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Study of T-DXd in Combination With Other Anticancer Agents for Patients With HER2-Low Advanced or Metastatic BC

Study of T-DXd in Combination With Other Anticancer Agents for Patients With HER2-Low Advanced or Metastatic BC1

DESTINY-Breast08 is a 2-part, Phase Ib, multicenter, open-label, modular, dose-finding and dose-expansion study of T-DXd combined with other anticancer agents in patients with HER2-low advanced/unresectable or metastatic BC.2

Study Design2,3

Study Design2,3

aPatients who have received CTX in the neoadjuvant or adjuvant setting are eligible, as long as they have had a disease-free interval of >12 months; bMolecularly defined subgroup of special interest, PD-L1(+); cMolecularly defined subgroup of special interest, AKT/PTEN/PIK3CA altered.

Endpoints1,2

Part 1:

  • The primary endpoints are safety, tolerability, and RDE evaluated according to modified toxicity probability interval-2 algorithm for the T-DXd combinations as assessed by AEs, serious AEs, DLTs, and laboratory findings.

Part 2:

  • The primary endpoints are safety and tolerability as assessed by AEs, serious AEs, and laboratory findings.
  • Secondary endpoints include ORR and PFS as determined by the investigator per RECIST version 1.1, OS, DOR, PK, and the presence of ADA of study drugs.

Key Eligibility Criteria

Key Eligibility Criteria1,2

Key Eligibility Criteria in DESTINY-Breast081,2
Key Inclusion Criteria Key Exclusion Criteria
Adults aged ≥18 years oldUncontrolled intercurrent illness
Pathologically documented BC that is advanced or metastatic;  has a history of HER2-low expression (IHC 2+/ ISH- or IHC 1+ [ISH- or untested] with a validated assay; locally confirmed), and is documented as HR positive or HR negative per ASCO/CAP guidelines in the metastatic settingUncontrolled or significant cardiovascular disease
Adequate tumour sample for biomarker assessmentHistory of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening

For patients with HR positive diseasea:

  • Part 1: ≥1 prior line of ET (±targeted therapy) and ≥1 prior line of chemotherapy for metastatic BC 
  • Part 2 (Modules 1, 4, and 5): Only 1 prior line of ET (±targeted therapy) and no prior chemotherapy in the metastatic setting 
Lung specific intercurrent clinically significant illnesses

For patients with HR negative diseaseb:

  • Part 1: ≥1 prior line of chemotherapy for metastatic BC
  • Part 2: no prior lines of therapy for metastatic BC (Module 2); 1 prior line of chemotherapy for metastatic BC (Modules 1 and 3)
Has spinal cord compression or clinically active CNS metastases
ECOG PS of 0 or 1Active primary immunodeficiency 

Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals 
 Prior treatment with an ADC containing an exatecan derivative that is a topoisomerase I inhibitor
aNote that there are no patients with HR positive disease in modules 2 and 3 of Part 2; bNote that there are no patients with HR negative disease in Modules 4 and 5 of Part 1 and 2.

Abbreviations

ADA = anti-drug antibody

;

ADC = antibody-drug conjugate

;

AE = adverse event

;

ASCO/CAP = American Society of Clinical Oncology/College of American Pathologists

;

BC = breast cancer

;

CTX = chemotherapy

;

DCO = data cut-off

;

DLT = dose limiting toxicity

;

DOR = duration of response

;

ET = endocrine therapy

;

ECOG = Eastern Cooperative Oncology Group

;

HER2 = human epidermal growth factor receptor 2

;

HR = hormone receptor

;

IHC = immunohistochemistry

;

ILD = interstitial lung disease

;

ISH = in-situ hybridization

;

MBC = metastatic breast cancer

;

ORR = objective response rate

;

OS = overall survival

;

PD-L1 = programmed cell death-ligand 1

;

PFS = progression-free survival

;

PI3KCA = phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha

;

PK = pharmacokinetics

;

PS = performance status

;

PTEN = phosphatase and tensin homolog

;

RECIST = Response Evaluation Criteria in Solid Tumors

;

RDE = recommended dose for expansion

;

RP2D = recommended phase 2 dose

;

T-DXd = trastuzumab deruxtecan

References

1. AstraZeneca. A phase 1b study of T-DXd combinations in HER2-low advanced or metastatic breast cancer (DB-08). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT04556773
2. André F, Hamilton EP, Loi S, et al. Dose-finding and -expansion studies of trastuzumab deruxtecan in combination with other anticancer agents in patients with advanced/metastatic HER2+ (DESTINY-Breast07) and HER2-low (DESTINY-Breast08) breast cancer [poster, supplement, and abstract]. Poster presented at: American Society of Clinical Oncology (ASCO) 2022 Congress; June 3-5, 2022; Chicago, IL. J Clin Oncol. 2022;40(suppl 16). Abs 3025. 
3. Jhaveri K, Hamilton E, Loi S, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in combination with other anticancer agents in patients with HER2-low metastatic breast cancer: a phase 1b, open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast08) [poster and abstract]. Poster presented at: San Antonio Breast Cancer Symposium (SABCS) Virtual Congress; December 8-11, 2020. Cancer Res. 2021;81(suppl 4). Abs OT-03-05. 

Document ID: 1592ad62-13a7-4b16-87ee-22c395bd8a67
Last updated: 09-December-2022

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