Antibody-drug Conjugate Information

General Information of This Antibody-drug Conjugate (ADC)

ADC ID	DRG0BBQSE
ADC Name	Enfortumab vedotin
Brand Name	Padcev
Synonyms	enfortumab vedotin; ASG-22ME; AGS-22M6E; ASG-22CE; Padcev; enfortumab vedotin-ejfv Click to Show/Hide
Organization	Seagen (Top20 MNC) (Originator);Agensys (Top20 MNC) (Originator)
Drug Status	Approved in 2019
Drug-to-Antibody Ratio	3.8~4
Structure
		2D MOL
Antibody Name	Enfortumab		Antibody Info
Antigen Name	Nectin-4 (NECTIN4)		Antigen Info
Payload Name	MMAE		Payload Info
Therapeutic Target	Microtubule (MT)		Target Info
Linker Name	Mc-Val-Cit-PABC		Linker Info
Conjugate Type	Random Cysteines
Combination Type	vedotin
Absorption	For enfortumab vedotin (1.25 mg/kg), mean C_max was 28 (ug/mL) and mean AUC was 111 (ug x day/mL) following the first treatment cycle (28 days). For unconjugated MMAE, mean C_max was 4.8 (ug/mL) and mean AUC was 69 (ug x day/mL) following the first treatment cycle (28 days). The Tmax of MMAE is 1-3 days following the end of the infusion.
Distribution	Given its structure, it is expected to be catabolized to smaller peptides, amino acids, unconjugated MMAE, and MMAE metabolites. MMAE is released from enfortumab vedotin via proteolytic cleavage by intracellular proteases and is metabolized primarily by CYP3A4 in vitro. The elimination half-lives of enfortumab vedotin and MMAE are 3.4 days and 2.4 days, respectively.
Metabolism	Given its structure, it is expected to be catabolized to smaller peptides, amino acids, unconjugated MMAE, and MMAE metabolites. MMAE is released from enfortumab vedotin via proteolytic cleavage by intracellular proteases and is metabolized primarily by CYP3A4 in vitro. The elimination half-lives of enfortumab vedotin and MMAE are 3.4 days and 2.4 days, respectively.
Toxicity	Patients experiencing an overdose are likely at an increased risk of severe adverse effects such as significant nausea, vomiting, neuropathy, or rash. Severe cutaneous adverse reactions, including fatal cases of SJS or TEN occurred in patients treated with PADCEV.
Special Approval(s)	Accelerated approval (FDA); Breakthrough therapy (FDA)

The indication landscape of This ADC(2027 Update)

The clinical trial pipeline of This ADC(2027 Update)

Indication

Phase 1

Phase 1/2

Phase 2

Phase 2/3

Phase 3

New Drug Application

Approved

Breast cancer

1 Trials

Trial ID
NCT04225117; jRCT2080225095; JapicCTI-205190

Colorectal cancer

1 Trials

Trial ID
NCT06553885

Endometrial cancer

1 Trials

Trial ID
NCT07139977

Gastric cancer

1 Trials

Trial ID
NCT04225117; jRCT2080225095; JapicCTI-205190

Gastroesophageal junction adenocarcinoma

1 Trials

Trial ID
NCT04225117; jRCT2080225095; JapicCTI-205190

Head and neck cancer

1 Trials

Trial ID
NCT04225117; jRCT2080225095; JapicCTI-205190

Kidney cancer

1 Trials

Trial ID
NCT03288545; EudraCT2018-001527-39; EUCT2023-503391-24-00

1 Trials

Trial ID
NCT03219333; EudraCT2017-003479-78

Liver cancer

1 Trials

Trial ID
NCT06553885

Lung cancer

1 Trials

Trial ID
NCT04225117; jRCT2080225095; JapicCTI-205190

Oesophageal cancer

1 Trials

Trial ID
NCT04225117; jRCT2080225095; JapicCTI-205190

Oral cavity cancer

1 Trials

Trial ID
NCT06145308

Pancreatic cancer

1 Trials

Trial ID
NCT05915351

Penile cancer

1 Trials

Trial ID
NCT06104618

Prostate cancer

1 Trials

Trial ID
NCT04754191

Small bowel cancer

1 Trials

Trial ID
NCT07347314

Testicular cancer

1 Trials

Trial ID
NCT06041503

Unspecific solid tumor

2 Trials

Trial ID
NCT02091999
NCT01409135

4 Trials

Trial ID
NCT04225117; jRCT2080225095; JapicCTI-205190
KCT0010025
NCT06891560
EUCT2024-515511-21-00

Urothelial cancer

3 Trials

Trial ID
NCT02091999
NCT03070990
NCT05014139; EudraCT2023-503388-40; EUCT2023-503388-40-00

1 Trials

Trial ID
NCT03288545; EudraCT2018-001527-39; EUCT2023-503391-24-00

6 Trials

Trial ID
NCT03474107; jRCT2080224027; JapicCTI-184086; EudraCT2017-003344-21; EUCT2024-517571-20-00
NCT05868265
NCT06041503
NCT03219333; EudraCT2017-003479-78
NCT05923190
NCT04995419; CTR20210922

2 Trials

Trial ID
NCT03924895; jRCT2031220686; EudraCT2023-504932-16; EudraCT2018-003809-26; EUCT2023-504932-16-00
TWCT00004427

ADC-specific functional property(2027 Update)

Binding Affinity

Click To Hide/Show 1 ADC-specific functional property Data

Dissocation Constant (Kd)	Binding Target	Description	Reference
Undisclosed	nectin-4	The EV antibody binds with high affinity and cross-reactivity with other nectin-expressing cells. specificity to nectin-4 expressing cells avoiding	[1]

