• Edith A Perez, Carlos Barrios, Wolfgang Eiermann, Masakazu Toi, Young-Hyuck Im, Pierfranco Conte, Miguel Martin, Tadeusz Pienkowski, Xavier Pivot, Howard Burris, Jennifer A Petersen, Sven Stanzel, Alexander Strasak, Monika Patre, and Paul Ellis.
• 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.
• J. Clin. Oncol. 2017 Jan 10; 35 (2): 141-148.

AbstractPurpose 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.

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