Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: Results From the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial

Martine Piccart-Gebhart, Eileen Holmes, Jośe Baselga, Evandro De Azambuja, Amylou Dueck, Giuseppe Viale, Jo Anne Zujewski, Aron Goldhirsch, Alison Armour, Kathleen I. Pritchard, Ann E. McCullough, Stella Dolci, Eleanor McFadden, Andrew P. Holmes, Liu Tonghua, Holger Eidtmann, Phuong Dinh, Serena Di Cosimo, Nadia Harbeck, Sergei TjulandinYoung Hyuck Im, Chiun Sheng Huang, Veronique Díeras, David W. Hillman, Antonio C. Wolff, Christian Jackisch, Istvan Lang, Michael Untch, Ian Smith, Frances Boyle, Binghe Xu, Henry Gomez, Thomas Suter, Richard D. Gelber, Edith A. Perez

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Abstract

Background Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2-positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain. Methods In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2-positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T. Results Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P # .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4%reduction was observed with T→L compared with T (HR, 0.96; 97.5%CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms. Conclusion Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care.

Original languageEnglish (US)
Pages (from-to)1034-1042
Number of pages9
JournalJournal of Clinical Oncology
Volume34
Issue number10
DOIs
StatePublished - Apr 1 2016

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Disease-Free Survival
Breast Neoplasms
Epidermal Growth Factor
Medical Futility
Therapeutics
Standard of Care
Exanthema
Diarrhea
Survival Rate
human ERBB2 protein
Trastuzumab
lapatinib
Liver
Incidence

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer : Results From the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial. / Piccart-Gebhart, Martine; Holmes, Eileen; Baselga, Jośe; De Azambuja, Evandro; Dueck, Amylou; Viale, Giuseppe; Zujewski, Jo Anne; Goldhirsch, Aron; Armour, Alison; Pritchard, Kathleen I.; McCullough, Ann E.; Dolci, Stella; McFadden, Eleanor; Holmes, Andrew P.; Tonghua, Liu; Eidtmann, Holger; Dinh, Phuong; Di Cosimo, Serena; Harbeck, Nadia; Tjulandin, Sergei; Im, Young Hyuck; Huang, Chiun Sheng; Díeras, Veronique; Hillman, David W.; Wolff, Antonio C.; Jackisch, Christian; Lang, Istvan; Untch, Michael; Smith, Ian; Boyle, Frances; Xu, Binghe; Gomez, Henry; Suter, Thomas; Gelber, Richard D.; Perez, Edith A.

In: Journal of Clinical Oncology, Vol. 34, No. 10, 01.04.2016, p. 1034-1042.

