Clinical necessity: Consensus on the safety of clinical application of urothelial carcinoma antibody conjugate drugs

Guide

A number of antibody conjugate drugs (ADCs) have been used in the treatment of urothelial carcinoma at home and abroad, including enrozumab (EV), gosatuzumab (SG) and widecitumab (study code: RC48).

At present, the use of ADC drugs in the treatment of advanced urothelial carcinoma in China has not been widely carried out, and there is a lack of experience in its rational application and adverse reaction management
.

The effective use of ADC drugs is of great significance to ensure and improve the efficacy of ADC drugs and the quality of life of patients, and the Urology Professional Committee of China Association for the Promotion and Exchange of Healthcare International and the Urology Professional Committee of China Research Hospital Association have formulated a consensus on the safety of clinical application of ADC drugs in patients with advanced urothelial cancer, aiming to promote the safe application of
ADC drugs in patients with urothelial carcinoma in China.
The main points of the medical pulse are as follows
.

Clinical specific implementation operations

1.
Rationalization of patient indications

There are three kinds of ADC drugs at home and abroad for the treatment of advanced urothelial carcinoma, namely EV, SG and RC48, which have shown superior efficacy
.

Table 1 ADC drug recommendations for advanced urothelial carcinoma

2.
Pre-medication evaluation and contraindications

(1) Adverse reactions related to ADC drug treatment can involve multiple organs throughout the body, and there are differences
between the adverse reaction spectra of each drug due to different antibodies and cytotoxic drugs.
Therefore, patients should undergo a thorough and systematic evaluation
prior to ADC therapy.
In addition to the routine performance status (ECOG performance status score), hematologic indicators, and comorbidities, the functional status of the target organ in which adverse reactions occur should also be evaluated
before medication.
If there is rash, itching, vitiligo, etc.
, it is necessary to record the location and severity of occurrence, evaluate the basic cardiopulmonary function, whether there is an underlying ocular disease, and the metabolic and endocrine system status such as blood sugar and blood lipids
.

(2) EV is not recommended for patients with active keratitis or corneal ulcer, and EV or RC48
is not recommended for patients with sensory or motor neuropathy of grade 2 or above.
Hypersensitivity to the active ingredient or any excipient in the ADC drug is a contraindication to ADC drugs
.

3.
Medication method and efficacy evaluation

(1) The dosage regimens and doses of the three ADC drugs are shown in Table 2, and the administered dose is calculated
according to body weight.
The department administering chemotherapy must have ECG monitoring, necessary rescue drugs and measures
.
Patients need ECG monitoring during infusion, and specialist nurses or physicians should closely monitor the infusion response at the bedside during the infusion (especially at the time of the first infusion) and observe it for at least 1 hour after the end of the infusion, especially in patients
taking the drug for the first time.

Table 2 ADC drug dosing regimen and dose

(2) Patients should be evaluated according to the efficacy evaluation criteria (RECIST1.
1) of solid tumors before and during treatment with ADC drugs, and pay attention to the evaluation
of patients' quality of life during ADC drug treatment.

Expert consensus recommends: According to the existing evidence-based medical evidence and the current situation in China, after discussion by the urological oncology multidisciplinary diagnosis (MDT) team, ADC drug
treatment should be received with the patient's knowledge and full communication.
Before and during medication, the patient's physical condition should be comprehensively evaluated, including the baseline status and treatment changes of each important organ, especially the adverse reactions that ADC drugs need to pay attention to, so as to ensure the safety of ADC drug treatment to the greatest extent
.
When using ADC drugs, they should be administered
strictly according to the recommended dosage regimen and dose.
Be alert to the occurrence of infusion reactions, and if necessary, give pretreatment medication to ensure the smooth progress of treatment, and evaluate according to RECIST1.
1 criteria during treatment
.

Management and control of clinical risk events

Adverse effects of ADC drugs vary
due to differences in antibodies, linkers, and cytotoxic drugs.
This consensus classifies the common adverse reactions of three ADC drugs according to different systems of adverse reactions, namely skin reactions, ocular toxicity, gastrointestinal reactions, hematological toxicity, neurotoxicity, hepatotoxicity, pulmonary toxicity, metabolic abnormalities and other adverse reactions
.

