Κυριακή, 27 Νοεμβρίου 2016

T-DM1 NOT INFERIOR TO HERCEPTIN-TAXANE COMBINATION

In the phase III MARIANNE trial reported in the Journal of Clinical Oncology, Perez et al found that ado-trastuzumab emtansine (formerly known as T-DM1; Kadcyla) was associated with noninferior progression-free survival compared with trastuzumab (Herceptin) plus taxane in patients with HER2-positive advanced breast cancer who had received no prior therapy for advanced disease. Tolerability was improved with ado-trastuzumab emtansine.
Study Details
In the trial, 1,095 patients from 241 sites in 38 countries were randomized 1:1:1 between July 2010 and May 2012 to receive trastuzumab plus taxane (n = 365), ado-trastuzumab emtansine (n = 367), or ado-trastuzumab emtansine plus pertuzumab (Perjeta; n = 363). In the trastuzumab/taxane control group, 257 patients received docetaxel and 96 received paclitaxel. Stratification factors were world region, prior neoadjuvant or adjuvant therapy, and visceral disease.
The primary endpoint was progression-free survival on independent review. The study was open label with regard to control group vs ado-trastuzumab emtansine–containing groups and blinded with regard to pertuzumab vs placebo in the ado-trastuzumab emtansine groups.
Progression-Free Survival Outcomes
Median follow-up was approximately 35 months in all 3 groups. Median progression-free survival was 13.7 months in the control group vs 14.1 months in the ado-trastuzumab emtansine group (stratified hazard ratio [HR] = 0.91, P = .31, vs control) and 15.2 months in the ado-trastuzumab emtansine plus pertuzumab group (stratified HR = 0.87, P = .14, vs control). Both experimental treatments met the noninferiority criterion. No significant improvement was observed with ado-trastuzumab emtansine plus pertuzumab vs ado-trastuzumab emtansine (stratified HR = 0.91, 97.5% confidence interval [CI] = 0.73–1.13).
Response rates were 67.9% in the control group, 59.7% with ado-trastuzumab emtansine, and 64.2% with ado-trastuzumab emtansine plus pertuzumab. Median response durations were 12.5, 20.7, and 21.2 months, respectively. In the first interim overall survival analysis, median overall survival had not been reached in any treatment group.
Adverse Events
Grade ≥ 3 adverse events occurred in 54.1% of the control group, 45.4% of the ado-trastuzumab emtansine group, and 46.2% of the ado-trastuzumab emtansine plus pertuzumab group; the most commonly reported adverse events were neutropenia (19.8%), febrile neutropenia (6.5%), and diarrhea (4.2%) in the control group, increased aspartate transaminase (6.6%), thrombocytopenia (6.4%), and anemia (4.7%) in the ado-trastuzumab emtansine group, and thrombocytopenia (7.9%), anemia (6.0%), and increased alanine transaminase (5.2%) in the ado-trastuzumab emtansine plus pertuzumab group. Left-ventricular ejection fraction of < 50% with a ≥ 15 percentage point decrease from baseline was observed in 4.5% of the control group, 0.8% in the ado-trastuzumab emtansine group, and 2.5% of the ado-trastuzumab emtansine plus pertuzumab group. Adverse events led to treatment discontinuation in 29.7%, 18.3%, and 19.1% of patients, respectively.
Median time to a clinically meaningful decrease in health-related quality of life (on Functional Assessment of Cancer Therapy–Breast assessment) from baseline was 3.6 months in the control group, 7.7 months with ado-trastuzumab emtansine, and 9.0 months with ado-trastuzumab emtansine plus pertuzumab.
The investigators concluded: “[Ado-trastuzumab emtansine] 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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