title: Trastuzumab Emtansine With or Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal Growth Factor Receptor 2-Positive, Advanced Breast Cancer: Primary Results From the Phase III MARIANNE Study.
abstract: Purpose Trastuzumab and pertuzumab are human epidermal growth factor receptor 2 (HER2) -targeted monoclonal antibodies, and trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the properties of trastuzumab with the cytotoxic activity of DM1. T-DM1 demonstrated encouraging efficacy and safety in a phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Combination T-DM1 and pertuzumab showed synergistic activity in cell culture models and had an acceptable safety profile in a phase Ib and II study. Methods In the MARIANNE study, 1,095 patients with centrally assessed, HER2-positive, advanced breast cancer and no prior therapy for advanced disease were randomly assigned 1:1:1 to control (trastuzumab plus taxane), T-DM1 plus placebo, hereafter T-DM1, or T-DM1 plus pertuzumab at standard doses. Primary end point was progression-free survival (PFS), as assessed by independent review. Results T-DM1 and T-DM1 plus pertuzumab showed noninferior PFS compared with trastuzumab plus taxane (median PFS: 13.7 months with trastuzumab plus taxane, 14.1 months with T-DM1, and 15.2 months with T-DM1 plus pertuzumab). Neither experimental arm showed PFS superiority to trastuzumab plus taxane. Response rate was 67.9% in patients who were treated with trastuzumab plus taxane, 59.7% with T-DM1, and 64.2% with T-DM1 plus pertuzumab; median response duration was 12.5 months, 20.7 months, and 21.2 months, respectively. The incidence of grade ≥ 3 adverse events was numerically higher in the control arm (54.1%) versus the T-DM1 arm (45.4%) and T-DM1 plus pertuzumab arm (46.2%). Numerically fewer patients discontinued treatment because of adverse events in the T-DM1 arms, and health-related quality of life was maintained for longer in the T-DM1 arms. Conclusion T-DM1 showed noninferior, but not superior, efficacy and better tolerability than did taxane plus trastuzumab for first-line treatment of HER2-positive, advanced breast cancer.
authors.affiliation: Edith A. Perez, Mayo Clinic, Jacksonville, FL; Howard Burris III, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; Jennifer A. Petersen, Genentech, South San Francisco, CA; Carlos Barrios, Pontifícia Universidade Católica do Rio Grande do Sul School of Medicine, Porto Alegre, Brazil; Wolfgang Eiermann, Interdisciplinary Oncology Center, Munich, Germany; Masakazu Toi, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Young-Hyuck Im, Samsung Medical Centre, Seoul, Korea; Pierfranco Conte, University of Padova and Istituto Oncologico Veneto, Padova, Italy; Miguel Martin, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Tadeusz Pienkowski, Postgraduate Medical Education Center, Warsaw, Poland; Xavier Pivot, University Hospital Jean Minjoz, Besançon, France; Sven Stanzel, Alexander Strasak, Monika Patre, F. Hoffmann-La Roche, Basel, Switzerland; and Paul Ellis, Guys Hospital and Sarah Cannon Research Institute, London, United Kingdom.
authors.forename: Edith A
authors.initials: EA
authors.lastname: Perez
authors.affiliation: Edith A. Perez, Mayo Clinic, Jacksonville, FL; Howard Burris III, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; Jennifer A. Petersen, Genentech, South San Francisco, CA; Carlos Barrios, Pontifícia Universidade Católica do Rio Grande do Sul School of Medicine, Porto Alegre, Brazil; Wolfgang Eiermann, Interdisciplinary Oncology Center, Munich, Germany; Masakazu Toi, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Young-Hyuck Im, Samsung Medical Centre, Seoul, Korea; Pierfranco Conte, University of Padova and Istituto Oncologico Veneto, Padova, Italy; Miguel Martin, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Tadeusz Pienkowski, Postgraduate Medical Education Center, Warsaw, Poland; Xavier Pivot, University Hospital Jean Minjoz, Besançon, France; Sven Stanzel, Alexander Strasak, Monika Patre, F. Hoffmann-La Roche, Basel, Switzerland; and Paul Ellis, Guys Hospital and Sarah Cannon Research Institute, London, United Kingdom.
