In the phase 3 CORRECT trial, regorafenib significantly improved overall survival vs placebo in patients with mCRC who progressed on standard therapies. CONSIGN (NCT01538680) was designed to provide regorafenib to patients with treatment-refractory mCRC who had no treatment alternatives, and to further characterize the safety of regorafenib (primary objective).
This prospective, single-arm study was carried out at 188 sites in 25 countries. Patients with mCRC who progressed after approved standard therapies and an ECOG PS 0─1 received regorafenib 160 mg QD for the first 3 weeks of each 4-week cycle. Treatment continued until progression, death, or unacceptable toxicity. The primary endpoint was safety. Progression-free survival (PFS) per investigator was the only efficacy variable assessed.
A total of 2872 patients were assigned from April 2012–December 2013; 2864 patients were treated. Median age was 62 yrs, ECOG PS 0/1 was 47%/53%, and 74% of patients had ≥3 prior regimens for metastatic disease. Median treatment duration was 2.5 months (range: 0–30); mean duration (SD) was 3.6 (3.8) months. The mean (SD) daily dose was 146 (19) mg. Treatment-emergent adverse events (TEAEs) led to dose reduction in 46% of patients and to treatment discontinuation in 25%. Regorafenib-related TEAEs (all grade) occurred in 91% of patients; the most common regorafenib-related grade ≥3 AEs are shown (Table). Treatment-emergent grade ≥3 laboratory toxicities included ALT (6%), AST (7%), and bilirubin (13%). One non-fatal case of severe drug-induced liver injury was identified by ongoing monitoring. Median PFS (95% CI) was 2.7 months (2.6─2.7).
|Patients with drug-related TEAEs, %||Regorafenib (N = 2864)|
|Grade ≥3* Hypertension HFSR Fatigue Diarrhea Hypophosphatemia||57 15 14 13 5 5|
|Leading to discontinuation||9|
*In ≥5% of patients; graded by NCI-CTCAE v4.0. HFSR, hand–foot skin reaction.
In this large, prospective study of regorafenib in patients with treatment-refractory mCRC, TEAEs were consistent with the known safety profile of regorafenib. Median PFS was in the range of that reported in phase 3 trials.
Clinical trial identification
E. Van Cutsem: Corporate-sponsored research: Bayer HealthCare. F. Ciardiello: Advisory board: Roche, Merck Serono, Bayer, Sanofi, Astellas, Amgen, Lilly. J.-F. Seitz: Advisory Board: Bayer, Sanofi, Lilly. R.D. Hofheinz: Advisory Board: Bayer HealthCare Corporate-sponsored research: Bayer HealthCare. U. Verma: Advisory Board: Bayer. R. Garcia-Carbonero: uncompensated Advisory Board: Bayer, Roche, Amgen, Sanofi, Merck; Corporate-sponsored research: Bayer, Roche, Amgen, Merck. A. Grothey: Advisory Board: Genentech/Roche, Bayer, Sanofi, Bristol-Myers Squibb, Eli-Lilly, Boston Biomedicals, Amgen; Corporate-sponsored research: Genentech/Roche, Bayer, Pfizer, Eisai, Sanofi, Eli-Lilly, Boston Biomedicals. A. Miriyala, J. Kalmus: stock ownership: Bayer Other substantive relationships: Bayer employee. J. Shapiro: stock ownership: Bayer, Pfizer Other substantive relationships: Bayer Employee. A. Falcone: Advisory Board: Amgen, Bayer, Roche, Merck-Serono, Sanofi, Lilly; Corporate-sponsored research: Roche, Merck-Serono, Sanofi. All other authors have declared no conflicts of interest.