Bystander Killing Effect

Click To Hide/Show 1 ADC-specific functional property Data

Bystander Killing Effect	Description	Reference
yes	Here we demonstrated that EV may promote multiple mechanisms of action including bystander cell killing and hallmarks of immunogenic cell death.EV demonstrated a bystander effect by release of the cell permeable MMAE from Nectin-4 positive cells to kill Nectin-4 negative cancer cells in an admixed cellular assay. (ICD) including ER stress, immune cell recruitment and activation. Click to Show/Hide	[1]

General Information of The ADMET Data Related to This ADC(2027 Update)

Absorption

Click To Hide/Show 21 Absorption Data Related to This Level

Standard Type	Value	Units	Description	Reference
Maximum Observed Concentration (C_max)	28	ug/mL	For enfortumab vedotin (1.25 mg/kg), mean C_max was 28 (ug/mL) and mean AUC was 111 (ug x day/mL) following the first treatment cycle (28 days).	[1]
Area Under the Concentration-Time Curve (AUC)	111	day*ug/mL	For enfortumab vedotin (1.25 mg/kg), mean C_max was 28 (ug/mL) and mean AUC was 111 (ug x day/mL) following the first treatment cycle (28 days).	[1]
Maximum Observed Concentration (C_max)	27	ug/mL	Phase 1 Clinical Study PK Parameters for Enfortumab Vedotin (Single Dose, 1.0mg/kg)	[2]
Maximum Observed Concentration (C_max)	38	ug/mL	Phase 1 Clinical Study PK Parameters for Enfortumab Vedotin (Single Dose, 1.25mg/kg)	[2]
Area Under the Concentration-Time Curve (AUC)	23	day*ug/mL	Phase 1 Clinical Study PK Parameters for Enfortumab Vedotin (Single Dose, 1.0mg/kg)	[2]
Area Under the Concentration-Time Curve (AUC)	32	day*ug/mL	Phase 1 Clinical Study PK Parameters for Enfortumab Vedotin (Single Dose, 1.25mg/kg)	[2]
Area Under the Concentration-Time Curve (AUC)	134	day*ug/mL	At Day 1, Phase 1 Clinical Study PK Parameters, following multiple intravenous doses of enfortumab vedotin 1.25 mg/kg	[2]
Area Under the Concentration-Time Curve (AUC)	93	day*ug/mL	At Day 15, Phase 1 Clinical Study PK Parameters, following multiple intravenous doses of enfortumab vedotin 1.25 mg/kg	[2]
Maximum Observed Concentration (C_max)	143	ug/mL	At Day 1, Phase 1 Clinical Study PK Parameters, following multiple intravenous doses of enfortumab vedotin 1.25 mg/kg	[2]
Maximum Observed Concentration (C_max)	112	ug/mL	At Day 15, Phase 1 Clinical Study PK Parameters, following multiple intravenous doses of enfortumab vedotin 1.25 mg/kg	[2]
Maximum Observed Concentration (C_max)	135	ug/mL	Single bolus injection 10 mg/kg Enfortumab Vedotin on mice model.	[3]
Area Under the Concentration-Time Curve (AUC)	336	day*ug/mL	Single bolus injection 10 mg/kg,0-Last Observable Time Point Enfortumab Vedotin on mice model.	[3]
Area Under the Concentration-Time Curve (AUC)	339	day*ug/mL	Single bolus injection 10 mg/kg,0-∞ Enfortumab Vedotin on mice model.	[3]
Maximum Observed Concentration (C_max)	26.6	ug/mL	Cycle 1, dose 1, day 1,n=125:PK parameters of ADC after administration of enfortumab vedotin 1.25 mg/kg in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum chemotherapy and a PD-1/L1 inhibitor in the EV-201 study Click to Show/Hide	[4]
Area Under the Concentration-Time Curve (AUC)	34.6	day*ug/mL	Cycle 1, dose 1, day 1,n=125:PK parameters of ADC after administration of enfortumab vedotin 1.25 mg/kg in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum chemotherapy and a PD-1/L1 inhibitor in the EV-201 study Click to Show/Hide	[4]
Maximum Observed Concentration (C_max)	26	ug/mL	Cycle 1, dose 3, day 15,n=125:PK parameters of ADC after administration of enfortumab vedotin 1.25 mg/kg in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum chemotherapy and a PD-1/L1 inhibitor in the EV-201 study Click to Show/Hide	[4]
Area Under the Concentration-Time Curve (AUC)	31.3	day*ug/mL	Cycle 1, dose 3, day 15,n=125:PK parameters of ADC after administration of enfortumab vedotin 1.25 mg/kg in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum chemotherapy and a PD-1/L1 inhibitor in the EV-201 study Click to Show/Hide	[4]
Maximum Observed Concentration (C_max)	24.5	ug/mL	Cycle 2, dose 1, day 1,n=125:PK parameters of ADC after administration of enfortumab vedotin 1.25 mg/kg in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum chemotherapy and a PD-1/L1 inhibitor in the EV-201 study Click to Show/Hide	[4]
Area Under the Concentration-Time Curve (AUC)	36.4	day*ug/mL	Cycle 2, dose 1, day 1,n=125:PK parameters of ADC after administration of enfortumab vedotin 1.25 mg/kg in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum chemotherapy and a PD-1/L1 inhibitor in the EV-201 study Click to Show/Hide	[4]
Maximum Observed Concentration (C_max)	26.3	ug/mL	Cycle 2, dose 3, day 15,n=125:PK parameters of ADC after administration of enfortumab vedotin 1.25 mg/kg in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum chemotherapy and a PD-1/L1 inhibitor in the EV-201 study Click to Show/Hide	[4]
Area Under the Concentration-Time Curve (AUC)	35.9	day*ug/mL	Cycle 2, dose 3, day 15,n=125:PK parameters of ADC after administration of enfortumab vedotin 1.25 mg/kg in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum chemotherapy and a PD-1/L1 inhibitor in the EV-201 study Click to Show/Hide	[4]

