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Safety of ADCs in MBC: Module

CME

Optimizing Outcomes and Quality of Life for Patients With Advanced Breast Cancer Through Effective Management of ADC-Associated Toxicities

Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™

Released: February 07, 2024

Expiration: February 06, 2025

Komal Jhaveri
Komal Jhaveri, MD, FACP
CME/CE Information

Activity

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Emergence of ADCs in Breast Cancer

The emergence of ADCs is rapidly changing the treatment landscape for patients with unresectable or metastatic breast cancer. Since the initial development and approval of trastuzumab emtansine (T-DM1) for patients with HER2-positive metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination, in the metastatic setting or developed disease recurrence within ≤6 months of completing adjuvant therapy, several novel ADCs have emerged for patients with advanced breast cancer.1-3

Currently, 2 ADCs are approved by the FDA in the HER2-negative and/or HER2-low metastatic setting: SG and T-DXd.2,3 SG is approved for patients with unresectable locally advanced or metastatic triple-negative breast cancer after ≥2 prior systemic therapies, at least one of them for metastatic disease. SG also is approved for patients with unresectable locally advanced or metastatic HR-positive/HER2-negative (IHC 0, IHC 1+, or IHC 2+/ISH-) breast cancer who have received endocrine-based therapy and ≥2 additional systemic therapies in the metastatic setting. T-DXd is approved for patients with unresectable or metastatic HER2-positive breast cancer after a prior anti-HER2–based regimen either in the metastatic setting or in the neoadjuvant or adjuvant setting and who have developed disease recurrence within 6 months of completing therapy. T-DXd also is approved for patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence within 6 months of completing adjuvant chemotherapy.

There are other novel and emerging ADCs with encouraging activity in patients with metastatic breast cancer. For example, datopotamab deruxtecan (Dato-DXd) is an investigational agent that already has shown promising activity in a phase III trial (NCT05104866). Other investigational ADCs in clinical development for patients with metastatic breast cancer include trastuzumab duocarmazine (NCT03262935), disitamab vedotin (NCT05904964), and patritumab deruxtecan (NCT04699630).

ADCs in HR-Positive Metastatic Breast Cancer

ADCs are made up of a monoclonal antibody linked to a small-molecule cytotoxic drug via a linker. There are clear differences between the 2 FDA-approved ADCs for patients with HER2-negative and/or HER2-low metastatic breast cancer, both in the target of interest and in the way in which the constructs are made. These differences may account for the unique toxicities and distinct safety profiles associated with each of these agents.

T‑DXd targets HER2, whereas the target for SG is TROP-2.4,5 Like SG, the target for Dato-DXd is TROP-2.6 When comparing the 2 TROP-2–targeted ADCs—FDA-approved SG and investigational Dato-DXd—there are differences in the drug-to-antibody ratios, linker technologies, and payloads.

T-DXd, SG, and Dato-DXd all have a topoisomerase‑I inhibitor payload, but there are slight differences in their payloads in that SG comprises a camptothecin derivative payload (SN‑38), whereas for both T‑DXd and Dato‑DXd, the payload is an exatecan derivative (DXd).4-6 Of note, the presence of the target on normal tissues, differences in the stability of the cytotoxic payloads, and how the linker is released from the conjugate may contribute to the development of some of the off‑target toxicities associated with these agents. Although T-DXd, SG, and Dato-DXd are administered intravenously, there are differences in their dosing schedules. T‑DXd is indicated for use at a dose of 5.4 mg/kg every 3 weeks, and SG is approved at a dose of 10 mg/kg on Days 1 and 8 of 21‑day cycles.4,5,7,8 In the phase III TROPION-Breast01 trial, Dato-DXd was administered intravenously at a dose of 6 mg/kg every 3 weeks.9 

There are also differences in the baseline characteristics of the patients enrolled on the phase III trials for HR-positive advanced breast cancer in which these agents were evaluated.4,5,7-9 In the phase III DESTINY-Breast04 trial of T‑DXd and the phase III TROPION-Breast01 trial of Dato-DXd, the ADCs were evaluated after disease progression on 1-2 previous chemotherapy regimens, whereas in the phase III TROPiCS-02 trial, SG was evaluated in patients who had received 2-4 previous treatments. Despite these differences in the patient populations, improvements in survival and objective response rates were seen with these 3 ADCs compared with chemotherapy of physician’s choice.

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