Expert consensus on the clinical application of antibody‐drug conjugates in the treatment of malignant tumors (2021 edition)

Abstract

Antibody‐drug conjugates (ADCs) are targeted biological agents composed of a cytotoxic drug linked to a monoclonal antibody through a linker. The monoclonal antibody targets tumor cells and transports small‐molecule cytotoxic drugs for specific delivery and minimal off‐target side effects. It is necessary for clinicians to understand the molecular characteristics and mechanisms of ADCs. Patients' survival mainly depends on the appropriate dose and course of treatment and also on proper management of adverse reactions. This consensus provides a systematic review of commercially available ADCs and further discusses the clinical application and management of ADCs.

This consensus summarizes the mechanisms, clinical applications, and safety management of the 14 currently approved antibody‐drug conjugates (ADCs), providing guidance for clinicians to better understand and use these drugs.

Abbreviations

ACEIs

angiotensin‐converting enzyme inhibitors

ADCs

antibody‐drug conjugates

AML

acute myelogenous leukemia

APL

acute promyelocytic leukemia

ARBs

angiotensin II receptor antagonists

ASCT

autologous stem cell transplantation

BBs

β‐blockers

BM

belantamab mafodotin

BR

bendamustine + rituximab

BV

brentuximab vedotin

CHL

classical Hodgkin lymphoma

CR

complete response

CS

cetuximab sarotalocan

DLBCL

diffuse large B‐cell lymphoma

DM1

maytansinoid

DOR

duration of response

DV

disitamab vedotin

ECG

electrocardiogram

EV

enfortumab vedotin

FL

follicular lymphoma

GEJ

gastroesophageal junction

GLS

global longitudinal strain

GO

gemtuzumab ozogamicin

HCL

hairy cell leukemia

HER2

human epidermal growth factor receptor 2

HR

hazard ratio

HSCT

hematopoietic stem cell transplantation

iDFS

invasive disease‐free survival rate

IgG1

immunoglobulin G1

IHC

Immunohistochemistry

ILD

interstitial lung disease

IO

Inotuzumab ozogamicin

IT

loncastuximab tesirine‐lpyl

LVEF

left ventricular ejection fraction

MMAE

monomethyl auristatin E

MP

moxetumomab pasudotox‐tdfk

NMPA

China National Medical Products Administration

ORR

objective response rate

PD‐1

programmed cell death‐1

PD‐L1

programmed cell death‐ligand 1

PFS

progression‐free survival

PV

polatuzumab vedotin

Q3W

every 3 weeks

SAE

severe adverse event

sALCL

systemic anaplastic large cell lymphoma

SG

sacituzumab govitecan‐hziy

T‐DM1

trastuzumab emtansine

TD

trastuzumab deruxtecan

TF‐011

tissue factor

TROP‐2

trophoblast cell surface antigen 2

TV

tisotumab vedotin

UC

urothelial cancer

1. INTRODUCTION

Antibody‐drug conjugates (ADCs) are targeted biological agents featured by coupling highly potent cytotoxic drugs with specific monoclonal antibodies through linkers, allowing the monoclonal antibody to act as carriers that transport the cytotoxic drug to target tumor cells [1]. The concept of ADCs stemmed from the “magic bullets” proposed by Paul Ehrlich, and the rapid progression with nonimmunogenic (especially humanized) monoclonal antibodies had made it technically possible [2]. The tumor‐specific antibodies allow selective delivery of small‐molecule cytotoxic drugs, reducing off‐target side effects while retaining antitumor properties to greatly improve the benefit‐risk ratio of antitumor therapy [3]. Therefore, ADCs have become one of the hotspots in precision therapy for cancer treatment in recent years. Currently, there are 14 ADCs approved for clinical treatment of hematological and solid tumors (Table 1), with more than 100 ongoing clinical studies of ADCs [2].

Table 1.

List of antibody‐drug conjugates that have been approved for marketing

Product name	Target	Cytotoxic drug	Indication	Approval
Gemtuzumab	CD33	Calicheamycin	CD33‐positive acute myelogenous leukemia	Approved in 2000, withdrawn in 2010 Re‐approved in the United States in 2017 Approved in EU in 2018
Brentuximab vedotin	CD30	Monomethyl auristatin E	Classical Hodgkin lymphoma; systemic anaplastic large cell lymphoma or CD30‐positive peripheral T‐cell lymphoma; primary CD30‐positive cutaneous anaplastic large cell lymphoma or CD30‐positive mycosis fungoides	Approved in the United States in 2011 Approved in EU in 2012 Approved in China in 2020
Trastuzumab emtansine	HER2	Maitansine derivative	HER2‐positive advanced breast cancer patients who were previously treated with trastuzumab and taxanes alone or in combination. Patients should meet one of the following criteria: pretreated metastatic disease; relapse during adjuvant therapy; relapse within 6 months after adjuvant therapy Adjuvant therapy for HER2‐positive early breast cancer patients with the residual invasive disease after taxane‐based and trastuzumab‐based neoadjuvant therapy	Approved in the United States in 2013 Approved in EU in 2013 Approved in Japan in 2013 Approved in China in 2020
Inotuzumab ozogamicin	CD22	Calicheamycin	Relapsed or refractory CD22‐positive B‐cell acute lymphoblastic leukemia in adults	Approved in the United States in 2017 Approved in EU in 2017
Polatuzumab vedotin‐piiq4	CD79b	Monomethyl auristatin E	In combination with bendamustine and rituximab for the treatment of relapsed or refractory diffuse large B‐cell lymphoma	Approved in the United States in 2019 Approved in EU in 2019
Enfortumab vedotin‐ejfv5	Nectin‐4	Monomethyl auristatin E	Adult patients with locally advanced or metastatic urothelial cancer (mUC) who have previously received a programmed death receptor‐1 (PD‐1) or programmed death‐ligand 1 (PD‐L1) inhibitor and platinum‐containing chemotherapy, or are ineligible for cisplatin‐containing chemotherapy and have previously received one or more prior lines of therapy	Approved in the United States in 2019
Trastuzumab deruxtecan‐nxki6	HER2	Exatecan derivative	Unresectable or metastatic HER2‐positive breast cancer with over 2 types of anti‐HER2 therapies for metastatic disease Locally advanced or metastatic HER2‐positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who had received trastuzumab	Approved in the United States in 2019 Approved in EU in 2021
Sacituzumab govitecan‐hziy	TROP‐2	SN‐38, the active metabolite of irinotecan	Unresectable locally advanced or metastatic triple‐negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease Locally advanced or metastatic urothelial cancer (mUC) who have previously received a platinum‐containing chemotherapy and either programmed death receptor‐1 or programmed death‐ligand 1 inhibitor	Approved in the United States in 2020 Approved in EU in 2021
Moxetumomab pasudotox‐tdfk	CD22	PE38	Relapsed or refractory hairy cell leukemia in adults with a history of the second‐line or first‐line therapy	Approved in the United States in 2018 Approved in EU in 2021
Belantamab mafodotin	BCMA	MMAF	Treatment of adults with relapsed or refractory multiple myeloma who have received at least 4 prior therapies, including an anti‐CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent	Approved in the United States in 2020 Approved in EU in 2020
Cetuximab sarotalocan	EGFR	IRDye700DX	Unresectable locally advanced or recurrent head and neck cancer	Approved in Japan in 2020
Loncastuximab tesirine‐lpyl	CD19	PBD	Relapsed or refractory large B‐cell lymphoma (LBCL) in adult patients who have received at least 2 types of systemic therapies, including diffuse large B‐cell lymphoma (DLBCL), DLBCL arising from low‐grade lymphoma, and high‐grade lymphoma	Approved in the United States in 2021
Vedetuximab	HER2	MMAE	Patients with HER2‐overexpressed locally advanced or metastatic gastric cancer (including GEJ adenocarcinoma) who have undergone two or more prior lines of systemic chemotherapies	Approved in 2021 in China
Tisotumab vedotin‐tftv	TF‐011	MMAE	Recurrent or metastatic cervical cancer with disease progression on or after chemotherapy	Approved the United States in 2021

Note: Deadline: December 31, 2021.

Abbreviations: HER2, human epidermal growth factor receptor 2; PD‐1, programmed death receptor 1; PD‐L1, programmed death receptor ligand 1; TROP‐2, trophoblast cell surface antigen 2.