Distribution

Click To Hide/Show 19 Distribution Data Related to This Level

Standard Type	Value	Units	Description	Reference
Area Under the Concentration-Time Curve (AUC)	111	day*ug/mL	For enfortumab vedotin (1.25 mg/kg), mean C_max was 28 (ug/mL) and mean AUC was 111 (ug x day/mL) following the first treatment cycle (28 days).	[1]
Volume of Distribution (V_d)	11	L	The estimated steady-state volume of distribution is 11 L.	[1]
Area Under the Concentration-Time Curve (AUC)	23	day*ug/mL	Phase 1 Clinical Study PK Parameters for Enfortumab Vedotin (Single Dose, 1.0mg/kg)	[2]
Area Under the Concentration-Time Curve (AUC)	32	day*ug/mL	Phase 1 Clinical Study PK Parameters for Enfortumab Vedotin (Single Dose, 1.25mg/kg)	[2]
Area Under the Concentration-Time Curve (AUC)	134	day*ug/mL	At Day 1, Phase 1 Clinical Study PK Parameters, following multiple intravenous doses of enfortumab vedotin 1.25 mg/kg	[2]
Area Under the Concentration-Time Curve (AUC)	93	day*ug/mL	At Day 15, Phase 1 Clinical Study PK Parameters, following multiple intravenous doses of enfortumab vedotin 1.25 mg/kg	[2]
Area Under the Concentration-Time Curve (AUC)	336	day*ug/mL	Single bolus injection 10 mg/kg,0-Last Observable Time Point Enfortumab Vedotin on mice model.	[3]
Area Under the Concentration-Time Curve (AUC)	339	day*ug/mL	Single bolus injection 10 mg/kg,0-∞ Enfortumab Vedotin on mice model.	[3]
Volume of Distribution (V_d)	78.1	mL/kg	Single bolus injection 10 mg/kg Enfortumab Vedotin on mice model.	[3]
Area Under the Concentration-Time Curve (AUC)	34.6	day*ug/mL	Cycle 1, dose 1, day 1,n=125:PK parameters of ADC after administration of enfortumab vedotin 1.25 mg/kg in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum chemotherapy and a PD-1/L1 inhibitor in the EV-201 study Click to Show/Hide	[4]
Area Under the Concentration-Time Curve (AUC)	31.3	day*ug/mL	Cycle 1, dose 3, day 15,n=125:PK parameters of ADC after administration of enfortumab vedotin 1.25 mg/kg in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum chemotherapy and a PD-1/L1 inhibitor in the EV-201 study Click to Show/Hide	[4]
Area Under the Concentration-Time Curve (AUC)	36.4	day*ug/mL	Cycle 2, dose 1, day 1,n=125:PK parameters of ADC after administration of enfortumab vedotin 1.25 mg/kg in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum chemotherapy and a PD-1/L1 inhibitor in the EV-201 study Click to Show/Hide	[4]
Area Under the Concentration-Time Curve (AUC)	35.9	day*ug/mL	Cycle 2, dose 3, day 15,n=125:PK parameters of ADC after administration of enfortumab vedotin 1.25 mg/kg in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum chemotherapy and a PD-1/L1 inhibitor in the EV-201 study Click to Show/Hide	[4]
Volume of Distribution (V_d)	3.47	L	Volume of distribution of enfortumab vedotin to the central ,on Base model: A total of 10,355 enfortumab vedotin concentration records were used. The final models, a linear 3-compartment model with first-order elimination for enfortumab vedotin. compartment Click to Show/Hide	[5]
Volume of Distribution (V_d)	5.5	L	Volume of distribution of enfortumab vedotin to the first ,on Base model: A total of 10,355 enfortumab vedotin concentration records were used. The final models, a linear 3-compartment model with first-order elimination for enfortumab vedotin. peripheral compartment Click to Show/Hide	[5]
Volume of Distribution (V_d)	2.78	L	Volume of distribution of enfortumab vedotin to the second ,on Base model: A total of 10,355 enfortumab vedotin concentration records were used. The final models, a linear 3-compartment model with first-order elimination for enfortumab vedotin. peripheral compartment Click to Show/Hide	[5]
Volume of Distribution (V_d)	3.63	L	Volume of distribution of enfortumab vedotin to the central ,on Final model: A total of 10,355 enfortumab vedotin concentration records were used. The final models, a linear 3-compartment model with first-order elimination for enfortumab vedotin. compartment Click to Show/Hide	[5]
Volume of Distribution (V_d)	5.79	L	Volume of distribution of enfortumab vedotin to the first peripheral compartment ,on Final model: A total of 10,355 enfortumab vedotin concentration records were used. The final models, a linear 3-compartment model with first-order elimination for enfortumab vedotin. Click to Show/Hide	[5]
Volume of Distribution (V_d)	3.42	L	Volume of distribution of enfortumab vedotin to the second peripheral compartment ,on Final model: A total of 10,355 enfortumab vedotin concentration records were used. The final models, a linear 3-compartment model with first-order elimination for enfortumab vedotin. Click to Show/Hide	[5]

