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The main points of clinical use of 8 ADC drugs

2021-04-27
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Antibody-Drug Conjugate (ADC) is a class of targeted biological agents that conjugate target-specific monoclonal antibodies to highly lethal cytotoxic drugs through a specific connector.Small molecule cytotoxic drugs can be efficiently delivered to target tumor cells by using monoclonal antibodies as the carrier. Therefore, ADC drugs have been one of the hot research directions in the field of tumor precision therapy in recent years. At present, 8 ADC drugs have been approved for clinical use in the world (including the fields of hematological tumors and solid tumors, Table 1).

Table 1 ADC drugs that have been approved for clinical use

Drug nameIndications
Enmetrastuzumab (T-DM1)Second-line treatment of advanced breast cancer with positive HER-2;Adjuvant therapy of breast cancer with residual lesions after anti-HER-2 neoadjuvant therapy
Verbutuximab (BV)Classic Hodgkin’s lymphoma;Systemic anaplastic large cell lymphoma or CD30 positive peripheral T cell lymphoma;Primary CD30 interdermal degenerative large cell lymphoma or CD30 positive herbiid granuloma
polatuzumab vedotin (PV)Combination of bendamustine and rituximab in the treatment of refractory or relapsed diffuse large B-cell lymphoma
trastuzumab deruxtecan (TD)Previously received ≥2 anti-HER-2 therapies, unresectable or metastatic HER-2 positive breast cancer
sacituzumab govitecan (SG)Metastatic triple-negative breast cancer that has received at least second-line treatment in the past
gemtuzumab ozogamicin (GO)CD33 positive acute myeloid leukemia
inotuzumab ozogamicin (IO)Adult relapsed or refractory CD22-positive precursor B-cell acute lymphoblastic leukemia
enfortumab vedotin (EV)Locally advanced or metastatic urothelial carcinoma with prior platinum-based chemotherapy and 1 PD-1/L1 inhibitor treatment.

Different ADC drugs have different adverse reactions due to different antibody and cytotoxic drugs.During the period of medication, the corresponding adverse reactions should be closely monitored, and the adverse reactions that may produce serious consequences should be actively prevented or given supportive treatment;In case of suspected adverse symptoms, close attention should be paid and timely diagnosis should be made. After the occurrence of adverse reactions, the corresponding treatment plan should be given. At the same time, the drug treatment plan should be adjusted to delay treatment or reduce dosage.For adverse reactions that are difficult to deal with, multidisciplinary consultation should be carried out in time to explore solutions.