Expert consensus recommends: ADC drugs due to the unique tissue structure and mechanism of action, different from previous chemotherapy drugs, targeted drugs and immunotherapy drugs, its adverse reactions mainly from the target monoclonal antibody off-target effect and coupled cytotoxic drugs, etc.
, can involve multiple organ systems, severe cases can be life-threatening, the treatment of adverse reactions should be fully combined with MDT mechanism, early detection, timely treatment, to avoid serious adverse reactions
。 The Nectin-4 molecule targeted by EV is associated with the expression of normal skin tissue and corneal epithelium, so the application of EV requires special attention to skin reaction and ocular toxicity, and regular dermatological and ophthalmic evaluation
.
Among the adverse reactions caused by ADC drug conjugation cytotoxic drugs, gastrointestinal reactions, bone marrow suppression, and neurotoxicity are common adverse reactions
.
SG-induced diarrhea and neutropenia are associated with a higher incidence, while EV and RC48 require particular attention for neurotoxicity
.
For ADC drugs combined with PD-1/PD-L1 monoclonal antibodies, a high degree of vigilance
should be exercised for possible more severe adverse effects.

The principle of dose reduction and discontinuation

ADC drug-related adverse reactions are mainly graded according to the evaluation criteria for common adverse reactions (CTCAE), and the treatment of reducing or discontinuing the drug according to the different levels of occurrence (Table 3).

Clinically, special adverse reactions should be paid attention to in the management of adverse reactions, and MDT consultation should be established and actively carried out to ensure the safety
of patients.
The general principle is that grade 1 adverse effects can be continued; Most of the grade 2 adverse reactions can continue to use the original dose, and some adverse reactions such as thrombocytopenia, neurotoxicity and corneal lesions need to be suspended, and continue to be used after recovery to grade 1; For grade 3 adverse reactions, ADC drug treatment should be suspended in time, and reduced therapy should be given after the adverse reactions return to grade 1; Grade 4 adverse reactions or repeated occurrence of Grade 3 reactions should consider discontinuation of treatment (Table 4).

Table 3 ADC drug dose reduction scheme

Table 4 Basic principles of ADC drug dose adjustment

Expert consensus recommends: for adverse reactions that may occur during the application of ADC drugs, active preventive treatment should be given before treatment; After medication, relevant adverse reactions should be closely monitored, timely diagnosis and corresponding treatment plan should be given, and drug treatment regimen should be re-evaluated, and treatment should be extended or reduced if necessary; For serious adverse reactions, the drug should be stopped in time, and multidisciplinary consultations should be actively carried out to explore solutions
.

Special population handling

1.
People with diabetes

ADC drugs affect glycolipid metabolism in the body, and it is recommended that diabetic patients stabilize blood sugar control before starting treatment
.
Both EVs and RC48 reported an incidence of elevated blood glucose of more than 10%, and SG reported an even lower incidence of elevated blood glucose, less than 1%.

2.
Eye diseases

EV therapy is not recommended for patients with active keratitis or corneal ulcers
.

3.
Renal insufficiency

Patients with renal insufficiency do not require adjustment of EV dose, including severe renal insufficiency (creatinine clearance < 30 mL/min).
<b10> SN-38 is practically not cleared from the kidneys, but there are no pharmacokinetic data
for renal insufficiency or end-stage renal disease.
RC48 does not require dose adjustment in patients with mild or moderate renal impairment, and there are no research data
in patients with severe renal impairment.

The expert consensus recommends that the basic organ function of patients before ADC drug treatment should be fully evaluated, and patients with specific underlying diseases should be applied under close monitoring after excluding contraindications to ensure the safety
of patients.

References:

[1] Urology Health Promotion Branch of China Association for International Promotion and Exchange of Healthcare Care, Urology Professional Committee of China Research Hospital Association.
Safety consensus on clinical application of urothelial carcinoma antibody conjugate drugs (1st edition)[J].
Journal of Modern Urology,2022,27(8):628-634.
)