With the recent approvals of Trastuzumab emtansine (T-DM1) and Gemtuzumab ozogamicin in China, the review of Trastuzumab deruxtecan (T-DXd, DS-8201) is progressing steadily, marking the arrival of a “future” where antibody-drug conjugates (ADCs) greatly benefit breast cancer patients in China.
ADCs achieve “precision targeting” of tumors and are referred to as “magic bullets,” changing the treatment landscape for HER2-positive and triple-negative breast cancers. Despite their impressive efficacy, adverse reactions are an unavoidable “other side” of any medication. Mismanagement can not only hinder treatment progress but also affect patient prognosis and quality of life. As the “primary observers,” patients must understand adverse reactions to provide timely feedback to healthcare professionals, potentially even “turning the tide”.
Recently, the Breast Cancer Group of the Oncology Physician Branch of the Chinese Medical Association and the International Medical Exchange Branch of the Chinese Anti-Cancer Association organized experts to jointly formulate the Chinese Expert Consensus on the Safety Management of Breast Cancer ADCs, which lists management consensus for common and noteworthy adverse reactions or events, providing us with valuable guidance~
Common Adverse Reactions Overview
01
Neutropenia
ADCs contain chemotherapy drug components, thus can cause neutropenia, with Gemtuzumab ozogamicin being the most pronounced. Patients undergoing treatment with Gemtuzumab ozogamicin may experience severe or even life-threatening neutropenia. The median time to first occurrence for any grade and grade ≥3 neutropenia is 19 and 17 days, respectively, with median durations of 8.5 and 8 days.
Management: Patients with neutropenia accompanied by fever or recurrent infections must immediately begin anti-infection treatment. Empirical antibiotic treatment should be chosen based on the patient’s risk level, and high-risk patients should receive antifungal prophylaxis.
Granulocyte colony-stimulating factor (G-CSF) is the standard medication for treating neutropenia. Patients receiving Gemtuzumab ozogamicin may consider G-CSF as secondary prophylaxis.
02
Anemia
Chemotherapy drugs induce anemia by directly damaging hematopoiesis, including the synthesis of red blood cell precursors. A decrease in red blood cell count often occurs after neutropenia and thrombocytopenia.
Management: For patients with anemia, the benefits and risks of transfusion should be assessed based on clinical symptoms, malignancy course, treatment response, comorbidity status, or underlying causes, and patient preferences should be considered to select appropriate symptomatic supportive treatment, including erythropoiesis-stimulating agents or red blood cell transfusions as necessary.
03
Cardiac Adverse Reactions
Cardiac adverse reactions generally manifest clinically as decreased exercise tolerance due to dyspnea or fatigue and fluid retention, such as swelling in the lower limbs or abdomen, difficulty lying flat, weight gain, etc. They may also be asymptomatic or accompanied by other cardiac or non-cardiac symptoms. The incidence of cardiac adverse reactions reported for T-DM1 and T-DXd is not high. T-DXd reported two cases (0.9%) of asymptomatic LVEF reduction without heart failure events; the incidence of LVEF reduction associated with T-DM1 is <2%, with severe heart failure events but no deaths.
Management: LVEF reduction is a known risk of Trastuzumab, listed in the black box warning of the T-DM1 package insert and the warnings and precautions in the T-DXd package insert. Routine cardiac function tests should be performed before starting treatment and LVEF should be re-evaluated every three months during treatment. Patients with a lower baseline LVEF should carefully assess the benefit-risk ratio before deciding to administer treatment.
LVEF reduction is associated with poor prognosis, and the best management model for LVEF reduction involves interdisciplinary collaboration.
04
Hepatobiliary Adverse Reactions
Meta-analysis shows that treatment with T-DM1 is associated with an increased risk of elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The black box warning in the T-DM1 package insert indicates that liver adverse reactions, liver failure, and deaths have occurred in patients receiving T-DM1 treatment.
Management: Liver function should be monitored before starting T-DM1 treatment and before each administration, and clinicians should be vigilant for clinical symptoms of portal hypertension and/or CT findings indicative of cirrhotic-like lesions.
For early and late-stage breast cancer patients, the dosing regimen for T-DM1 differs; any level of liver nodular regenerative hyperplasia in early or late-stage breast cancer patients necessitates termination of T-DM1 treatment. Late-stage breast cancer patients experiencing drug-induced liver injury should permanently discontinue treatment after ruling out other causes.
05
Gastrointestinal Adverse Reactions
Targeted therapies independently induce a range of gastrointestinal adverse reactions, which can enhance the adverse reactions induced by traditional chemotherapy drugs when used in combination.
Nausea, vomiting, and diarrhea are common and severe gastrointestinal adverse reactions among patients treated with Gemtuzumab ozogamicin. The median time to occurrence and duration for any grade diarrhea related to Gemtuzumab ozogamicin is 14.0 and 8.0 days, respectively, with grade ≥3 diarrhea occurring at 15 and 6 days, respectively. T-DXd and T-DM1 also report gastrointestinal adverse reactions, with relatively mild severity.