Apart from an adequate understanding of ADCs' development and mechanism, a standardized workflow also contributes to the survival outcome of the patients. Clinical application of ADCs involves four critical steps: patient screening, dose selection, treatment course decision, as well as management of adverse reactions [4]. Therefore, this consensus aims to systematically review ADCs available in the market, clarify their usage, and discuss patient management for clinicians. ADCs that have been approved over the world are the focus of this consensus (Table 2).

Table 2.

Common ADCs and recommended dosages

Product name	Indication	Common dosing regimens and doses
Gemtuzumab	Adults and children ≥1 month with naive CD33‐positive AML	Induction phase: 3 mg/m2 (Days 1, 4, 7) in combination with daunorubicin and cytarabine Consolidation phase: 3 mg/m2 (Day 1) in combination with daunorubicin and cytarabine
	Adults and children ≥1 month with naive CD33‐positive AML	Induction phase: 6 mg/m2 (Day 1), 3 mg/m2 (Day 8) Consolidation phase: 2 mg/m2 (Day 1) every 4 weeks. For patients without evidence of disease progression after induction, the treatment was continued until eight cycles
	Adults and children ≥2 years with relapsed or refractory CD33‐positive AML	3 mg/m2 (Daya 1, 4, 7)
Brentuximab vedotin	Consolidation therapy for CHL patients with a high risk of relapse or progression after ASCT CHL who is not eligible for ASCT, after the failure of ASCT, or after the failure of at least two types of multiagent chemotherapy SALCL after the failure of at least one type of multiagent chemotherapy Primary cutaneous anaplastic large cell lymphoma or CD30‐positive mycosis fungoides with a history of systemic therapy	1.8 mg/kg (maximum dose of 180 mg) every 3 weeks
	Untreated staged III and IV CHL	1.2 mg/kg (maximum dose of 120 mg) every 2 weeks (up to 12 cycles) in combination with chemotherapy
	Untreated sALCL or other CD30‐expressing peripheral T‐cell lymphoma	1.8 mg/kg (maximum dose of 180 mg) every 3 weeks (six to eight cycles) in combination with chemotherapy
Trastuzumab emtansine	HER2 positive advanced breast cancer patients who were previously treated with trastuzumab and taxanes alone or in combination. Patients should meet one of the following criteria: pretreated metastatic disease; relapse during adjuvant therapy; relapse within 6 months after adjuvant therapy Adjuvant therapy for HER2 positive early breast cancer patients with the residual invasive disease after taxane‐based and trastuzumab‐based neoadjuvant therapy	3.6 mg/kg every 3 weeks until disease progression or intolerable toxicity, or up to 14 cycles of adjuvant therapy for patients with early breast cancer
Inotuzumab ozogamicin	Relapsed or refractory B‐cell acute lymphoblastic leukemia in adults	Cycle 1 (21 days): 0.8 mg/m2 (Day 1), 0.5 mg/m2 (Day 8), 0.5 mg/m2 (Day 15) Subsequent cycle doses depend on the response of patients to treatment: Patients with CR or CRi: 0.5 mg/m2 (Day 1), 0.5 mg/m2 (Day 8), 0.5 mg/m2 (Day 15) every 28 days Patients without CR or CRi: 0.8 mg/m2 (Day 1), 0.5 mg/m2 (Day 8), 0.5 mg/m2 (Day 15) every 28 days
Polatuzumab vedotin‐piiq4	Adult patients with pretreated diffuse large B‐cell lymphoma who are not eligible for hematopoietic stem cell transplantation	1.8 mg/kg (Day 1) every 3 weeks (six cycles of 21 days) in combination with bendamustine and rituximab
Enfortumab vedotin‐ejfv5	Adult patients with locally advanced or metastatic urothelial cancer (mUC) who have previously received a programmed death receptor‐1 (PD‐1) or programmed death‐ligand 1 (PD‐L1) inhibitor and platinum‐containing chemotherapy, or are ineligible for cisplatin‐containing chemotherapy and have previously received one or more prior lines of therapy	1.25 mg/kg (maximum dose of 125 mg infused over 30 min) on Days 1, 8, and 15 (in 28‐day cycles) until disease progression or intolerable adverse reactions
Trastuzumab deruxtecan‐nxki6	Unresectable or metastatic HER2‐positive breast cancer with over two types of anti‐HER2 therapies for metastatic disease Locally advanced or metastatic HER2‐positive gastric or GEJ adenocarcinoma who had received trastuzumab	5.4 mg/kg every 3 weeks until disease progression or intolerable adverse reactions
Sacituzumab govitecan‐hziy	Unresectable locally advanced or metastatic triple‐negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease Locally advanced or metastatic urothelial cancer (mUC) who have previously received a platinum‐containing chemotherapy and either programmed death receptor‐1 or programmed death‐ligand 1 inhibitor	10 mg/kg on Days 1 and 8 (21‐day cycles) until disease progression or intolerable adverse reactions
Moxetumomab pasudotox‐tdfk	Relapsed or refractory hairy cell leukemia in adults with a history of the second‐ or first‐line therapy	0.04 mg/kg on Days 1, 3, and 5 (28‐day cycles) for six cycles or until disease progression or intolerable adverse reactions
Belantamab mafodotin	Treatment of adults with relapsed or refractory multiple myeloma who have received at least four prior therapies, including an anti‐CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent	2.5 mg/kg every 3 weeks until disease progression or intolerable adverse reactions
Cetuximab sarotalocan	Unresectable locally advanced or recurrent head and neck cancer	640 mg/m2 (body surface area), intravenously, over 2 h daily. 20–28 h after intravenous drip, the lesion site was irradiated with a laser
Loncastuximab tesirine‐lpyl	Relapsed or refractory large B‐cell lymphoma in adult patients who have received at least 2 lines of systemic therapies, including DLBCL not otherwise specified, DLBCL arising from low‐grade lymphoma, and high‐grade lymphoma	0.15 mg/kg every 3 weeks for two cycles, then 0.075 mg/kg every 3 weeks until disease progression or intolerable toxicity
Vedetuximab	HER2‐overexpressing locally advanced or metastatic gastric cancer (including gastroesophageal junction adenocarcinoma) who have received at least 2 types of systemic chemotherapies	2.5 mg/kg every 2 weeks until disease progression or intolerable adverse reactions
Tisotumab vedotin‐tftv	Adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy	2.0 mg/kg (up to a maximum of 200 mg) intravenously once every 3 weeks until disease progression or intolerable adverse reactions

Abbreviations: AML, acute myelogenous leukemia; ASCT, autologous stem cell transplantation; CHL, classical Hodgkin lymphoma; CR, complete response; CRi, complete response with incomplete blood count recovery; HER2, human epidermal growth factor receptor 2; PD‐1, programmed death receptor 1; PD‐L1, programmed death receptor ligand 1; sALCL, systemic anaplastic large cell lymphoma.

The diversity of ADCs' targets and mechanisms posed many difficulties in summarizing currently approved ADCs for multiple malignant tumors. The professional Committee on Clinical Research of Oncology Drugs, Chinese Anticancer Association; Expert Committee for Monitoring the Clinical Application of Antitumor Drugs; Breast Cancer Expert Committee of National Cancer Quality Control Center in conjunction with Cancer Chemotherapy Quality Control Expert Committee of Beijing Cancer Treatment Quality Control and Improvement Center, jointly organized and invited specialists in diagnosis and treatment of various oncology disciplines and interdisciplinary specialists in related fields to draft this consensus. It is expected to promote the clinical research of ADCs, standardize their clinical application, and enhance the safety management of ADCs.

1.1. Definition of ADCs

ADCs are a class of targeted biopharmaceuticals composed of a highly potent cytotoxic drug conjugated to a target‐specific monoclonal antibody through specific linkers. ADCs usually have three components: an antibody with high specificity and affinity, a stable linker, and an effective small‐molecule cytotoxic drug [4, 5].

1.2. Clinical application

ADCs are innovative antitumor drugs with novel mechanisms. Previous clinical data indicates good efficacy and safety of ADCs for the treatment of cancer. This consensus aims to facilitate the standard and safe use of ADCs to benefit more cancer patients.

1.3. Multidisciplinary management

The adverse reactions of ADCs are dependent on a variety of factors, such as physiological function and positive rate of nontumor tissue targets, the nature of linkers, the number and type of cytotoxic drugs, and bystander effect. Specific adverse reactions should be closely observed to administrate symptomatic treatment when appropriate. Consultations with medical experts of specific disciplines help to minimize adverse reactions and to improve quality of life.

