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Oncologist. 2019 Feb;24(2):185-192. doi: 10.1634/theoncologist.2018-0072. Epub 2018 Sep 6.

Regorafenib for Patients with Metastatic Colorectal Cancer Who Progressed After Standard Therapy: Results of the Large, Single-Arm, Open-Label Phase IIIb CONSIGN Study.

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Digestive Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium
Department of Experimental Medicine, Università degli studi della Campania Luigi Vanvitelli, Naples, Italy.
Clinica di Oncologia Medica, Azienda Ospedaliero Universitaria Ospedali Riuniti, Ancona, Italy.
Medical Oncology, IRCCS Ospedale San Martino IST, Genova, Italy.
Department of Oncology and Advanced Technologies, Oncology Unit, Azienda Ospedaliera S. Maria Nuova/IRCCS, Reggio Emilia, Italy.
Department of Digestive Oncology, Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France.
Medical Oncology, University Hospital A. Gemelli, Rome, Italy.
Department of Medical Oncology, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France.
Center for Oncological Research, Antwerp University Hospital, Edegem, Belgium.
Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel.
Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.
Interdisciplinary Tumor Center, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany.
Department of Oncology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
Service d'Oncologie Médicale, Hôpital Saint-Antoine Paris and Sorbonne Universités, UPMC Paris 06, Paris, France.
Department of Oncology and Haematology, Division of Oncology, University Hospital of Modena, Modena, Italy.
Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS), Sevilla, Spain.
Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.
Clinical Statistics, Global Clinical Oncology, Bayer AG, Berlin, Germany.
Benefit Risk Management, Bayer HealthCare Pharmaceuticals, Whippany, New Jersey, USA.
Development, Oncology, Bayer AG, Berlin, Germany.
Department of Medical Oncology, University of Pisa, Pisa, Italy.
Department of Oncology, Fondazione Poliambulanza, Brescia, Italy.



In the phase III CORRECT trial, regorafenib significantly improved survival in treatment-refractory metastatic colorectal cancer (mCRC). The CONSIGN study was designed to further characterize regorafenib safety and allow patients access to regorafenib before market authorization.


This prospective, single-arm study enrolled patients in 25 countries at 186 sites. Patients with treatment-refractory mCRC and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1 received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle. The primary endpoint was safety. Progression-free survival (PFS) per investigator assessment was the only efficacy evaluation.


In total, 2,872 patients were assigned to treatment and 2,864 were treated. Median age was 62 years, ECOG PS 0/1 was 47%/53%, and 74% had received at least three prior regimens for metastatic disease. Median treatment duration was three cycles. Treatment-emergent adverse events (TEAEs) led to dose reduction in 46% of patients. Regorafenib-related TEAEs led to treatment discontinuation in 9%. Grade 5 regorafenib-related TEAEs occurred in <1%. The most common grade ≥3 regorafenib-related TEAEs were hypertension (15%), hand-foot skin reaction (14%), fatigue (13%), diarrhea (5%), and hypophosphatemia (5%). Treatment-emergent grade 3-4 laboratory toxicities included alanine aminotransferase (6%), aspartate aminotransferase (7%), and bilirubin (13%). Ongoing monitoring identified one nonfatal case of regorafenib-related severe drug-induced liver injury per DILI Working Group criteria. Median PFS (95% confidence interval [CI]) was 2.7 months (2.6-2.7).


In CONSIGN, the frequency and severity of TEAEs were consistent with the known safety profile of regorafenib. PFS was similar to reports of phase III trials. NCT01538680.


Patients with metastatic colorectal cancer (mCRC) who fail treatment with standard therapies, including chemotherapy and monoclonal antibodies targeting vascular endothelial growth factor or epidermal growth factor receptor, have few treatment options. The multikinase inhibitor regorafenib was shown to improve survival in patients with treatment-refractory mCRC in the phase III CORRECT (N = 760) and CONCUR (N = 204) trials. However, safety data on regorafenib for mCRC in a larger number of patients were not available. The CONSIGN trial, carried out prospectively in more than 2,800 patients across 25 countries, confirmed the safety profile of regorafenib from the phase III trials and reinforced the importance of using treatment modifications to manage adverse events.


Metastatic colorectal cancer; Prospective studies; Regorafenib; Toxicities

Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

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