17 TROPION-Breast05: A Phase 3 Study of Datopotamab Deruxtecan (Dato-DXd) With or Without Durvalumab Versus Chemotherapy (CT) Plus Pembrolizumab in Patients (pts) With PD-L1–Positive Locally Recurrent Inoperable or Metastatic Triple-Negative Breast Cancer (TNBC)

17 TROPION-Breast05: A Phase 3 Study of Datopotamab Deruxtecan (Dato-DXd) With or Without Durvalumab Versus Chemotherapy (CT) Plus Pembrolizumab in Patients (pts) With PD-L1–Positive Locally Recurrent Inoperable or Metastatic Triple-Negative Breast Cancer (TNBC)

Background

Current first-line standard of care for patients with metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (combined positive score [CPS] of 10 or greater) is pembrolizumab (Keytruda) plus chemotherapy (CT), but prognosis remains poor and new treatment options are needed. Datopotamab deruxtecan (Dato-DXd) consists of a humanized anti-TROP2 IgG1 monoclonal antibody (mAb) conjugated to a potent Topo-I inhibitor via a plasma-stable tetrapeptide-based tumor-selective cleavable linker. Durvalumab is a selective, high-affinity human IgG1 mAb that blocks interaction of PD-L1 with PD-1 and CD80 by binding to PD-L1. In the phase 1 TROPION-PanTumor01 study (NCT03401385), Dato-DXd monotherapy showed a manageable safety profile and encouraging efficacy in patients with heavily pretreated metastatic TNBC (confirmed objective response rate [ORR] was 32% in all patients and 44% in Topo-I inhibitor-naive with measurable disease at baseline). In the phase 1b/2 BEGONIA study, Dato-DXd plus durvalumab showed durable responses in unresectable locally advanced or metastatic TNBC (ORR, 79%; median duration of response [DOR], 15.5 months; median progression-free survival [PFS], 13.8 months). The phase 3 TROPION-Breast05 trial (NCT06103864) will evaluate Dato-DXd with or without durvalumab vs investigator’s choice of CT (ICC; paclitaxel, nab-paclitaxel or gemcitabine plus carboplatin) plus pembrolizumab in PD-L1 positive locally recurrent inoperable or metastatic TNBC.

Methods

TROPION-Breast05 is a phase 3, randomized, open-label, 3-arm, multicenter, international study; it will randomize about 625 patients (aged 18 years or older) with histologically or cytologically documented locally recurrent inoperable or metastatic PD-L1 positive (CPS 10 or greater) TNBC that has not been previously treated with CT or targeted systemic anticancer therapy in the locally recurrent inoperable or metastatic setting, and an ECOG performance status of 0 to 1. Patients with active brain metastases, history of another primary malignancy, or prior exposure to Topo-I ADC or TROP2-targeted therapy are not eligible. Patients will be randomly assigned 1:1 to arm 1 (6 mg/kg of intravenous Dato-DXd every 3 weeks plus 1120 mg of intravenous durvalumab every 3 weeks) or arm 2 (ICC plus pembrolizumab), or in selected countries including the United States, 1:1:1 to arms 1, 2, or 3 (Dato-DXd alone). Once about 75 patients are randomized to arm 3, it will close, and all countries will continue with 1:1 randomization. The primary end point of the study is PFS by blinded independent central review per RECIST 1.1. Secondary end points include overall survival, ORR, DOR, investigator-assessed PFS, clinical benefit rate at 24 weeks, patient-reported outcomes, pharmacokinetics, immunogenicity, and safety.