2. CLINICAL DATA AND RELEVANT CONSENSUS ON ADCS

Currently, there are 14 ADCs used in clinical practice worldwide. Twelve have been approved by the US FDA, 9 by the European Union, 3 by China, and 1 drug only has been marketed in Japan (Table 1).

2.1. Hematologic neoplasm

2.1.1. Brentuximab vedotin (BV)

BV (SGN‐35) is a class of potent ADCs confirmed in clinical practice. It is composed of a monoclonal antibody targeting CD30 (recombinant chimeric immunoglobulin G1 (IgG1) produced by recombinant DNA technology in Chinese hamster ovary cells) covalently linked to the antimicrotubule drug monomethyl auristatin E (MMAE) (the average ratio of MMAE to the monoclonal antibody is 4:1). MMAE interferes with tubulin polymerization and disrupts mitosis, which, in turn, induces cell cycle arrest and apoptosis [6]. In addition to direct cytotoxicity of MMAE upon binding to CD30‐positive lymphocytes, BV enhances antitumor effects also by antibody‐dependent phagocytosis, immunogenic cell death, and bystander killing.

Initially, two phase II studies confirmed the efficacy of BV in classical Hodgkin lymphoma (CHL) and systemic anaplastic large cell lymphoma (sALCL) [7, 8]. After BV treatment, the objective response rate (ORR) in relapsed or refractory CHL (n = 102) was up to 75%, and the 5‐year survival rate was 41% [7], while the ORR and 5‐year survival rate in relapsed or refractory sALCL (n = 58) were up to 86% and 60%, respectively [8]. Subsequently, a phase III study AETHERA (n = 329) concerning relapsed or refractory Hodgkin's lymphoma further confirmed that 16 cycles of consolidation therapy with BV significantly improved median progression‐free survival PFS compared with placebo after autologous stem cell transplantation (ASCT) (42.9 and 24.1 months, respectively, p = 0.0013) [9]. The most common adverse effects of BV are infection, nausea, fatigue, diarrhea, peripheral sensory and motor neuropathy, neutropenia, hyperglycemia, and rashes. The incidence of hyperglycemia ≥ grade 3 is about 3%. The most common adverse reaction (28%) in patients treated with BV is peripheral motor neuropathy, but grade 2 adverse reactions are prominent. About 13% of patients experience infusion‐related reactions (IRRs) [1].

In 2011, the US FDA granted BV approval for patients with Hodgkin lymphoma after failure of ASCT or at least two cycles of multiagent chemotherapy in non‐ASCT candidates. BV was also indicated for patients with sALCL after the failure of at least one cycle of multiagent chemotherapy. In May 2020, it was officially approved by National Medical Product Administration for marketing, and the indications approved in China are relapsed or refractory sALCL or CHL.

2.1.2. Polatuzumab vedotin (PV)

PV is composed of a recombinant humanized CD79b (a B‐cell receptor component highly expressed in most patients with malignant lymphoma) monoclonal antibody, a cleavable linker, and MMAE cytotoxic agents. After endocytosis and adapter cleavage by PV, the released MMAE inhibits cell mitosis and induces apoptosis [10].

ROMULUS phase Ib‐II study (n = 39) showed that the ORR and complete response (CR) rate of patients with relapsed or refractory diffuse large B‐cell lymphoma (DLBCL) after PV plus rituximab treatment were 54% and 21%, while those of patients with follicular lymphoma (FL) (n = 20) were 70% and 45%, respectively [11]. In addition, the median PFS and overall survival (OS) of patients with DLBCL after PV treatment were 5.6 and 20.1 months, while those of patients with FL were 15.3 months and not achieved, respectively [11]. PV plus otuzumab achieved an ORR of 52% in relapsed or refractory DLBCL (n = 21) and 78% in FL (n = 23) [10]. In patients with relapsed or refractory DLBCL who were eligible for hematopoietic stem cell transplantation (HSCT), the CR rate assessed by positron emission tomography was significantly higher for the P‐BR (PV + bendamustine + rituximab) regimen (40%) compared to the BR (bendamustine + rituximab) regimen (18%, p = 0.026). The time of disease control was also significantly prolonged (10.3 and 4.1 months, p = 0.032), and the OS was prolonged nearly threefold in the P‐BR regimen group (12.4 and 4.7 months, p = 0.0023) [12]. The common PV‐related adverse reactions included leukopenia (40%), anemia (11%), and peripheral sensory neuropathy (9%) [10].

In 2019, FDA approved the PV + bendamustine + rituximab scheme for refractory or relapsed diffuse large B‐cell lymphoma.

2.1.3. Gemtuzumab ozogamicin (GO)

GO consists of a recombinant humanized IgG4‐targeted CD33 monoclonal antibody; a hydrazone containing, acid‐labile, redox‐sensitive disulfide linker; and a cytotoxic drug with a calicheamicin derivative (N‐acetyl‐gamma‐sporinomycin‐ dimethyl). Calicheamicin is a potent cytotoxic enediyne antibiotic that causes double‐strand breaks and ultimately cell death by binding to the minor groove of DNA [13].

In 2000, GO (9 mg/m², twice on Days 1 and 15) was approved by FDA for patients with relapsed CD33‐positive acute myelogenous leukemia (AML) who are aged ≥ 60 years and not eligible for cytotoxic chemotherapy, based on positive findings from three phase II single‐arm studies in CD33‐positive patients with relapsed AML (Studies 201, 202, 203) [14]. However, the post‐marketing phase III study (SWOGS0106, n = 637) demonstrated no significant benefit from GO compared with conventional induction chemotherapy despite severe safety problems (such as high incidence of hepatotoxicity and prolonged cytopenia) associated with GO [15]. In 2010, GO was withdrawn from the market due to efficacy and safety concerns. However, subsequent clinical studies conducted by independent investigators (e.g., ALFA‐0701, n = 280) after the withdrawal showed that a fractionated dosing strategy with a low dose (e.g., GO 3 mg/m², three doses on Days 1, 4, and 7) could overcome the barriers [16]. The 3‐year event‐free survival rate was significantly higher in the GO combination group than that in the standard chemotherapy group (40.8% vs. 17.1%, respectively; p = 0.0003). The median event‐free survival was also significantly prolonged (15.6 vs. 9.7 months, respectively; p = 0.0026), and the risk of death due to adverse reactions was not increased [16]. In the subsequent AML‐19 study (n = 237), the low‐dose fractionated dosing strategy did not increase the incidence of adverse events and associated mortality while improving therapeutic efficacy [17]. Therefore, GO was re‐approved by FDA in 2017. The most common severe adverse reactions related to GO included neutropenia, thrombocytopenia, and IRRs [1, 16].

Currently, GO has been approved by FDA for adults with newly diagnosed CD33‐positive AML and adults or children (aged over 2 years) with relapsed or refractory CD33‐positive AML. The National Comprehensive Cancer Network guidelines recommend GO for the subsequent treatment of high‐risk acute promyelocytic leukemia (APL); or in combination with all‐trans retinoic acid ± arsenic trioxide for relapsed APL; or in combination with standard chemotherapy regimens (cytarabine + daunorubicin) for CD33‐positive AML.

2.1.4. Inotuzumab ozogamicin (IO)

IO consists of a recombinant humanized IgG4 monoclonal antibody targeting CD‐22, an acid‐dependent 4‐(4‐acetylphenoxy) butyrate linker, and a calicheamicin derivative (N‐acetyl‐γ‐calicheamicin‐dimethyl). Calicheamicin is a class of potent DNA alkylating agents isolated from soil microbial environments. After binding to the cell surface CD22 receptor, the high‐affinity antibody component in the IO is rapidly endocytosed, internalized, and transported into lysosomes. Then calicheamicin is released to bind to the DNA minor groove to induce double‐strand breaks and apoptosis [18].

INO‐VATE ALL, the phase III randomized study, was the pivotal trial for the approval of IO in patients with the first or second relapse of ALL (n = 326) [19]. It was demonstrated that IO significantly improved CR rate (80.7% and 29.4%, p < 0.001) and prolonged sustained response (4.6 and 3.1 months, p = 0.03), median PFS (5.0 and 1.8 months, p < 0.001), and median OS (7.7 and 6.7 months, p = 0.04) compared with standard chemotherapy [19]. In addition, the proportion of patients receiving HSCT in the IO group was significantly higher than that in the standard therapy group (41% and 11%; p < 0.001). The incidence of severe adverse events (SAEs) in the IO group was similar to that of the standard therapy group (48% and 46%). The most common adverse reactions included fever, thrombocytopenia, neutropenia, elevated transaminase levels, nausea, headache, and fatigue. Liver‐related toxicities (elevated transaminase levels, hyperbilirubinemia, and sinusoidal obstruction syndrome) were more common in the IO group than in the standard therapy group, especially in patients receiving HSCT at risk for sinusoidal obstruction syndrome [19].