authors.forename: Carlos
authors.initials: C
authors.lastname: Barrios
authors.affiliation: Edith A. Perez, Mayo Clinic, Jacksonville, FL; Howard Burris III, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; Jennifer A. Petersen, Genentech, South San Francisco, CA; Carlos Barrios, Pontifícia Universidade Católica do Rio Grande do Sul School of Medicine, Porto Alegre, Brazil; Wolfgang Eiermann, Interdisciplinary Oncology Center, Munich, Germany; Masakazu Toi, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Young-Hyuck Im, Samsung Medical Centre, Seoul, Korea; Pierfranco Conte, University of Padova and Istituto Oncologico Veneto, Padova, Italy; Miguel Martin, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Tadeusz Pienkowski, Postgraduate Medical Education Center, Warsaw, Poland; Xavier Pivot, University Hospital Jean Minjoz, Besançon, France; Sven Stanzel, Alexander Strasak, Monika Patre, F. Hoffmann-La Roche, Basel, Switzerland; and Paul Ellis, Guys Hospital and Sarah Cannon Research Institute, London, United Kingdom.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Eiermann
authors.affiliation: Edith A. Perez, Mayo Clinic, Jacksonville, FL; Howard Burris III, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; Jennifer A. Petersen, Genentech, South San Francisco, CA; Carlos Barrios, Pontifícia Universidade Católica do Rio Grande do Sul School of Medicine, Porto Alegre, Brazil; Wolfgang Eiermann, Interdisciplinary Oncology Center, Munich, Germany; Masakazu Toi, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Young-Hyuck Im, Samsung Medical Centre, Seoul, Korea; Pierfranco Conte, University of Padova and Istituto Oncologico Veneto, Padova, Italy; Miguel Martin, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Tadeusz Pienkowski, Postgraduate Medical Education Center, Warsaw, Poland; Xavier Pivot, University Hospital Jean Minjoz, Besançon, France; Sven Stanzel, Alexander Strasak, Monika Patre, F. Hoffmann-La Roche, Basel, Switzerland; and Paul Ellis, Guys Hospital and Sarah Cannon Research Institute, London, United Kingdom.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Toi
authors.affiliation: Edith A. Perez, Mayo Clinic, Jacksonville, FL; Howard Burris III, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; Jennifer A. Petersen, Genentech, South San Francisco, CA; Carlos Barrios, Pontifícia Universidade Católica do Rio Grande do Sul School of Medicine, Porto Alegre, Brazil; Wolfgang Eiermann, Interdisciplinary Oncology Center, Munich, Germany; Masakazu Toi, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Young-Hyuck Im, Samsung Medical Centre, Seoul, Korea; Pierfranco Conte, University of Padova and Istituto Oncologico Veneto, Padova, Italy; Miguel Martin, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Tadeusz Pienkowski, Postgraduate Medical Education Center, Warsaw, Poland; Xavier Pivot, University Hospital Jean Minjoz, Besançon, France; Sven Stanzel, Alexander Strasak, Monika Patre, F. Hoffmann-La Roche, Basel, Switzerland; and Paul Ellis, Guys Hospital and Sarah Cannon Research Institute, London, United Kingdom.
authors.forename: Young-Hyuck
authors.initials: YH
authors.lastname: Im
authors.affiliation: Edith A. Perez, Mayo Clinic, Jacksonville, FL; Howard Burris III, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; Jennifer A. Petersen, Genentech, South San Francisco, CA; Carlos Barrios, Pontifícia Universidade Católica do Rio Grande do Sul School of Medicine, Porto Alegre, Brazil; Wolfgang Eiermann, Interdisciplinary Oncology Center, Munich, Germany; Masakazu Toi, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Young-Hyuck Im, Samsung Medical Centre, Seoul, Korea; Pierfranco Conte, University of Padova and Istituto Oncologico Veneto, Padova, Italy; Miguel Martin, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Tadeusz Pienkowski, Postgraduate Medical Education Center, Warsaw, Poland; Xavier Pivot, University Hospital Jean Minjoz, Besançon, France; Sven Stanzel, Alexander Strasak, Monika Patre, F. Hoffmann-La Roche, Basel, Switzerland; and Paul Ellis, Guys Hospital and Sarah Cannon Research Institute, London, United Kingdom.
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Conte
authors.affiliation: Edith A. Perez, Mayo Clinic, Jacksonville, FL; Howard Burris III, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; Jennifer A. Petersen, Genentech, South San Francisco, CA; Carlos Barrios, Pontifícia Universidade Católica do Rio Grande do Sul School of Medicine, Porto Alegre, Brazil; Wolfgang Eiermann, Interdisciplinary Oncology Center, Munich, Germany; Masakazu Toi, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Young-Hyuck Im, Samsung Medical Centre, Seoul, Korea; Pierfranco Conte, University of Padova and Istituto Oncologico Veneto, Padova, Italy; Miguel Martin, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Tadeusz Pienkowski, Postgraduate Medical Education Center, Warsaw, Poland; Xavier Pivot, University Hospital Jean Minjoz, Besançon, France; Sven Stanzel, Alexander Strasak, Monika Patre, F. Hoffmann-La Roche, Basel, Switzerland; and Paul Ellis, Guys Hospital and Sarah Cannon Research Institute, London, United Kingdom.
