Regorafenib for Patients with Metastatic Colorectal Cancer Who Progressed After Standard Therapy

Results of the Large, Single-Arm, Open-Label Phase IIIb CONSIGN Study

Eric Van Cutsem, Erika Martinelli, Stefano Cascinu, Alberto Sobrero, Maria Banzi, Jean François Seitz, Carlo Barone, Marc Ychou, Marc Peeters, Baruch Brenner, Ralf Dieter Hofheinz, Evaristo Maiello, Thierry André, Andrea Spallanzani, Rocio Garcia-Carbonero, Yull E. Arriaga, Udit Verma, Axel Grothey, Christian Kappeler, Ashok Miriyala & 3 others Joachim Kalmus, Alfredo Falcone, Alberto Zaniboni

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalOncologist
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Colorectal Neoplasms
Therapeutics
Disease-Free Survival
Safety
regorafenib
Hypophosphatemia
Chemical and Drug Induced Liver Injury
Survival
Patient Safety
Aspartate Aminotransferases
Alanine Transaminase
Bilirubin
Epidermal Growth Factor Receptor
Vascular Endothelial Growth Factor A
Fatigue
Diarrhea
Monoclonal Antibodies
Research Personnel
Confidence Intervals

Keywords

  • Metastatic colorectal cancer
  • Prospective studies
  • Regorafenib
  • Toxicities

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Regorafenib for Patients with Metastatic Colorectal Cancer Who Progressed After Standard Therapy : Results of the Large, Single-Arm, Open-Label Phase IIIb CONSIGN Study. / Van Cutsem, Eric; Martinelli, Erika; Cascinu, Stefano; Sobrero, Alberto; Banzi, Maria; Seitz, Jean François; Barone, Carlo; Ychou, Marc; Peeters, Marc; Brenner, Baruch; Hofheinz, Ralf Dieter; Maiello, Evaristo; André, Thierry; Spallanzani, Andrea; Garcia-Carbonero, Rocio; Arriaga, Yull E.; Verma, Udit; Grothey, Axel; Kappeler, Christian; Miriyala, Ashok; Kalmus, Joachim; Falcone, Alfredo; Zaniboni, Alberto.

In: Oncologist, 01.01.2018.

Research output: Contribution to journalArticle

Van Cutsem, E, Martinelli, E, Cascinu, S, Sobrero, A, Banzi, M, Seitz, JF, Barone, C, Ychou, M, Peeters, M, Brenner, B, Hofheinz, RD, Maiello, E, André, T, Spallanzani, A, Garcia-Carbonero, R, Arriaga, YE, Verma, U, Grothey, A, Kappeler, C, Miriyala, A, Kalmus, J, Falcone, A & Zaniboni, A 2018, 'Regorafenib for Patients with Metastatic Colorectal Cancer Who Progressed After Standard Therapy: Results of the Large, Single-Arm, Open-Label Phase IIIb CONSIGN Study', Oncologist. https://doi.org/10.1634/theoncologist.2018-0072
Van Cutsem, Eric ; Martinelli, Erika ; Cascinu, Stefano ; Sobrero, Alberto ; Banzi, Maria ; Seitz, Jean François ; Barone, Carlo ; Ychou, Marc ; Peeters, Marc ; Brenner, Baruch ; Hofheinz, Ralf Dieter ; Maiello, Evaristo ; André, Thierry ; Spallanzani, Andrea ; Garcia-Carbonero, Rocio ; Arriaga, Yull E. ; Verma, Udit ; Grothey, Axel ; Kappeler, Christian ; Miriyala, Ashok ; Kalmus, Joachim ; Falcone, Alfredo ; Zaniboni, Alberto. / Regorafenib for Patients with Metastatic Colorectal Cancer Who Progressed After Standard Therapy : Results of the Large, Single-Arm, Open-Label Phase IIIb CONSIGN Study. In: Oncologist. 2018.
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abstract = "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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TY - JOUR

T1 - Regorafenib for Patients with Metastatic Colorectal Cancer Who Progressed After Standard Therapy

T2 - Results of the Large, Single-Arm, Open-Label Phase IIIb CONSIGN Study

AU - Van Cutsem, Eric

AU - Martinelli, Erika

AU - Cascinu, Stefano

AU - Sobrero, Alberto

AU - Banzi, Maria

AU - Seitz, Jean François

AU - Barone, Carlo

AU - Ychou, Marc

AU - Peeters, Marc

AU - Brenner, Baruch

AU - Hofheinz, Ralf Dieter

AU - Maiello, Evaristo

AU - André, Thierry

AU - Spallanzani, Andrea

AU - Garcia-Carbonero, Rocio

AU - Arriaga, Yull E.

AU - Verma, Udit

AU - Grothey, Axel

AU - Kappeler, Christian

AU - Miriyala, Ashok

AU - Kalmus, Joachim

AU - Falcone, Alfredo

AU - Zaniboni, Alberto

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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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KW - Prospective studies

KW - Regorafenib

KW - Toxicities

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