Table 2 Common adverse reactions related to ADC drugs and precautions

Adverse reactionsPrecautions
Hematological Adverse ReactionPerform a complete blood count check before the application of ADC drugs. For patients who do not meet the treatment requirements, the drugs should be used with caution, and the drugs can be used after the blood indicators return to normal or the supportive treatment has returned to normal. Regularly monitor blood cell counts during treatment, and consider preventive medications for secondary prevention.
Infusion reactionFor patients at risk, corticosteroids, acetaminophen, and/or diphenhydramine should be pre-administered to minimize the risk of IRR.Monitor whether there is an infusion reaction during infusion and at least 1h after infusion.For patients with infusion reaction, infusion can be interrupted in time and symptomatic treatment with steroid hormones or antihistamines can be given.For patients with severe transfusion reactions, permanent discontinuation of the drug is recommended.
Peripheral neuropathyWhen severe peripheral neuropathy (Grade 3) occurs during ADC treatment, if the patient is unable to walk due to limb weakness and needs tools to assist in walking, or because of limb numbness and pain, after treatment with medications for neuralgia, life If the quality is still severely affected, causing difficulties in life, ADC treatment should be suspended; if symptoms improve and the patient is able to take care of themselves, consider restarting treatment and adjust the ADC dose to a lower level; if more serious neuropathy occurs (Grade 4), when the patient’s life is endangered, ADC treatment should be terminated immediately.
Liver toxicityRoutine liver function tests, and timely intervention when abnormal liver function occurs
Pulmonary toxicityDuring treatment, suggest that patients in a cough, dyspnea, fever, and/or deterioration of any new respiratory symptoms, should immediately report, at the same time pay close attention to whether patients with interstitial lung disease symptoms, signs and imaging changes, timely find evidence of interstitial lung disease, suspected in patients with interstitial lung disease respiratory consultation, please.For asymptomatic (grade 1) interstitial lung disease, steroid corticosteroid therapy (such as ≥0.5mg/kg prednisolone or other hormones with equivalent dose titer) should be considered, and treatment can be continued.If symptomatic (grade 2 or higher) interstitial lung disease is present, corticosteroid therapy (such as ≥1mg/kg prednisolone or other hormone with equivalent dose titer) should be initiated immediately.After stable symptom control and improved shadow absorption on radiography, corticosteroid dose should be gradually reduced and maintained for a relatively long course of treatment (e.g. 4 weeks).Patients diagnosed with symptomatic (grade 2 or higher) interstitial lung disease should be permanently discontinued.If the symptoms continue to worsen, multidisciplinary consultation is recommended and active intervention is recommended to avoid developing into a fatal outcome.
Adverse gastrointestinal reactionsGastrointestinal reactions are common adverse reactions of ADC drugs, including nausea, vomiting, and diarrhea. They are usually mild. If severe gastrointestinal reactions occur, they need to be closely monitored and actively treated.
CardiotoxicityCardiotoxicity is a common toxicity of anti-HER-2 drugs, usually manifested as a decrease in left ventricular ejection fraction (LVEF).Before application of TD and T – DM1, dealing with patients with comprehensive assessment, including personal history and family history, fully correct cardiovascular disease risk factors, such as cardiovascular disease, the basis of standard treatment combined record baseline electrocardiogram and echocardiography, always received anthracycline-based drugs to treat patients, need to determine baseline troponin and natriuretic peptide.During treatment, electrocardiogram and echocardiography should be rechecked dynamically and regularly. If necessary, the detection of myocardial markers such as brain natriuretic peptide or amino-terminal brain natriuretic peptide, cardiac troponin I or hypersensitive troponin should be improved.Objectively evaluate cardiac function and the risk of cardiotoxic events, early detection, timely diagnosis and treatment.In patients with baseline hypertension, angiotensin-converting enzyme inhibitors or angiotensin-Ⅱ receptor antagonists and beta-blockers are preferred antihypertensive agents.For patients with asymptomatic cardiac insufficiency, please cardiovascular specialist consultation, taking angiotensin converting enzyme inhibitors or angiotensin Ⅱ receptor antagonist and beta blockers, on the basis of ADC and drug treatment may continue to increase LVEF monitoring frequency (e.g., 1 times every 4 weeks), absolute values such as LVEF < 50% (down by 16% or higher),Or in the normal range but the decrease of LVEF ≥10% during treatment, ADC medication should be suspended, and angiotensin-converting enzyme inhibitors or angiotensin-Ⅱ receptor antagonists and β-blockers should be given, and LVEF should be reexamined within 3-4 weeks, and treatment should be carried out after LVEF returns to normal.If the reduction of LVEF is irreversible or severely reduced, or the occurrence of symptomatic congestive heart failure, medication should be permanently discontinued, and if necessary, consult a cardiovascular specialist for consultation, and timely diagnose and treat heart failure with reference to the standard procedures recommended by guidelines such as Anthracyclines Cardiotoxicity Prevention and Treatment Guidelines (2020) issued by the Chinese Society of Clinical Oncology.

References:

Chinese Anti-Cancer Association Cancer Drug Clinical Research Professional Committee, National Anti-Cancer Drug Clinical Application Monitoring Expert Committee, National Cancer Quality Control Center Breast Cancer Expert Committee, etc. Expert consensus on the clinical application of antibody-drug conjugates in the treatment of malignant tumors (2020 edition) [J]. Chinese Journal of Medical Frontiers (Electronic Edition), 2021, 13(1): 1-15.

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