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TROP2-directed ADC

CompoundDatopotamab deruxtecan (in collaboration with Daiichi Sankyo)Datopotamab deruxtecan-dlnk (in collaboration with Daiichi Sankyo, Inc., Basking Ridge, NJ, US)

Area under investigation

Advanced solid tumors, Colorectal cancer, Gastric cancer, HER2-low breast cancer, HR-positive/HER2-negative breast cancer, mCRPC, NSCLC, Ovarian cancer, TNBC, BTCs, Cervical cancer, Endometrial cancer, SCLC, Metastatic urothelial carcinoma, HER2 IHC 0 metastatic breast cancer, Muscle Invasive Urothelial Carcinoma

Scientific PillarAntibody-Drug Conjugates

 

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TROPION-Breast05 trial overview

Tumor

Locally recurrent inoperable or metastatic PD-L1-positive TNBC not previously treated with chemotherapy or targeted systemic anticancer therapy in this setting

Trial Identifier

NCT06103864

Phase

III

Stage

Stage IV

Regimen

Dato-DXd + durvalumab; investigator's choice of CT (paclitaxel, nab-paclitaxel, or gemcitabine + carboplatin) with pembrolizumab; Dato-DXd monotherapy

Visit ct.gov

Study Design

Inclusion criteria

The key inclusion criteria1-3 are –

  • Age ≥18 years
  • Histologically or cytologically documented locally recurrent inoperable, which cannot be treated with curative intent, or metastatic TNBC, as defined by the ASCO-CAP guidelines
  • ECOG PS 0 or 1
  • Mandatory FFPE metastatic or locally recurrent inoperable tumor sample
  • PD-L1-positive TNBC based on PD-L1 22C3 assay (CPS ≥10) from a central laboratory
  • No prior chemotherapy or targeted systemic anti-cancer therapy for metastatic or locally recurrent inoperable breast cancer
    ‒ Patients with recurrent disease will be eligible if they have completed treatment for Stage I-III breast cancer, if indicated, and ≥6 months have elapsed between completion of treatment with curative intent and the first documented recurrence
  • Eligible for one of the ICC options (paclitaxel, nab-paclitaxel, or gemcitabine + carboplatin)
  • Measurable disease as per RECIST v1.1
  • Adequate bone marrow reserve and organ function

 

References:

  1. Study NCT06103864. ClinicalTrials.gov website. 
  2. Graff SL, et al. Poster presented at: Miami Breast Cancer Conference; March 7-10, 2024; Miami, Florida. Poster 19. 
  3. Schmid P, et al. Poster presented at: ESMO BC; May 15-17, 2024; Berlin, Germany. Poster 261TiP

Exclusion criteria

The key exclusion criteria1-3 are –

  • Severe or uncontrolled medical conditions including systemic diseases, history of allogeneic organ transplant and active bleeding diseases, ongoing or active infection, significant cardiac or psychological conditions
  • History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before C1D1 and of low potential risk for recurrence
  • Neoplastic spinal cord compression or active brain metastases, leptomeningeal carcinomatosis or history of leptomeningeal carcinomatosis
    ‒ Patients with treated clinically inactive brain metastases that are no longer symptomatic, who require no treatment with corticosteroids or anticonvulsants, may be included in the study if they have recovered from acute toxic effects of radiotherapy
  • Uncontrolled infection requiring IV antibiotics, antivirals or antifungals
  • Active or uncontrolled hepatitis B or C virus infection
  • Known HIV infection that is not well controlled
  • Uncontrolled or significant cardiac disease
  • History of non-infectious ILD/pneumonitis (including radiation pneumonitis) that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening
  • Severe pulmonary function compromise
  • Clinically significant corneal disease
  • Active or prior documented autoimmune or inflammatory disorders
  • Prior exposure to any treatment including ADC containing a chemotherapeutic agent targeting topoisomerase I and TROP2-directed therapy
  • Any concurrent anti-cancer treatment

TROPION-Breast05 overview model

TROPION-Breast05 trial overview

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Target Overview

Trophoblast cell-surface antigen 2 (TROP2) is a transmembrane glycoprotein that is broadly expressed in solid tumors, including lung, breast, bladder, gastric, head and neck, ovarian, pancreatic, and prostate cancers.1-3

While the physiological function of TROP2 is still under investigation, preclinical evidence suggests that it is involved in multiple intracellular signaling pathways and may promote cell proliferation, cell survival, invasion, and metastasis.3-7

TROP2 levels are higher in tumor tissues vs baseline expression in corresponding normal tissues across various tumor types.6

Compound Overview

Datopotamab deruxtecana (Dato-DXd) is a TROP2 directed ADC composed of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a potent topoisomerase I inhibitor payload (an exatecan derivative [DXd]) via a plasma-stable, tumor-selective, tetrapeptide-based cleavable linker.7,8,9

Dato-DXd induces selective tumor cell death and is specifically designed to reduce systemic exposure to the topoisomerase I inhibitor payload.7,8,10

The released payload has a high cell membrane permeability, which enables a bystander antitumor effect resulting in elimination of both TROP2 expressing tumor cells and neighboring cells present in the tumor microenvironment.10

aIn collaboration with Daiichi Sankyo, Inc., Basking Ridge, NJ, US.

