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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

Overview
Clinical Trials
Abbreviations

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 deruxtecan^a (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.

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TROPION-Breast03 trial overview

Tumor

TNBC (Stage I-III) who have residual invasive disease in the breast and/or axillary lymph nodes at surgical resection following neoadjuvant systemic therapy

Trial Identifier

NCT05629585

Phase

III

Stage

Stage I-III

Regimen

Dato-DXd ± durvalumab; investigator's choice of therapy (capecitabine or pembrolizumab or capecitabine + pembrolizumab)

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Study Design

Inclusion criteria

The key inclusion criteria^1-5 are -

Age ≥18 years at the time of screening
Histologically confirmed invasive TNBC per ASCO/CAP guidelines^4,5
Negative for ER with <1% of tumor cells positive for ER on IHC
Negative for PR with <1% of tumor cells positive for PR on IHC
Negative for HER2 with 0 or 1+ intensity on IHC, or 2+ intensity on IHC and no evidence of amplification on ISH

Residual invasive disease in the breast and/or axillary lymph node(s) at surgical resection following neoadjuvant therapy
Completed at least 6 cycles of neoadjuvant therapy containing an anthracycline and/or a taxane with or without platinum chemotherapy, with or without pembrolizumab
No evidence of locoregional or distant relapse
Surgical removal of all clinically evident disease in the breast and lymph nodes
ECOG PS 0 or 1 with no deterioration over the previous 2 weeks prior to randomization
FFPE tumor sample from residual invasive disease at surgery for tissue-based analysis
No adjuvant systemic therapy
If post-operative radiation therapy is given, ≤6 weeks between the completion of radiation therapy and date of randomization. If no post-operative radiation therapy is given, an interval of no more than 16 weeks between the date of breast surgery and randomization
Eligible for one of the therapy options listed as ICT (capecitabine, pembrolizumab, or capecitabine + pembrolizumab), per investigator assessment
Radiotherapy (if indicated) delivered before the start of study intervention
No known germline BRCA1 or BRCA2 mutation
Adequate bone marrow reserve and organ function within 7 days before randomization

References:

1. Study NCT05629585. ClinicalTrials.gov website.

2. Bardia A, Pusztai L, Albain K, et al. Ther Adv Med Oncol. 2024;16:17588359241248336.

3. Bardia A et al. Poster presented at: St. Gallen International Breast Cancer Conference; March 15-18, 2023; Vienna, Austria. Poster P018.

4. Wolff AC et al. Arch Pathol Lab Med. 2018;142(11):1364-1382.

5. Allison KH et al. Arch Pathol Lab Med. 2020;144(5):545–563.

Exclusion criteria

The key exclusion criteria^1-5 are -

Stage IV (metastatic) TNBC
History of prior invasive BC, or evidence of recurrent disease following preoperative therapy and surgery
Severe or uncontrolled medical conditions including systemic diseases, history of allogeneic organ transplant and active bleeding diseases, ongoing or active infection, serious chronic gastrointestinal conditions associated with diarrhea
Persistent toxicities caused by previous anticancer therapy
Active or prior documented autoimmune or inflammatory disorders
Clinically significant corneal disease
Active or uncontrolled hepatitis B/C or active tuberculosis infection
Current or history of (non-infectious) ILD/pneumonitis that required steroids, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening
Clinically severe pulmonary function compromise resulting from intercurrent pulmonary illnesses
Prior exposure to a PD-1/PD-L1 inhibitor other than pembrolizumab
Prior participation in any T-DXd or Dato-DXd study regardless of treatment assignment^a

^aTrastuzumab deruxtecan (T-DXd, DS-8201), known as fam-trastuzumab deruxtecan-nxki in the United States only. Datopotamab deruxtecan (Dato-DXd), known as datopotamab deruxtecan-dlnk in United States only.

Study Locator

Explore further trial details, understand eligibility criteria and speak to clinical trial navigators for the TROPION-Breast03 trial via the Breast Cancer Study Locator website.

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Abbreviations

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