Metabolism

Click To Hide/Show 11 Metabolism Data Related to This Level

Standard Type	Value	Units	Description	Reference
Area Under the Concentration-Time Curve (AUC)	111	day*ug/mL	For enfortumab vedotin (1.25 mg/kg), mean C_max was 28 (ug/mL) and mean AUC was 111 (ug x day/mL) following the first treatment cycle (28 days).	[1]
Area Under the Concentration-Time Curve (AUC)	23	day*ug/mL	Phase 1 Clinical Study PK Parameters for Enfortumab Vedotin (Single Dose, 1.0mg/kg)	[2]
Area Under the Concentration-Time Curve (AUC)	32	day*ug/mL	Phase 1 Clinical Study PK Parameters for Enfortumab Vedotin (Single Dose, 1.25mg/kg)	[2]
Area Under the Concentration-Time Curve (AUC)	134	day*ug/mL	At Day 1, Phase 1 Clinical Study PK Parameters, following multiple intravenous doses of enfortumab vedotin 1.25 mg/kg	[2]
Area Under the Concentration-Time Curve (AUC)	93	day*ug/mL	At Day 15, Phase 1 Clinical Study PK Parameters, following multiple intravenous doses of enfortumab vedotin 1.25 mg/kg	[2]
Area Under the Concentration-Time Curve (AUC)	336	day*ug/mL	Single bolus injection 10 mg/kg,0-Last Observable Time Point Enfortumab Vedotin on mice model.	[3]
Area Under the Concentration-Time Curve (AUC)	339	day*ug/mL	Single bolus injection 10 mg/kg,0-∞ Enfortumab Vedotin on mice model.	[3]
Area Under the Concentration-Time Curve (AUC)	34.6	day*ug/mL	Cycle 1, dose 1, day 1,n=125:PK parameters of ADC after administration of enfortumab vedotin 1.25 mg/kg in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum chemotherapy and a PD-1/L1 inhibitor in the EV-201 study Click to Show/Hide	[4]
Area Under the Concentration-Time Curve (AUC)	31.3	day*ug/mL	Cycle 1, dose 3, day 15,n=125:PK parameters of ADC after administration of enfortumab vedotin 1.25 mg/kg in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum chemotherapy and a PD-1/L1 inhibitor in the EV-201 study Click to Show/Hide	[4]
Area Under the Concentration-Time Curve (AUC)	36.4	day*ug/mL	Cycle 2, dose 1, day 1,n=125:PK parameters of ADC after administration of enfortumab vedotin 1.25 mg/kg in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum chemotherapy and a PD-1/L1 inhibitor in the EV-201 study Click to Show/Hide	[4]
Area Under the Concentration-Time Curve (AUC)	35.9	day*ug/mL	Cycle 2, dose 3, day 15,n=125:PK parameters of ADC after administration of enfortumab vedotin 1.25 mg/kg in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum chemotherapy and a PD-1/L1 inhibitor in the EV-201 study Click to Show/Hide	[4]

Excretion

Click To Hide/Show 23 Excretion Data Related to This Level

Standard Type	Value	Units	Description	Reference
Area Under the Concentration-Time Curve (AUC)	111	day*ug/mL	For enfortumab vedotin (1.25 mg/kg), mean C_max was 28 (ug/mL) and mean AUC was 111 (ug x day/mL) following the first treatment cycle (28 days).	[1]
Elimination Half-Life (t_1/2)	3.4	days	The elimination half-lives of enfortumab vedotin and MMAE are 3.4 days and 2.4 days, respectively	[1]
Clearance (CL)	0.1	L/h	The mean clearance of enfortumab vedotin and free MMAE was 0.10 L/h and 2.7 L/h, respectively. The clearance of MMAE appears to be limited by its rate of release from enfortumab vedotin.	[1]
Area Under the Concentration-Time Curve (AUC)	23	day*ug/mL	Phase 1 Clinical Study PK Parameters for Enfortumab Vedotin (Single Dose, 1.0mg/kg)	[2]
Area Under the Concentration-Time Curve (AUC)	32	day*ug/mL	Phase 1 Clinical Study PK Parameters for Enfortumab Vedotin (Single Dose, 1.25mg/kg)	[2]
Elimination Half-Life (t_1/2)	28	days	Phase 1 Clinical Study PK Parameters for Enfortumab Vedotin (Single Dose, 1.25mg/kg)	[2]
Elimination Half-Life (t_1/2)	33	days	Phase 1 Clinical Study PK Parameters for Enfortumab Vedotin (Single Dose, 1.25mg/kg)	[2]
Area Under the Concentration-Time Curve (AUC)	134	day*ug/mL	At Day 1, Phase 1 Clinical Study PK Parameters, following multiple intravenous doses of enfortumab vedotin 1.25 mg/kg	[2]
Area Under the Concentration-Time Curve (AUC)	93	day*ug/mL	At Day 15, Phase 1 Clinical Study PK Parameters, following multiple intravenous doses of enfortumab vedotin 1.25 mg/kg	[2]
Elimination Half-Life (t_1/2)	1.53	days	Single bolus injection 10 mg/kg Enfortumab Vedotin on mice model.	[3]
Area Under the Concentration-Time Curve (AUC)	336	day*ug/mL	Single bolus injection 10 mg/kg,0-Last Observable Time Point Enfortumab Vedotin on mice model.	[3]
Area Under the Concentration-Time Curve (AUC)	339	day*ug/mL	Single bolus injection 10 mg/kg,0-∞ Enfortumab Vedotin on mice model.	[3]
Clearance (CL)	29.4	mL/day/kg	Single bolus injection 10 mg/kg Enfortumab Vedotin on mice model.	[3]
Area Under the Concentration-Time Curve (AUC)	34.6	day*ug/mL	Cycle 1, dose 1, day 1,n=125:PK parameters of ADC after administration of enfortumab vedotin 1.25 mg/kg in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum chemotherapy and a PD-1/L1 inhibitor in the EV-201 study Click to Show/Hide	[4]
Area Under the Concentration-Time Curve (AUC)	31.3	day*ug/mL	Cycle 1, dose 3, day 15,n=125:PK parameters of ADC after administration of enfortumab vedotin 1.25 mg/kg in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum chemotherapy and a PD-1/L1 inhibitor in the EV-201 study Click to Show/Hide	[4]
Area Under the Concentration-Time Curve (AUC)	36.4	day*ug/mL	Cycle 2, dose 1, day 1,n=125:PK parameters of ADC after administration of enfortumab vedotin 1.25 mg/kg in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum chemotherapy and a PD-1/L1 inhibitor in the EV-201 study Click to Show/Hide	[4]
Area Under the Concentration-Time Curve (AUC)	35.9	day*ug/mL	Cycle 2, dose 3, day 15,n=125:PK parameters of ADC after administration of enfortumab vedotin 1.25 mg/kg in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum chemotherapy and a PD-1/L1 inhibitor in the EV-201 study Click to Show/Hide	[4]
Clearance (CL)	0.101	L/h	Clearance of enfortumab vedotin ,on Base model: A total of 10,355 enfortumab vedotin concentration records were used. The final models, a linear 3-compartment model with first-order elimination for enfortumab vedotin. Click to Show/Hide	[5]
Clearance (CL)	0.00437	L/h	Intercompartment clearance of enfortumab vedotin to the first peripheral compartment ,on Base model: A total of 10,355 enfortumab vedotin concentration records were used. The final models, a linear 3-compartment model with first-order elimination for enfortumab vedotin. Click to Show/Hide	[5]
Clearance (CL)	0.0381	L/h	Intercompartment clearance of enfortumab vedotin to the second ,on Base model: A total of 10,355 enfortumab vedotin concentration records were used. The final models, a linear 3-compartment model with first-order elimination for enfortumab vedotin. peripheral compartment Click to Show/Hide	[5]
Clearance (CL)	0.11	L/h	Clearance of enfortumab vedotin ,on Final model: A total of 10,355 enfortumab vedotin concentration records were used. The final models, a linear 3-compartment model with first-order elimination for enfortumab vedotin. Click to Show/Hide	[5]
Clearance (CL)	0.00446	L/h	Intercompartment clearance of enfortumab vedotin to the first peripheral compartment ,on Final model: A total of 10,355 enfortumab vedotin concentration records were used. The final models, a linear 3-compartment model with first-order elimination for enfortumab vedotin. Click to Show/Hide	[5]
Clearance (CL)	0.0397	L/h	Intercompartment clearance of enfortumab vedotin to the second peripheral compartment ,on Final model: A total of 10,355 enfortumab vedotin concentration records were used. The final models, a linear 3-compartment model with first-order elimination for enfortumab vedotin. Click to Show/Hide	[5]

