TBCRC 019: phase II trial of nab-PAC with/without the anti-death receptor 5 monoclonal antibody tigatuzumab in patients with triple negative breast cancer
Mené sur 60 patientes atteintes d'un cancer métastatique du sein triplement négatif, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse objective, et la toxicité de l'ajout du tigazumumab au nab-paclitaxel
Purpose: 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). Experimental Design: 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 x 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. Results: Among 64 patients (60 treated; TIG/nab-PAC n=39 and nab-PAC n=21), there were 3 complete remissions (CRs), 8 partial remissions (PRs; 1 almost CR), 11 stable diseases (SDs) and 17 progressive diseases (PDs) in the TIG/nab-PAC arm (ORR=28%), and no CRs, 8 PRs, 4 SDs and 9 PDs in nab-PAC arm (ORR=38%). There was a numerical increase in CRs and several patients had prolonged PFS (1025+, 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. Conclusions: 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-DR-5 agents. ROCK pathway activation merits further evaluation.