Antibody-drug Conjugates Poised To Have Major Impact On Breast Cancer Treatment
$30 billion market predicted within five years.
Antibody-drug conjugates (ADCs) are rapidly becoming one of the more important therapeutics in targeted cancer treatment. Increasingly, biopharmaceutical companies are focusing their research on targeted therapeutics with ADCs an important part of their research efforts. ADCs represent a unique therapeutic application that combines the properties of monoclonal antibodies and the potent cell-killing activity of cytotoxic drugs. ADCs are linked via a chemical linker to a biologically active or cytotoxic drug. The monoclonal antibodies that have been developed are highly specific and may have antitumor activity as well. This cytotoxic effect of monoclonal antibodies is in many instances insufficient to completely eradicate a tumor. However, the efficacy and specificity of the drug are dramatically increased when a potent highly cytotoxic, small-molecule drug is attached to this monoclonal antibody. Since these ADCs can deliver highly cytotoxic payloads directly to tumor cells they can achieve high lethality toward targeted tumor cells, leaving healthy cells unharmed.
ADCs exert their activity by (1) selective binding of the antibody to the tumor, (2) internalization, and (3) release of the cytotoxic payload leading to cytotoxic cell death. ADCs deliver a “deactivated” cytotoxin to specific cancer cells. Once attached to the tumor cell internalization takes place. The drug enters the lysosomes (sac-like compartment inside a cell that has enzymes that can break down cellular components that need to be destroyed). The lysosomes are then degraded after which the cytotoxin is released having gained its full cancer-killing potential. Therefore, the unique property of ADCs is that they act as “armed antibodies” that dispatch highly potent anticancer chemotherapy directly to cancer cells while at the same time, leaving healthy tissues unaffected.
One of the earliest and most used ADCs is called Ado-trastuzumab emtansine also known as T-DM1 (Kadcyla®). This drug combines the anti-HER2 antibody, trastuzumab (Herceptin) linked to the anti-mitotic agent mertansine. The use of this drug has two strategies. First the anti-HER2 activity of trastuzumab and the targeted intracellular delivery of mertansine. Mertansine interferes with mitosis and promotes apoptosis (programmed cell death). It is currently used in patients with advanced breast cancer who have failed first-line therapy.
Sacituzumab Govitecan in metastatic triple-negative breast cancer
The results of the phase 3 “ASCENT” trial were published in a recent issue of the New England Journal of Medicine by Bardia et al. The ADC used in this study was sacituzumab govitecan (SG) (Trodelvy®) with Sacituzumab being the monoclonal antibody and Govitecan, the cytotoxic agent. The monoclonal antibody targets a gene called Trop-2, which is expressed in multiple tumor types including breast cancer. This was a randomized trial comparing SG with chemotherapy of the physician’s choice. Patients in the study had to have triple-negative breast cancer and failed two or more previous standard chemotherapy regimens for unresectable locally advanced or metastatic disease. Previous treatments had to include a taxane. A total of 529 patients were enrolled in the two years beginning November 2017 at 88 sites in seven countries. 235 patients were assigned to receive SG and 233 patients received standard chemotherapy. The median progression-free survival for patients taking SG was 5.6 months compared to 1.7 months for those in the chemotherapy arm. The median overall survival was 12.1 months for those patients taking SG versus 6.7 months for those taking chemotherapy. The percentage of patients with an objective response to SG was 35% versus 5% with chemotherapy. The most common adverse treatment-related adverse events of any grade were neutropenia (63% with SG and 43% with chemotherapy) and diarrhea (59% for SG and 12% for chemotherapy).
Conclusion
“Sacituzumab govitecan is a first-in-class, Trop-2–directed antibody–drug conjugate; it showed a significant benefit with respect to progression-free and overall survival as compared with standard-of-care chemotherapy.”
Dr. Alan Stolier, MD, FACS, clinical breast oncologist, shares his expert medical perspective with a series of educational and scientific articles.
