July 2015, Special ASCO Edition

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T-DM1 Not Superior to Standard of Care in First-Line Metastatic Breast Cancer

Breast Cancer

The standard of care for previously untreated HER2-positive metastatic breast cancer remains taxane/trastuzumab/pertuzumab, according to results from the MARIANNE trial, which evaluated trastuzumab emtansine (T-DM1) in this setting. While T-DM1 was not inferior to trastuzumab/taxane (HT), it did not improve outcomes over the control arm and, therefore, does not merit a first treatment option, experts said.

“MARIANNE was a valiant trial,” said study discussant Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center, New York City, “but taxane, trastuzumab, and pertuzumab remains our first-line standard of care, with T-DM1 a preferred second-line option….Our treatment guidelines for 2015 remain unchanged.”

The long-awaited results from the phase 3 MARIANNE trial were presented by Paul Ellis, MD, of Guy’s Hospital and Sarah Cannon Research Institute, London, England, who reported, “T-DM1 and T-DM1 plus pertuzumab demonstrated a noninferior progression-free survival compared to HT, but they were not found to be superior to it.”

The international randomized MARI­ANNE trial enrolled 1095 previously untreated patients with locally advanced or metastatic HER2-positive breast cancer. It evaluated 3 arms: trastuzumab plus docetaxel or paclitaxel (physician’s choice) (HT); T-DM1 plus placebo; and T-DM1 plus pertuzumab. The primary end point was assessment of progression-free survival by independent review, with determinations of both noninferiority and superiority.

Median progression-free survival was 13.7 months with HT compared with 14.1 months with T-DM1 (hazard ratio [HR], 0.91; P = .31) and 15.2 months with T-DM1/pertuzumab (HR, 0.87; P = .14). The results satisfied the noninferiority boundary.

At this first interim analysis, median overall survival has not been reached in any arm, and the overall survival curves are essentially overlapping, Ellis noted.

Objective responses were 59.7% with T-DM1, 67.9% with HT, and 64.2% with T-DM1/pertuzumab. Although response rates were lower in the T-DM1 arms, patients who responded to this agent enjoyed a much longer duration of response: 20.7 months with T-DM1 and 21.2 months with T-DM1/pertuzumab, compared with 12.5 months with HT.

Health-related quality of life was also maintained longer in patients receiving T-DM1, who had a median time to a “clinically meaningful decrease from baseline” of about 8 to 9 months versus just 3.6 months with HT.

“This suggests that health-related quality of life was prolonged in patients treated with T-DM1,” Ellis suggested.

Patients treated with T-DM1 had fewer grade ?3 adverse events and fewer discontinuations because of adverse events. Pertuzumab did not contribute to toxicity, nor did it contribute to benefit—unlike what was observed in the landmark CLEOPATRA trial, where it improved overall survival. The role of pertuzumab in adjuvant breast cancer is being further explored in the phase 3 APHINITY trial.

Discussing the study, Modi predicted that, lacking any benefit in progression-free survival in MARIANNE, T-DM1 is unlikely to show a survival advantage in the early-stage setting (neoadjuvant or adjuvant), though several trials are under way in early breast cancer.

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