Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate composed of trastuzumab bound to the cytotoxic microtubule inhibitor emtansine (DM1, derivative of maytansine) by a stable linker. Trastuzumab targets the conjugate to HER2 receptors, and the linker releases the cytotoxic agent when the compound is internalized via receptor endocytosis. Trastuzumab emtansine has been found to be active in trastuzumab (Herceptin)- and lapatinib (Tykerb)-resistant disease, as well as in trastuzumab-naive tumors, and the conjugate appears to maintain the antitumor activity of trastuzumab.
Results of the international, open-label phase III EMILIA trial, recently reported by Velma and colleagues in The New England Journal of Medicine,1 indicate that trastuzumab emtansine improves survival compared with capecitabine (Xeloda)/lapatinib in patients with advanced HER2-positive breast cancer who had previously received trastuzumab.
In the EMILIA trial, 991 patients with advanced breast cancer who had previously been treated with trastuzumab and a taxane were randomly assigned to trastuzumab emtansine, 3.6 mg/kg IV every 21 days (n = 495), or oral lapatinib, 1,250 mg/d and oral capecitabine 1,000 mg/m2 twice daily on days 1 to 14 of each 21-day treatment cycle (n = 496). Patients had to have progressive disease during or after the most recent treatment for locally advanced or metastatic disease or within 6 months after treatment for early disease. Patients also had to have a left-ventricular ejection fraction ≥ 50% and ECOG performance status of 0 or 1 and could have measurable or nonmeasurable disease.
The trastuzumab emtansine and lapatinib/capecitabine groups were well matched for age (median 53 years in both; ranges, 25–84 and 24–83 years), race (white in 72% and 75%), ECOG performance status (0 in 60% and 63%), site of disease involvement (visceral in 67% and 68%), hormone receptor status (both estrogen receptor–negative and progesterone receptor–negative in 41% and 45%), and number of prior chemotherapy regimens for locally advanced or metastatic disease (> 1 in 39% of both groups). Prior therapy included an anthracycline in 61% of both groups and endocrine therapy in 41% of both groups; 3% of trastuzumab emtansine patients and 4% of lapatinib/capecitabine patients had received a biologic agent other than trastuzumab.
The trial was initially designed with progression-free survival on independent review as the primary endpoint, but the protocol was amended while data were still blinded to include overall survival as a coprimary endpoint and to increase enrollment to adequately power the study to detect an overall survival difference. The first interim analysis of overall survival occurred at the time of the primary progression-free survival analysis; a second interim overall survival analysis was performed when 50% of projected events for the final overall survival analysis had occurred. Median follow-up to the first data cutoff date was approximately 13 months; median follow-up to the second interim analysis of overall survival was approximately 19 months.
Median progression-free survival on independent review was 9.6 months in the trastuzumab emtansine group vs 6.4 months in the lapatinib/capecitabine group, yielding a significant 35% reduction in risk for progression or death with trastuzumab emtansine (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.55–0.77, P < .001). There was consistent benefit across most clinical subgroups, with a less definitive benefit in patients aged 75 years or older and in those with nonvisceral or nonmeasurable disease.
At the first interim analysis of overall survival, trastuzumab emtansine was associated with a 38% reduction in risk of death (HR = 0.62, 95% CI = 0.48–0.81, P = .0005), but the difference did not meet the criterion for significance according to the prespecified stopping boundary (P = .0003). At the second interim analysis, median overall survival was 30.9 months in the trastuzumab emtansine group vs 25.1 months in the lapatinib/capecitabine group, representing a significant 32% reduction in risk of death (HR = 0.68, 95% CI = 0.55–0.85, P < .001). Estimated survival rates were 85.2% in the trastuzumab emtansine group vs 78.4% in the lapatinib/capecitabine group at 1 year and 64.7% vs 51.8% at 2 years.
The objective response rate was higher in the trastuzumab emtansine group (43.6% vs 30.8%, P < .001), and the median duration of response was longer (12.6 vs 6.5 months).
Reduced Overall Toxicity
The most frequent adverse events of any grade in trastuzumab emtansine–treated patients were nausea (39.2% vs 44.7% with lapatinib/capecitabine), fatigue (35.1% vs 27.9%), thrombocytopenia (28.0% vs 2.5%), diarrhea (23.3% vs 79.7%), and elevated AST (22.4% vs 9.4%). The overall incidence of bleeding events was higher with trastuzumab emtansine (29.8% vs 15.8%, including grade 3 or 4 events in 1.4% vs 0.8%). In addition to diarrhea, palmar-plantar erythrodysesthesia was more common in the lapatinib/capecitabine group (58.0% vs 1.2%), as was hyperbilirubinemia (8.2% vs 1.2%).
Grade 3 or 4 adverse events were less common in the trastuzumab emtansine group (40.8% vs 57.0%), with the most frequent being thrombocytopenia (12.9% vs 0.2%) and elevated AST (4.3% vs 0.8%). Grade 3 or 4 adverse events that were more common in the lapatinib/capecitabine group included diarrhea (20.7% vs 1.6%) and palmar-plantar erythrodysesthesia (16.4% vs 0%).
Serious adverse events occurred in 15.5% of trastuzumab emtansine patients and in 18.0% of lapatinib/capecitabine patients. Dose reductions occurred more frequently in the lapatinib/capecitabine group (27.3% for lapatinib and 53.4% for capecitabine) than in the trastuzumab emtansine group (16.3%), as did discontinuation of treatment due to adverse events (7.6% for lapatinib and 9.4% for capecitabine compared with 5.9% for trastuzumab emtansine).
Left-ventricular ejection fraction ≥ 45% was maintained in 97.1% of the trastuzumab emtansine group and 93.0% of the lapatinib/capecitabine group; 1.7% and 1.6%, respectively, had left-ventricular ejection fraction < 50% and ≥ 15% below baseline value, and three patients in each group developed left-ventricular ejection fraction < 40%. One trastuzumab emtansine recipient developed grade 3 left-ventricular systolic dysfunction.
Four deaths in the lapatinib/capecitabine group (due to coronary artery disease, multiorgan failure, coma, and hydrocephalus) and one death in the trastuzumab emtansine group (due to metabolic encephalopathy after CNS progression) were attributed to adverse events occurring within 30 days of the last dose of study medication.
As concluded by the investigators, “The safety profile of T-DM1 and the improved progression-free and overall survival with this agent, as compared with standard HER2-directed therapy, provide clinical evidence that intracellular delivery of the cytotoxic agent specifically to HER2-overexpressing cells improves the therapeutic index by minimizing exposure to normal tissue.… [Our] study shows that T-DM1 has therapeutic potential, across a heterogeneous population of patients, for the treatment of advanced, HER2-positive breast cancer that has progressed during or after treatment with trastuzumab and a taxane.” ■
1. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med October 1, 2012 (early release online).