Dr Davis on the Utility of ADCs in Breast Cancer

Andrew Davis, MD, assistant professor, medicine, Division of Medical Oncology, Washington University School of Medicine, medical oncologist, Siteman Cancer Center, discusses the use of antibody-drug conjugates (ADCs) in patients with breast cancer, highlighting recent updates with these agents in the treatment paradigm.

Currently, 3 ADCs have been granted FDA approval for patients with breast cancer: ado-trastuzumab emtansine (Kadcyla; T-DM1), fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd), and sacituzumab govitecan-hziy (Trodelvy), Davis begins. Among them, T-DM1 stands as the pioneering agent, primarily prescribed for patients with advanced or metastatic HER2-positive breast cancer, he states. Additionally, it has been authorized for use as adjuvant therapy in patients with HER2-positive early-stage breast cancer who retain residual disease after neoadjuvant therapy and surgery, Davis explains.

The recent approvals of T-DXd and sacituzumab govitecan for patients with breast cancer have sparked renewed interest in the realm of ADCs, he continues. This interest extends beyond breast cancer, encompassing a wide spectrum of other cancer types, Davis reports. The surge in interest has led to significant advancements and expansions in the potential applications of ADCs within the field of oncology, he notes, adding that this resurgence is revitalizing therapeutic options andopening new avenues for treating various cancers, thereby enhancing oncological care.

T-DXd, in particular, has generated promising results in clinical trials, showing efficacy in HER2-positive cancers resistant to other therapies, Davis reports. Sacituzumab govitecan, on the other hand, has had activity in triple-negative breast cancer and other solid tumors, offering new hope for patients with historically challenging-to-treat malignancies, he says.

As research continues to evolve, the development of ADCs remains an area of active investigation and innovation, Davis expands. These therapies combine the targeted specificity of monoclonal antibodies with the potent cytotoxic effects of chemotherapeutic drugs, aiming to deliver treatments directly to cancer cells and minimize systemic toxicity, he concludes.

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Andrew Davis, MD, discusses the use of antibody-drug conjugates in breast cancer, highlighting recent updates with these agents in the treatment paradigm.

Dr Davis on the Investigation of Neratinib Plus Trastuzumab Deruxtecan in Advanced HER2+ Solid Tumors

Andrew Davis, MD, assistant professor of medicine, Division of Medical Oncology, Washington University School of Medicine, medical oncologist, Siteman Cancer Center, discusses an ongoing phase 1 trial (NCT05372614) investigating the combination of neratinib and fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with metastatic HER2-positive solid tumors.

The trial is examining the safety and efficacy of combining the antibody-drug conjugate (ADC) trastuzumab deruxtecan with neratinib, an oral TKI, Davis begins. This study was designed based on preclinical evidence derived from work by Ron Bose, MD, PhD, of Siteman Cancer Center, showing that neratinib enhanced the uptake of trastuzumab deruxtecan in patient-derived xenograft models of 

-mutated, HER2–non-overexpressing breast cancer, he adds.

The phase 1 trial is including patients with metastatic solid tumors harboring HER2-overexpression(immunohistochemistry 3+), 

 mutations. Patients must have received at least 1 prior line of systemic therapy in the advanced setting to enroll.

The primary objectives are to assess safety and tolerability of the combination, and secondary objectives include evaluating pharmacokinetics, preliminary efficacy, and potential biomarkers of response.

Davis emphasizes that understanding the interaction between ADCs and TKIs could lead to enhanced efficacy without significant additional toxicity. The data generated from this trial will provide critical insights into the combination therapy's safety profile and its potential to improve outcomes for patients with metastatic HER2-positive solid tumors, he explains.

There remains a need for more data regarding ADC-based combinations in the treatment of patients with solid tumors, and findings from this trial could help inform these types of approaches, Davis concludes.

Andrew Davis, MD, discusses an ongoing phase 1 trial combining neratinib and trastuzumab deruxtecan in metastatic HER2-positive solid tumors.

Dr Davis on the Potential For ADCs to Continue to Reshape Breast Cancer Treatment 

Andrew Davis, MD, assistant professor of medicine, Division of Medical Oncology, Washington University School of Medicine, medical oncologist, Siteman Cancer Center, discusses how the continued development of antibody-drug conjugates (ADCs) could reshape the breast cancer treatment paradigm. He also explains how the continued emergence of different ADCs within the breast cancer space will also present new questions that should be addressed in future clinical trials to maximize the benefits of these agents for patients.

Davis notes that with approximately 200 different ADCs are currently in preclinical and clinical development across various tumor types, including breast cancer. Given the volume of ADCs currently under development, these agents have the potential to transform the treatment landscape across various tumor types, Davis continues, adding that the emergence of additional ADCs will also present novel clinical questions regarding their role within the oncology space.

As more ADCs are developed, there will be a need to evaluate different payloads and their sequencing in clinical trials, Davis says. Determining the optimal sequencing for ADCs with different payloads will be crucial for optimizing their therapeutic impact, he notes.

Davis also emphasizes the necessity of exploring novel payloads. For example, some ADCs that have already reached clinical practice feature topoisomerase I inhibitor payloads, and ongoing clinical trials are exploring payloads that would differentiate these novel ADCs, Davis continues.

Furthermore, Davis addresses the importance of learning more about and improving upon the structural and delivery aspects of current ADCs. Using novel approaches regarding the design and engineering of ADCs, including the linker used, the agent’s chemistry, and the drug-to-antibody ratio, will play a critical role in the efficacy and safety profiles of novel agents under investigation in clinical trials, he says. Specifically for safety, changes in design could help improve off-target toxicity, and Davis concludes by noting that those in the field of breast cancer are eagerly awaiting data for a number of novel ADCs.

Andrew Davis, MD, discusses how antibody-drug conjugates could continue to reshape the breast cancer treatment paradigm.

Andrew Davis, MD

Articles

Dr Davis on the Utility of ADCs in Breast Cancer

Dr Davis on the Investigation of Neratinib Plus Trastuzumab Deruxtecan in Advanced HER2+ Solid Tumors

Dr Davis on the Potential For ADCs to Continue to Reshape Breast Cancer Treatment