MARIANNE: A phase III, randomized study of trastuzumab-DM1 (T-DM1) with or without pertuzumab (P) compared with trastuzumab (H) plus taxane for first-line treatment of HER2-positive, progressive, or recurrent locally advanced or metastatic breast cancer (MBC).

Abstract

TPS102 Background: T-DM1 is a unique antibody-drug conjugate (ADC) composed of H, a stable thioether linker, and the highly potent cytotoxic agent DM1 (derivative of maytansine). In a randomized phase II trial, single-agent T-DM1 had comparable efficacy to H + docetaxel in the first-line treatment of HER2-positive locally advanced or MBC. P is the first HER2-directed dimerization inhibitor for the treatment of HER2-positive BC. T-DM1 and P bind to different epitopes on HER2, and have distinct mechanisms of action suggesting that the combination may result in more complete blockade of HER2. T-DM1 + P showed synergistic antitumor effects in preclinical models, and preliminary phase Ib/II trial results showed acceptable tolerability and promising efficacy in patients with MBC. Methods: MARIANNE BO22589 (trial registry #NCT01120184) is the first phase III study to evaluate the combination of a targeted antibody and an ADC for first-line MBC. This systemic chemotherapy-sparing combination has the potential to establish a new treatment paradigm by optimizing efficacy while minimizing toxicity. Patients are randomized 1:1:1 to each arm (T-DM1 arms are blinded for P; H + taxane arm is open-label): H + taxane (H 8 mg/kg loading dose, then 6 mg/kg + docetaxel 75 mg/m2 q3w, or H 4 mg/kg loading dose, then 2 mg/kg + paclitaxel 80 mg/m2 qw); T-DM1 (3.6 mg/kg) q3w + P (840 mg loading dose, then 420 mg) q3w; or T-DM1 + placebo. Key eligibility criteria include centrally-confirmed HER2-positive MBC and no history of cardiopulmonary dysfunction. The primary endpoint is progression-free survival by independent review facility. Secondary endpoints include safety, overall response rate, overall survival, duration of response and quality of life. Enrollment began in July 2010, and as of January 31, 2011, 141 patients have been recruited, well ahead of schedule. Target enrollment is 1092 patients across ~310 sites globally. The independent Data Monitoring Committee which assesses safety data has recently recommended continuation of the study without modification. Brisk completion of accrual and data analyses are eagerly awaited.