American Society of Clinical Oncology (ASCO) 2015
ASCO 2015 Abstract 507. Phase III, randomized study of trastuzumab emtansine (T-DM1) ± pertuzumab (P) vs trastuzumab + taxane (HT) for first-line treatment of HER2-positive MBC: Primary results from the MARIANNE study.
Paul Anthony Ellis, Carlos H. Barrios, Wolfgang Eiermann, Masakazu Toi, Young-Hyuck Im, Pier Franco Conte, Miguel Martin, Tadeusz Pienkowski, Xavier B. Pivot, Howard A. Burris, Alexander Strasak, Monika Patre, Edith A. Perez; Guy’s Hospital and Sarah Cannon Research Institute, London, United Kingdom; PUCRS School of Medicine, Porto Alegre, Brazil; Interdisciplinary Oncology Center, Munich, Germany; Graduate School of Medicine, Kyoto University, Kyoto, Japan; Samsung Medical Center, Seoul, South Korea; Department of Surgery, Oncology and Gastroenterology, University of Padova and Istituto Oncologico Veneto, Padova, Italy; Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense de Madrid, Madrid, Spain; Postgraduate Medical Education Center, Warsaw, Poland; University Hospital Jean Minjoz, Besançon, France; Sarah Cannon Research Institute, Tennessee Oncology, PLLC, Nashville, TN; F. Hoffmann-La Roche Ltd, Basel, Switzerland; F. Hoffmann-La Roche Ltd., Basel, Switzerland; Mayo Clinic, Jacksonville, FL
Background: In phase II and III studies, treatment with T-DM1 or with P + H + docetaxel has shown statistically significant increases in progression-free survival (PFS) and overall survival (OS) vs control regimens in patients with HER2-positive MBC. The combination of T-DM1 + P resulted in synergistic inhibition of tumor cell line proliferation in vitro. This and preliminary data from a phase II clinical trial provided the rationale for further study.
Methods: In MARIANNE (NCT01120184), patients with centrally assessed HER2-positive (IHC3+ or ISH+) progressive/recurrent locally advanced BC or previously untreated MBC with a ≥ 6-month interval since treatment in the (neo)adjuvant setting with taxanes or vinca alkaloids were randomized 1:1:1 to HT (docetaxel or paclitaxel + H), T-DM1 (T-DM1 + placebo, hereafter T-DM1), or T-DM1 + P, at standard doses. The primary end point was PFS assessed by independent review. Comparisons between HT and T-DM1 or T-DM1 + P were considered separately. PFS was tested first for non-inferiority and for superiority only if non-inferiority was achieved.
Results: At the clinical cutoff date, September 16, 2014, 365 patients had been randomized to HT, 367 to T-DM1, and 363 to T-DM1 + P. In each arm, approximately 31% of patients had prior (neo) adjuvant treatment with HER2-directed therapy. Approximately 37% overall had de novo disease. The study met the PFS non-inferiority end point, but not the superiority end point. OS was similar across treatment arms.
Conclusions: These data demonstrate non-inferiority in PFS between T-DM1–containing arms and control. T-DM1–containing regimens were associated with a different toxicity profile than the control regimen. Clinical trial information: NCT01120184
CARE Faculty Perspective:
- The MARIANNE study is one of the largest trials of anti-HER-2 therapies as 1st line treatment of HER2+ metastatic breast cancer (MBC).
- A significant limitation of the MARIANNE study design is the lack of a contemporary standard control arm. As the landscape of therapy changes, this can be a risk in the design of future trials while awaiting maturity of results from current fully enrolled trials. With the clinically significant results from the CLEOPATRA trial (of improved PFS and OS) for the combination of docetaxel, trastuzumab and pertuzumab as 1st line therapy, the lack of such an arm in MARIANNE could have impacted applicability of results.
- The MARIANNE study did not meet its primary end-point. The median follow up on the study was 35 months. The median PFS was 13.7 months, 14.1 months and 15.2 months for HT, T-DM1 and T-DM1+P respectively. Median OS was not reached in any of the arms yet.
- Adverse events leading to discontinuation of any treatment component was less in the T-DM1 arms (19% vs 29.7%). The toxicity profile was otherwise as expected within the treatment arms.
- The MARIANNE study does not change the current treatment algorithm of HER2+ MBC. Currently in medically fit patients, the standard of care should be docetaxel, pertuzumab and trastuzumab as 1st line therapy and then sequentially T-DM1 as 2nd line therapy.
- The results from MARIANNE however did alter the statistical plan and total accrual to the adjuvant T-DM1 + pertuzumab adjuvant trial (KAITLAN).
- Future trials investigating combinations of active agents in MBC should build in mandatory cross over to ensure upfront combination therapy is truly superior to sequential use for the endpoint of OS.
- CARE Oncology Faculty