In 2017, IO was approved by the FDA and European Medicines Agency for the treatment of relapsed or refractory B‐cell acute lymphoblastic leukemia in adults.

2.1.5. Moxetumomab pasudotox‐tdfk (MP)

MP is formed by fusing the binding domain of an anti‐CD22 antibody with the toxin. CD22 is a type I transmembrane protein mainly expressed in mature B lymphocytes and plays an important role in B cell signaling. The CD22 density in hairy cell leukemia (HCL) cells is higher than that in normal cells, making it a therapeutic target for the treatment of HCL. After binding to CD22, MP is internalized and processed by cells. The release of modified proteotoxins inhibits protein translation and leads to apoptosis.

A single‐arm, multicenter study was conducted on 80 patients with relapsed or refractory HCL previously treated with at least two types of therapies to assess the efficacy and safety of MP. The primary endpoint was durable CR, defined as CR lasting >180 days with a hematologic response. The follow‐up results (median 16.7 months) showed that the primary endpoint was achieved. The OOR was 75% with the CR of 41%. The durable CR (primary endpoint) after MP treatment was 30%. Most patients with a CR achieved durable response (73%, 24/33) and negative minimal residual disease (MRD) status (82%, 27/33) [20].

In September 2018, MP was approved by FDA for adult patients with relapsed or refractory HCL who have received one or two lines of previous therapy.

2.1.6. Belantamab mafodotin (BM)

The antibody component of BM is glycosylated IgG1 targeting BCMA, a protein expressed on normal B lymphocytes and multiple myeloma cells, and the small‐molecule component is microtubule inhibitor MMAF [21]. Upon binding to BCMA, BM is internalized and MMAF is then released by proteolysis. The released MMAF disrupts the intracellular microtubule network to induce cell cycle arrest and apoptosis. BM has strong antitumor activity against multiple myeloma cells mediated by MMAF‐induced apoptosis, antibody‐dependent cytotoxicity (ADCC), and antibody‐dependent cellular phagocytosis (ADCP).

DREAMM‐2 was a randomized, open‐label, two‐arm, phase II study, including 196 heavily pretreated relapsed or refractory multiple myeloma patients [22]. They had received standard therapy but progressed after seven (median) regimens. They were resistant and/or intolerant to immunomodulatory drugs, proteasome inhibitors, and anti‐CD38 antibodies. The patients were randomized into two groups and prescribed BM at a dose of 2.5 or 3.4 mg/kg every 3 weeks (Q3W). The ORR was 31%. The median OS was not reached [22]. Forty percent of patients in the 2.5 mg/kg cohort reported serious adverse events. The most common grade 3/4 adverse events are keratopathy, thrombocytopenia, and anemia [22, 23].

In August 2020, BM was approved by FDA for the treatment of relapsed or refractory multiple myeloma in adults who had received at least four types of therapies, including anti‐CD38 monoclonal antibodies, proteasome inhibitors, and immunomodulators.

2.1.7. Loncastuximab tesirine‐lpyl (LT)

LT contains a humanized antihuman CD19 monoclonal antibody conjugated to pyrrolobenzodiazepine (PBD) dimer cytotoxin by a linker. Upon binding to CD19‐expressing cells, LT is internalized by the cells and subsequently releases the cytotoxin. The cytotoxin irreversibly binds to DNA producing strong interstrand crosslinks. The linked DNA strands, unable to separate, disrupt DNA replication and lead to cell death.

The LOTIS 2 study was a multicenter, open‐label, single‐arm, phase II clinical trial, which assessed the efficacy and safety of LT in patients with relapsed or refractory DLBCL who had received at least two types of systemic therapies [24]. The results showed that the ORR and CR rates were 48.3% (70/145 cases) and 24.1% (35/145 cases) for LT therapy, respectively. In this study, LT was generally tolerable, and the most common grade ≥3 adverse events with an incidence ≥10% included neutropenia (25.5%), febrile neutropenia (3.4%), thrombocytopenia (17.9%), increased GGT (16.6%), and anemia (10.3%) [24].

In April 2021, LT received accelerated approval for relapsed/refractory large B‐cell lymphoma who had received at least two lines of therapy before, including DLBCL not otherwise specified, DLBCL caused by low‐grade lymphoma, and high‐grade B‐cell lymphoma.

2.2. Solid tumors

2.2.1. Trastuzumab emtansine (T‐DM1)

T‐DM1 is the first approved ADC in solid tumors and consists of recombinant humanized antihuman epidermal growth factor receptor 2 (HER2) IgG1 monoclonal antibody trastuzumab, a nonreduced thioether linker, and tubulin inhibitor maytansinoid (DM1) [25]. One trastuzumab antibody is covalently coupled to 3.5 DM1 on average. T‐DM1 binds to the HER2 receptor and forms a complex, which enters target cells via receptor‐mediated endocytosis. The antibody component in T‐DM1 is degraded in lysosomes, releasing DM1 into the cytoplasm to induce cell cycle arrest and apoptosis.

2.2.1.1. HER2 positive early breast cancer

The KATHERINE study was an international, multicenter phase III clinical trial. A total of 1486 patients with HER2 positive breast cancer without pathological CR (pCR) after neoadjuvant therapy of trastuzumab were included. The patients were randomly given 14 cycles of T‐DM1 or 14 cycles of trastuzumab. After a median follow‐up of 41 months, the 3‐year invasive disease‐free survival rate (iDFS) in the T‐DM1 group was 88.3% compared to 77.0% in the trastuzumab group (hazrad ratio [HR] = 0.50, p < 0.001) [26]. The incidence of adverse reactions was higher in the T‐DM1 group compared with the trastuzumab group (the incidence of grade ≥3 adverse reactions was approximately 25.7% and 15.4%, respectively) [26].

2.2.1.2. Advanced HER2‐positive breast cancer

The approval and use of T‐DM1 in HER2‐positive advanced breast cancer were supported by two phase III clinical studies, EMILIA [27] and TH3RESA [28]. The results of the EMILIA study (n = 991) showed that T‐DM1 significantly prolonged median PFS (9.6 and 6.4 months; HR = 0.65, p < 0.001) and median OS (30.9 and 25.1 months; HR = 0.68; p < 0.001) compared with lapatinib + capecitabine patients with HER2‐positive advanced breast cancer pretreated by taxanes and trastuzumab. The incidence of grade ≥3 adverse reactions was lower in the T‐DM1 group (41% and 57%, respectively) [27]. The TH3RESA study (n = 602) also showed that T‐DM1 (22.7 and 6.2 months, respectively, both p < 0.005) improved median OS and PFS of the patients compared with physician‐selected therapy (15.8 and 3.3 months for the median OS [29] and median PFS, respectively) [29].

Since 2013, T‐DM1 has been approved by FDA and China National Medical Products Administration (NMPA) for HER2‐positive advanced breast cancer or early breast cancer with residual disease after neoadjuvant therapy.

2.2.2. Enfortumab vedotin (EV)

EV consists of recombinant humanized anti‐Nectin‐4 (an adhesion molecule involved in cell adhesion by recruiting cadherins and regulating cytoskeletal rearrangements) monoclonal antibodies, enzymatic cleavage linkers, and cytotoxic drugs of MMAE. More than 50% of urothelial cancers are positive for Nectin‐4 protein expression, and the highest level is detected in bladder cancer samples using immunohistochemistry. Therefore, Nectin‐4 is an ideal ADC target for urothelial cancer [30].

The efficacy and safety of EV were compared with physician‐selected chemotherapy (standard docetaxel, paclitaxel, or vinflunine) for the treatment of patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum‐containing chemotherapy and had disease progression during or after treatment with a programmed cell death‐1 (PD‐1) or PD‐L1 inhibitor in the phase III EV‐301 study (n = 608). The results showed that OS was longer in the EV group than in the chemotherapy group (12.88 and 8.97 months, respectively; HR = 0.70, p = 0.001) and so did PFS (5.55 and 3.71 months, respectively; HR = 0.62, p < 0.001). The incidence of treatment‐related adverse events was similar in the two groups (93.9% in the EV group and 91.8% in the chemotherapy group); the incidence of events of grade 3 or higher was also similar in the two groups (51.4% and 49.8%, respectively) [31].

