When a new therapy almost doubles the survival rate of current standard-of-care treatments, it’s time to pay attention! Many of us probably know one or more people with breast cancer, as it is the second leading cause of cancer for women in the United States. While the incidence of breast cancer in women is increasing by about 0.6% each year, several effective therapies in clinical use have contributed to the steady decline in breast cancer-related deaths since the 1990s. Despite these therapeutic advancements, triple-negative breast cancer (TNBC) remains a particularly challenging form of breast cancer to treat, and metastatic disease survival rates remain poor. To address the need for new therapies for metastatic TNBC (mTNBC), a new class of antibody-drug conjugates were tested. Sacituzumab govitecan (SG) therapy was designed to interact with a common membrane protein on mTNBC cells and deliver a payload of chemotherapy to those specific cells. Two publications, one in 2021 and a second in 2024 in the Journal of Clinical Oncology demonstrate the efficacy and safety of a Phase III clinical trial on SG treatment of mTNBC. The trial data showed an overall survival rate of ~7 months with various chemotherapies and almost 12 months for those treated with the new SG therapy. “This is the first study to show that compared to standard single-agent chemotherapy, an antibody-drug conjugate improves outcomes, including overall survival, for patients with metastatic triple-negative breast cancer,” shared Dr. Sara Hurvitz, a senior author on these publications and current Director of the Clinical Research Division at Fred Hutchinson Cancer Center.
The antibody-drug conjugate (ADC) SG therapy is thought to function by first interacting with the trophoblast cell surface antigen 2 (Trop2), which is expressed in more than 80% of all TNBCs. This Trop-2 “homing beacon” helps the antibody portion—that’s the sacituzumab part—of the drug to recognize the location of target cancer cells. The second function of SG therapy is to release the cytotoxic or cell-killing drug—as you probably guessed already, that’s the govitecan—to these tumor sites. This new SG therapy was evaluated for safety in humans and efficacy against mTNBC in a Phase III clinical trial that included 529 total mTNBC patients; 262 patients received the treatment of physician’s choice (TPC), and 267 were given SG therapy. Following the completion of the clinical trial the median months of progression-free survival (PFS) and overall survival (OS) were calculated. These findings highlight a striking improvement from 1.7 to 4.8 months for PFS and 6.9 to 11.8 months for OS with the new SG therapy compared to TPC. These findings that SG therapy almost doubles survival for mTNBC patients compared to other chemotherapies did not go unnoticed and was promptly approved for immediate use in the U.S. and other countries.
To determine if the SG therapy is more effective for mTNBC cancer cells that express abundant Trop2 homing factor, additional comparisons between various chemotherapy regimens and SG therapy were made for patients separated based on Trop2 protein abundance. “Surprisingly, although this ADC [SG chemotherapy] targets Trop2, its benefit compared to standard chemotherapy was notable regardless of the level of expression of Trop2,” commented Dr. Hurvitz. This was an important observation and suggests that “testing for Trop2 expression is not necessary when selecting patients for this therapy.”
However, “these results lead one to wonder why an ADC, which is targeted against a tumor antigen, is working better than chemotherapy even in tumors with low to moderate levels of expression,” continued Dr. Hurvitz. She explained one possibility, “This likely relates to the potency of the chemo payload and to the fact that the hydrolysable linker does not require the ADC to be taken up within the Trop2 expressing cancer cell to release the chemotherapy payload. Thus, a tumor with heterogeneous expression of Trop2 exposed to the ADC may have enough expression to home the ADC into the region of the tumor, allowing release of the payload, and leading to killing of tumor cells with variable Trop2 expression levels (a so-called bystander effect).” Therefore, a little Trop2 protein on cancer cells can go a long way by recruiting the SG therapy bombs to general tumor areas for regional cell killing with the release of the cytotoxic therapy. To support the continued generation of new therapies for mTNBC and identify potential challenges of ADCs, ongoing work by Dr. Patrick Paddison, a Professor in Human Biology, and Dr. Darien Reed Perino, a Physician and Research Associate in the Clinical Research Division at Fred Hutchinson Cancer Center, aim to evaluate the mechanisms of response and resistance to Trop2 directed ADCs.
This Phase III clinical trial confirms the safety and efficacy of SG for mTNBC, and its rapid implementation will benefit many patients irrespective of Trop2 protein abundance on cancer cells. This antibody-drug conjugate is the first to be used in treating mTNBC and its success in doubling progression-free survival and overall survival may increase the study of other ADCs to treat mTNBC.
The spotlighted research was funded by Gilead Sciences, Inc.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium member Dr. Sara Hurvitz contributed to this work.
Bardia A, Rugo HS, Tolaney SM, Loirat D, Punie K, Oliveira M, Brufsky A, Kalinsky K, Cortés J, Shaughnessy JO, Diéras V, Carey LA, Gianni L, Piccart-Gebhart M, Loibl S, Yoon OK, Pan Y, Hofsess S, Phan SC, Hurvitz SA. 2024. Final Results From the Randomized Phase III ASCENT Clinical Trial in Metastatic Triple-Negative Breast Cancer and Association of Outcomes by Human Epidermal Growth Factor Receptor 2 and Trophoblast Cell Surface Antigen 2 Expression. J Clin Oncol. 29:JCO2301409.