General Information of The Activity Data Related to This ADC

Identified from the Human Clinical Data

Click To Hide/Show 6 Activity Data Related to This Level

Standard Type	NCT Number	Clinical Status	Clinical Trial Description
Objective Response Rate (ORR)	NCT04223856	Phase 3	An open-label, randomized, controlled phase 3 study of enfortumab vedotin in combination with pembrolizumab versus chemotherapy alone in previously untreated locally advanced or metastatic urothelial cancer. Click to Show/Hide
Objective Response Rate (ORR)	NCT03219333	Phase 2	A single-arm, open-label, multicenter study of enfortumab vedotin (ASG-22CE) for Treatment of patients with locally advanced or metastatic urothelial cancer who previously received immune checkpoint inhibitor (CPI) Therapy. Click to Show/Hide
Objective Response Rate (ORR)	NCT03219333	Phase 2	A single-arm, open-label, multicenter study of enfortumab vedotin (ASG-22CE) for treatment of patients with locally advanced or metastatic urothelial cancer who previously received immune checkpoint inhibitor (CPI) therapy. Click to Show/Hide
Objective Response Rate (ORR)	NCT03070990	Phase 1	An open-label, randomized, phase 1 safety and pharmacokinetic study of enfortumab vedotin (ASG-22CE) in Japanese patients with locally advanced or metastatic urothelial carcinoma.
Objective Response Rate (ORR)	NCT02091999	Phase 1	A phase 1 study of the safety and pharmacokinetics of escalating doses of ASG-22CE given as monotherapy in subjects with metastatic urothelial cancer and other malignant solid tumors that express nectin-4. Click to Show/Hide
Undisclosed	NCT03474107	Phase 3	An open-label, randomized phase 3 study to evaluate enfortumab vedotin vs chemotherapy in subjects with previously treated locally advanced or metastatic urothelial cancer (EV-301).

Discovered Using Patient-derived Xenograft Model

Click To Hide/Show 9 Activity Data Related to This Level

Standard Type	Value	Units	Animal Model (No. of PDX)
Tumor Growth Inhibition value (TGI)	≈ 30.8	%	Bladder cancer PDX model (PDX: AG-B1)
Tumor Growth Inhibition value (TGI)	≈ 33.9	%	Pancreatic cancer PDX model (PDX: AG-Panc4)
Tumor Growth Inhibition value (TGI)	≈ 45	%	Breast cancer PDX model (PDX: AG-Br7)
Tumor Growth Inhibition value (TGI)	≈ 68.8	%	Pancreatic cancer PDX model (PDX: AG-Panc4)
Tumor Growth Inhibition value (TGI)	≈ 80.7	%	Bladder cancer PDX model (PDX: AG-B1)
Tumor Growth Inhibition value (TGI)	≈ 93.8	%	Breast cancer PDX model (PDX: AG-Br7)
Tumor Growth Inhibition value (TGI)	≈ 97.6	%	Breast cancer orthotopic PDX model (PDX: AG-Br7)
Tumor Growth Inhibition value (TGI)	≈ 97.7	%	Breast cancer orthotopic PDX model (PDX: AG-Br7)
Tumor Growth Inhibition value (TGI)	≈ 98.7	%	Bladder cancer PDX model (PDX: AG-B1)

