31 TIP TROPION-Breast03: Datopotamab Deruxtecan (Dato-DXd) ± Durvalumab vs Investigator’s Choice of Therapy (ICT) for Triple-Negative Breast Cancer (TNBC) with Residual Disease Following Neoadjuvant Therapy

Background

Patients (pts) with residual invasive disease after neoadjuvant therapy for TNBC have a high risk of recurrence. Dato-DXd is a novel humanized anti–trophoblast cell surface protein 2 (TROP2) IgG1 mAb attached via a stable, cleavable linker to a topoisomerase I inhibitor (deruxtecan). In early phase studies, Dato-DXd alone or combined with anti–PD-L1 mAb durvalumab, demonstrated encouraging antitumor activity in pts with advanced/metastatic TNBC. TROPION-Breast03 will investigate the efficacy and safety of a new ADC/ immunotherapy combination, Dato-DXd ± durvalumab, vs ICT in pts with TNBC and residual invasive disease after neoadjuvant therapy, to potentially improve outcomes in this high-risk population.

Materials and Methods

This phase 3, randomized, open-label, 3-arm, multicenter, international study (NCT05629585) will recruit ~1075 pts across ~300 sites. Eligible pts ≥18 yrs have histologically-confirmed stage I–III TNBC and residual invasive disease (no locoregional/distant relapse) after ≥6 cycles of neoadjuvant therapy (including an anthracycline and/or a taxane ± carboplatin ± pembrolizumab [pembro]). Other key inclusion criteria: ECOG PS 0/1, no adjuvant systemic therapy, radiotherapy completion prior to study intervention, no known germline BRCA1/BRCA2 mutations, and an available FFPE tumor sample from the residual invasive disease at surgery. Pts who have received neoadjuvant PD-(L)1 inhibitors other than pembro will be excluded. At randomization, pts will be stratified by the extent of residual disease (<1 or ≥1 cm) and prior neoadjuvant therapy (pembro [yes/no] or platinum chemotherapy [yes/no]) and be allocated (2:1:2) to receive Dato-DXd (6 mg/kg IV Q3W × 8 cycles) + durvalumab (1120 mg IV Q3W × 9 cycles), Dato-DXd alone, or ICT (capecitabine and/ or pembro). Only pts who have received neoadjuvant pembro can receive pembro-based ICT. Pts will continue treatment until study completion, disease recurrence, or unacceptable toxicity. Primary end point: invasive disease-free survival (iDFS) per investigator assessment (Dato-DXd + durvalumab vs ICT). Secondary end points: distant DFS (key), iDFS (Dato-DXd vs ICT; key), overall survival (key), pharmacokinetics, immunogenicity, safety, and patient-reported outcomes. Exploratory end points include assessment of biomarkers (TROP2, PD-L1, ctDNA).

Status

Enrolment across all arms commenced in November 2022.

AFFILIATIONS:

Aditya Bardia,¹ Lajos Pusztai,² Kathy Albain,³ Kevin Kalinsky,⁴ Dawn Herman,⁵ William Barlow,⁶ Claudine Isaacs,⁷ Micah Maxwell,⁸ Nadia Harbeck,⁹ Priyanka Sharma¹⁰

¹Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA.

²Yale University, New Haven, CT.

³Loyola University Chicago Stritch School of Medicine, Cardinal Bernradin Cancer Center, Loyola University Medical Center, Maywood, IL.

⁴Winship Cancer Institute at Emory University, Atlanta, GA.

⁵Herbert Irving Comprehensive Cancer Center at Columbia University, New York, NY.

⁶University of Washington, Seattle, WA.

⁷Georgetown University, Washington, DC.

⁸AstraZeneca, Gaithersburg, MD.

⁹Breast Center, LMU University Hospital, Munich, Germany.

¹⁰The University of Kansas Medical Center, Kansas City, MO.