In recent years, several antibody-drug conjugates (ADCs) were approved across a variety of solid tumors. This presents challenges when managing a multitude of treatment-related adverse events, some of which may lead clinicians into unfamiliar territory. This series of educational activities focuses on appropriate management of ADC-related adverse events in breast, lung, gastric, and bladder cancers.
HER2-Directed ADCs in Breast Cancer
HER2-Directed ADCs in Breast Cancer
Welcome to CME on ReachMD. This episode is part of our MinuteCME curriculum and is titled “HER2-Directed ADCs in Breast Cancer”.
Prior to beginning the activity, please be sure to review the faculty and commercial support disclosure statements as well as the learning objectives.
This is CME on ReachMD, and I'm Dr. Sara Hurvitz, Professor of Medicine and Medical Oncologist at UCLA.
The treatment of HER2 positive breast cancer has been revolutionized by the development of HER2-targeted therapies, including HER2-directed antibodies, tyrosine kinase inhibitors, and most recently antibody-drug conjugates [ADCs], which selectively deliver chemotherapy to HER2-overexpressing cancer cells. While these drugs have demonstrated significant antitumor efficacy, there are unique side effects to be aware of.
The first ADC to be approved for HER2-positive breast cancer was trastuzumab emtansine, or T-DM1. Until very recently, this therapy was the standard second-line treatment for metastatic disease and also is now standard adjuvant treatment for patients who have residual disease after standard neoadjuvant chemotherapy and HER2-directed therapy.
The efficacy of T-DM1 is highly dependent on high expression of HER2 on the tumor cell. This ADC has a fairly good therapeutic index, meaning its toxicity is relatively low compared to standard chemotherapy, as off-target toxicity is limited.
Patients may experience thrombocytopenia with this agent, especially in the first several cycles, as well as transaminase elevations. Thus, patients should have bloodwork done at the time of infusion to monitor for these toxicities.
Rarely, nodular regenerative hyperplasia may occur for which T-DM1 should be permanently discontinued, and evaluation by a hepatologist is certainly warranted.
Neuropathy may also develop over time, though uncommonly is this severe.
Rarely, patients may experience interstitial lung disease or cardiomyopathy. Thus, monitoring patients for symptoms and periodic cardiac function monitoring is called for. Referral to a pulmonologist or cardiologist may be warranted if one of these side effects were to develop.
Trastuzumab deruxtecan, or T-DXd, was the second ADC to be approved for metastatic HER2-positive breast cancer. It was approved in the third-line setting and beyond based on the single-arm phase 2 DESTINY-Breast01 clinical trial in 2019 and more recently, in the fall of 2021, was demonstrated significant benefits compared to T-DM1 in the second-line setting in the DESTINY-Breast03 trial. This drug has stunning antitumor efficacy for breast cancer but is associated with important side effects.
In contrast to T-DM1, the cytotoxic payload of T-DXd is membrane permeable, leading to bystander effects and a broader toxicity profile more similar to chemotherapy.
Patients may experience significant nausea, which is usually manageable with pre-medication and PRN [pro re nata/as-needed] medications. Patients may also have neutropenia, febrile neutropenia, diarrhea, fatigue, and alopecia with this drug.
One potentially life-threatening toxicity is interstitial lung disease [ILD]. The management of this side effect often requires the involvement of a pulmonologist to evaluate and co-manage patients who develop symptomatic ILD. Any patient with symptomatic ILD should permanently discontinue T-DXd, initiate steroids, and see a pulmonologist. For those patients with asymptomatic grade 1 ILD seen only on imaging, T-DXd should be held and, in my opinion, patients should be considered for a pulmonology evaluation.
Please note a presentation relating to this topic was presented at ASCO 2022, titled Monitoring and Management of ILD Pneumonitis Among Patients with Metastatic Breast Cancer Treated with Trastuzumab Deruxtecan.
Unfortunately, that's all the time we have today. To summarize, ADCs have shown significant benefits for patients with HER2-positive breast cancer, but they are associated with unique side effects, some of which may call for a multidisciplinary collaboration with hepatology, pulmonology, or cardiology to optimally manage.
Thank you so much. I hope this has been helpful.