Discovered Using Cell Line-derived Xenograft Model

Click To Hide/Show 2 Activity Data Related to This Level

Standard Type	Value	Units	Cell Line	Disease Model
Tumor Growth Inhibition value (TGI)	≈ 26	%	NCI-H322M cells	Minimally invasive lung adenocarcinoma
Tumor Growth Inhibition value (TGI)	≈ 83.6	%	NCI-H322M cells	Minimally invasive lung adenocarcinoma

Revealed Based on the Cell Line Data

Click To Hide/Show 4 Activity Data Related to This Level

Standard Type	Value	Units	Cell Line	Disease Model
Half Maximal Inhibitory Concentration (IC50)	1.2	ng/mL	PC-3 cells	Prostate carcinoma
Half Maximal Inhibitory Concentration (IC50)	3.4	ng/mL	PC-3 cells	Prostate carcinoma
Half Maximal Inhibitory Concentration (IC50)	4.7	ng/mL	PC-3 cells	Prostate carcinoma
Half Maximal Inhibitory Concentration (IC50)	37.8	ng/mL	T-47D cells	Invasive breast carcinoma

Full List of Activity Data of This Antibody-drug Conjugate

Identified from the Human Clinical Data

Click To Hide/Show 6 Activity Data Related to This Level

Experiment 1 Reporting the Activity Date of This ADC				[6]
Efficacy Data	Objective Response Rate (ORR)	73.30%
Patients Enrolled	Histologically documented locally advanced/metastatic urothelial carcinoma (la/mUC) (including squamous differentiation and mixed cell types), an Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a 5-point scale; higher scores indicate greater disability), and an investigator-assessed life expectancy of 3 or more months.
Administration Dosage	1.25 mg/kg once daily on days 1 and 8 intravenously once daily in 3-week cycles.
*Related Clinical Trial*
NCT Number	NCT04223856	Clinical Status	Phase 3
Clinical Description	An open-label, randomized, controlled phase 3 study of enfortumab vedotin in combination with pembrolizumab versus chemotherapy alone in previously untreated locally advanced or metastatic urothelial cancer.
Primary Endpoint	Safety: Seven patients (15.60%) experienced a serious TRAE, with no serious TRAE occurring more than once. TRAEs led to dose reductions in 14 (31.10%) patients and discontinuations in 11 (24.40%) patients and were not mutually exclusive. Peripheral sensory neuropathy was the most common TRAE leading to either dose reduction (six patients, 13.30%) or treatment discontinuation (four patients, 8.90%). No patients discontinued therapy because of a skin reaction or hyperglycemia. One patient (2.20%) died because of a TRAE (multiple organ dysfunction syndrome). Click to Show/Hide
Other Endpoint	The confirmed objective response rate after a median of nine cycles was 73.30% with a complete response rate of 15.60%. The median DOR and median OS were 25.60 months and 26.10 months, respectively.
Experiment 2 Reporting the Activity Date of This ADC				[7]
Efficacy Data	Objective Response Rate (ORR)	44%	High Nectin-4 expression (NECTIN4+++)
Patients Enrolled	Locally advanced or metastatic urothelial carcinoma who were previously treated with platinum chemotherapy and antiPD-1/L1 therapy.
Administration Dosage	1.25 mg/kg (intravenously on days 1, 8, and 15 of every 28-day cycle).
*Related Clinical Trial*
NCT Number	NCT03219333	Clinical Status	Phase 2
Clinical Description	A single-arm, open-label, multicenter study of enfortumab vedotin (ASG-22CE) for Treatment of patients with locally advanced or metastatic urothelial cancer who previously received immune checkpoint inhibitor (CPI) Therapy.
Primary Endpoint	Confirmed objective response rate was 44.00% (95% CI, 35.10% to 53.20%), including 12.00% complete responses.
Other Endpoint	Median duration of response was 7.60 months (range, 0.95 to 11.30 months).
Experiment 3 Reporting the Activity Date of This ADC				[8]
Efficacy Data	Objective Response Rate (ORR)	51.68%	High Nectin-4 expression (NECTIN4+++)
Patients Enrolled	Locally advanced or metastatic urothelial carcinoma previously treated with PD-1 or PD-L1 inhibitors; an Eastern Cooperative Oncology Group performance status score of 2 or less who were considered ineligible for cisplatin at enrolment and who had not received platinum-containing chemotherapy in the locally advanced or metastatic setting.
Administration Dosage	Intravenously at a dose of 1.25 mg/kg on days 1, 8, and 15 of every 28-day cycle.
*Related Clinical Trial*
NCT Number	NCT03219333	Clinical Status	Phase 2
Clinical Description	A single-arm, open-label, multicenter study of enfortumab vedotin (ASG-22CE) for treatment of patients with locally advanced or metastatic urothelial cancer who previously received immune checkpoint inhibitor (CPI) therapy.
Primary Endpoint	The confirmed objective response rate was 51.68% (46 of 89 patients; 95% CI 41.00-62.00), with 18 (20.22%) of 89 patients achieving a complete response and 28 (31.46%) achieving a partial response.
Other Endpoint	Duration of response, progression-free survival, objective response rate, overall survival, safety, and tolerability, plasma or serum pharmacokinetic parameters of enfortumab vedotin, MMAE, and total antibody, and incidence of antitherapeutic antibody to enfortumab vedotin.
Experiment 4 Reporting the Activity Date of This ADC				[9]
Efficacy Data	Objective Response Rate (ORR)	35.30%	Moderate Nectin-4 expression (NECTIN4++)
Patients Enrolled	Histologically confirmed, locally advanced or metastatic transitional cell carcinoma of the urothelium (ie, cancer of the bladder, renal pelvis, ureter, or urethra), or UC with squamous differentiation or mixed cell types and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Administration Dosage	1.00 mg/kg (Arm A) or 1.25 mg/kg (Arm B) on Days 1, 8, and 15 of each 28-day cycle.
*Related Clinical Trial*
NCT Number	NCT03070990	Clinical Status	Phase 1
Clinical Description	An open-label, randomized, phase 1 safety and pharmacokinetic study of enfortumab vedotin (ASG-22CE) in Japanese patients with locally advanced or metastatic urothelial carcinoma.
Primary Endpoint	Safety/tolerability of EV, EV PK profile.
Experiment 5 Reporting the Activity Date of This ADC				[10]
Efficacy Data	Objective Response Rate (ORR)	43%	High Nectin-4 expression (NECTIN4+++)
Patients Enrolled	Nectin-4positive solid tumors, including mUC, who progressed on 1 prior chemotherapy regimen or who were ineligible for cisplatin chemotherapy.
Administration Dosage	Weight-based doses (0.50, 0.75, 1.00, and 1.25 mg/kg) through 30-minute infusion on days 1, 8, and 15 of a 28-day cycle.
*Related Clinical Trial*
NCT Number	NCT02091999	Clinical Status	Phase 1
Clinical Description	A phase 1 study of the safety and pharmacokinetics of escalating doses of ASG-22CE given as monotherapy in subjects with metastatic urothelial cancer and other malignant solid tumors that express nectin-4.
Primary Endpoint	The determination of safety/tolerability, recommended phase II dose (RP2D), and pharmacokinetic (PK) profile of EV.
Other Endpoint	Antitumor activity,including confirmed investigator-assessed ORR (RECIST version 1.1), duration of response (DoR), progression-free survival (PFS), and overall survival (OS).
Experiment 6 Reporting the Activity Date of This ADC				[11]
Patients Enrolled	Histologically or cytologically confirmed urothelial carcinoma (including differentiation in squamous cells or in multiple cell types), radiologically documented metastatic or unresectable locally advanced disease at baseline, and an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1 (scores range from 0 to 4, with higher scores indicating greater disability). Click to Show/Hide
Administration Dosage	Intravenous infusion over 30 minutes on days 1, 8, and 15 of a 28-day cycle.
*Related Clinical Trial*
NCT Number	NCT03474107	Clinical Status	Phase 3
Clinical Description	An open-label, randomized phase 3 study to evaluate enfortumab vedotin vs chemotherapy in subjects with previously treated locally advanced or metastatic urothelial cancer (EV-301).
Primary Endpoint	Overall survival was prolonged with enfortumab vedotin compared with chemotherapy (HR=0.70 [95% CI: 0.56-0.89];.
Other Endpoint	Median overall survival: 12.88 vs 8.97 months, respectively). Progression-free survival was also longer in the enfortumab vedotin group compared with the chemotherapy group (HR=0.62 [95% CI: 0.51-0.75]; P<0.00001; median progression-free survival: 5.55 vs 3.71 months, respectively).