The efficacy and safety of EV in patients with locally advanced or metastatic urothelial carcinoma previously treated with PD‐1 or PD‐L1 inhibitors were assessed in the EV‐201 phase II trial, the cohort 2 (n = 89) of which included adult patients who were ineligible for cisplatin‐containing chemotherapy and had not received platinum‐containing chemotherapy in the locally advanced or metastatic setting. The results showed that ORR was 52%, with CR achieving 20% and PR achieving 31%. 55% of patients had grade 3 or worse treatment‐related adverse events. The most common grade 3 or 4 treatment‐related adverse events were neutropenia (9%), maculopapular rash (8%), and fatigue (7%). Treatment‐related serious adverse events occurred in 17% of patients [32].

Since 2019, EV was approved by FDA for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC) who have previously received a PD‐1 or PD‐L1 inhibitor and platinum‐containing chemotherapy, or are ineligible for cisplatin‐containing chemotherapy and have previously received one or more prior lines of therapy.

2.2.3. Trastuzumab deruxtecan (TD)

TD (DS‐8201) contains a recombinant humanized anti‐HER2 IgG1 monoclonal antibody (trastuzumab), a cleavable peptidyl linker, and a camptothecin analog (CPT or topoisomerase I inhibitor). In both HER2 overexpressing and HER2 low‐expressing tumors, the efficacy of TD with the same dose is good [33].

2.2.3.1. Breast cancer

The DESTINY‐Breast 01 phase II study (n = 184) showed that in patients with HER2‐positive metastatic breast cancer pretreated by trastuzumab and T‐DM1, the ORR was 60.9% in patients treated with TD (n = 112, 95% confidence interval [CI], 53.4–68.0) [33]. During a median follow‐up of 20.5 months, the median PFS was 16.4 months (95% CI, 12.7‐NE) [34]. The common grade ≥3 adverse reactions of TD included neutropenia (20.7%), anemia (8.7%), and nausea (7.6%). The incidence of interstitial lung disease (ILD) was 13.6%, among which the incidence of grade 1/2 ILD and grade 3/4 ILD was 10.9% and 0.5%, respectively. Of note, four patients (2.2%) died due to ILD [34]

In European Society for Medical Oncology 2021, the positive result of DESTINY‐Breast03, a multicenter, open‐label, randomized phase III study, is released. It compared the efficacy and safety of TD vs T‐DM1 in patients with HER2 positive metastatic breast cancer (mBC) previously treated with trastuzumab and taxane. The hazard ratio (HR) for PFS was 0.2840 (p = 7.8 × 10⁻²²); median PFS not reached for TD versus 6.8 months for T‐DM1. TD demonstrated a highly statistically significant and clinically meaningful improvement in PFS versus T‐DM1 in patients previously treated with trastuzumab and taxane for HER2 + mBC [35].

2.2.3.2. Gastric cancer

In the DESTINY‐Gastric 01 phase II trial (n = 187), the efficacy of TD in patients with HER2‐positive advanced gastric cancer was assessed. The study included patients with HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who received at least two cycles of therapies. All patients were randomly administered either TD (6.4 mg/kg, every 3‐week cycle) or chemotherapy. The results showed that TD significantly improved ORR (51% and 14%, respectively, p < 0.001) and OS (12.5 and 8.4 months, respectively; HR = 0.59, p = 0.01) compared with chemotherapy. The most common grade ≥3 adverse reactions included neutropenia (51% for TD, 24% for chemotherapy), anemia (38% for TD, 23% for chemotherapy), leukopenia (21% for TD, 11% for chemotherapy), and loss of appetite (17% for TD, 13% for chemotherapy). ILD or pneumonitis was observed in a total of 12 (10%) patients in the TD group [36].

In 2019, TD was approved by FDA for the treatment of HER2‐positive, unresectable, or metastatic breast cancer in adults who have received ≥2 lines of anti‐HER2 therapies. In 2020, TD was approved by the Japanese Ministry of Health, Labour and Welfare for the treatment of HER2‐positive unresectable advanced or recurrent gastric cancer TD was officially approved by FDA in 2021 for the treatment of locally advanced or metastatic HER2‐positive gastric or GEJ adenocarcinoma pretreated by trastuzumab.

2.2.4. Cetuximab sarotalocan (CS)

CS is a novel product of photoimmune ADC, including water‐soluble silicon phthalocyanine derivative IRDye700DX linked with cetuximab. Twenty‐four hours after drug administration, CS is accumulated on the surface of EGFR‐positive tumor cells. Near‐infrared light at a wavelength of 690 nm is then used to illuminate the tumor site to induce antitumor effects of CS and activate immune responses. Drugs and near‐infrared rays are used to destroy cancer cells. Near‐infrared light can enter living tissues without causing tissue damage. However, the near‐infrared light is able to destroy the cytoplasmic membrane of cells bound with antibodies.

In a phase I clinical trial, three patients with unresectable cervical squamous cell carcinoma were treated with laser beam irradiation at 690 nm 20–28 h after Akalux® was administered at a dose of 640 mg/m². The results showed that partial response was achieved in two patients. The primary adverse reactions included facial edema, fatigue, erythema, dysphagia, tongue edema, and sore throat [37].

In September 2020, CS and BioBlade laser medical device was approved by the Japanese Ministry of Health, Labor and Welfare for the treatment of unresectable locally advanced or recurrent head and neck cancer.

2.2.5. Sacituzumab govitecan‐hziy (SG)

SG (IMMU‐132) is an ADC generated by binding of SN‐38 (an active metabolite of irinotecan) to hRS7 specifically, which is an antibody against trophoblast cell surface antigen 2 (TROP‐2), with a high drug‐to‐antibody ratio. TROP‐2 is a cell surface glycoprotein encoded by the TACSTD2 gene, which is overexpressed in a variety of tumors, including breast, colon, and lung cancers. But it is lowly expressed in normal tissues. The binding of hRS7 to TROP‐2 could deliver a high concentration of SN‐38 into cancer cells for antitumor effects [38].

The efficacy and safety of SG were compared with physician‐selected chemotherapy (eribulin, capecitabine, gemcitabine, or vinorelbine) as the third‐line therapy of metastatic triple‐negative breast cancer (mTNBC) in the phase III ASCENT study (n = 529). The results showed that SG significantly prolonged the PFS of patients without brain metastases (5.6 and 1.7 months, respectively; HR = 0.41, p < 0.0001) and also prolonged their OS (12.1 and 6.7 months, respectively; HR = 0.48, p < 0.0001), while the safety was consistent with the previous study [39].

The TROPHY‐U‐01 study was a multi‐cohort, open‐label registrational phase II trial. Cohort 1 included patients with unresectable locally advanced or metastatic UC, which developed progression after treatment by platinum‐based chemotherapy and immune checkpoint inhibitors. The primary endpoint was ORR, and secondary endpoints included safety, duration of response (DOR), PFS, and OS. For SG therapy, the ORR was 27% (31/113, 95% CI: 19.5–36.6), and the median PFS and OS were 5.4 months (95% CI: 3.5–7.2 months) and 10.9 months (95% CI: 9.0–13.8 months), respectively. Regarding safety, treatment‐related adverse events ≥ grade 3 included neutropenia (35%), leukopenia (18%), anemia (14%), diarrhea (10%), and febrile neutropenia (10%). The treatment was discontinued in 6% of these patients due to treatment‐related adverse events [40].

In 2020 and 2021, the FDA has successively accelerated and formally approved SG for adult patients with unresectable locally advanced or mTNBC who have received two or more prior systemic therapies, at least one of them for metastatic disease. In April 2021, the FDA granted accelerated approval to SG for patients with locally advanced or mUC who have previously received platinum‐containing chemotherapy and either programmed death receptor‐1 (PD‐1) or programmed death‐ligand 1 (PD‐L1) inhibitor. The efficacy and safety of SG have also been verified in the Chinese bridging study Phase IIb EVER‐132‐001 study, and it is expected to be launched in China in 2022, bringing benefits to Chinese triple‐negative breast cancer patients.

2.2.6. Disitamab vedotin (DV)

Vedetuximab (DV) is the first ADC independently developed in China. It consists of a monoclonal anti‐HER2 antibody, cleavable linker by cathepsin and MMAE. Disitamab is a self‐developed antibody with high affinity and high endocytosis efficiency, which binds to the HER2 protein and enters cancer cells via endocytosis. The linker is cleavable in tumor cells so that the small‐molecule cytotoxic drug MMAE is rapidly released, which has high toxicity and bystander effects and can effectively kill cancer cells.

