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The MARIANNE trial is the first Phase III study to assess the efficacy of T-DM1 in the first-line setting.38 This trial randomized 1,095 patients with metastatic HER2-positive breast cancer to treatment with trastuzumab and a taxane (HT), T-DM1 plus placebo, or T-DM1 plus pertuzumab. The primary objective of the trial was PFS, SERCA noninferiority, and superiority, assessed by an independent review. Secondary end points were OS, ORR and patient safety, tolerability, and patient-reported outcome. The characteristics of patients were well balanced between the groups. A total of 44�C45 patients per arm did not receive any prior therapy. The median PFS was 13.7 months with HT, 14.1 months with T-DM1, and 15.2 months with T-DM1 and pertuzumab. Both T-DM1-containing arms demonstrated noninferior PFS to that of the control arm. However, treatment with T-DM1 alone or combined with pertuzumab was not superior to HT. There was no difference in OS or response rate; however, patients responding to T-DM1 had Luminespib in vitro a longer duration of response than those responding to HT. There were fewer high-grade adverse events in patients treated with T-DM1 versus HT. Neutropenia and diarrhea were more common in patients treated with HT, and thrombocytopenia was more common in patients treated with T-DM1. It is difficult to put in context the results of MARIANNE for the first-line treatment of HER2-positive metastatic breast cancer when one considers the outstanding results from the CLEOPATRA trial, which recently established the combination of trastuzumab, pertuzumab, and docetaxel as the first-line treatment in this setting. In the CLEOPATRA trial, at an updated median follow-up of 50 months, the median OS was improved from 40.8 months with trastuzumab and docetaxel to 56.5 months when pertuzumab was added (HR 0.68, Pselleck kinase inhibitor containing trastuzumab, pertuzumab, and a taxane, which would have helped in further defining the role of T-DM1 in the first-line setting. The clinical impact of MARIANNE resides in the lack of benefit of adding pertuzumab to T-DM1 or T-DM1 alone compared to the historical standard of a taxane and trastuzumab. The equivalent results between the T-DM1 arms show no additional benefit with the addition of pertuzumab, demonstrating that the differential biological action of dual HER2 blockade depends largely on the partner drug. These results reject the simplistic idea that T-DM1 is a taxane combined with trastuzumab and teach us about the complexity of the HER2 activation pathway. Given the lack of benefit seen with the addition of pertuzumab to T-DM1, it is unlikely that a future clinical trial would compare this combination with the CLEOPATRA regimen, leaving T-DM1 solely as an indication in the second-line setting and beyond.