Discovered Using Patient-derived Xenograft Model

Click To Hide/Show 9 Activity Data Related to This Level

Experiment 1 Reporting the Activity Date of This ADC				[12]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 30.80%	High Nectin-4 expression (NECTIN4+++)
Method Description	AGS-22M6E induces efficient tumor cell killing in PDX models of a bladder cancer cell with Nectin-4 high expression, dosed every 4 days at 0.4 mg/kg for 5 times.
In Vivo Model	Bladder cancer PDX model (PDX: AG-B1)
Experiment 2 Reporting the Activity Date of This ADC				[12]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 33.90%	Moderate Nectin-4 expression (NECTIN4++)
Method Description	AGS-22M6E induces efficient tumor cell killing in PDX models of a pancreatic cancer cell with Nectin-4 moderate expression, dosed every 4 days at 1 mg/kg for 6 times.
In Vivo Model	Pancreatic cancer PDX model (PDX: AG-Panc4)
Experiment 3 Reporting the Activity Date of This ADC				[12]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 45%	High Nectin-4 expression (NECTIN4+++)
Method Description	AGS-22M6E induces efficient tumor cell killing in PDX models of a breast cancer cell with Nectin-4 high expression, dosed every 4 days at 1 mg/kg for 6 times.
In Vivo Model	Breast cancer PDX model (PDX: AG-Br7)
Experiment 4 Reporting the Activity Date of This ADC				[12]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 68.80%	Moderate Nectin-4 expression (NECTIN4++)
Method Description	AGS-22M6E induces efficient tumor cell killing in PDX models of a pancreatic cancer cell with Nectin-4 moderate expression, dosed every 4 days at 3 mg/kg for 6 times.
In Vivo Model	Pancreatic cancer PDX model (PDX: AG-Panc4)
Experiment 5 Reporting the Activity Date of This ADC				[12]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 80.70%	High Nectin-4 expression (NECTIN4+++)
Method Description	AGS-22M6E induces efficient tumor cell killing in PDX models of a bladder cancer cell with Nectin-4 high expression, dosed every 4 days at 0.8 mg/kg for 5 times.
In Vivo Model	Bladder cancer PDX model (PDX: AG-B1)
Experiment 6 Reporting the Activity Date of This ADC				[12]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 93.80%	High Nectin-4 expression (NECTIN4+++)
Method Description	AGS-22M6E induces efficient tumor cell killing in PDX models of a breast cancer cell with Nectin-4 high expression, dosed every 4 days at 3 mg/kg for 6 times.
In Vivo Model	Breast cancer PDX model (PDX: AG-Br7)
Experiment 7 Reporting the Activity Date of This ADC				[12]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 97.60%	High Nectin-4 expression (NECTIN4+++)
Method Description	AGS-22M6E induces efficient tumor cell killing in orthotopic PDX models of a breast cancer cell with Nectin-4 high expression, established in mammary fat pads of SCID mice, dosed single 10 mg/kg.
In Vivo Model	Breast cancer orthotopic PDX model (PDX: AG-Br7)
Experiment 8 Reporting the Activity Date of This ADC				[12]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 97.70%	High Nectin-4 expression (NECTIN4+++)
Method Description	AGS-22M6E induces efficient tumor cell killing in orthotopic PDX models of a breast cancer cell with Nectin-4 high expression, established in mammary fat pads of SCID mice, dosed twice 5 mg/kg.
In Vivo Model	Breast cancer orthotopic PDX model (PDX: AG-Br7)
Experiment 9 Reporting the Activity Date of This ADC				[12]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 98.70%	High Nectin-4 expression (NECTIN4+++)
Method Description	AGS-22M6E induces efficient tumor cell killing in PDX models of a bladder cancer cell with Nectin-4 high expression, single 4 mg/kg dose.
In Vivo Model	Bladder cancer PDX model (PDX: AG-B1)