2.2.6.1. Gastric cancer

Gastric cancer C008 study is an open‐label, multicenter, single‐arm phase II clinical trial for patients with HER2‐overexpressing (defined as HER2 2+ or 3+ by immunohistochemistry) locally advanced or metastatic gastric cancer (including GEJ adenocarcinoma) who had received at least two lines of systemic chemotherapy regimens. The primary endpoint of the study was ORR, which was assessed by Independent Review Committee (IRC). The IRC‐evaluated ORR was 24.4%. In the general population, the median PFS was 4.1 months, and the median OS was 7.9 months. The analysis showed that the ORR of the patients pretreated with trastuzumab was 27% for DV, and that of patients treated by the third‐line therapy was 25% [41].

2.2.6.2. Urothelial carcinoma

In the C005 study, 43 subjects with HER2‐overexpressing (2+ or 3+ indicated by IHC) urothelial carcinoma were treated with DV therapy, and the confirmed ORR (cORR) was up to 51.2%. The median PFS was 6.9 months, and the median OS reached 13.9 months [42].

In the C009 study, patients with HER2‐overexpressing (2+ or 3+ indicated by IHC) locally advanced or metastatic urothelial carcinoma were enrolled, which developed progression after treatment by conventional chemotherapeutic agents. The ORR of the patients treated with DV was 50.0%, the median PFS was 5.1 months, and the median DOR was 8.3 months. The patients achieved a median OS of 14.2 months even though most of them received the third‐line therapy. Each subgroup showed clinical benefits, with an SAE incidence of 6.3% [43].

The C014 study enrolled the first‐line population who failed or refused platinum‐based chemotherapy. Among the 17 patients with efficacy assessed at least once, the ORR was 94.1%. Of these patients, 10 patients who did not receive any treatment achieved CR or PR, and the ORR was 100%. Generally, the adverse reactions were relatively controllable. The incidence of grade 3/4 adverse reactions was 31.6%, including fatigue and elevated transaminases. The clinical study is still ongoing [44].

2.2.6.3. Breast cancer

In the integrated analysis of C001 and C003 studies, a total of 118 patients were included for DV treatment. 70 patients (59.3%) were HER2‐positive, while 48 patients (40.7%) had low expression of HER2. For the treatment with DV (2.0 mg/kg), the ORR of the low HER2 expression subgroup was 39.6%, and the median PFS was 5.7 months. The ORR of the patients with HER2 2 + & FISH‐ was 42.9%, and the median PFS was 6.6 months. Due to the impact of the COVID‐19 pandemic, the treatment was delayed for some patients with HER2 1+, but the ORR still reached 30.8%, and the median PFS was 5.5 months. There were no treatment‐related deaths due to SAEs in any treatment group in the study, indicating good safety [45].

2.2.7. Tisotumab vedotin (TV)

TV is comprised of a human monoclonal antibody specific for tissue factor (TF‐011) conjugated to MMAE through a linker that can be cleaved by a protease. TF‐011 is an antigen expressed on the surface of cervical cancer cells. TV releases MMAE after endocytosis, which disrupts the microtubule network of dividing cells, leading to cell cycle arrest and cell death.

TV demonstrated favorable antitumor activity and manageable adverse events in previously treated patients with recurrent or metastatic cervical cancer. In a single‐arm, phase II clinical study of 102 patients, the ORR was 24%, of which 7 patients achieved CR [46]. The most common adverse events included alopecia, epistaxis, nausea, conjunctivitis, fatigue, and dry eye [46], and the most common grade 3/4 adverse events included anemia and fatigue, vomiting, and anemia [46, 47].

Based on the results of the phase II trial, TV received accelerated FDA approval in 2021 for the treatment of adult patients with recurrent or metastatic cervical cancer that has progressed after prior chemotherapy.

3. CONSENSUS ON SAFETY MANAGEMENT OF ADCS

There are various adverse reactions to diverse ADCs since antibodies and cytotoxic drugs are different. The noticeable adverse reactions are classified according to the organs and tissues affected: hematological adverse reactions, IRRs, neurotoxicity, hepatotoxicity, pulmonary toxicity, digestive system disease, cardiotoxicity, infection, skin and subcutaneous disease, tumor lysis syndrome, metabolic toxicity, eye disorders, and central neurotoxicity (Table 3). During medication, the corresponding adverse reactions should be closely monitored, and the adverse reactions related to potential severe outcomes are prevented or provided with supportive treatment. When adverse reactions are suspected, they should be closely observed with timely diagnosis. Once adverse reactions are confirmed, they would be managed properly, and the ADC regimen may be adjusted (delayed or dose reduction) for patients' benefit. ADCs should be timely withdrawn upon severe adverse reactions, and refractory adverse reactions may need multidisciplinary consultation. This consensus briefly introduces the safety management of some adverse reactions of a high incidence or special interest.

Table 3.

Common ADCs‐related adverse reactions

Classification of adverse reactions	Drugs	Adverse reactions
Hematologic adverse reactions	Sacituzumab govitecan‐hziy	Decreased activity of uridine diphosphate glucuronosyltransferase 1A1
	Polatuzumab vedotin‐piiq	Inotuzumab Ozogamicin
	Inotuzumab ozogamicin	Inotuzumab Ozogamicin
	Loncastuximab tesirine‐lpyl	Neutropenia
	Sacituzumab govitecan‐hziy	Severe neutropenia
	Trastuzumab emtansine	Thrombocytopenia
	Belantamab mafodotin	Thrombocytopenia
	Brentuximab vedotin	Hematologic toxicity
	Fam‐trastuzumab deruxtecan‐nxki	Neutropenia
	Moxetumomab Pasudotox‐tdfk	Decreased lymphocyte count
	Disitamab vedotin	leukopenia
Infusion‐related reactions	Brentuximab vedotin	Allergic reaction and infusion reaction
	Sacituzumab govitecan‐hziy	Allergy
	Enfortumab vedotin‐ejfv	Infusion site extravasations
	Inotuzumab ozogamicin	Infusion‐related reactions
	Polatuzumab vedotin‐piiq	Infusion‐related reactions
	Trastuzumab emtansine	Infusion‐related reactions, hypersensitivity
Neurotoxicity	Disitamab vedotin	hypoesthesia
	Trastuzumab emtansine	Neurotoxicity
	Brentuximab vedotin	Peripheral neuropathy
	Vedetuximab	Neurotoxicity
	Polatuzumab vedotin‐piiq	Peripheral neuropathy
	Enfortumab vedotin‐ejfv	Peripheral neuropathy
	Tisotumab vedotin	Peripheral neuropathy
Hepatotoxicity	Trastuzumab emtansine	Hepatotoxicity
	Brentuximab vedotin	Hepatotoxicity
	Vedetuximab	Hepatotoxicity
	Polatuzumab vedotin‐piiq	Hepatotoxicity
	Loncastuximab tesirine‐lpyl	Hepatotoxicity
	Inotuzumab ozogamicin	Hepatotoxicity, including hepatic veno‐occlusive disease
Pulmonary toxicity	Trastuzumab emtansine	Pulmonary toxicity
	Brentuximab vedotin	Pulmonary toxicity
	Fam‐trastuzumab deruxtecan‐nxki	Interstitial lung disease and pneumonia
Digestive disorders	Sacituzumab govitecan‐hziy	Nausea, vomiting
	Sacituzumab govitecan‐hziy	Severe diarrhea
	Brentuximab vedotin	Gastrointestinal complications
Cardiotoxicity	Inotuzumab ozogamicin	QT prolongation
	Trastuzumab emtansine	Left ventricular dysfunction
	Fam‐trastuzumab deruxtecan‐nxki	Left ventricular dysfunction
Infection	Polatuzumab vedotin‐piiq	Serious opportunistic infection
	Brentuximab vedotin	Serious and opportunistic infection
Skin and subcutaneous tissue disorders	Enfortumab vedotin‐ejfv	Skin reactions
	Brentuximab vedotin	Severe dermatological reactions
Tumor lysis syndrome	Brentuximab vedotin	Tumor lysis syndrome
	Polatuzumab vedotin‐piiq	Tumor lysis syndrome
Metabolic toxicity	Enfortumab vedotin‐ejfv	Hyperglycemia
Eye disorder	Enfortumab vedotin‐ejfv	Eye disorders
	Belantamab mafodotin	Keratitis
	Tisotumab vedotin	Conjunctivitis, dry eye, and ulcerative keratitis
Central neurotoxicity	Polatuzumab vedotin‐piiq	Progressive multifocal leukoencephalopathy
Vascular disorders	Trastuzumab emtansine	Hemorrhage

3.1. Hematological adverse reactions

Hematological adverse reactions are common for ADCs, including pancytopenia, neutropenia, thrombocytopenia, and so forth. Severe hematological adverse reactions may further lead to an increased risk of bleeding and infection. Therefore, a complete blood count test is recommended before ADC administration. Caution should be exercised in patients who do not meet treatment requirements. When the blood parameters return to normal naturally or after supportive treatment, ADCs are prescribed. Blood counts are monitored periodically during the treatment, while prophylactic medication is also considered for secondary prevention.

