Breast cancer remains the most frequently diagnosed cancer among women, though it also affects men. Triple-negative breast cancer (TNBC), which accounts for 10 to 15 percent of breast cancer cases, is one of the most aggressive subtypes and has limited treatment options. This form of cancer tends to occur more often in younger women, significantly impacting patients and their families.
On October 19, 2023, results from the international clinical trial “Ascent-03” were revealed, indicating that antibody-drug conjugates (ADCs) may establish a new standard for first-line treatment of metastatic TNBC. This trial was led by researchers from the International Breast Cancer Center (IBCC)-Pangaea Oncology in Barcelona and the IOB Institute of Oncology in Madrid.
ADCs function like a “Trojan horse,” targeting specific receptors on the surface of cancer cells while delivering a hidden payload of chemotherapy directly into those cells. Upon binding to the receptor, the ADC releases the chemotherapy, selectively destroying the tumor cell. According to Javier Cortés, the director of IBCC-Pangaea Oncology and the lead author of the study published in “The New England Journal of Medicine,” “This study demonstrates how Trojan horses are the best option for newly diagnosed metastatic TNBC, confirming that when these drugs are approved by regulatory agencies, they should be considered as a first choice for these patients.”
The phase III “Ascent-03” trial included 558 previously untreated patients with locally advanced, unresectable, or metastatic TNBC at the time of diagnosis. Patients were recruited from 229 centers across 30 countries. Notably, participants were ineligible for other treatments, such as PD-1 or PD-L1 inhibitors, due to the lack of overexpression of these proteins or biomarkers.
Patients were divided into two groups: one received the ADC sacituzumab govitecan, while the other was treated with conventional chemotherapy. The study”s primary endpoint, progression-free survival, was 9.7 months for those treated with sacituzumab govitecan compared to 6.9 months for the chemotherapy group. The objective response rate was 48 percent in the ADC group, with a response duration of 12.2 months, significantly longer than the 7.2 months observed in the chemotherapy group.
Dr. Cortés highlighted that they achieved a 38 percent improvement in disease control, noting, “We have enhanced the median time until disease progression by nearly three months. Furthermore, patients responding to this treatment will require it for a much longer duration—over a year compared to about seven months with chemotherapy.”
Regarding toxicity, 66 percent of patients receiving sacituzumab govitecan experienced adverse events, primarily neutropenia (43 percent), diarrhea (9 percent), and leukopenia (7 percent). In the chemotherapy group, adverse events occurred in 62 percent of patients, with neutropenia (41 percent), anemia (16 percent), and leukopenia (13 percent). Treatment discontinuation was lower in the sacituzumab govitecan group, at four percent, compared to 12 percent in the chemotherapy group.
A New Direction in Treatment
Dr. Cortés, who will present these findings at the European Society for Medical Oncology (ESMO) Congress, called this study the “definitive” confirmation that ADCs should be utilized as a first-line treatment for all types of metastatic breast tumors. He emphasized the need for continued research on the significance of these Trojan horses in other cancers and treatment lines.
The study”s conclusions mark a substantial advancement, offering patients diagnosed with metastatic TNBC a new treatment option that could improve their prognosis. Dr. Cortés explained that there are two groups of patients with TNBC: one where 35 to 40 percent express the PD-L1 protein, and another where they do not. “Now, we know both groups should be treated with Trojan horses. Moreover, for PD-L1 positive patients, we will add immunotherapy, combining it with the Trojan horse. In contrast, PD-L1 negative patients will receive the Trojan horse without immunotherapy,” he elaborated.
Additionally, he noted that these new results open avenues for researching combinations of ADCs with other drugs, particularly immunotherapy, in all types of triple-negative cancer, regardless of PD-L1 expression, as well as exploring combinations of different conjugates and the potential application in early-stage TNBC, aiming to cure more patients.
