Antibody-drug Conjugate Information

General Information of This Antibody-drug Conjugate (ADC)
ADC ID
DRG0DAKKB
ADC Name
Patritumab deruxtecan
Synonyms
HER3-DXd; U3-1402; U3-1402a; Patritumab-DX-8951 conjugate
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Organization
Daiichi Sankyo Co., Ltd.; AstraZeneca PLC; Baxter Oncology GmbH; BSP Pharmaceuticals SpA
Drug Status
Phase 3
Indication
In total 5 Indication(s)
Non-small cell lung cancer [ICD11:2C25]
Phase 3
Colorectal cancer [ICD11:2B91]
Phase 2
EGFR(+) non-small cell lung cancer [ICD11:2C25]
Phase 2
Breast cancer [ICD11:2C60-2C65]
Phase 1
HER2(+) breast cancer [ICD11:2C60-2C65]
Phase 1
Drug-to-Antibody Ratio
8
Structure
Antibody Name
Patritumab
  Antibody Info 
Antigen Name
Receptor tyrosine-protein kinase erbB-3 (ERBB3)
  Antigen Info 
Payload Name
DX-8951 derivative (DXd)
  Payload Info 
Therapeutic Target
DNA topoisomerase 1 (TOP1)
  Target Info 
Linker Name
Mc-Gly-Gly-Phe-Gly
  Linker Info 
Conjugate Type
Random conjugation through reduced inter-chain cysteines.
Combination Type
Deruxtecan
Special Approval(s)
Breakthrough therapy(FDA)
Puchem SID
472419773 , 402425703 , 440234710 , 480403218 , 481988081
ChEBI ID
CHEMBL4594611
General Information of The Activity Data Related to This ADC
Identified from the Human Clinical Data
Click To Hide/Show 1 Activity Data Related to This Level
Standard Type NCT Number Clinical Status Clinical Trial Description
Objective Response Rate (ORR)  NCT03260491
Phase 1
A multicenter, open-label phase 1 study of U3-1402 in subjects with metastatic or unresectable non-small cell lung cancer.
Discovered Using Patient-derived Xenograft Model
Click To Hide/Show 4 Activity Data Related to This Level
Standard Type Value Units Animal Model (No. of PDX)
Tumor Growth Inhibition value (TGI) 
≈ 40.3
%
Non-small cell lung cancer PDX model (PDX: DFCI-306)
Tumor Growth Inhibition value (TGI) 
≈ 78.3
%
Non-small cell lung cancer PDX model (PDX: DFCI-259)
Tumor Growth Inhibition value (TGI) 
≈ 82.2
%
Non-small cell lung cancer PDX model (PDX: DFCI-161)
Tumor Growth Inhibition value (TGI) 
≈ 86.2
%
Non-small cell lung cancer PDX model (PDX: DFCI-284)
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) 
≈ 78.5
%
B16-F10 cells
Mouse melanoma
Tumor Growth Inhibition value (TGI) 
≈ 95.1
%
MDA-MB-453 cells
Breast adenocarcinoma
Full List of Activity Data of This Antibody-drug Conjugate
Identified from the Human Clinical Data
Click To Hide/Show 1 Activity Data Related to This Level
Experiment 1 Reporting the Activity Date of This ADC [1]
Efficacy Data Objective Response Rate (ORR)
39.00%
Patients Enrolled
In dose escalation phase, pts with metastatic or unresectable non-small cell lung cancer (NSCLC) with EGFR activating mutation after disease progression during/after EGFR TKI therapy; In Dose Expansion phase, pts with metastatic or unresectable NSCLC with EGFR activating mutation or squamous or non-squamous NSCLC with disease progression during/after systemic treatment for locally advanced or metastatic disease.