authors.forename: Miguel
authors.initials: M
authors.lastname: Martin
authors.affiliation: Edith A. Perez, Mayo Clinic, Jacksonville, FL; Howard Burris III, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; Jennifer A. Petersen, Genentech, South San Francisco, CA; Carlos Barrios, Pontifícia Universidade Católica do Rio Grande do Sul School of Medicine, Porto Alegre, Brazil; Wolfgang Eiermann, Interdisciplinary Oncology Center, Munich, Germany; Masakazu Toi, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Young-Hyuck Im, Samsung Medical Centre, Seoul, Korea; Pierfranco Conte, University of Padova and Istituto Oncologico Veneto, Padova, Italy; Miguel Martin, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Tadeusz Pienkowski, Postgraduate Medical Education Center, Warsaw, Poland; Xavier Pivot, University Hospital Jean Minjoz, Besançon, France; Sven Stanzel, Alexander Strasak, Monika Patre, F. Hoffmann-La Roche, Basel, Switzerland; and Paul Ellis, Guys Hospital and Sarah Cannon Research Institute, London, United Kingdom.
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Pienkowski
authors.affiliation: Edith A. Perez, Mayo Clinic, Jacksonville, FL; Howard Burris III, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; Jennifer A. Petersen, Genentech, South San Francisco, CA; Carlos Barrios, Pontifícia Universidade Católica do Rio Grande do Sul School of Medicine, Porto Alegre, Brazil; Wolfgang Eiermann, Interdisciplinary Oncology Center, Munich, Germany; Masakazu Toi, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Young-Hyuck Im, Samsung Medical Centre, Seoul, Korea; Pierfranco Conte, University of Padova and Istituto Oncologico Veneto, Padova, Italy; Miguel Martin, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Tadeusz Pienkowski, Postgraduate Medical Education Center, Warsaw, Poland; Xavier Pivot, University Hospital Jean Minjoz, Besançon, France; Sven Stanzel, Alexander Strasak, Monika Patre, F. Hoffmann-La Roche, Basel, Switzerland; and Paul Ellis, Guys Hospital and Sarah Cannon Research Institute, London, United Kingdom.
authors.forename: Xavier
authors.initials: X
authors.lastname: Pivot
authors.affiliation: Edith A. Perez, Mayo Clinic, Jacksonville, FL; Howard Burris III, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; Jennifer A. Petersen, Genentech, South San Francisco, CA; Carlos Barrios, Pontifícia Universidade Católica do Rio Grande do Sul School of Medicine, Porto Alegre, Brazil; Wolfgang Eiermann, Interdisciplinary Oncology Center, Munich, Germany; Masakazu Toi, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Young-Hyuck Im, Samsung Medical Centre, Seoul, Korea; Pierfranco Conte, University of Padova and Istituto Oncologico Veneto, Padova, Italy; Miguel Martin, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Tadeusz Pienkowski, Postgraduate Medical Education Center, Warsaw, Poland; Xavier Pivot, University Hospital Jean Minjoz, Besançon, France; Sven Stanzel, Alexander Strasak, Monika Patre, F. Hoffmann-La Roche, Basel, Switzerland; and Paul Ellis, Guys Hospital and Sarah Cannon Research Institute, London, United Kingdom.
authors.forename: Howard
authors.initials: H
authors.lastname: Burris
authors.affiliation: Edith A. Perez, Mayo Clinic, Jacksonville, FL; Howard Burris III, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; Jennifer A. Petersen, Genentech, South San Francisco, CA; Carlos Barrios, Pontifícia Universidade Católica do Rio Grande do Sul School of Medicine, Porto Alegre, Brazil; Wolfgang Eiermann, Interdisciplinary Oncology Center, Munich, Germany; Masakazu Toi, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Young-Hyuck Im, Samsung Medical Centre, Seoul, Korea; Pierfranco Conte, University of Padova and Istituto Oncologico Veneto, Padova, Italy; Miguel Martin, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Tadeusz Pienkowski, Postgraduate Medical Education Center, Warsaw, Poland; Xavier Pivot, University Hospital Jean Minjoz, Besançon, France; Sven Stanzel, Alexander Strasak, Monika Patre, F. Hoffmann-La Roche, Basel, Switzerland; and Paul Ellis, Guys Hospital and Sarah Cannon Research Institute, London, United Kingdom.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Petersen
authors.affiliation: Edith A. Perez, Mayo Clinic, Jacksonville, FL; Howard Burris III, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; Jennifer A. Petersen, Genentech, South San Francisco, CA; Carlos Barrios, Pontifícia Universidade Católica do Rio Grande do Sul School of Medicine, Porto Alegre, Brazil; Wolfgang Eiermann, Interdisciplinary Oncology Center, Munich, Germany; Masakazu Toi, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Young-Hyuck Im, Samsung Medical Centre, Seoul, Korea; Pierfranco Conte, University of Padova and Istituto Oncologico Veneto, Padova, Italy; Miguel Martin, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Tadeusz Pienkowski, Postgraduate Medical Education Center, Warsaw, Poland; Xavier Pivot, University Hospital Jean Minjoz, Besançon, France; Sven Stanzel, Alexander Strasak, Monika Patre, F. Hoffmann-La Roche, Basel, Switzerland; and Paul Ellis, Guys Hospital and Sarah Cannon Research Institute, London, United Kingdom.
