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Clinical Trial
. 2025 Jun 4;30(6):oyaf080.
doi: 10.1093/oncolo/oyaf080.

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

Jean-Frédéric Blanc  1 , Mohamed Bouattour  2   3 , Ludovic Gauthier  4 , Emmanuel Deshayes  5   6 , Sophie Guillemard  5 , Yann Touchefeu  7 , Fabienne Portales  8 , Christophe Borg  9 , Lobna Harguem  10 , Rosine Guimbaud  11 , Laurent Mineur  12 , Marc Ychou  8 , Thibault Mazard  6   8 , Eric Assenat  8   13
Affiliations
Clinical Trial

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

Jean-Frédéric Blanc et al. Oncologist. .

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.

Keywords: biliary tract cancer; modified GEMOX; regorafenib; stanniocalcin 1.

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Conflict of interest statement

J.-F.B. received honoraria for speaking or consulting roles from Bayer, AstraZeneca, MSD, Servier, Incyte, Jazz Pharmaceutical, Tahio. M.B. received speaker fees from Bayer, MSD, Sirtex Medical, and Roche, and advisory board fees from Bayer, MSD, Sirtex Medical, Eisai, AstraZeneca, Ipsen, Servier, Taiho, and BMS. Y.T. received board fees and speakers invitations from Bayer. C.B. received honoraria from Amgen, Bayer, Beigine, Biocartis, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Merck, Pfizer, Pierre Fabre, Roche, Sanofi, SeqOne, Servier, and Takeda. L.M. received personal fees from Servier, Amgen, Sanofi, Astrazeneca, Pfizer, Merck, Amgen, Bayer Ipesen, Lilly, and Roche. He also received honoraria from Sanofi, Eisai, Servier, Ipsen, Amgen, and Merck and for consulting role from Sanofi, Sandoz, Kephren, Bayer, Merck, Ipsen, Erytech, Lilly, and Servier. He also received research grants from Sanofi, Merck, and Chugai. T.M. received honoraria for speaking or consulting roles from Servier, Pierre Fabre, Merck Serono, AAA, Sanofi, Galapagos, and research grants from Amgen, and Roche. He also received travel grants from Pierre Fabre, Merck Serono, and Sanofi. E.A. received honoraria for speaking or consulting roles from Roche, Novartis, MSD, AstraZeneca, Bayer, Ipsen, Boston, Incyte, Servier, and AAA. All other authors have declared no conflicts of interest.

Figures

Figure 1.
Figure 1.
Kaplan–Meier survival curves in phase II randomized, controlled study. (A) Progression-free survival and (B) overall survival curves in all patients.
Figure 2.
Figure 2.
Kaplan–Meier survival curves according to tumor location in phase II randomized, controlled study. Overall survival in patients with an (A) intrahepatic or (B) an extrahepatic primary tumor location.
Figure 3.
Figure 3.
Kaplan–Meier survival curves, defined by the median STC1 dosage (exploratory data). (A) Progression-free survival and (B) overall survival curves in patients selected for the dosage ancillary study (n = 36). Abbreviations: PFS, progression-free survival; OS, overall survival.
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