Management of Metastatic Breast Cancer with Second-Generation Antibody–Drug Conjugates: Focus on Glembatumumab Vedotin (CDX-011, CR011-vcMMAE)

Exploiting the highly targeted nature of monoclonal antibodies to deliver selectively to tumor cells a cytotoxic payload is an attractive concept and the successful precedents of the recent past set the stage for broader applications in the future. Antibody–drug conjugates may currently hold an unprecedented potential; however, there are multiple unique challenges in their development, and the recent successes have come hand in hand with significant technologic advances in their chemistry and manufacturing. Over the years, multiple factors have been identified to affect the pharmacokinetic and pharmacodynamic properties of an antibody–drug conjugate, but many important details remain to be further investigated. These factors pertain to the target antigen, antibody, conjugate, linker, as well as the nature of the malignancy under treatment. Glembatumumab vedotin is an antibody–drug conjugate targeting glycoprotein non-metastatic B (GPNMB) expressed in multiple malignancies, including breast cancer. The expression of this protein has been associated with an aggressive malignant phenotype, invasive growth, angiogenesis, and generation of skeletal metastases. Glembatumumab vedotin is currently in early stages of clinical development in melanoma and breast cancer. Although in unselected patients with metastatic breast cancer glembatumumab vedotin was not superior to other agents, by virtue of its target being frequently and highly expressed in triple-negative breast cancer, its activity was particularly promising in this subset of patients. Results from the clinical studies in breast cancer as well as companion studies in melanoma indicate that a biomarker-informed approach is the optimal pathway for the future development of this drug.