Ado-trastuzumab emtansine for the treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer.

PURPOSE: An update on completed and ongoing clinical trials of ado-trastuzumab emtansine for the treatment of metastatic breast cancer (MBC) is presented. SUMMARY: Ado-trastuzumab emtansine (Kadcyla, Genentech), the first U.S.-approved antibody-drug conjugate for MBC, is indicated for use as a single-agent therapy in patients with human epidermal growth factor receptor 2 (HER2)-positive MBC who have received prior treatment with unconjugated trastuzumab and a taxane-based regimen. The standard dosage of ado-trastuzumab is 3.6 mg/kg i.v. every three weeks. In completed Phase II or III clinical trials, ado-trastuzumab was found to confer significant survival and quality-of-life benefits. The largest of those trials (the EMILIA study, n = 991) showed that ado-trastuzumab was superior to a regimen of lapatinib plus capecitabine in terms of progression-free survival (9.6 months versus 6.4 months, p < 0.001) and overall survival (30.9 months versus 25.1 months, p < 0.001); it also had a more favorable tolerability profile, with lower rates of treatment-limiting adverse effects. The most common adverse effects of ado-trastuzumab are thrombocytopenia (reported in about 12% of clinical trial participants overall) and increased transaminase levels. Two ongoing Phase III trials-the TH3RESA study (slated for completion in June 2015) and the MARIANNE study (estimated completion in 2016)-may help determine the optimal role of ado-trastuzumab relative to other HER2-targeted agents and its potential use as a front-line therapy for both heavily pretreated and treatment-naive patients with MBC. CONCLUSION: With a novel targeted mechanism of action, ado-trastuzumab is an effective treatment option for HER2-positive MBC in previously treated patient populations.

The role of denosumab for prevention of skeletal-related complications in multiple myeloma.

OBJECTIVE: To evaluate the use of denosumab for the prevention of skeletal-related events (SREs) in patients with osteolytic lesions associated with multiple myeloma (MM). DATA SOURCES: MEDLINE/Ovid (1946-April week 3, 2013), EMBASE (1980-2013 week 16), abstracts of the American Society of Clinical Oncology (1983-April 22, 2013), American Society of Hematology (2004-April 22, 2013), European Hematology Association (1994-April 22, 2013), and the European Society for Medical Oncology (1990-April 22, 2013) were searched using the terms denosumab and multiple myeloma. STUDY SELECTION AND DATA EXTRACTION: Clinical trials comparing the efficacy of denosumab with that of bisphosphonates in preventing or delaying SREs in patients with MM were included. Trials solely evaluating bone turnover markers were excluded. One Phase 2 trial, 1 Phase 3 trial, and 1 post hoc Phase 3 analysis were included. DATA SYNTHESIS: A Phase 2 trial compared denosumab to bisphosphonate continuation in patients with elevated urinary N-telopeptide levels (uNTX) despite bisphosphonate therapy. Denosumab patients experienced fewer SREs; however, this was not statistically significant. A Phase 3 trial compared denosumab to zoledronic acid in patients with at least 1 osteolytic lesion. Denosumab delayed the time to a first SRE by 16% (median 20.6 vs 16.3 months; p = 0.0007 for noninferiority). Superiority of denosumab was not reached. A post hoc analysis revealed less favorable survival in MM patients treated with denosumab (HR 2.26; 95% CI 1.13-4.50). The incidence of overall adverse effects was similar between each group in both studies. CONCLUSIONS: Denosumab may be an alternative for the prevention of SREs in patients with MM with deteriorating renal function. Because of the high cost of the drug, low percentage of MM patients in the available studies, and the potential for their decreased survival, use of denosumab should be limited.