authors.forename: Sven
authors.initials: S
authors.lastname: Stanzel
authors.affiliation: Edith A. Perez, Mayo Clinic, Jacksonville, FL; Howard Burris III, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; Jennifer A. Petersen, Genentech, South San Francisco, CA; Carlos Barrios, Pontifícia Universidade Católica do Rio Grande do Sul School of Medicine, Porto Alegre, Brazil; Wolfgang Eiermann, Interdisciplinary Oncology Center, Munich, Germany; Masakazu Toi, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Young-Hyuck Im, Samsung Medical Centre, Seoul, Korea; Pierfranco Conte, University of Padova and Istituto Oncologico Veneto, Padova, Italy; Miguel Martin, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Tadeusz Pienkowski, Postgraduate Medical Education Center, Warsaw, Poland; Xavier Pivot, University Hospital Jean Minjoz, Besançon, France; Sven Stanzel, Alexander Strasak, Monika Patre, F. Hoffmann-La Roche, Basel, Switzerland; and Paul Ellis, Guys Hospital and Sarah Cannon Research Institute, London, United Kingdom.
authors.forename: Alexander
authors.initials: A
authors.lastname: Strasak
authors.affiliation: Edith A. Perez, Mayo Clinic, Jacksonville, FL; Howard Burris III, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; Jennifer A. Petersen, Genentech, South San Francisco, CA; Carlos Barrios, Pontifícia Universidade Católica do Rio Grande do Sul School of Medicine, Porto Alegre, Brazil; Wolfgang Eiermann, Interdisciplinary Oncology Center, Munich, Germany; Masakazu Toi, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Young-Hyuck Im, Samsung Medical Centre, Seoul, Korea; Pierfranco Conte, University of Padova and Istituto Oncologico Veneto, Padova, Italy; Miguel Martin, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Tadeusz Pienkowski, Postgraduate Medical Education Center, Warsaw, Poland; Xavier Pivot, University Hospital Jean Minjoz, Besançon, France; Sven Stanzel, Alexander Strasak, Monika Patre, F. Hoffmann-La Roche, Basel, Switzerland; and Paul Ellis, Guys Hospital and Sarah Cannon Research Institute, London, United Kingdom.
authors.forename: Monika
authors.initials: M
authors.lastname: Patre
authors.affiliation: Edith A. Perez, Mayo Clinic, Jacksonville, FL; Howard Burris III, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; Jennifer A. Petersen, Genentech, South San Francisco, CA; Carlos Barrios, Pontifícia Universidade Católica do Rio Grande do Sul School of Medicine, Porto Alegre, Brazil; Wolfgang Eiermann, Interdisciplinary Oncology Center, Munich, Germany; Masakazu Toi, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Young-Hyuck Im, Samsung Medical Centre, Seoul, Korea; Pierfranco Conte, University of Padova and Istituto Oncologico Veneto, Padova, Italy; Miguel Martin, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Tadeusz Pienkowski, Postgraduate Medical Education Center, Warsaw, Poland; Xavier Pivot, University Hospital Jean Minjoz, Besançon, France; Sven Stanzel, Alexander Strasak, Monika Patre, F. Hoffmann-La Roche, Basel, Switzerland; and Paul Ellis, Guys Hospital and Sarah Cannon Research Institute, London, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Ellis
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy*; D001952:Bridged-Ring Compounds / Q000008:administration & dosage*; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D008453:Maytansine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008875:Middle Aged; D011788:Quality of Life; D011897:Random Allocation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D043823:Taxoids / Q000008:administration & dosage*; D000068878:Trastuzumab / Q000008:administration & dosage*
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D001952:Bridged-Ring Compounds; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; C080625:taxane; C508053:ERBB2 protein, human; C485206:pertuzumab