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Administration Dosage
Dose of 3.20, 4.80, 5.60, 6.40, iv Q3W in Dose Escalation phase; EGFR mutant pts at 5.60 mg/kg IV, Q3W, and EGFR wild-type pts at RDE IV, Q3W, in Dose Expansion phase.
Related Clinical Trial
NCT Number NCT03260491  Clinical Status Phase 1
Clinical Description A multicenter, open-label phase 1 study of U3-1402 in subjects with metastatic or unresectable non-small cell lung cancer.
Primary Endpoint
The confirmed ORR by blinded independent central review (BICR) was 39.00% [95% confidence interval (CI), 26.00-52.40] in patients who received HER3-DXd at a dose of 5.60 mg/kg i.v. once every 3 weeks. There was 1 complete response (CR) and 21 partial responses (PR); 19 patients had stable disease (SD) as a best response.
Other Endpoint
At a median follow-up of 10.20 months, median PFS was 8.20 (95% CI, 4.40-8.30) months (16 of 57 patients were ongoing without events), and the median OS was not reached at the time of data cutoff (95% CI, 9.40-NE months; 35 of 57 patients were ongoing without events).
Discovered Using Patient-derived Xenograft Model
Click To Hide/Show 4 Activity Data Related to This Level
Experiment 1 Reporting the Activity Date of This ADC [2]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 40.30% (Day 28) Negative HER3 expression (HER3-; IHC H score=1)
Method Description
Single-agent efficacy of HER3DXd in EGFR inhibitorresistant models of NSCLC. The dose was ten mg/kg HER3DXd or IgG control, weekly.
In Vivo Model Non-small cell lung cancer PDX model (PDX: DFCI-306)
Experiment 2 Reporting the Activity Date of This ADC [2]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 78.30% (Day 28) High HER3 expression (HER3+++; IHC H score=202)
Method Description
Single-agent efficacy of HER3DXd in EGFR inhibitorresistant models of NSCLC. The dose was ten mg/kg HER3DXd or IgG control, weekly.
In Vivo Model Non-small cell lung cancer PDX model (PDX: DFCI-259)
Experiment 3 Reporting the Activity Date of This ADC [2]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 82.20% (Day 38) Moderate HER3 expression (HER3++; IHC H score=181)
Method Description
Single-agent efficacy of HER3DXd in EGFR inhibitorresistant models of NSCLC. The dose was ten mg/kg HER3DXd or IgG control, weekly.
In Vivo Model Non-small cell lung cancer PDX model (PDX: DFCI-161)
Experiment 4 Reporting the Activity Date of This ADC [2]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 86.20% (Day 22) High HER3 expression (HER3+++; IHC H score=248)
Method Description
Single-agent efficacy of HER3DXd in EGFR inhibitorresistant models of NSCLC. The dose was ten mg/kg HER3DXd or IgG control, weekly.
In Vivo Model Non-small cell lung cancer PDX model (PDX: DFCI-284)
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 [3]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 78.50% (Day 7) Positive HER3 expression (HER3 +++/++)
Method Description
U3-1402 (30 mg/kg body weight in 200 uL ABS, weekly), ABS (200 L, weekly; vehicle), anti-PD-1 antibody (10 mg/kg body weight in 200 L PBS, twice a week), or a combination of U3-1402 and anti-PD-1 were received intraperitoneal injections.
In Vivo Model B16-F10 CDX model
In Vitro Model Mouse melanoma B16-F10 cells CVCL_0159
Experiment 2 Reporting the Activity Date of This ADC [4]
Efficacy Data Tumor Growth Inhibition value (TGI) ≈ 95.10% (Day 21) Positive HER3 expression (HER3+++/++)
Method Description
U3-1402 (6 m ug/kg, every seven days x3) induces efficient tumor cell killing in cell line-derived models of breast cancer cell line MDA-MB-453 with HER2 expression with high expression.
In Vivo Model MDA-MB-453 CDX model
In Vitro Model Breast adenocarcinoma MDA-MB-453 cells CVCL_0418
References
Ref 1 Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor-Resistant, EGFR-Mutated Non-Small Cell Lung Cancer. Cancer Discov. 2022 Jan;12(1):74-89.
Ref 2 EGFR Inhibition Enhances the Cellular Uptake and Antitumor-Activity of the HER3 Antibody-Drug Conjugate HER3-DXd. Cancer Res. 2022 Jan 1;82(1):130-141.
Ref 3 Two drugs for advanced HER2-positive breast cancer (Enhertu and Tukysa). Med Lett Drugs Ther. 2020 Nov 16;62(1611):182-184.
Ref 4 A Novel HER3-Targeting Antibody-Drug Conjugate, U3-1402, Exhibits Potent Therapeutic Efficacy through the Delivery of Cytotoxic Payload by Efficient Internalization. Clin Cancer Res. 2019 Dec 1;25(23):7151-7161. doi: 10.1158/1078-0432.CCR-19-1745. Epub 2019 Aug 30.

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