How to Use ADCs? Managing Adverse Reactions? Expert Recommendations

*For reference by medical professionals only

How to Use ADCs? Managing Adverse Reactions? Expert Recommendations

Antibody-drug conjugates (ADCs) have become a new hotspot in the field of anti-tumor therapy, with explorations in the treatment of breast cancer, lung cancer, gastric cancer, colorectal cancer, and other types of cancer. With the approval and clinical entry of drugs such as Trastuzumab Deruxtecan, Ado-trastuzumab emtansine, and Enfortumab vedotin in China, the treatment options for ADCs have become a challenge for clinicians.
The Oncology Forum combines the National Comprehensive Cancer Network (NCCN) guidelines, the Chinese Society of Clinical Oncology (CSCO) guidelines, and recommendations from international experts on Medscape to share clinical issues regarding the use of ADCs in metastatic breast cancer.
When to Use ADCs? Insights from NCCN and CSCO Guidelines
The 2023 v4 NCCN Breast Cancer Guidelines recommend the following for the use of ADCs:
  • Trastuzumab Deruxtecan is recommended for the second-line treatment of HR+/HER2- breast cancer patients with visceral crisis or recurrence after endocrine therapy, with HER2 IHC1+ or 2+/ISH negative;
  • Patients without indications for Trastuzumab Deruxtecan may choose Ado-trastuzumab emtansine.
  • For triple-negative breast cancer patients, Ado-trastuzumab emtansine is recommended for second-line treatment;
  • Non-gBRCA1/2 mutation and HER2 IHC1+ or 2+/ISH negative triple-negative breast cancer patients are recommended to use Trastuzumab Deruxtecan.
  • HER2+ breast cancer patients are recommended to use Trastuzumab Deruxtecan for second-line treatment;
  • HER2+ breast cancer patients are recommended to use Enfortumab vedotin for third-line treatment;
In the 2023 CSCO guidelines, the use of ADCs is recommended as follows:
  • For HER2+ breast cancer patients who do not achieve pathological complete response with trastuzumab + pertuzumab, adjuvant treatment post-surgery should use Enfortumab vedotin;
  • For HER2+ recurrent metastatic breast cancer, after H treatment failure, Enfortumab vedotin or Trastuzumab Deruxtecan may be considered.
How to Select the Appropriate ADC for Breast Cancer Patients?
Professor Armaghani:
When using ADCs for metastatic breast cancer patients, many factors need to be considered, including the presence of brain metastases, previous lines of treatment, the patient’s condition, any comorbidities, and the drug administration schedule. These factors will determine the order and type of ADC used.
For example, for HR+/HER2 low-expressing metastatic breast cancer patients, Trastuzumab Deruxtecan and Ado-trastuzumab emtansine can be considered. Based on the results of the DESTINY-Breast04 study, I recommend Trastuzumab Deruxtecan as the next treatment option after endocrine therapy. Based on the TROIC-02 study, Ado-trastuzumab emtansine may be considered for subsequent treatments (after endocrine therapy and at least two additional systemic therapies). Trial data show that Trastuzumab Deruxtecan and Ado-trastuzumab emtansine are excellent treatment options, with better efficacy and tolerance compared to chemotherapy.
Professor Bardia:
Currently, ADCs targeting overexpressed antigens in metastatic breast cancer are being developed. Since different ADCs target different antigens and have different payloads, if a patient is resistant to a certain ADC, other ADCs may be considered. For instance, after progression on Trastuzumab Deruxtecan in HR+/HER2 low-expressing metastatic breast cancer patients, Ado-trastuzumab emtansine may be considered.
Professor Tarantino:
Currently, three ADCs are approved for the treatment of metastatic breast cancer, and clinical use should reference the inclusion criteria of these ADC clinical studies, adverse events, and patient preferences.
HER2+ metastatic breast cancer patients typically first receive Trastuzumab Deruxtecan. Based on the DESTINY-Breast03 study, Trastuzumab Deruxtecan significantly improves overall survival (OS) compared to Enfortumab vedotin. Enfortumab vedotin is usually used upon progression, although there may be cross-resistance between anti-HER2 ADCs, making other options sometimes preferable.