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Jaffer A. Ajani, MD
Professor, Department of Gastrointestinal Medical Oncology
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Research: Daiichi Sankyo
Consulting Fees: AstraZeneca, Daiichi Sankyo
Justin Gainor, MD
Director, Center for Thoracic Cancers
Director, Targeted Immunotherapy
Massachusetts General Hospital
Contracted Research: Adaptimmune, Alexo, Ariad/Takeda, Array, BMS, Blueprint, Genentech/ Roche, Jounce, Merck, Moderna, Novartis, Scholar Rock, and Tesaro
Consulting Fees: Agios, Amgen, Ariad/Takeda, Array, AstraZeneca, BMS, Clovis Oncology, EMD Serono, Genentech, Glyde Bio, Helsinn, Incyte, Jounce, Karyopharm, Loxo, Merck, Mirati, Novartis, Oncorus, Pfizer, and Regeneron
Sara Hurvitz, MD
Professor of Medicine
David Geffen School of Medicine, UCLA
Santa Monica, CA
Contracted Research: Ambrx, Amgen, Arvinas, AstraZeneca, Bayer, CytomX, Daiichi Sankyo, Dignitana, Eli Lilly, Genentech/Roche, Gilead, GSK, Immunomedics, MacroGenics, Novartis, OBI Pharma, Orinove, Pfizer, Phoenix Molecular Designs, Ltd., Pieris, PUMA, Radius, Sanofi, Seattle Genetics/Seagen, Zymeworks
Preclinical Work: Ambrx, Samumed
National/International PI: Daiichi Sankyo, GNE/Roche, Novartis, SeaGen
Steering Committee: Daiichi-Sankyo/AZ, GNE/Roche, Lilly, Novartis, Sanofi
Uncompensated consulting/ad boards: 4DPharma, Ambrx, Amgen, Artios, Arvinas, Biotheranostics, Daiichi Sankyo, Dantari, Eli Lilly, Genentech/Roche, Immunomedics, MacroGenics, NKMax, Novartis, Pieris, Pyxis, Seagen
Gopa Iyer, MD
Associate Attending Physician
Section Head, Urothelial Carcinoma
Memorial Sloan Kettering Cancer Center
New York, NY
Research: Aadi Biosciences, Janssen, Mirati Therapeutics, SeaGen
Consulting Fees: Basilea, EMD Serono, Flare Therapeutics, Gilead, Loxo Oncology, Silverback Therapeutics, The Lynx Group
- Jorge Bacigalupo, PSM has nothing to disclose.
- Cindy Davidson has nothing to disclose.
- Ann Early has nothing to disclose.
- Nicole Fox, DNP, MSN-Ed., RN, OCN has nothing to disclose.
- Anna Trentini has nothing to disclose.
After participating in this educational activity, participants should be better able to:
- Describe the components of an antibody-drug conjugate (ADC) that may cause adverse events (AEs)
- Recognize AEs that lead to treatment interruption or discontinuation
- Recommend an approach for managing the key AEs associated with ADCs
- Design a mitigation plan for AEs in patients at high risk for ADC-related AEs
This activity is designed to meet the educational needs of medical oncologists, pulmonologists, urologists, pathologists, oncology nurse practitioners, physician assistants, oncology nurses, oncology pharmacists, and other HCPs managing patients with solid tumors.
In support of improving patient care, Global Learning Collaborative (GLC) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC) to provide continuing education for the healthcare team.
Global Learning Collaborative (GLC) designates this Enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Global Learning Collaborative (GLC) designates this activity for 1 hour of nursing contact hours. Nurses should claim only the credit commensurate with the extent of their participation in the activity.
Global Learning Collaborative (GLC) has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1 AAPA Category 1 CME credits. Approval is valid until 06/30/2023. PAs should claim only the credit commensurate with the extent of their participation in the activity.
This curriculum has been approved for 1.0 contact hours 0.1 CEUs by Global Learning Collaborative (GLC). GLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. The Universal Activity Number for this program is UAN JA0006235-0000-22-029-H01-P. This learning activity is enduring-based. Your CE credits will be electronically submitted to the NABP upon successful completion of the activity. Pharmacists with questions can contact NABP customer service (firstname.lastname@example.org).
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This activity is supported by independent educational grants from AstraZeneca and Daiichi Sankyo.
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