Integrated Safety Analysis Shows Favorable Safety Profile of Single-Agent Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer
The antibody-drug conjugate ado-trastuzumab emtansine (Kadcyla) is currently indicated in the United States for treatment of patients with HER2-positive metastatic breast cancer who previously received trastuzumab (Herceptin) and a taxane and who have either received prior therapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy. As presented in the Journal of Clinical Oncology, Diéras et al have performed an integrated safety analysis of the use of single-agent ado-trastuzumab emtansine in patients with HER2-positive metastatic breast cancer.
The analysis included a total of 884 patients in six studies who received ado-trastuzumab emtansine 3.6 mg/kg every 3 weeks and included follow-up data from patients in an extension study. Patients received a median of 10 doses and had a median treatment duration of 6.3 months, with 28% having treatment for >1 year.
Averse Event Profile
The most common adverse events of any grade were fatigue (46%), nausea (43%), thrombocytopenia (32%), headache (29%), constipation (27%), and epistaxis (25%). The most common grade 3 or 4 adverse events were thrombocytopenia (11.9%, 2.4% grade 4), increased AST (4.3%), hypokalemia (3.3%), fatigue (3.3%), and increased ALT (3.1%). Peripheral neuropathy (including all relevant preferred terms) of any grade occurred in 29% of patients. Serious adverse events occurred in 19.8% of patients. Adverse events resulted in dose reduction in 17.2% of patients and to treatment discontinuation in 7.0%.
Adverse events on study or within 30 days of the last ado-trastuzumab emtansine dose led to death in 12 patients (1.4%). Of these events, seven were suspected to be related to ado-trastuzumab emtansine treatment, including hepatic failure, hepatic failure and encephalopathy (in one patient), hepatic function abnormal, bacterial sepsis, neutropenic sepsis, and metabolic encephalopathy.
Adverse Events of Special Interest
Among patients with grade 3 or 4 thrombocytopenia, 44% experienced grade 1 bleeding (primarily epistaxis), 4% grade 2 bleeding (primarily epistaxis), and 5% grade 3 to 4 bleeding. Four patients (0.5%) had a postbaseline left-ventricular ejection fraction < 40% and 1.8% had an left-ventricular ejection fraction decline of ≥ 15 percentage points to < 50%. Four patients (0.5%) discontinued ado-trastuzumab emtansine due to cardiac disorders (atrial fibrillation, left ventricular dysfunction, decreased ejection fraction in two). Pneumonitis-related adverse events occurred in 1.1% of patients (grade 3, 4, and 5 in one patient each). Infusion-related reactions and hypersensitivity (1.4%) occurred in 6.9% of patients. Eye disorders occurred in 9% of patients (87% grade 1).
The incidence of grade ≥ 3 adverse events was higher in patients aged ≥ 65 years vs < 65 years (52% vs 44%) and in Asian vs white patients (64% vs 42%), with the higher incidence in Asian patients largely reflecting a higher incidence of grade ≥ 3 thrombocytopenia (44% vs 11%).
The investigators concluded, “In this analysis of 884 [ado-trastuzumab emtansine]–exposed patients, grade 3 or greater [adverse events] were infrequent and typically asymptomatic and manageable. This favorable safety profile makes [ado-trastuzumab emtansine] treatment suitable for exploration in other breast cancer settings.”
Véronique Diéras, MD, of the Institut Curie Paris, is the corresponding author for the Journal of Clinical Oncology article.
The data reported in the Journal of Clinical Oncology article are from studies sponsored by Genentech and F. Hoffmann-La Roche. For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