Management: The black box warning in the Gemtuzumab ozogamicin package insert indicates the possibility of severe diarrhea, necessitating monitoring and administration of fluids and electrolytes as needed. It is recommended to premedicate with antiemetics before starting treatment. If there are no contraindications, atropine can be used for pre-treatment and control of any severity of early-onset diarrhea. In cases of late-onset diarrhea, the cause of infection should be evaluated, and if no other causes are found, loperamide should be administered immediately, starting with a dose of 4 mg, followed by 2 mg for each subsequent episode, with a maximum daily dose of 16 mg. Loperamide should be discontinued 12 hours after diarrhea resolution. For patients with persistent diarrhea, the previously mentioned regimen of loperamide 4 mg + 2 mg every 2 hours should be followed; if there is no improvement after 24 hours, octreotide 100-150 mg three times daily should be considered. Severe diarrhea may require hospitalization.
06
Neurological Adverse Reactions
Peripheral neuropathy is not always reversible, with common symptoms including numbness (hypoesthesia) and sensory abnormalities, which may be accompanied by pain, weakness, and loss of deep tendon reflexes. Studies have shown that symptoms of peripheral neuropathy often appear by the third cycle.
Vidisicimab has reported a high incidence of neurological adverse reactions in studies of breast cancer, urothelial carcinoma, and gastric cancer, with hypoesthesia being the most pronounced (approximately 60% across all grades in breast cancer and urothelial carcinoma). Neurological adverse reactions related to Gemtuzumab ozogamicin are all grade 1-2.
Management: Currently, there are no effective drugs to prevent or treat chemotherapy-induced neuropathy. Duloxetine is the only evidence-based drug for painful peripheral neuropathy, but its efficacy is limited. Based on clinical experience, dexamethasone pre-treatment may help reduce the incidence of neuropathy.
Management of peripheral neuropathy induced by ADC treatment can refer to guidelines for managing chemotherapy-induced peripheral neuropathy; for intolerable neuropathy and/or functional impairment, dose delays, reductions, switching regimens, or discontinuation of ADC treatment may be considered.
07
Musculoskeletal Adverse Reactions
T-DM1 and Gemtuzumab ozogamicin have reported varying categories and degrees of musculoskeletal pain and joint pain, with current reports being grade 1-2, requiring no special management. In rare severe cases, dose adjustments and symptomatic supportive treatment may be performed.
08
Infusion Reactions
Infusion reactions typically present as flushing, chills, fever, dyspnea, hypotension, wheezing, bronchospasm, and tachycardia. The incidence of infusion-related reactions for T-DM1 is 1.4%-1.6%, while for T-DXd it is 2.6%.
Management: Patients should be closely monitored for infusion reactions, especially during the first infusion. The first infusion duration for T-DM1 and T-DXd should be >90 minutes; if well tolerated, subsequent infusions may be >30 minutes. The first infusion duration for Gemtuzumab ozogamicin should be >3 hours; if well tolerated, subsequent infusions can be maintained at 1-2 hours. Patients should be observed for symptoms or signs at least 30 minutes during and after the Gemtuzumab ozogamicin infusion. If an infusion reaction occurs, the infusion speed should be slowed or paused; if severe or life-threatening infusion reactions occur, treatment should be permanently discontinued. Patients who have had severe infusion-related reactions or hypersensitivity reactions to any drug component of the ADC should not use this drug.
Prior to each infusion of Gemtuzumab ozogamicin, antipyretic agents, H1 and H2 receptor blockers can be premedicated, and patients with a history of infusion reactions may use glucocorticoids. Additionally, a dual (e.g., dexamethasone combined with 5-HT3 receptor antagonists or NK1 receptor antagonists) or triple premedication regimen (where the third drug can be selected based on indications) may be implemented.
Conclusion
Most serious or dose-limiting adverse reactions from ADC treatments are mediated by cytotoxic drugs and/or their metabolites, and common adverse reactions overlap significantly with those seen in conventional chemotherapy.
However, as ADCs are “components” with many parts and a newer technology, they also have unique adverse reactions that may be mechanistically unclear, catching those unfamiliar with them off guard and potentially leading to fatal adverse reactions—requiring special attention to adverse reactions.
References
The Breast Cancer Group of the Oncology Physician Branch of the Chinese Medical Association, The International Medical Exchange Branch of the Chinese Anti-Cancer Association. Chinese Expert Consensus on the Safety Management of Breast Cancer Antibody-Drug Conjugates [J]. Chinese Journal of Oncology, 2022, 44(9):913-927.
DOI: 10.3760/cma.j.cn112152-20220521-00360
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Note: This article is for informational purposes only and does not provide professional medical advice. Please consult a qualified healthcare professional for specific medical guidance.
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