References

1. Shvartsur A, Bonavida B. Genes Cancer. 2015;6(3-4):84-105. 2. Goldenberg DM, Stein R, Sharkey RM. Oncotarget. 2018;9(48):28989-29006. 3. Lenárt S, Lenárt P, Šmarda J, et al. Cancers (Basel). 2020;12(11):3328. 4. Jiang A, Gao X, Zhang D, et al. Oncol Lett. 2013;6(2):375-380. 5. Li Z, Jiang X, Zhang W. Biochem Biophys Res Commun. 2016;470:197-204. 6. Trerotola M, Cantanelli P, Guerra E, et al. Oncogene. 2013;32(2):222-233. 7. Okajima D, Yasuda S, Maejima T, et al. Mol Cancer Ther. 2021;20(12):2329-2340. 8. Ogitani Y, Aida T, Hagihara K, et al. Clin Cancer Res. 2016;22(20):5097-5108. 9. Shiose Y, Ochi Y, Kuga H, et al. Biol Pharm Bull. 2007;30(12):2365-2370. 10. Nakada T, Sugihara K, Jikoh T, et al. Chem Pharm Bull (Tokyo). 2019;67(3):173-185.

 

Loading......

TROPION-Breast05 trial overview

Tumor

Locally recurrent inoperable or metastatic PD-L1-positive TNBC not previously treated with chemotherapy or targeted systemic anticancer therapy in this setting

Trial Identifier

NCT06103864

Phase

III

Stage

Stage IV

Regimen

Dato-DXd + durvalumab; investigator's choice of CT (paclitaxel, nab-paclitaxel, or gemcitabine + carboplatin) with pembrolizumab; Dato-DXd monotherapy

Visit ct.gov

Study Design

Inclusion criteria

The key inclusion criteria1-3 are –

  • Age ≥18 years
  • Histologically or cytologically documented locally recurrent inoperable, which cannot be treated with curative intent, or metastatic TNBC, as defined by the ASCO-CAP guidelines
  • ECOG PS 0 or 1
  • Mandatory FFPE metastatic or locally recurrent inoperable tumor sample
  • PD-L1-positive TNBC based on PD-L1 22C3 assay (CPS ≥10) from a central laboratory
  • No prior chemotherapy or targeted systemic anti-cancer therapy for metastatic or locally recurrent inoperable breast cancer
    ‒ Patients with recurrent disease will be eligible if they have completed treatment for Stage I-III breast cancer, if indicated, and ≥6 months have elapsed between completion of treatment with curative intent and the first documented recurrence
  • Eligible for one of the ICC options (paclitaxel, nab-paclitaxel, or gemcitabine + carboplatin)
  • Measurable disease as per RECIST v1.1
  • Adequate bone marrow reserve and organ function

 

References:

  1. Study NCT06103864. ClinicalTrials.gov website. 
  2. Graff SL, et al. Poster presented at: Miami Breast Cancer Conference; March 7-10, 2024; Miami, Florida. Poster 19. 
  3. Schmid P, et al. Poster presented at: ESMO BC; May 15-17, 2024; Berlin, Germany. Poster 261TiP

Exclusion criteria

The key exclusion criteria1-3 are –

  • Severe or uncontrolled medical conditions including systemic diseases, history of allogeneic organ transplant and active bleeding diseases, ongoing or active infection, significant cardiac or psychological conditions
  • History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before C1D1 and of low potential risk for recurrence
  • Neoplastic spinal cord compression or active brain metastases, leptomeningeal carcinomatosis or history of leptomeningeal carcinomatosis
    ‒ Patients with treated clinically inactive brain metastases that are no longer symptomatic, who require no treatment with corticosteroids or anticonvulsants, may be included in the study if they have recovered from acute toxic effects of radiotherapy
  • Uncontrolled infection requiring IV antibiotics, antivirals or antifungals
  • Active or uncontrolled hepatitis B or C virus infection
  • Known HIV infection that is not well controlled
  • Uncontrolled or significant cardiac disease
  • History of non-infectious ILD/pneumonitis (including radiation pneumonitis) that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening
  • Severe pulmonary function compromise
  • Clinically significant corneal disease
  • Active or prior documented autoimmune or inflammatory disorders
  • Prior exposure to any treatment including ADC containing a chemotherapeutic agent targeting topoisomerase I and TROP2-directed therapy
  • Any concurrent anti-cancer treatment

TROPION-Breast05 overview model

TROPION-Breast05 trial overview

Take me to ClinicalTrials.Gov

You are now leaving the AstraZeneca Oncology Portfolio.
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Abbreviations