Research output: Contribution to journalArticle

Piccart-Gebhart, M, Holmes, E, Baselga, J, De Azambuja, E, Dueck, A, Viale, G, Zujewski, JA, Goldhirsch, A, Armour, A, Pritchard, KI, McCullough, AE, Dolci, S, McFadden, E, Holmes, AP, Tonghua, L, Eidtmann, H, Dinh, P, Di Cosimo, S, Harbeck, N, Tjulandin, S, Im, YH, Huang, CS, Díeras, V, Hillman, DW, Wolff, AC, Jackisch, C, Lang, I, Untch, M, Smith, I, Boyle, F, Xu, B, Gomez, H, Suter, T, Gelber, RD & Perez, EA 2016, 'Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: Results From the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial', Journal of Clinical Oncology, vol. 34, no. 10, pp. 1034-1042. https://doi.org/10.1200/JCO.2015.62.1797
Piccart-Gebhart, Martine ; Holmes, Eileen ; Baselga, Jośe ; De Azambuja, Evandro ; Dueck, Amylou ; Viale, Giuseppe ; Zujewski, Jo Anne ; Goldhirsch, Aron ; Armour, Alison ; Pritchard, Kathleen I. ; McCullough, Ann E. ; Dolci, Stella ; McFadden, Eleanor ; Holmes, Andrew P. ; Tonghua, Liu ; Eidtmann, Holger ; Dinh, Phuong ; Di Cosimo, Serena ; Harbeck, Nadia ; Tjulandin, Sergei ; Im, Young Hyuck ; Huang, Chiun Sheng ; Díeras, Veronique ; Hillman, David W. ; Wolff, Antonio C. ; Jackisch, Christian ; Lang, Istvan ; Untch, Michael ; Smith, Ian ; Boyle, Frances ; Xu, Binghe ; Gomez, Henry ; Suter, Thomas ; Gelber, Richard D. ; Perez, Edith A. / Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer : Results From the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial. In: Journal of Clinical Oncology. 2016 ; Vol. 34, No. 10. pp. 1034-1042.
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title = "Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: Results From the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial",
abstract = "Background Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2-positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain. Methods In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2-positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80{\%} power to detect a hazard ratio (HR) of 0.8 for L+T versus T. Results Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P # .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16{\%} reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5{\%} CI, 0.70 to 1.02; P = .048), and a 4{\%}reduction was observed with T→L compared with T (HR, 0.96; 97.5{\%}CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms. Conclusion Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care.",
author = "Martine Piccart-Gebhart and Eileen Holmes and Jośe Baselga and {De Azambuja}, Evandro and Amylou Dueck and Giuseppe Viale and Zujewski, {Jo Anne} and Aron Goldhirsch and Alison Armour and Pritchard, {Kathleen I.} and McCullough, {Ann E.} and Stella Dolci and Eleanor McFadden and Holmes, {Andrew P.} and Liu Tonghua and Holger Eidtmann and Phuong Dinh and {Di Cosimo}, Serena and Nadia Harbeck and Sergei Tjulandin and Im, {Young Hyuck} and Huang, {Chiun Sheng} and Veronique D{\'i}eras and Hillman, {David W.} and Wolff, {Antonio C.} and Christian Jackisch and Istvan Lang and Michael Untch and Ian Smith and Frances Boyle and Binghe Xu and Henry Gomez and Thomas Suter and Gelber, {Richard D.} and Perez, {Edith A.}",
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TY - JOUR

T1 - Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer

T2 - Results From the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial

AU - Piccart-Gebhart, Martine

AU - Holmes, Eileen

AU - Baselga, Jośe

AU - De Azambuja, Evandro

AU - Dueck, Amylou

AU - Viale, Giuseppe

AU - Zujewski, Jo Anne

AU - Goldhirsch, Aron

AU - Armour, Alison

AU - Pritchard, Kathleen I.

AU - McCullough, Ann E.

AU - Dolci, Stella

AU - McFadden, Eleanor

AU - Holmes, Andrew P.

AU - Tonghua, Liu

AU - Eidtmann, Holger

AU - Dinh, Phuong

AU - Di Cosimo, Serena

AU - Harbeck, Nadia

AU - Tjulandin, Sergei

AU - Im, Young Hyuck

AU - Huang, Chiun Sheng

AU - Díeras, Veronique

AU - Hillman, David W.

AU - Wolff, Antonio C.

AU - Jackisch, Christian

AU - Lang, Istvan

AU - Untch, Michael

AU - Smith, Ian

AU - Boyle, Frances

AU - Xu, Binghe

AU - Gomez, Henry

AU - Suter, Thomas

AU - Gelber, Richard D.

AU - Perez, Edith A.

PY - 2016/4/1

Y1 - 2016/4/1

N2 - Background Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2-positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain. Methods In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2-positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T. Results Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P # .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4%reduction was observed with T→L compared with T (HR, 0.96; 97.5%CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms. Conclusion Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care.

AB - Background Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2-positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain. Methods In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2-positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T. Results Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P # .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4%reduction was observed with T→L compared with T (HR, 0.96; 97.5%CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms. Conclusion Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care.

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U2 - 10.1200/JCO.2015.62.1797

DO - 10.1200/JCO.2015.62.1797

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