TBCRC 019: A Phase II Trial of Nanoparticle Albumin-Bound Paclitaxel with or without the Anti-Death Receptor 5 Monoclonal Antibody Tigatuzumab in Patients with Triple-Negative Breast Cancer

• Published in: Clinical cancer research Vol. 21; no. 12; pp. 2722 - 2729
• Main Authors: Forero-Torres, Andres, Varley, Katherine E, Abramson, Vandana G, Li, Yufeng, Vaklavas, Christos, Lin, Nancy U, Liu, Minetta C, Rugo, Hope S, Nanda, Rita, Storniolo, Anna M, Traina, Tiffany A, Patil, Sujata, Van Poznak, Catherine H, Nangia, Julie R, Irvin, Jr, William J, Krontiras, Helen, De Los Santos, Jennifer F, Haluska, Paul, Grizzle, William, Myers, Richard M, Wolff, Antonio C
• Format: Journal Article
• Language: English
• Published: United States 15.06.2015
• Subjects: Adult; Aged; Antibodies, Monoclonal, Humanized - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biopsy; Female; Humans; Middle Aged; Nanoparticles - administration & dosage; Nanoparticles - therapeutic use; Paclitaxel - administration & dosage; Paclitaxel - therapeutic use; Receptors, TNF-Related Apoptosis-Inducing Ligand - antagonists & inhibitors; Retreatment; Treatment Outcome; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - mortality; Triple Negative Breast Neoplasms - pathology
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-14-2780

Tigatuzumab (TIG), an agonistic anti-DR5 antibody, triggers apoptosis in DR5(+) human tumor cells without crosslinking. TIG has strong in vitro/in vivo activity against basal-like breast cancer cells enhanced by chemotherapy agents. This study evaluates activity of TIG and chemotherapy in patients with metastatic triple-negative breast cancer (TNBC). Randomized 2:1 phase II trial of albumin-bound paclitaxel (nab-PAC) ± TIG in patients with TNBC stratified by prior chemotherapy. Patients received nab-PAC weekly × 3 ± TIG every other week, every 28 days. Primary objective was within-arm objective response rate (ORR). Secondary objectives were safety, progression-free survival (PFS), clinical benefit, and TIG immunogenicity. Metastatic research biopsies were required. Among 64 patients (60 treated; TIG/nab-PAC n = 39 and nab-PAC n = 21), there were 3 complete remissions (CR), 8 partial remissions (PR; 1 almost CR), 11 stable diseases (SD), and 17 progressive diseases (PD) in the TIG/nab-PAC arm (ORR, 28%), and no CRs, 8 PRs, 4 SDs, and 9 PDs in the nab-PAC arm (ORR, 38%). There was a numerical increase in CRs and several patients had prolonged PFS (1,025+, 781, 672, 460, 334) in the TIG/nab-PAC arm. Grade 3 toxicities were 28% and 29%, respectively, with no grade 4-5. Exploratory analysis suggests an association of ROCK1 gene pathway activation with efficacy in the TIG/nab-PAC arm. ORR and PFS were similar in both. Preclinical activity of TIG in basal-like breast cancer and prolonged PFS in few patients in the combination arm support further investigation of anti-DR5 agents. ROCK pathway activation merits further evaluation.