3.1.1. Thrombocytopenia

In the global population, the incidence of all‐grade thrombocytopenia is approximately 20% to 38% and the incidence of grade ≥3 thrombocytopenia is approximately 2%–13% in T‐DM1‐treated patients [48]. The risk of this adverse event in the Asian population is higher, the incidence of all‐grade thrombocytopenia is 52.5%–69.8%, and the incidence of grade ≥ 3 thrombocytopenia is about 29.8%–45% [27, 28, 29, 48, 49, 50, 51]. For patients treated with T‐DM1, routine blood test is recommended regularly before the first treatment, on the first day of each treatment cycle (i.e., before T‐DM1 treatment every 3 weeks), and at 30 days after drug administration. Platelet count should be monitored in a standardized manner during T‐DM1 treatment. In the event of thrombocytopenia, the dose should be adjusted promptly, the risk of bleeding should be assessed, and intervention should be performed at the same time. Recommendations for dose modification: For patients with grade 2 (early patients) and grade 3 thrombocytopenia, T‐DM1 is stopped until recovery to ≤grade 1 thrombocytopenia. The drug of the same dose is resumed after recovery. Dose reduction is considered if the treatment is delayed twice for early patients due to grade 2 or 3 thrombocytopenia. The management of patients with grade 4 thrombocytopenia is similar to those with grade 3 thrombocytopenia, but the dose is reduced (3.6–3.0 mg/kg; 3.0–2.4 mg/kg) when T‐DM1 is restarted. If early patients experience a similar event at 2.4 mg/kg, T‐DM1 termination is considered. If grade 3 or 4 thrombocytopenia occurs in patients with advanced disease and does not resolve to ≤grade 1 thrombocytopenia within 42 days, T‐DM1 is terminated. For patients with ≥ grade 3 thrombocytopenia, it is recommended to prescribe recombinant human interleukin‐11 or recombinant human thrombopoietin with the reference to Chinese Expert Consensus on Diagnosis and Treatment of Thrombocytopenia Associated with Cancer Chemotherapy (2019 edition). If the patients are poorly responsive to conventional platelet‐elevating therapy, hematologists are consulted as early as possible, and corresponding examination and management are recommended. The potential application of platelet receptor agonists (such as Eltrombopag) in this field remains to be further investigated.

3.1.2. Neutropenia

Neutropenia is one of the most common adverse reactions of ADCs and may be related to the primary disease, nature of the target cells, or myelosuppressive effects of cytotoxic drugs [50]. G‐CSF prophylaxis may be given for patients at high risk for febrile neutropenia (>20%) or at moderate risk (10%–20%) but with other risk factors. Prophylactic anti‐infective therapy may be considered when the absolute neutrophil count is expected to <100 cells/mm³ and last for more than 1 week. If the body temperature is >38℃, empirical antibiotic treatment is given promptly with indicated examinations. Medication may be adjusted promptly after the pathogen is identified [51].

3.2. Infusion reactions

IRRs are common adverse reactions in patients treated with ADCs, and the incidence is approximately 2.5%–13% [1]. The main symptoms include fever, chills, occasional nausea, vomiting, pain, headache, vertigo, dyspnea, hypotension, rashes, and fatigue. Symptoms of severe IRRs include dyspnea, hypotension, wheezing, bronchospasm, tachycardia, respiratory distress, supraventricular tachyarrhythmia, and urticaria [52].

For the patients with related risks, corticosteroids, acetaminophen, and/or diphenhydramine are prescribed in advance to minimize the risk of IRR. IRRs are monitored during the infusion and at least 1 h after infusion. For patients with IRRs, infusion may be stopped promptly, and symptomatic treatment with steroids or antihistamines may be given. Permanent discontinuation is recommended for patients with severe IRRs.

3.3. Peripheral neuropathy

PV, EV, BV, T‐DM1, and DV may lead to peripheral neuropathy, and the incidence of peripheral neuropathy of different severity varies across reports (13%–62%), but grades 1 and 2 peripheral neuropathy is prominent [12, 27, 42, 49, 53, 54]. Peripheral neuropathy is particularly evident in ADCs with MMAE payloads. Peripheral neuropathy must be dynamically monitored during treatment with the drugs mentioned above. ADC‐associated peripheral neuropathy is mainly manifested as sensory nerve injuries, such as various neuralgia symptoms, including hypoesthesia, hyperesthesia, paresthesia, and burning pain. In severe cases, they may develop limb weakness, squatting disability, walking disability, and even sickbed. When the patient develops peripheral neuropathy, vitamin B is prescribed for trophic nerve therapy. For the symptom of neuralgia, symptomatic treatment with gabapentin, pregabalin, amitriptyline, venlafaxine, or duloxetine may be considered. If necessary, patients should be referred to the neurology department for the diagnosis, differential diagnosis, and treatment of peripheral neuropathy.

In case of severe peripheral neuropathy (grade 3) during ADC treatment, such as walking disability due to limb weakness, walking with assistive devices, or threatened quality of life due to limb numbness and pain after drug treatment, ADC treatment should be suspended. If the symptoms are improved and the patient can take care of himself/herself, ADC treatment may be restarted with a lower dose. In case of more severe neuropathy (grade 4), which endangers the patient's life, ADC treatment is terminated immediately.

3.4. Hepatotoxicity

FDA previously published a warning of GO‐related hepatotoxicity, including severe or fatal veno‐occlusive disease (VOD). In the ALFA‐0701 study, 5% of patients experienced VOD during or after treatment with GO [55]. The median time to VOD onset was about 9 days after initiation of GO (range, 2–298 days), and 83.3% of VOD appeared within 28 days. The following characteristics are associated with a higher risk of VOD: patients treated with high‐dose GO, those with moderate or severe liver injury before treatment (an 8.7‐fold increased risk), those receiving GO after HSCT, or those receiving HSCT after GO treatment (a 2.6‐ to 2.9‐fold increased risk). ¹ GO treatment must be terminated immediately once the patient develops VOD or related signs. If the total bilirubin level is increased to ≥2‐fold upper limit of normal (ULN) or aspartate transaminase (AST) and/or alanine transaminase (ALT) ≥ 2.5 × ULN, GO treatment should be delayed until total bilirubin recovers to <2 × ULN and AST and ALT recover to <2.5 × ULN.

Other hepatotoxic ADCs include BV, PV, and T‐DM1. Liver function tests should be routinely performed to allow timely intervention when liver function is abnormal [56].

3.5. Pulmonary toxicity

Clinical studies on TD demonstrated an incidence of ILD ranging from 9% to 13.6%, 2.6% of which are fatal ILD or pneumonitis. Therefore, TD therapy is contraindicated for patients with respiratory symptoms [33]. During TD treatment, it is recommended that patients with cough, dyspnea, fever, and/or any new worsening respiratory symptoms are promptly reported and signs, symptoms, and imaging changes of ILD are closely observed to promptly find evidence of ILD. Respiratory consultation is recommended for suspected ILD. For asymptomatic (grade 1) ILD, corticosteroid therapy (such as ≥ 0.5 mg/kg prednisolone or other hormones with equivalent dose potency) is considered while TD therapy is continued. In the event of symptomatic (grade 2 or higher) ILD, corticosteroids (e.g., ≥1 mg/kg prednisolone or equivalent) are prescribed immediately. After the symptomatic control and absorption of pulmonary shadow as suggested by imaging, the dose of corticosteroids should be gradually reduced for relatively prolonged treatment (e.g., 4 weeks). For patients diagnosed as symptomatic (grade 2 or higher) ILD, ADC should be permanently discontinued. Multidisciplinary consultation is recommended upon gradually worsening symptoms, and aggressive intervention is considered to avoid death.

