The restrictive therapeutic index of chemotherapy has led to the emergence of antibody-drug conjugates (ADCs), medicines that combine the specificity of monoclonal antibodies (mAbs) with the cytotoxic effects of chemotherapy to deliver cytotoxic payloads to cancer cells. This targeted approach can reduce the side effects of chemotherapy and improve the effectiveness of treatment. Several ADCs, including ado-trastuzumab emtansine (Kadcyla), sacituzumab govitecan-hziy (Trodelvy), and fam-trastuzumab deruxtecan-nxki (Enhertu), are currently approved for treating some types of breast cancer (BC).
The ADC trastuzumab emtansine was approved specifically for treating human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer (mBC) in patients who have previously been treated with trastuzumab and a taxane (paclitaxel or docetaxel) and who have already been treated for mBC or have developed tumor recurrence within 6 months of receiving adjuvant therapy. The US Food and Drug Administration (FDA) approval was based on the results of the EMILIA study, a phase 3 clinical trial that compared treatment with trastuzumab emtansine vs capecitabine + lapatinib in participants with HER2+, locally advanced, or metastatic BC. This trial emerged from the need for well-tolerated, HER2-directed therapies for patients with this type of cancer. Trastuzumab emtansine consists of trastuzumab, a mAb that targets HER2 (which is overexpressed in about 20% of BCs ), linked to emtansine, a cytotoxic payload that inhibits cell division. The trastuzumab emtansine group had a median overall survival (OS) of 29.9 months vs 25.9 months in the capecitabine + lapatinib group, for a hazard ratio (HR) of 0.75 (95% CI: 0.64, 0.88).
Another ADC, sacituzumab govitecan, targets the Trop-2 protein, which is overexpressed in BC . This ADC includes a mAb that is linked to SN-38, a cytotoxic payload that inhibits DNA replication. Triple-negative breast cancer (TNBC) is a subtype of BC that does not have receptors for estrogen, progesterone, or HER2—making it more difficult to treat than other forms of BC. Sacituzumab govitecan is used to treat patients with metastatic TNBC who have received at least 2 prior therapies for metastatic disease. Sacituzumab govitecan is also approved for the treatment of patients with unresectable locally advanced or metastatic hormone-receptor–positive (HR+ ), and HER2-negative (HER2−) BC who have received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting. Sacituzumab govitecan was the first Trop-2–directed ADC to demonstrate OS benefit in patients with HR+/HER2− mBC who had received prior endocrine-based therapy and at least 2 chemotherapies. It is now also recommended as a Category 1 preferred treatment for metastatic HR+/HER2− BC by the National Comprehensive Cancer Network.
The results of the TROPiCS-02 study , which led to the FDA approval of sacituzumab govitecan, demonstrated a median OS of 14.4 months with sacituzumab govitecan vs 11.2 months with treatment of physician’s choice (HR, 0.79; 95% CI: 0.65, 0.96; P = 0.02). This represents a 3.2-month improvement in survival and a 21% reduction in the risk for patient death. Before this medicine was approved, there were limited options to offer patients with BC after endocrine-based therapy and chemotherapy.