Regorafenib for Patients with Metastatic Colorectal Cancer Who Progressed After Standard Therapy: Results of the Large, Single-Arm, Open-Label Phase IIIb CONSIGN Study
Open accessAbstract
Background: 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. Methods: 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. Results: 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). Conclusion: 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. ClinicalTrials.gov: NCT01538680. Implications for Practice: 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.
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The CONSIGN study demonstrated a reasonable toxicity profile for most patients treated with regorafenib.
“the CONSIGN study was a Phase IIIB study that evaluated the safety profile of regorafenib and demonstrated a reasonable toxicity profile for most patients [60].”
From Update on Targeted Therapy and Immunotherapy for Metastatic Colorectal Cancer (2024) · cites this paper as [60]
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- Authors
- Van Cutsem, E., Martinelli, E., Cascinu, S., Sobrero, A., Banzi, M., Seitz, J.-F., Barone, C., Ychou, M., Peeters, M., Brenner, B., Hofheinz, R. D., Maiello, E., André, T., Spallanzani, A., Garcia-Carbonero, R., Arriaga, Y. E., Verma, U., Grothey, A., Kappeler, C., Miriyala, A., Kalmus, J., Falcone, A., & Zaniboni, A.
- Affiliations
- Digestive Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium
- University of Campania "Luigi Vanvitelli" (IT)
- Azienda Ospedaliero-Universitaria delle Marche (IT)
- Ospedale Policlinico San Martino (IT)
- Santa Maria Nuova Hospital (IT)
- Aix-Marseille Université (FR)
- Agostino Gemelli University Polyclinic (IT)
- Institut Regional du Cancer de Montpellier (FR)
- Antwerp University Hospital (BE)
- Tel Aviv University (IL)
- Heidelberg University (DE)
- Casa Sollievo della Sofferenza (IT)
- Hôpital Saint-Antoine (FR)
- Azienda Ospedaliero-Universitaria di Modena (IT)
- Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS), Sevilla, Spain
- The University of Texas Southwestern Medical Center (US)
- Mayo Clinic (US)
- Bayer (Germany) (DE)
- Bayer (United States) (US)
- University of Pisa (IT)
- Fondazione Poliambulanza Istituto Ospedaliero (IT)
- ORCID
- Venue
- The Oncologist
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-09-06
- Volume
- 24
- Issue
- 2
- Pages
- 185-192
- ISSN
- 1083-7159 (ISSN-L)
- 1549-490X
- PMC
- PMC6369948
- OpenAlex
- W2891319811
- Cited by
- 142
- References
- 15
- Citations by year
- 2026: 11 · 2025: 8 · 2024: 27 · 2023: 21 · 2022: 20 · 2021: 25 · 2020: 19 · 2019: 11
- FWCI
- 5.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Oncologist (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, other-oa)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Lirias (submittedVersion)
- Funders
- Bayer
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Health Sciences › Medicine › Surgery › Intraperitoneal and Appendiceal Malignancies
- Keywords
- regorafenib, metastatic colorectal cancer, refractory disease, drug safety, adverse events, progression-free survival, drug-induced liver injury, hypertension, hand-foot skin reaction, hepatotoxicity
- MeSH terms
- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Neoplasm Metastasis, Phenylurea Compounds, Prospective Studies, Pyridines, Colorectal Neoplasms, Disease Progression
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