In addition, lethal pulmonary events concerning T‐DM1 and BV have also been reported. Warnings for ILD are available in the T‐DM1 and BV labels. The incidence of pneumonitis and radiation pneumonitis for T‐DM1 is 0.8%–1.1% and 1.8% [26, 29] , respectively, and the incidence of pulmonary toxicity events is 5% and 3% for BV + ABVD and placebo + ABVD, respectively [52].

3.6. Gastrointestinal adverse reactions

Mild gastrointestinal reactions, including nausea, vomiting, and diarrhea, are common adverse reactions of ADCs and rarely have a significant consequence. Severe gastrointestinal reactions require close observation and appropriate treatment.

SG is emetogenic, and the incidence of nausea, vomiting, and diarrhea is 69%, 49%, and 63%, respectively. ADC therapy must be suspended if the patients develop uncontrollable grade 3/4 gastrointestinal reactions. ADC dose reduction is recommended after recovery, along with supportive treatment, such as antiemetic and antidiarrheal drugs. If grade ≥3 gastrointestinal reactions occur repeatedly, discontinuation of ADC therapy should be considered.

BV may cause severe gastrointestinal complications, including fatal acute pancreatitis, intestinal perforation, bleeding, erosion, ulceration, intestinal obstruction, enterocolitis, neutropenic colitis, and intestinal obstruction. Lymphoma with gastrointestinal involvement may increase the risk of gastrointestinal perforation. In case of new or worsening gastrointestinal symptoms, including severe abdominal pain, immediate diagnosis and appropriate treatment are recommended, and a specialist is consulted if necessary.

3.7. Cardiotoxicity

Cardiotoxicity is a common toxic reaction of anti‐HER2 drugs, usually manifested as decreased left ventricular ejection fraction (LVEF). All patients should be evaluated (including personal and family history) before administration of TD and T‐DM1. Cardiovascular disease and other risk factors must be controlled, and concomitant underlying cardiovascular disease treated. Patients who have received previous treatment with anthracyclines should record baseline electrocardiogram (ECG), echocardiography, troponin, and natriuretic peptide levels. During the treatment, ECG and echocardiography are dynamically performed, and myocardial markers, such as brain natriuretic peptide or N‐terminal brain natriuretic peptide, cardiac troponin I or high‐sensitivity troponin, are detected if necessary. Frequent evaluation of cardiac function and risk of related cardiotoxic events allows timely diagnosis and treatment. For patients with baseline hypertension, the preferred antihypertensive drugs are angiotensin‐converting enzyme inhibitors (ACEI) or angiotensin II receptor antagonists (ARB), and β‐blockers (BB). Consultation with a cardiovascular specialist is necessary for patients with asymptomatic cardiac insufficiency. ADCs may be continued on top of ACEI/ARB/BB, and the frequency of LVEF monitoring must be increased (such as once every 4 weeks). ADCs must be suspended if the absolute LVEF value is <50% (decreased ≥16%), or LVEF is decreased by ≥10% during treatment; ACEI/ARB/BB should be given, and ADC therapy can resume if re‐examination of LVE at 3–4 weeks shows that LVEF returns to normal. If LVEF reduction is unrecoverable or severely reduced, or symptomatic congestive heart failure occurs, ADCs must be permanently discontinued. Consultation with cardiovascular specialists is recommended when necessary, for early diagnosis and treatment of heart failure according to the standard procedures proposed by the Guidelines for the Prevention and Treatment of Anthracycline Cardiotoxicity (2020) issued by the Chinese Society of Clinical Oncology.

Compared with the change of LVEF, the predictive value of global longitudinal strain (GLS) for cardiotoxicity is higher, and GLS abnormalities may appear about 3 months earlier than LVEF decreases [57, 58, 59]. This may provide a time window for the cardioprotective therapy, which may mitigate cardiotoxicity and avoid interruption of anticancer therapy.

4. CONSENSUS ON ADCS SAFETY CARE

4.1. Before administration

The drug is prepared accordingly, following the doctor's advice. The patient's medication history (including ADCs) is evaluated. The drug is prepared immediately before use, and the prepared drug is recommended to be administered within 2 h. The drug is recommended to be prepared by the center of intravenous drugs preparation. Venous Evaluation: If the peripheral vein is not suitable for a puncture, the central vein is recommended for infusion and the infusion apparatus is selected according to the drug instructions.

4.2. During administration

The patient's information is checked, and intravenous access is established, followed by infusion according to the manual.

4.3. After administration

Fever, chills, or other IRRs of the patient are observed for at least 90 min after the initial dose, and at least 30 min after the subsequent dose.

4.4. Safety health education

The patients seek prompt medical assistance if they experience symptoms of IRRs (flushing, shivering, fever, dyspnea, hypotension, or palpitation).

5. PROSPECTS

5.1. Design of ADCs

With breakthroughs in molecular biology techniques, such as small molecule screening and protein recombination, there have been great advances in the development and design of ADCs. The versatility of antibodies, discovery of neoantigens, screening of novel cytotoxic drugs, and development of integration methods are the main directions of ADCs research in the future. In addition, ADC may also be coupled with other drugs rather than cytotoxic drugs, such as small‐molecule kinase inhibitors and PROTAC protein degradation agents. There are more than 80 ADCs currently under clinical research, of which ADCs TAA013, ARX788, and A166, developed in China, have shown good outcomes in early clinical studies of breast cancer, gastric cancer, and urothelial cancer [43, 60, 61, 62, 63, 64]. The clinical data related to next‐generation ADCs will facilitate ADC design in the future.

5.2. Combined therapy

The efficacy of ADCs may be better when used in combination with other drugs. For example, AXL‐107‐MMAE combined with MAPK pathway inhibitors synergistically inhibits tumor growth [65]. Combination therapy may enhance the activity of individual agents, reduce the risk of drug resistance, and further improve efficacy. Similarly, Indatuximab Ravtansine plus lenalidomide and dexamethasone significantly show increased antitumor activity [66]. The combination of ADCs with immune checkpoint inhibitors is also a promising direction [67].

5.3. Dose and regimen optimization

The remarketing experience of GO suggested that dose and regimen optimization may be as important as ADC design in clinical practice: the high‐frequency and low‐dose regimens may improve the benefit‐risk ratio of drugs.

5.4. Safety management

Prevention and management of adverse reactions are critical for the efficacy of ADC therapy and the prognosis of patients. It is necessary to recognize and prevent potential adverse events of diverse ADCs as early as possible. The symptoms and parameters of patients during ADC treatment should be monitored. Multidisciplinary and appropriate therapeutic measures in addition to safety management may allow continuous use of ADCs to obtain the greatest antitumor effects despite unavoidable adverse effects. For the adverse events that cannot be relieved by conventional treatments, timely consultation with specialists and multidisciplinary management are recommended for the patients.

6. SUMMARY

ADCs are featured by high specificity of antibodies and high antitumor activity of small‐molecule cytotoxic drugs, the safety of which is good due to the directional release property. it is reasonable to develop ADC for hematologic malignancies and solid tumors in various stages. For the design of ADC, the feasibility of each component is assessed, and the stability and efficacy of all components are also evaluated. The leading directions of ADC research include the identification of highly specific and homogeneously expressed tumor antigens, the development of novel linkers allowing for controlled cytotoxicity, and the exploration of more efficient intracellular and paracellular cytotoxic drugs. In addition to the drug design and development, optimization of clinical processes, such as patient selection, dose and cycle designation, combined regimens, and long‐term management of adverse effects may further improve the efficacy of ADC and therapeutic outcomes for patients. Therefore, comprehensive advancement in ADC mechanism, drug development, and proper clinical management is the future of ADCs.

AUTHOR CONTRIBUTIONS

Fei Ma: Project administration (Lead), writing – review & editing (Lead). Binghe Xu: Project administration (Lead), writing – review & editing (Lead). Jiayu Wang, Yongkun Sun, Yuqin Song, Tienan Zhu et al: Writing–original draft (Lead). Yi Ba, Jinfei Chen, Xia Chen et al: Writing–review & editing (Equal).

CONFLICTS OF INTEREST

All authors declare that there is no conflict of interest except Professor Fei Ma, Tong Sun, Binghe Xu, who are members of Cancer Innovation Editorial Board. To minimize bias, they were excluded from all editorial decision‐making related to the acceptance of this article for publication.

ETHICS STATEMENT

Not applicable.

INFORMED CONSENT

Not applicable.

Ma F, Xu B. Expert consensus on the clinical application of antibody‐drug conjugates in the treatment of malignant tumors (2021 edition). Cancer Innovation. 2022;1:3–24. 10.1002/cai2.8

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.