Antibody-Drug Conjugates (ADCs) for Breast Cancer: 5 Things to Know

Kate M. O'Rourke

Disclosures

November 11, 2022

Antibody-drug conjugates (ADCs), a class of potent biopharmaceutical agents that target specific cancer cells, are associated with an improved therapeutic index. The three ADCs currently approved as immunotherapy for breast cancer are trastuzumab emtansine, trastuzumab deruxtecan, and sacituzumab govitecan.

Here are five things to know about the role that these ADCs play in treating breast cancer.

1. Trastuzumab emtansine (T-DM1), approved in 2013, was the first ADC approved for HER2-positive breast cancer.

T-DM1 has several mechanisms of action, including the anti-tumor effects of trastuzumab and those of emtansine, a cytotoxic antimicrotubular agent released within the target cells upon degradation of the human epidermal growth factor receptor 2 (HER2)–T-DM1 complex in lysosomes. The cytotoxic effects of T-DM1 probably vary from patient to patient, depending on intracellular concentrations of the drug in cancer cells: High intracellular accumulation of DM1 results in rapid apoptosis and somewhat lower levels in impaired cellular trafficking and mitotic catastrophe, whereas the lowest concentrations of T-DM1 levels are associated with poor therapeutic response.

Although primary resistance to T-DM1 in HER2-positive metastatic breast cancer (MBC) seems to be infrequent, most patients will develop acquired drug resistance. Although the manner in which resistance develops is not completely understood, it may be due to the limited binding of trastuzumab to cancer cells. Impairment of T-DM1's cytotoxic effects may result from inefficient internalization or greater recycling of HER2–T-DM1 complex, or reduced lysosomal degradation of trastuzumab or intracellular trafficking of HER2. In addition, multidrug resistance proteins that pump emtansine out of cancer cells may compromise the effects of T-DM1. 

2. A second ADC, trastuzumab deruxtecan (T-DXd), was approved in 2020 for HER2-low MBC.

DESTINY-Breast03, a phase 3, multicenter, open-label, randomized trial, compared the efficacy and safety of trastuzumab deruxtecan (T-DXd) vs T-DM1 in patients with HER2-positive MBC previously treated with trastuzumab and a taxane. Among the 524 patients enrolled in the trial who were alive at 12 months, 75.8% of patients receiving T-DXd had no disease progression at 12 months, compared with 34.1% of those receiving T-DM1 (hazard ratio [HR] for progression or death from any cause, 0.28; P < .001). Regarding survival, 94.1% of patients in the T-DXd group and 85.9% of patients in the T-DM1 group were alive at 12 months (HR for death, 0.55; prespecified significance boundary not reached). There was a complete or partial response in 79.7% of the patients who received T-DXd and in 34.2% who received T-DM1. The incidence of treatment-related adverse events (any grade) was 98.1% in the T-DXd group and 86.6% in the T-DM1 group; the incidence of drug-related adverse events (grade 3 or 4) was 45.1% and 39.8%, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis grade < 4) occurred in 10.5% of patients receiving T-DXd and in 1.9% of those receiving T-DM1.

3. Results from the DESTINY-Breast04 trial established T-DXd as the new standard of care for patients with HER2-low MBC.

On the basis of findings from the DESTINY-Breast04 randomized phase 3 trial, presented at the 2022 American Society of Clinical Oncology (ASCO) annual meeting, T-DXd is the new standard of care for patients with HER2-low MBC. In the trial, which had 557 patients, T-DXd improved median progression-free survival (PFS) by 4.8 months and median overall survival (OS) by 6.6 months compared with standard single-agent chemotherapy in a heavily pretreated population. Patients in DESTINY-Breast04 had one to two prior lines of chemotherapy for metastatic disease, and those with endocrine receptor–positive disease were refractory to endocrine therapy. On the basis of 18.4 months of median follow-up, there was a 50% reduction in the risk for disease progression or death in the T-DXd group (PFS, 9.9 months vs 5.1 months; HR, 0.50; P < .0001), and a 36% reduction in the risk for death (median OS, 23.4 vs 16.8 months; HR, 0.64; P = .0010). The researchers of DESTINY-Breast04 noted, "After T-DXd binds to HER2 and becomes internalized, the membrane-permeable topoisomerase I inhibitor payload is liberated from the monoclonal antibody, which then kills the targeted tumor cells and neighboring tumor cells by causing catastrophic DNA damage."

With respect to treatment-emergent adverse events (grade ≥ 3), the overall safety profile was similar between the T-DXd and chemotherapy groups. Patients in the T-DXd group had more left ventricular dysfunction (4.6% vs 0.0%) and more interstitial lung disease or pneumonitis (12.1% vs 0.6%) than did patients in the chemotherapy group. Three patients treated with T-DXd died of interstitial lung disease or pneumonitis. 

4. Phase 3 of the TROPiC-02 trial evaluated sacituzumab govitecan for triple-negative MBC.

Sacituzumab govitecan is an ADC that targets the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers. It is coupled to SN-38 (a topoisomerase I inhibitor) through a proprietary hydrolysable linker. According to the phase 3 TROPiCS-02 study presented at the 2022 ASCO meeting, sacituzumab govitecan demonstrated significantly improved PFS over chemotherapy (physician's choice) in patients with hormone receptor–positive, HER2-negative MBC previously treated with endocrine therapy, a CDK4/6 inhibitor, and a median of three lines of chemotherapy. There were 543 patients enrolled in the trial. The median PFS was 5.5 months with sacituzumab govitecan and 4.0 months with chemotherapy of physician's choice (HR, 0.66; P = .0003). Key adverse events with sacituzumab govitecan included neutropenia, diarrhea, and nausea. In the study, treatment-related adverse events (grade ≥ 3) with sacituzumab govitecan and chemotherapy were neutropenia (51% vs 38%) and diarrhea (9% vs 1%).

5. The ASCENT trial found significantly longer PFS and OS with sacituzumab govitecan than single-agent chemotherapy in triple-negative MBC.

The ASCENT phase 3 trial compared sacituzumab govitecan vs single-agent chemotherapy in 468 patients (median age, 54 years) with triple-negative breast cancer without brain metastases. Patients were randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients). All of the patients had been previously treated with taxanes. The median PFS was 5.6 months in the sacituzumab govitecan group and 1.7 months in the chemotherapy group (HR for disease progression or death, 0.41; P < .001). The median OS was 12.1 months in patients receiving sacituzumab govitecan and 6.7 months in patients receiving chemotherapy (HR for death, 0.48; P < .001). An objective response was observed in 35% of patients receiving sacituzumab govitecan compared with 5% of patients receiving chemotherapy. The following adverse events (grade ≥ 3) were observed in the sacituzumab govitecan vs chemotherapy groups, respectively: neutropenia (51% vs 33%), leukopenia (10% vs 5%), diarrhea (10% vs < 1%), anemia (8% vs 5%), and febrile neutropenia (6% vs 2%). There were three deaths associated with adverse events in each group; none of the deaths were considered to be associated with sacituzumab govitecan.

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