Journal Article

Regorafenib plus modified gemcitabine-oxaliplatin in patients with advanced biliary tract cancer. The randomized phase Ib/II BREGO study

Bouattour, Mohamed, Blanc, Jean-Frédéric, Harguem, Lobna, Mazard, Thibault, Gauthier, Ludovic, Deshayes, Emmanuel, Guimbaud, Rosine, Ychou, Marc, Assenat, Eric, Borg, Christophe, Mineur, Laurent, Touchefeu, Yann, Guillemard, Sophie, Portales, Fabienne

2025

Overview

Abstract Background New therapeutic options are needed for biliary tract cancer (BTC). Regorafenib, a multikinase inhibitor, shows promise in refractory digestive cancers and may be beneficial with conventional chemotherapy for BTC. Patients and Methods The BREGO study evaluated regorafenib with modified gemcitabine-oxaliplatin (mGEMOX) in advanced or metastatic BTC. Phase I determined the recommended dose (RP2D) of regorafenib (80, 120 or 160 mg, days 1-14) combined with mGEMOX (gemcitabine 900 mg.m−2 IV, 30 min, followed by oxaliplatin 80mg.m−2 IV, 120 min, days 1 and 8). Phase II randomized (1:2) patients to mGEMOX alone (arm A) or mGEMOX + regorafenib (arm B, RP2D, days 1-14), assessing efficacy and safety, with the primary outcome being progression-free survival (PFS). Metabolic tumor features and response were also assessed. Results In phase Ib, 22 patients were enrolled; in phase II, 66 patients (arm A, n = 24; arm B, n = 42). Four dose-limiting toxicities were observed, but no maximum tolerated dose was reached. The RP2D was 160 mg.d−1. Median PFS (7.2 vs7.8 months; P = .825) and overall survival (15.1 vs 13.5 months; P = .356) were similar between arms. However, posttreatment 18F-FDG tumor uptake (SULpeak) significantly correlated with PFS (P = .001) and OS (P = .016). Baseline plasma stanniocalcin 1 levels < 265 pg.mL−1 were associated with longer PFS (P = .030) and OS (P = .060) in both arms. Conclusions Combining regorafenib and mGEMOX is feasible as first-line treatment for BTC but did not increase PFS as expected in the phase II cohort. Identifying new biomarkers can help target patients with advanced BTCs who may benefit from regorafenib-associated therapy. Trial registration number ClinicalTrials.gov, NCT02386397.

• Publisher: Oxford University Press
• Subject: Adult / Aged / Angiogenesis / Antineoplastic Combined Chemotherapy Protocols / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - pharmacology / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Biliary Tract Neoplasms / Biliary Tract Neoplasms - drug therapy / Biliary Tract Neoplasms - pathology / Biomarkers / Cancer / Cancer therapies / Chemotherapy / Chemotherapy, Combination / Cholangiocarcinoma / Colorectal cancer / Combination therapy / Deoxycytidine / Deoxycytidine - administration & dosage / Deoxycytidine - analogs & derivatives / Deoxycytidine - pharmacology / Deoxycytidine - therapeutic use / Dosage and administration / Drug therapy / Female / Gastroenterology / Gemcitabine / Growth factors / Hospitals / Human health and pathology / Humans / Hépatology and Gastroenterology / Kinases / Life Sciences / Liver cancer / Male / Medical prognosis / Medical research / Metabolism / Metastasis / Middle Aged / Oncology / Oxaliplatin / Oxaliplatin - administration & dosage / Oxaliplatin - pharmacology / Oxaliplatin - therapeutic use / Patients / Pharmaceutical sciences / Pharmacology / Phenylurea Compounds / Phenylurea Compounds - administration & dosage / Phenylurea Compounds - pharmacology / Phenylurea Compounds - therapeutic use / Pyridines / Pyridines - administration & dosage / Pyridines - pharmacology / Pyridines - therapeutic use / Testing / Toxicity