A Bardia1, S M Tolaney2, K Punie3, D Loirat4, M Oliveira5, K Kalinsky6, A Zelnak7, P Aftimos8, F Dalenc9, S Sardesai10, E Hamilton11, P Sharma12, S Recalde13, E C Gil14, T Traina15, J O'Shaughnessy16, J Cortes17, M Tsai18, L Vahdat19, V Diéras20, L A Carey21, H S Rugo22, D M Goldenberg23, Q Hong24, M Olivo24, L M Itri24, S A Hurvitz25. 1. Massachusetts General Hospital, Harvard Medical School, Boston, USA. 2. Medical Oncology, Dana-Farber Cancer Institute, Boston, USA. 3. Department of General Medical Oncology and Multidisciplinary Breast Centre, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium. 4. Medical Oncology Department and D3i, Institut Curie, Paris, France. 5. Hospital Universitari Vall d'Hebron, Barcelona, Spain. 6. Columbia University Irving Medical Center, New York, USA; Winship Cancer Institute, Emory University, Atlanta, USA. 7. Northside Hospital, Atlanta, USA. 8. Institut Jules Bordet - Université Libre de Bruxelles, Brussels, Belgium. 9. Institut Claudius Regaud, Toulouse, France. 10. The Ohio State University Wexner Medical Center, Columbus, USA. 11. Sarah Cannon Research Institute/Tennessee Oncology, Nashville, USA. 12. University of Kansas Medical Center, Westwood, USA. 13. Institut Catala d'Oncologia Hospitalet, Barcelona, Spain. 14. Hospital Universitario 12 de Octubre, Madrid, Spain. 15. Memorial Sloan Kettering Cancer Center, New York, USA. 16. Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, USA. 17. International Breast Cancer Center (IBCC), Quiron Group, Madrid & Barcelona, Spain. 18. VPCI Oncology Research, Minneapolis, USA. 19. MSK-Norwalk Hospital Partnership, Norwalk, USA. 20. Centre Eugène Marquis, Rennes, France. 21. University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, USA. 22. University of California San Francisco Comprehensive Cancer Center, San Francisco, USA. 23. Immunomedics, Inc., Morris Plains, USA; Center for Molecular Medicine and Immunology, Mendham, USA. 24. Immunomedics, Inc., Morris Plains, USA; Department of Clinical Development, Gilead Sciences, Inc., Morris Plains, USA. 25. Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles, USA. Electronic address: shurvitz@mednet.ucla.edu.
Abstract
BACKGROUND: The pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-trophoblast cell-surface antigen 2 (anti-Trop-2) antibody-drug conjugate linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy treatment of physician's choice (TPC) in previously treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes. PATIENTS AND METHODS: Patients with mTNBC refractory to or progressing after two or more prior chemotherapies, with one or more in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline. RESULTS: Of 468 assessable patients, 290 had Trop-2 expression data [64% (n = 151 SG) versus 60% (n = 139 TPC)] and 292 had known BRCA1/2 mutation status [63% (n = 149 SG) versus 61% (n = 143 TPC)]. Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38%, and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression, respectively. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations. CONCLUSIONS: SG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup.
BACKGROUND: The pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-trophoblast cell-surface antigen 2 (anti-Trop-2) antibody-drug conjugate linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy treatment of physician's choice (TPC) in previously treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes. PATIENTS AND METHODS: Patients with mTNBC refractory to or progressing after two or more prior chemotherapies, with one or more in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline. RESULTS: Of 468 assessable patients, 290 had Trop-2 expression data [64% (n = 151 SG) versus 60% (n = 139 TPC)] and 292 had known BRCA1/2 mutation status [63% (n = 149 SG) versus 61% (n = 143 TPC)]. Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38%, and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression, respectively. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations. CONCLUSIONS: SG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup.
Authors: James T Coates; Sheng Sun; Ignaty Leshchiner; Nayana Thimmiah; Elizabeth E Martin; Daniel McLoughlin; Brian P Danysh; Kara Slowik; Raquel A Jacobs; Kahn Rhrissorrakrai; Filippo Utro; Chaya Levovitz; Elyssa Denault; Charlotte S Walmsley; Avinash Kambadakone; James R Stone; Steven J Isakoff; Laxmi Parida; Dejan Juric; Gad Getz; Aditya Bardia; Leif W Ellisen Journal: Cancer Discov Date: 2021-08-17 Impact factor: 39.397
Authors: Rachel Yoder; Bruce F Kimler; Joshua M Staley; Kelsey Schwensen; Yen Y Wang; Karissa Finke; Anne O'Dea; Lauren Nye; Manana Elia; Gregory Crane; Richard McKittrick; Robert Pluenneke; Sheshadri Madhusudhana; Larry Beck; Anuj Shrestha; Larry Corum; Mark Marsico; Shane R Stecklein; Andrew K Godwin; Qamar J Khan; Priyanka Sharma Journal: NPJ Breast Cancer Date: 2022-07-11