Discovered Using Cell Line-derived Xenograft Model

Click To Hide/Show 2 Activity Data Related to This Level

Experiment 1 Reporting the Activity Date of This ADC					[12]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 26%	High Nectin-4 expression (NECTIN4+++)
Method Description	AGS-22M6E induces efficient tumor cell killing in PDX models of a lung adenocarcinoma cell with Nectin-4 high expression, dosed every 4 days at 1 mg/kg for 5 times.
In Vivo Model	NCI-H322M CDX model
In Vitro Model	Minimally invasive lung adenocarcinoma	NCI-H322M cells		CVCL_1557
Experiment 2 Reporting the Activity Date of This ADC					[12]
Efficacy Data	Tumor Growth Inhibition value (TGI)	≈ 83.60%	High Nectin-4 expression (NECTIN4+++)
Method Description	AGS-22M6E induces efficient tumor cell killing in PDX models of a lung adenocarcinoma cell with Nectin-4 high expression, dosed every 4 days at 3 mg/kg for 5 times.
In Vivo Model	NCI-H322M CDX model
In Vitro Model	Minimally invasive lung adenocarcinoma	NCI-H322M cells		CVCL_1557

Revealed Based on the Cell Line Data

Click To Hide/Show 4 Activity Data Related to This Level

Experiment 1 Reporting the Activity Date of This ADC				[12]
Efficacy Data	Half Maximal Inhibitory Concentration (IC50)	1.2 ng/mL
Method Description	The inhibitory activity of AGS-22M6, AGS-22M6E ADC, and an isotype control ADC were added to various cancer cell lines in vitro and cell viability was measured after 5 days.
In Vitro Model	Prostate carcinoma	PC-3 cells	CVCL_0035
Experiment 2 Reporting the Activity Date of This ADC				[12]
Efficacy Data	Half Maximal Inhibitory Concentration (IC50)	3.4 ng/mL
Method Description	The inhibitory activity of AGS-22M6, AGS-22M6E ADC, and an isotype control ADC were added to various cancer cell lines in vitro and cell viability was measured after 5 days.
In Vitro Model	Prostate carcinoma	PC-3 cells	CVCL_0035
Experiment 3 Reporting the Activity Date of This ADC				[12]
Efficacy Data	Half Maximal Inhibitory Concentration (IC50)	4.7 ng/mL
Method Description	The inhibitory activity of AGS-22M6, AGS-22M6E ADC, and an isotype control ADC were added to various cancer cell lines in vitro and cell viability was measured after 5 days.
In Vitro Model	Prostate carcinoma	PC-3 cells	CVCL_0035
Experiment 4 Reporting the Activity Date of This ADC				[12]
Efficacy Data	Half Maximal Inhibitory Concentration (IC50)	37.8 ng/mL
Method Description	The inhibitory activity of AGS-22M6, AGS-22M6E ADC, and an isotype control ADC were added to various cancer cell lines in vitro and cell viability was measured after 5 days.
In Vitro Model	Invasive breast carcinoma	T-47D cells	CVCL_0553

References

Ref 1	FDA Approval Summary: Enfortumab Vedotin for Locally Advanced or Metastatic Urothelial Carcinoma
Ref 2	Physiologically based pharmacokinetic model to predict drug-drug interactions with the antibody-drug conjugate enfortumab vedotin
Ref 3	Clinical Overview of Enfortumab Vedotin in the Management of Locally Advanced or Metastatic Urothelial Carcinoma
Ref 4	Clinical Pharmacology of the Antibody-Drug Conjugate Enfortumab Vedotin in Advanced Urothelial Carcinoma and Other Malignant Solid Tumors
Ref 5	Population Pharmacokinetic Modeling and Exposure-Response Analysis for the Antibody-Drug Conjugate Enfortumab Vedotin in Locally Advanced or Metastatic Urothelial Carcinoma
Ref 6	Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. J Clin Oncol. 2023 Jan 1;41(1):22-31.
Ref 7	Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019 Oct 10;37(29):2592-2600.
Ref 8	Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV201): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2021 Jun;22(6):872-882.
Ref 9	A phase I study of enfortumab vedotin in Japanese patients with locally advanced or metastatic urothelial carcinoma. Invest New Drugs. 2020 Aug;38(4):1056-1066.
Ref 10	EV-101: A Phase I Study of Single-Agent Enfortumab Vedotin in Patients With Nectin-4-Positive Solid Tumors, Including Metastatic Urothelial Carcinoma. J Clin Oncol. 2020 Apr 1;38(10):1041-1049.
Ref 11	Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135.
Ref 12	Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models. Cancer Res. 2016 May 15;76(10):3003-13.

Antibody-drug Conjugate Information

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Correspondence

Prof. Feng ZHU (zhufeng@zju.edu.cn)

Prof. Xiaowu DONG (dongxw@zju.edu.cn)

Prof. Luo FANG (fangluo@zjcc.org.cn)