A Phase III, Open-label, Randomized Study of Datopotamab Deruxtecan (Dato-DXd) Versus Investigator’s Choice of Single-Agent Chemotherapy in Patients who are not Candidates for PD 1/PD L1 Inhibitor Therapy in First-line Locally Recurrent Inoperable or Metastatic Triple-negative Breast Cancer (TROPION Breast02)
The primary objectives of the study are to demonstrate superiority of Dato-DXd relative to ICC by assessment of PFS in participants with locally recurrent inoperable or metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitor therapy, per BICR and to demonstrate superiority of Dato-DXd relative to ICC by assessment of OS in participants with locally recurrent inoperable or metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitor therapy.
- Experimental: Dato-DXd
- Active Comparator: Investigators Choice of Chemotherapy (ICC)
- Participant must be ≥ 18 years (≥ 20 years in Japan) at the time of screening. Type of Participant and Disease Characteristics
- Histologically or cytologically documented locally recurrent inoperable or metastatic TNBC. TNBC is defined as:
- Negative for ER with < 1% of tumor cells positive for ER on IHC.
- Negative for progesterone receptor with < 1% of tumor cells positive for progesterone receptor on IHC.
- Negative for HER2 with 0 or 1+ intensity on IHC or 2+ intensity on IHC and negative by in situ hybridization per the ASCO-CAP HER2 guideline
- No prior chemotherapy or targeted systemic therapy for metastatic or locally recurrent inoperable breast cancer.
- Not a candidate for PD-1/PD-L1 inhibitor therapy, defined as:
- Participants whose tumors are PD-L1-negative, or
- Participants whose tumors are PD-L1-positive and have:
- relapsed after prior PD-1/PD-L1 inhibitor therapy for early-stage breast cancer,
- comorbidities precluding PD-1/PD-L1 inhibitor therapy, or
- no regulatory access to pembrolizumab [participant's country does not have regulatory approval at the time of screening]).
- At least 1 measurable lesion not previously irradiated that qualifies as a RECIST 1.1 TL at baseline and can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI), and is suitable for accurate repeated measurements.
- ECOG PS 0 or 1 with no deterioration over the previous 2 weeks prior to baseline or day of first dosing.
- Eligible for one of the chemotherapy options listed as ICC (paclitaxel, nab-paclitaxel, capecitabine, carboplatin, or eribulin), per investigator assessment.
- Has had an adequate treatment washout period before Cycle 1 Day 1, defined as:
- Major surgery: ≥ 3 weeks.
- Radiation therapy including palliative radiation to chest: ≥ 4 weeks (palliative radiation therapy to other areas ≥ 2 weeks).
- Corticosteroid therapy for central nervous system metastatic disease: > 3 days.
- Anti-cancer therapy including hormonal therapy: ≥ 3 weeks (for small molecule targeted agents: ≥ 2 weeks or 5 half-lives, whichever is longer).
- Antibody-based anti-cancer therapy: ≥ 4 weeks with the exception of receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors (eg, denosumab for the treatment of bone metastases).
- Chloroquine/hydroxychloroquine: > 14 days.
- Written confirmation of tumor sample needs to be available prior to enrolment and tumor samples should be available prior to randomization. All participants must have a FFPE metastatic (excluding bone) or locally recurrent inoperable tumour sample (block preferred, or a minimum of 20 freshly cut slides) available, collected ≤ 3 months prior to screening. If neither an adequate FFPE block nor the minimum of 20 slides are available from the most recent biopsy, or if a biopsy is not feasible for safety reasons, and this is clearly documented, an archival tumor specimen obtained before the diagnosis of locally recurrent inoperable or metastatic breast cancer may be submitted, pending approval by the Global Study Team.
- Participants with a history of previously treated neoplastic spinal cord compression or clinically inactive brain metastases, who require no treatment with corticosteroids or anticonvulsants may be included in the study, if they have recovered from acute toxic effects of radiotherapy. A minimum of 2 weeks must have elapsed between the end of radiotherapy and study enrolment. A minimum of 3 days must have elapsed between the end of corticosteroid therapy for central nervous system metastatic disease and study enrolment.
- Adequate organ and bone marrow function within 7 days before day of first dosing as follows:
- Haemoglobin ≥ 9.0 g/dL (red blood cell/plasma transfusion is not allowed within 1 week prior to screening assessment).
- Absolute neutrophil count ≥ 1.5 × 10^9/L (granulocyte colony stimulating factor administration is not allowed within 1 week prior to screening assessment).
- Platelet count ≥ 100 × 10^9/L (platelet transfusion is not allowed within 1 week prior to screening assessment).
- Total bilirubin (TBL) ≤ 1.5 × upper limit of normal (ULN) if no liver metastases or < 3 × ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline.
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN for AST/ALT (< 5 × ULN in participants with liver metastases).
- Calculated CrCL ≥ 30 mL/minute as determined by Cockcroft Gault
- International normalized ratio (INR) or prothrombin time, and either partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT): ≤ 1.5 × ULN.
- Minimum life expectancy of 12 weeks.
- Sex: Male or female. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
- Reproduction: Negative pregnancy test (serum) for women of childbearing potential.
- Female participants must be at least 1-year post-menopausal, surgically sterile, or using at least 1 highly effective form of birth control (a highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly.) Women of childbearing potential who are sexually active with a nonsterilized male partner must agree to use at least 1 highly effective method of birth control. They should have been stable on their chosen method of birth control for a minimum of 3 months before entering the study and continue for at least 7 months after the last dose. Female participants must refrain from egg cell donation and breastfeeding while on study and for at least 7 months after the last dose of study drug. Any nonsterilized male partner of a woman of childbearing potential must use a male condom plus spermicide (condom alone in countries where spermicides are not approved) throughout this period.
- Male participants who intend to be sexually active with a female partner of childbearing potential must be surgically sterile or use an acceptable method of contraception from the time of screening throughout the total duration of the study and the drug washout period (at least 4 months after the last dose of study intervention) to prevent pregnancy in a partner. Male participants must not donate or bank sperm during this same time period. Not engaging in heterosexual activity (sexual abstinence) for the duration of the study and drug washout period is an acceptable practice, if this is the preferred usual lifestyle of the participant. Periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception.
- Informed Consent: Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
- Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of sample for optional genetic research that supports Genomic Initiative.