Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer

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.

Keywords: BRCA; triple-negative breast cancer; trophoblast cell-surface antigen 2.

Conflict of interest statement

Disclosure AB: consultancy/advisory role with Biotheranostics Inc., Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics, Taiho, Sanofi, Daiichi Sanyo/AstraZeneca, Puma, Philips, Eli Lilly, and Foundation Medicine; research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics; travel/accommodations/expenses from Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics, Taiho, and Sanofi. SMT: research funding from Bristol Myers Squibb, Eisai, Immunomedics, Genentech/Roche, Pfizer, Novartis, Nektar, Merck, AstraZeneca, Eli Lilly, and Exelixis. KP: consultancy/advisory role with AstraZeneca, Eli Lilly, Novartis, Pfizer, Pierre Fabre, Hoffmann-La Roche, Vifor Pharma, and European Centre for Clinical Research Training; speaker’s bureau with Eli Lilly, Mundipharma, Novartis, Pfizer, and Hoffmann-La Roche; research funding from Sanofi; expert testimony for Hoffmann-La Roche; travel/accommodations/expenses from AstraZeneca, Novartis, Pfizer, PharmaMar, and Hoffmann-La Roche. DL: consultancy/advisory role with Novartis, Merck Sharp & Dohme (MSD), and Roche. MO: research funding from Immunomedics, Roche, Genentech, PUMA Biotechnology, AstraZeneca, Seattle Genetics, Boehringer Ingelheim, and Novartis; expenses from Roche, Genentech, PUMA Biotechnology, AstraZeneca, Seattle Genetics, and Novartis; non-financial support from Roche, Pierre Fabre, Eisai, GP Pharma, Grünenthal, and Novartis. KK: employment (spouse) with Array Biopharma, Pfizer, and Grail; consultancy/advisory role with Immunomedics, Pfizer, Eisai, Eli Lilly, Amgen, and AstraZeneca; institutional research funding from Immunomedics, Novartis, Incyte, Genentech/Roche, Eli Lilly, Pfizer, Calithera Biosciences, Acetylon, Seattle Genetics, Amgen, Zentalis Pharmaceuticals, and CytomX Therapeutics; research funding (spouse) from Array Biopharma, Pfizer, and Grail. AZ: consultancy roles with Novartis and Pfizer. PA: travel/accommodations/expenses from Boehringer Ingelheim, MacroGenics, Amvure, Synthon, Servier, G1 Therapeutics, Roche, Novartis, Amgen, Radius, MSD, and Pfizer. SS: advisory role with Immunomedics, Novartis, and Biotheranostics. EH: consultancy/advisory role with Genentech/Roche, Boehringer Ingelheim, Novartis, Dantari, Eli Lilly, Merck, Puma Biotechnology, Silverback Therapeutics, CytomX, Pfizer, Mersana, Black Diamond, H3 Biomedicine, Daiichi Sankyo, AstraZeneca, Arvinas, Deciphera Pharmaceuticals, Eisai, and SeaGen; institutional research funding from OncoMed, Genentech/Roche, Zymeworks, Rgenix, ArQule, Clovis, Silverback Therapeutics, Millennium, Acerta Pharma, Sermonix Pharmaceuticals, Torque, Black Diamond, Karyopharm, Infinity Pharmaceuticals, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Fochon, Molecular Templates, Onconova Therapeutics, Dana-Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, SeaGen, Puma Biotechnology, Compugen, TapImmune, Eli Lilly, Pfizer, H3 Biomedicine, Takeda, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, MacroGenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, Merck, PharmaMar, Olema, Polyphor, Immunogen, Plexxikon, Amgen, Akesobio Australia, and Shattuck Labs. PS: consultancy role with Immunomedics. ECG: consultancy role with Pfizer, Roche, AstraZeneca, Novartis, and Eli Lilly; speaker’s bureau with Roche, Pfizer, and Eli Lilly. TT: consultancy/advisory role with Genentech/Roche, Pfizer, AstraZeneca, Merck, Puma Biotechnology, Advaxis, Celgene, Innocrin Pharma, Genomic Health, Bristol Myers Squibb, Samsung, Athenex, Aduro Biotech, Halozyme, Daiichi Sankyo, Ionis, and Seattle Genetics; speaker’s bureau with Roche/Genentech; research funding from Eisai, Pfizer, Novartis, Innocrin Pharma, AstraZeneca, Astellas Pharma, Immunomedics, Genentech/Roche, Daiichi Sankyo, Carrick Pharm.JO: consultancy/advisory role with AbbVie, Agendia, AstraZeneca, Bristol Myers Squibb, Celgene, Eisai, Genentech, Immunomedics, Jounce Therapeutics, Eli Lilly, Merck, Novartis, Pfizer, Puma Biotechnology, Roche, and Seattle Genetics. JC: consultancy/advisory role with Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceuticals, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Eli Lilly, Servier, MSD, GlaxoSmithKline (GSK), Leuko, Bioasis, and Clovis Oncology; speaker’s bureau for Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Eli Lilly, MSD, and Daiichi Sankyo; institutional research funding from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffman-La Roche, Guardant Health, MSD, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London; ownership interest in MedSIR. LV: consultancy role with Berg Pharma, Seattle Genetics, Polyphor, Immunomedics, and Osmol Therapeutics; speaker’s bureau with Eisai; contracted research with Roche, OncoTherapy Science, Arvinas, Genentech, Seattle Genetics, and Immunomedics. VD: consultancy/advisory role with Roche/Genentech, Novartis, Eli Lilly, Pfizer, AstraZeneca, Eisai, AbbVie, MSD, Daiichi Sankyo, and Seattle Genetics; speaker’s bureau for Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca, and Daiichi Sankyo; travel/accommodations/expenses from Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca, and Daiichi Sankyo. LAC: royalties (spouse) from Falcon Therapeutics; research funding from Innocrin Pharma, Syndax, Immunomedics, Novartis, and NanoString Technologies; institutional research funding from Sanofi-Aventis, Novartis, G1 Therapeutics, Genentech/Roche, and GSK. HSR: consultancy/advisory role with Samsung and Puma; research funding from Pfizer, Novartis, Eli Lilly, Genentech/Roche, MacroGenics, OBI, Merck, Eisai, Immunomedics, Daiichi, Seattle Genetics, and Odonate; travel/accommodations/expenses from Daiichi, Mylan, Pfizer, Merck, AstraZeneca, Novartis, and MacroGenics. DMG: intellectual property rights/patent holder at Immunomedics; ownership interest with Immunomedics; other interests with Center for Molecular Medicine & Immunology. QH, MO, LMI: employment with Immunomedics. SAH: research funding from Ambrx, Amgen, Arvinas, Bayer, Daiichi Sankyo, Genentech/Roche, GSK, Immunomedics, Eli Lilly, MacroGenics, Novartis, Pfizer, OBI Pharma, Pieris, PUMA, Radius, Sanofi, Seattle Genetics, and Dignitana; ownership interest with NKMax. All other authors have declared no conflicts of interest.

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