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  • 1L

    first line

  • ADA

    anti-drug antibody

  • ADC

    antibody drug conjugate

  • AE

    adverse event

  • AJCC

    American Joint Committee on Cancer

  • ALK

    anaplastic lymphoma kinase

  • ALT

    alanine aminotransferase

  • anti-HBc

    anti–hepatitis B core antibody

  • anti-HBs

    anti–hepatitis B surface antibody

  • ASCO/CAP

    American Society of Clinical Oncology / College of American Pathologists

  • AST

    aspartate aminotransferase

  • AUC

    area under the curve

  • BC

    breast cancer

  • bev

    bevacizumab

  • BICR

    blinded independent central review

  • BID

    twice daily

  • BRAF

    v-raf murine sarcoma viral oncogene homolog B1

  • BRCA

    breast cancer susceptibility gene

  • C1D1

    Cycle 1 Day 1

  • CAP/CLIA

    College of American Pathologists/Clinical Laboratory Improvement Amendments

  • CBR

    clinical benefit rate

  • CDK

    cyclin-dependent kinase

  • CHF

    congestive heart failure

  • CPS

    combined positive score

  • CR

    complete response

  • CRT

    chemoradiotherapy

  • CT

    chemotherapy

  • CTCAE

    Common Terminology Criteria for Adverse Events

  • ctDNA

    circulating tumor DNA

  • DAR

    drug-to-antibody ratio

  • Dato-DXd

    datopotamab deruxtecan

  • DCO

    data cut-off

  • DCR

    disease control rate

  • DDFS

    distant disease-free survival

  • DFI

    disease-free interval

  • DFS

    disease-free survival

  • DNA

    deoxyribonucleic acid

  • DoR

    duration of response

  • ECG

    electrocardiogram

  • ECHO

    echocardiogram

  • ECOG PS

    Eastern Cooperative Oncology Group Performance Score

  • EFS

    event-free survival

  • EGFR

    epidermal growth factor receptor

  • EORTC-IL

    European Organization for Research and Treatment of Cancer-Item Library

  • ER

    estrogen receptor

  • ESMO

    European Society for Medical Oncology

  • ET

    endocrine therapy

  • FFPE

    formalin-fixed paraffin-embedded

  • GHS

    global health status

  • HBsAg

    HBV surface antigen

  • HBV

    hepatitis B virus

  • HCV

    hepatitis C virus

  • HER2

    human epidermal growth factor receptor 2

  • HIV

    human immunodeficiency virus

  • HR

    hormone receptor

  • HRT

    hormone replacement therapy

  • ICC

    investigator’s choice of chemotherapy

  • ICT

    investigator's choice therapy

  • iDFS (IDFS)

    invasive disease-free survival

  • IgG

    immunoglobulin G

  • IHC

    immunohistochemistry

  • ILD

    interstitial lung disease

  • ISH

    in-situ hybridization

  • ITT

    intention to treat

  • IV

    intravenous

  • KRAS

    Kirsten rat sarcoma viral oncogene homolog

  • LVEF

    left ventricular ejection fraction

  • LVI

    lymphovascular invasion

  • mBC

    metastatic breast cancer

  • MET

    hepatocyte growth factor receptor

  • mNSCLC

    metastatic NSCLC

  • MUGA

    multigated acquisition

  • NEC

    large cell neuroendocrine carcinoma

  • NSCLC

    non-small cell lung cancer

  • NTRK

    neurotrophic tyrosine receptor kinase

  • ORR

    overall or objective response rate

  • OS

    overall survival

  • OSE

    ocular surface events

  • pCR

    pathological complete response

  • PD-1

    programmed cell death-1

  • PD-L1

    programmed cell death ligand-1

  • PD-L2

    programmed cell death ligand-2

  • pDC

    plasmacytoid dendritic cell

  • PFS

    progression-free survival

  • PFS2

    time to second progression or death

  • PI

    prescribing information

  • PK

    pharmacokinetics

  • PO

    per oral

  • PR

    partial response

  • PtCh

    platinum-based chemotherapy

  • Q3W

    every 3 weeks

  • Q4W

    every 4 weeks

  • Q6W

    every 6 weeks

  • Q9W

    every 9 weeks

  • QoL

    quality of life

  • QTcF

    QT interval corrected by Fridericia’s formula

  • QW

    every week

  • RANKL

    receptor activator of nuclear factor kappa B ligand

  • RECIST

    Response Evaluation Criteria in Solid Tumors

  • RECIST v1.1

    Response Evaluation Criteria in Solid Tumors version 1.1

  • RET

    rearranged during transfection

  • RNA

    ribonucleic acid

  • ROS1

    ROS proto-oncogene 1

  • RT

    radiotherapy

  • SCLC

    small cell lung cancer

  • SoC

    standard of care

  • T-DXd

    fam-trastuzumab deruxtecan-nxki in US only; trastuzumab deruxtecan in other regions of world

  • TFST

    time to first subsequent therapy

  • TNBC

    triple-negative breast cancer

  • TOP1i

    topoisomerase 1 inhibitor

  • TPS

    tumor proportion score

  • TROP2

    trophoblast cell-surface antigen 2

  • tSCLC

    transformed small cell lung cancer

  • TSST

    time to start of second subsequent therapy

  • TTD

    time to deterioration

  • UFT

    tegafur-uracil

  • ULN

    upper limit of normal

  • VPI

    visceral pleural invasion

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