Antibody-drug conjugates (ADCs), a class of potent biopharmaceutical agents that target specific cancer cells, are associated with relevant antitumor activity across breast cancer subtypes. Medscape recently spoke with experts in metastatic breast cancer (MBC) — Avan J. Armaghani, MD; Aditya Bardia, MD, MPH; and Paolo Tarantino, MD — about sequencing ADCs for patients with MBC. Read on for their insights.
What sequencing strategies do you follow at each step of therapy for patients with MBC?
Armaghani: Sequencing ADCs in patients with MBC requires consideration of many factors unique to the patient, including the presence or absence of brain metastasis, number of prior lines of therapy received, performance status of the patient and other comorbidities, and dosing schedule of the drug. These factors will determine not only how to sequence ADCs but also which to use. For example, in patients with HR+, HER2-low MBC with overall good performance status, trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan are two therapies that can be considered. In a patient with overall good performance status, I would first recommend T-DXd as the next line of therapy following endocrine therapy per findings from the DESTINY- Breast04 study. Based on the TROPICS-2 study, sacituzumab govitecan can be considered in subsequent line of therapy (endocrine therapy and at least two additional systemic therapies). Trial data show that T-DXd and sacituzumab govitecan are excellent therapy options, ones that are more effective and better tolerated when compared with infusional chemotherapy.
Bardia: There are multiple ADCs in development to target antigens overexpressed in MBC. The composition of the ADC (ie, antigen selectivity, stability of linker, and type of toxic payload) are important considerations that could impact efficacy-toxicity ratio, therapeutic sequencing, and combination strategies. Determining resistance to antibody vs payload could help with optimal therapeutic sequencing of ADCs for patients with breast cancer. For example, if resistance is driven by the antibody portion, then switching the antibody portion could still have efficacy; for example, sacituzumab govitecan works after T-DXd in HR+/HER2-low MBC.
Tarantino: There are currently three ADCs approved to treat MBC. Sequencing strategies for patients with MBC are generally dependent on the inclusion criteria from trials demonstrating the benefit of these ADCs and are also based on differences in toxicity profiles and patient preferences.
Patients with HER2 MBC generally receive T-DXd first, based on findings from the DESTINY-Breast03 trial showing significant overall survival improvement with T-DXd compared with trastuzumab emtansine (T-DM1). T-DM1 is often utilized at progression, although other options are sometimes preferred due to concerns with cross-resistance among anti-HER2 ADCs administered in immediate sequence.
In order to use T-DXd, HER2-low expression needs to be detected on the tumor cells. Approximately 70% of all HR+/HER2-negative tumors have HER2-low expression (most cases). T-DXd is generally utilized as a second-line chemotherapy after exhausting endocrine treatment options and one line of chemotherapy per findings from DESTINY-Breast04. Although sacituzumab govitecan is generally considered in the third- or fourth-line setting given that it was tested among more pretreated patients in the TROPiCS-02 trial, it may be considered earlier for patients with HER2-0 tumors, who are not eligible for T-DXd.
In patients with triple-negative breast cancer (TNBC) with HER2-low expression, studies (DESTINY-Breast04 and ASCENT) showed that T-DXd and sacituzumab govitecan outperformed conventional chemotherapy among patients with relapsed or refractory MBC ["outperformed" meaning that T-DXd and sacituzumab govitecan significantly increased progression-free survival and overall survival]. The decision of which of these ADCs to use as second-line treatment generally relies on an informed discussion with the patient, one that balances the activity and toxicity of each drug and considers key differences between their respective clinical trials. Sacituzumab govitecan, however, is currently the only ADC option for patients with HER2-0 TNBC.
How do you recognize and manage ADC toxicities?
Armaghani: The development of this therapeutic class of medications presents a new challenge in recognizing and managing associated toxicities. It is important that clinicians be well informed of the commonly reported adverse events (AEs) and the symptoms of ADC therapy, and understand the severity or grade of the AE to determine the appropriate action plan — eg, reduce dose, hold or discontinue the medication, and prescribe treatments to manage the side effects and symptoms. For example, interstitial lung disease (ILD)/pneumonitis, which can be life-threatening, is a well-known adverse reaction that can occur with T-DXd. Since early intervention is key, it is therefore imperative to closely monitor and educate patients on signs and symptoms of ILD such as new-onset shortness of breath, cough, etc., to ensure proper treatment and recovery for patients.
Bardia: Each ADC has different toxicities. The toxic payload is the major determinant of toxicity, though internalization efficiency, bystander effect, and payload metabolism are all important consideration that could impact toxicities associated with ADC. Toxicities associated with T-DXd include nausea, myelosuppression, and pneumonitis, while common AEs with sacituzumab govitecan include neutropenia, nausea, and diarrhea. Early recognition and management of toxicities are critical, particularly for serious AEs such as pneumonitis. ADC toxicity can usually be managed with supportive treatment and dose reductions.
Tarantino: The most common toxicities associated with ADCs correlate with their cytotoxic payload; thus, management does not differ substantially from conventional chemotherapies. Nonetheless, some important differences exist among the toxicity profiles of ADCs.
For instance, T-DXd is associated with a relatively high incidence of nausea. The establishment of guidelines on the prophylactic use of antiemetics has decreased the severity of this side effect. In addition to nausea, about 10%-15% of patients receiving T-DXd are expected to develop ILD, a potentially serious condition that requires prompt recognition, drug discontinuation, and corticosteroid treatment. Thanks to improvements in the detection and management of ILD, the mortality rate from ILD has dropped from 2.7% (as observed in the early DESTINY-Breast01 trial) to 0% (as observed in the DESTINY-Breast03 trial).
Sacituzumab govitecan can be associated with severe neutropenia and diarrhea, respectively requiring treatment with growth factors (granulocyte colony-stimulating factors and granulocyte-macrophage colony-stimulating factors) and antidiarrheal agents. Alopecia is more common with sacituzumab govitecan than with other ADCs. At Dana-Farber Cancer Institute, we are leading a study looking at the potential benefit of scalp cooling to prevent alopecia caused by sacituzumab govitecan and T-DXd, and hope to report the first results soon.
Avan J. Armaghani, MD
Assistant Member, Department of Breast Oncology, Moffitt Cancer Center, University of South Florida, Tampa, Florida
Avan J. Armaghani, MD, has disclosed no relevant financial relationships.
Aditya Bardia, MD, MPH
Director, Breast Cancer Research; Associate Professor, Harvard Medical School; Attending Physician, Massachusetts General Hospital, Boston, Massachusetts
Aditya Bardia, MD, MPH, has disclosed the following relevant financial relationships:
Serves in a consultant/advisory board role for: Pfizer; Novartis; Genentech; Merck; Radius Health; Immunomedics/Gilead; Sanofi; Daiichi Pharma/Astra Zeneca; Phillips; Eli Lilly; Foundation Medicine
Received contracted research/grant (to institution) from: Genentech; Novartis; Pfizer; Merck; Sanofi; Radius Health; Immunomedics/Gilead; Daiichi Pharma/Astra Zeneca; Eli Lilly
Paolo Tarantino, MD, PhD candidate
Advanced Research Fellow, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
Paolo Tarantino, MD, has disclosed the following relevant financial relationships:
Serves in an advisory/consultant role for: AstraZeneca; Daiichi Sankyo; Gilead; Eli Lilly
Lead image: Nenitorx/Dreamstime
Image 1: Avan J. Armaghani, MD
Image 2: Aditya Bardia, MD, MPH
Image 3: Paolo Tarantino, MD
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Cite this: How Groundbreaking ADCs Are Helping More Patients With MBC - Medscape - Aug 08, 2023.