HER2 low expression is an indication for the use of Trastuzumab Deruxtecan, with approximately 70% of HR+/HER2- breast cancer patients exhibiting low HER2 expression. According to the results of the Destiny Breast04 study, T-DXd is typically used as a second-line option after first-line chemotherapy and endocrine therapy failure. According to the TROIC-02 trial, Ado-trastuzumab emtansine is usually suitable for third-line or fourth-line treatment, but breast cancer patients with HER2 zero expression may use it earlier.
In HER2 low-expressing triple-negative breast cancer patients, the DESTINY-Breast04 study and ASCENT study show that Trastuzumab Deruxtecan and Ado-trastuzumab emtansine outperform conventional chemotherapy, significantly improving progression-free survival and overall survival in triple-negative breast cancer patients. However, for HER2 zero-expressing triple-negative breast cancer, Ado-trastuzumab emtansine is recommended.
How to Manage Adverse Events of ADCs?
Professor Armaghani:
Clinicians must fully understand the adverse events and symptoms of ADCs and develop appropriate treatment measures based on their severity—such as dose reduction, continuation of treatment, or discontinuation, and using other treatments to control adverse events. For life-threatening interstitial lung disease (ILD), early intervention is key, so close monitoring of patients for signs and symptoms of ILD, such as shortness of breath and cough, is essential.
Professor Bardia:
Each ADC has a different toxicity profile. The effective payload of cytotoxic drugs is the main determinant of toxicity. The main adverse events of Trastuzumab Deruxtecan include nausea, bone marrow suppression, and pneumonia, while common adverse reactions of Ado-trastuzumab emtansine include neutropenia, nausea, and diarrhea. Early recognition and management of toxicity are crucial, especially for serious adverse reactions like pneumonia. ADC toxicity can often be controlled with supportive treatment and dose reduction.
Professor Tarantino:
The most common toxicities associated with ADCs are related to their cytotoxic payloads, so the management of adverse events is not fundamentally different from traditional chemotherapy. Nevertheless, there are some important differences in the toxicity profiles of ADCs.
For example, the incidence of nausea with Trastuzumab Deruxtecan is relatively high and can be prevented with antiemetics. In addition to nausea, about 10%-15% of patients receiving Trastuzumab Deruxtecan are expected to develop ILD, necessitating prompt identification, discontinuation, and treatment with corticosteroids.
Ado-trastuzumab emtansine can lead to severe neutropenia and diarrhea that require symptomatic treatment. Compared to other ADCs, alopecia is more common in the Ado-trastuzumab emtansine group.
More Oncology Frontier Information
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References:
[1] 2023 v4 NCCN Breast Cancer Guidelines.
[2] 2023 Chinese Society of Clinical Oncology Breast Cancer Diagnosis and Treatment Guidelines
[3] https://www.medscape.com/viewarticle/995201?src=#vp_1

Expert Profiles

How to Use ADCs? Managing Adverse Reactions? Expert Recommendations

Paolo Tarantino, MD, PhD candidate

Advanced Research Fellow, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts

How to Use ADCs? Managing Adverse Reactions? Expert Recommendations

Avan J. Armaghani, MD

Assistant Member, Department of Breast Oncology, Moffitt Cancer Center, University of South Florida, Tampa, Florida

How to Use ADCs? Managing Adverse Reactions? Expert Recommendations

Aditya Bardia, MD, MPH

Director, Breast Cancer Research; Associate Professor, Harvard Medical School; Attending Physician, Massachusetts General Hospital, Boston, Massachusetts

Oncology Forum, also known as “Medical Forum Network Oncology,” is a professional platform for oncology practitioners, committed to providing cutting-edge medical information to support cancer prevention and treatment.At Oncology Forum, you can find rich medical content including new drug information, cutting-edge research, guideline updates, and clinical cases.
Cover image source: Pixabay
This article is original: Oncology Forum
Author: Tang Ying
How to Use ADCs? Managing Adverse Reactions? Expert Recommendations
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