TROPION-Breast02: Datopotamab deruxtecan for locally recurrent inoperable or metastatic triple-negative breast cancer

Figures & data

Figure 1. Overview of the monoclonal antibody datopotamab deruxtecan.

(A) Design of datopotamab deruxtecan monoclonal antibody and (B) proposed mechanism of action of datopotamab deruxtecan.

Panel A previously presented at the 2019 World Conference on Lung Cancer [32]. Panel B reproduced with kind permission of the authors with permission from [33].

DXd: Deruxtecan; IgG1: Immunoglobulin G1; mAb: Monoclonal antibody; TROP2: Trophoblast cell surface antigen 2.

Table 1. Study interventions.

Arm 1: Dato-DXd

Dato-DXd 6.0 mg/kg iv. on day 1, Q3W

Arm 2: ICC

For patients with no prior taxane exposure, or with prior taxane exposure in the neoadjuvant or adjuvant setting and DFI >12 months: • Paclitaxel 80 mg/m^2 iv. on days 1, 8, and 15, Q3W • Nab-paclitaxel 100 mg/m^2 iv. on days 1, 8, and 15, Q4W For patients with prior taxane exposure and DFI ≤12 months: • Capecitabine 1000 or 1250 mg/m^2 orally twice daily on days 1–14, Q3W; choice of dose will be determined by standard institutional practice • Eribulin mesylate 1.4 mg/m^2 iv. on days 1 and 8, Q3W • Carboplatin AUC 6 (using Calvert formula)^† iv. on day 1, Q3W; maximum carboplatin dose will not exceed 900 mg

† Calvert formula: total dose (mg) = (target AUC [mg/ml/minute]) × (GFR [ml/minute] + 25). GFR is estimated by calculating CrCL using the Cockroft-Gault equation and is capped at 125 ml/minute for patients who have normal renal function.

AUC: Area under the curve; CrCl: Creatinine clearance; Dato-DXd: Datopotamab deruxtecan; DFI: Disease-free interval; GFR: Glomerular filtration rate; ICC: Investigator’s choice of chemotherapy; iv.: Intravenous; Q3/4W: Every 3/4 weeks.

Figure 2. TROPION-Breast02 study design.

*PD-L1 negative, previous PD-1/PD-L1 inhibitor therapy for early-stage breast cancer, comorbidities precluding PD-1/PD-L1 inhibitor therapy, or PD-L1 positive with no regulatory access to PD-1/PD-L1 inhibitor therapy (no regulatory approval in country).

^†DFI defined as the time between completion of treatment with curative intent (either surgery or last dose of systemic anticancer therapy) and first documented local or distant disease recurrence. Adjuvant radiation therapy is not considered treatment with curative intent for the purpose of calculating. No minimum DFI was specified; patients could have had any length of time between curative-intent treatment and disease recurrence.

^‡If no prior taxane, or prior taxane in the (neo)adjuvant setting and DFI >12 months, paclitaxel or nab-paclitaxel; if prior taxane and DFI ≤12 months: capecitabine, carboplatin, or eribulin mesylate.

^§Response assessment: scan Q6W for 48 weeks, then Q9W until RECIST v1.1, regardless of study intervention, discontinuation or start of subsequent anticancer therapy.

BICR: Blinded independent central review; CPS: Combined positive score; Dato-DXd: Datopotamab deruxtecan; DCR: Disease control rate; DFI: Disease-free interval; DoR: Duration of response; ECOG PS: Eastern Cooperative Oncology Group Performance Status; IA: Investigator’s assessment; iv.: Intravenous; ORR: Objective response rate; OS: Overall survival; PD-1: Programmed cell death protein-1; PD-L1: Programmed cell death-ligand 1; PFS: Progression-free survival; PFS2: Time to second progression or death; PRO: Patient-reported outcome; Q3/4/6/9W: Every 3/4/6/9 weeks; RECIST v1.1: Response Evaluation Criteria in Solid Tumours version 1.1; TNBC: Triple-negative breast cancer; TROP2: Trophoblast cell surface protein 2.

Table 2. Key inclusion criteria.

Inclusion criteria

• Age ≥18 years at the time of screening • Histologically or cytologically documented locally recurrent inoperable or metastatic TNBC, defined as: – Negative for ER with <1% of tumor cells positive for ER on IHC [38] – Negative for PgR with <1% of tumor cells positive for PgR 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 [5] • 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: – Patients whose tumors are PD-L1-negative^†, or – Patients whose tumors are PD-L1-positive^† and have: a. relapsed after prior PD-1/PD-L1 inhibitor therapy for early-stage breast cancer, b. comorbidities precluding PD-1/PD-L1 inhibitor therapy, or c. no regulatory access to PD-1/PD-L1 inhibitor therapy at time of screening (participant’s country does not have regulatory approval at the time of screening) • At least 1 measurable lesion per RECIST 1.1, not previously irradiated that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have short axis ≥15 mm) with CT or MRI, and is suitable for accurate repeated measurements • ECOG PS 0 or 1 • Eligible for one of the ICC options 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 – Anticancer therapy including hormonal therapy: ≥3 weeks (for small molecule targeted agents: ≥2 weeks or five half-lives, whichever is longer) – Antibody-based anticancer therapy: ≥4 weeks with the exception of RANKL inhibitors – Chloroquine/hydroxychloroquine: >14 days • Tumor sample available prior to randomization, collected ≤3 months prior to screening • Adequate organ and bone marrow function within 7 days before day of first dosing • Minimum life expectancy of 12 weeks • Willing to use an adequate method of contraception throughout the study or (for female patients) be at least 1 year post-menopausal, surgically sterile, or using one highly effective form of birth control • Negative pregnancy test (serum) for women of childbearing potential

