdu216supp_fig2a.tif"></media><media xlink:role="associated-file" mimetype="image" mime-subtype="tiff" xlink:href="supp_mdu216_mdu216supp_fig2b.tif"></media><media xlink:role="associated-file" mimetype="image" mime-subtype="tiff" xlink:href="supp_mdu216_mdu216supp_fig3.tif"></media><media xlink:role="associated-file" mimetype="image" mime-subtype="tiff" xlink:href="supp_mdu216_mdu216supp_fig4.tif"></media><media xlink:role="associated-file" mimetype="image" mime-subtype="tiff" xlink:href="supp_mdu216_mdu216supp_fig5a.tif"></media><media xlink:role="associated-file" mimetype="image" mime-subtype="tiff" xlink:href="supp_mdu216_mdu216supp_fig5b.tif"></media><media xlink:role="associated-file" mimetype="application" mime-subtype="msword" xlink:href="supp_mdu216_mdu216supp_table1.docx"></media><media xlink:role="associated-file" mimetype="application" mime-subtype="msword" xlink:href="supp_mdu216_mdu216supp_table2.docx"></media></supplementary-material></sec></body><back><ack><title>acknowledgements</title><p>We gratefully acknowledge the patients, their families and their caregivers for participation in this study. 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Jean-Marc Tourani, Antoine Serre), Spain (Josep Del Campo, Javier Lavernia, José Trigo, Lara Iglesias, Ricardo Hitt, Antonio López Pousa, Almudena Garcia) and USA (Tanguy Seiwert, Darryl Hamilton, Mercedes Porosnicu, Mark Agulnik, Yungpo Su, Bonnie Glisson, Bhoomi Mehrotra, Tien Hoang (PI), Dimitrios Colevas, Mark Kozloff, Frank Worden, Paul O'Brien, Scott Okuno, Neil Hayes, Stuart Wong, Eric Lester, Romnee Clark, Ann Zimrin).</p></sec></sec></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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