† PD-L1 status tested prospectively during screening by a sponsor-designated central laboratory using the commercially available PD-L1 IHC 22C3 pharmDx assay (Dako North America, Inc., Carpinteria, CA, USA) to determine PD-L1 CPS. This result will be used to exclude patients with CPS ≥10 who are potentially eligible to be treated with pembrolizumab-containing treatment regimens.

ASCO-CAP: American Society of Clinical Oncology - College of American Pathologists; CPS: Combined positive score; CT: Computed tomography; ECOG PS: Eastern Cooperative Oncology Group Performance Status; ER: Estrogen receptor; HER2: Human epidermal growth factor receptor 2; ICC: Investigator’s choice of chemotherapy; IHC: Immunohistochemistry; MRI: Magnetic resonance imaging; PD-1: Programmed cell death protein-1; PD-L1: Programmed cell death-ligand 1; PgR: Progesterone receptor; RANKL: Receptor activator of nuclear factor kappa-B ligand; RECIST: Response Evaluation Criteria in Solid Tumour; TNBC: Triple-negative breast cancer.

Table 3. Key exclusion criteria.

Exclusion criteria

• As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, uncontrolled hypertension, history of allogeneic organ transplant and active bleeding diseases, ongoing or active infection, or significant cardiac or psychological conditions) which, in the investigator’s opinion, makes it undesirable for the patient to participate in the study or that would jeopardise compliance with the protocol • History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence (per investigator assessment) • Persistent toxicities caused by previous anticancer therapy, excluding alopecia, not yet improved to Grade ≤1 or baseline. Grade 2 toxicities (defined as no worsening to Grade >2 for at least 3 months prior to first dosing and managed with standard-of-care treatment) may be eligible at the discretion of the investigator and sponsor • Uncontrolled infection requiring iv. antibiotics, antivirals or antifungals; suspected infections (e.g., prodromal symptoms); or inability to rule out infections • Known active or uncontrolled hepatitis B or C virus infection • Known HIV infection that is not well controlled • Uncontrolled or significant cardiac disease including myocardial infarction or uncontrolled/unstable angina within 6 months prior to cycle 1 day 1; CHF (New York Heart Association Class II to IV); uncontrolled or significant cardiac arrhythmia; uncontrolled hypertension (resting SBP >180 mmHg or DBP >110 mmHg) • Mean resting corrected QTcF >470 ms regardless of gender, obtained from triplicate 12-lead ECGs performed at screening • Uncontrolled hypercalcemia • History of non-infectious ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening • Clinically severe pulmonary function compromise resulting from intercurrent clinically significant pulmonary illnesses • Leptomeningeal carcinomatosis • Clinically significant corneal disease • Known active tuberculosis infection • Prior exposure to any treatment (including ADC) containing a chemotherapeutic agent targeting topoisomerase I, TROP2-targeted therapy, prior treatment with same ICC agent, or chloroquine/hydroxychloroquine without an adequate treatment washout period of >14 days prior to randomization • Any concurrent anticancer treatment • Concurrent use of hormonal therapy for non-cancer-related conditions • Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 3 weeks of the first dose of study intervention or an anticipated need for major surgery during the study • Receipt of live, attenuated vaccine within 30 days prior to the first dose of study treatment • Concomitant use of chronic systemic corticosteroids or other immunosuppressive medications, except for managing adverse events • Previous treatment in the present study • Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks prior to first dose of study intervention, randomization into a prior T-DXd or Dato-DXd study regardless of treatment assignment, or concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study • Known severe hypersensitivity to Dato-DXd (or any of the excipients of the product) and known history of severe hypersensitivity reactions to other monoclonal antibodies

ADC: Antibody-drug conjugate; CHF: Congestive heart failure; Dato-DXd: Datopotamab deruxtecan; DBP: Diastolic blood pressure; ECG: Electrocardiogram; ICC: Investigator’s choice of chemotherapy; ILD: Interstitial lung disease; IV: Intravenous; ms: Millisecond; QTcF: Corrected QT interval formula; SBP: Systolic blood pressure; T-DXd: Trastuzumab deruxtecan; TROP2: Trophoblast cell surface antigen 2.

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