Published Results Confirm Regorafenib Safety, Efficacy in mCRC


Safety and efficacy findings for regorafenib in patients with previously treated metastatic colorectal cancer were consistent with previous phase III results.

Eric Van Cutsem, MD, PhD

Safety and efficacy findings for regorafenib (Stivarga) in patients with previously treated metastatic colorectal cancer (mCRC) were consistent with previous phase III results, according to findings from the phase IIIb CONSIGN trial, now published in The Oncologist.1

The median progression-free survival (PFS) was 2.7 months (95% CI, 2.6-2.7) with regorafenib, including 2.8 months (95% CI, 2.7-2.9) in the KRAS wild-type cohort and 2.5 months (95% CI, 2.4-2.6) in the KRAS mutant group. Twenty-three percent of patients had PFS greater than 4 months.

Hypertension (15%) was the most common grade ≥3 treatment-emergent adverse event (TEAE), followed by hand-foot skin reaction (14%), fatigue (13%), diarrhea (5%), and hypophosphatemia (5%). Treatment-emergent grade 3/4 laboratory toxicities included bilirubin (13%), AST increase (7%), and ALT increase (6%).

Seven percent of patients experienced grade 4 TEAEs. Drug-related grade 4 TEAEs were rare, occurring in only 3% of patients. Investigators observed a single, nonfatal incidence of regorafenib-related severe liver injury.

“Patients with mCRC who fail treatment with standard therapies, including chemotherapy and monoclonal antibodies targeting VEGF or EGFR, 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,” lead author Eric van Cutsem, MD, University Hospitals Gasthuisberg/Leuven, Leuven, Belgium, and colleagues wrote.

“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 2800 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,” continued van Cutsem, et al.

The prospective, open-label, single-arm, “real-world” CONSIGN trial compared regorafenib with placebo in patients who progressed after approved standard therapies for mCRC. Of the 2872 patients assigned to treatment, 2864 patients were treated. Nine percent (n = 268) of patients were aged ≥75 years, and the median patient age was 62 years (range, 19-89).

Fifty-three percent of patients had an ECOG performance status of 1, with the remaining 47% having a status of 0. Fifty-one percent of patients had KRAS mutations. Nearly all patients (96%) had received prior bevacizumab (Avastin) and 74% had received ≥3 prior treatment regimens for metastatic disease.

Patients received regorafenib at 160 mg once daily for the first 3 weeks of each 4-week cycle until disease progression, death, or unacceptable toxicity. Treatment beyond progression was per investigator’s discretion. The median duration of treatment was 2.5 months (range, 0.03-30.4), and the mean daily dose, assessed only on days that a dose was administered, was 146 mg. Including interruptions, patients received 75% of the mean planned dose.

Overall, 46% required dose reduction due to TEAEs. Nine percent discontinued treatment due to regorafenib-related TEAEs. Forty-nine percent of patients had at least 1 dose reduction and 84% had at least 1 treatment interruption or delay. Ninety-nine percent of patients had at least 1 TEAE, and TEAEs were responsible for 91% of dose reductions. TEAEs (61%) and patient error (27%) were the most common reasons for dose interruptions. There were 13 patient deaths in the trial determined to be regorafenib related.

The FDA approved regorafenib in September 2012 for the treatment of patients with metastatic CRC who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type, an anti-EGFR therapy. The approval was based on the phase III CORRECT trial, which randomized 760 patients in a 2:1 ratio to receive regorafenib (160 mg orally once daily on a 3-weeks-on/1-weekoff cycle; n = 505) or placebo (n = 255).

The median overall survival (OS) was 6.4 months with regorafenib versus 5.0 months with placebo (HR 0.77; 95% CI, 0.64-0.94; P = .0052).2 The median PFS was 1.9 months versus 1.7 months, respectively (HR, 0.49; 95% CI, 0.42-0.58; P <.0001).

In CORRECT, 20% of patients required dose reductions. The most common grade 3 AEs with regorafenib included hand-foot syndrome was (16.6%), fatigue (9.2%), hypertension (7.2%), diarrhea (7%), and rash or skin desquamation (5.8%).

Results from CORRECT were later confirmed by the phase III CONCUR trial. In CONCUR, 204 Asian patients with treatment-refractory metastatic CRC were assigned in a 2:1 ratio to receive either regorafenib at 160 mg once daily (n = 136) or placebo (n = 68) on days 1 to 21 of each 28-day cycle.

The median OS was 8.8 months with regorafenib compared with 6.3 months with placebo (HR, 0.55; 95% CI, 0.40-0.77; P = .00016). The median PFS was 3.2 versus 1.7 months, respectively (HR, 0.31; 95% CI, 0.22-0.44; P <.0001).3

In May 2018, the NCCN updated its guidelines for regorafenib use in previously treated patients with metastatic disease based on results from the phase II dose optimization ReDOS trial.4 The new dosing scheme calls for a starting dose of 80 mg/daily, escalating to 120 mg/daily, and concluding with 160 mg/daily. Patients stay on each dose for 7 days, then receive 160 mg on days 1 to 21 every 28 days for subsequent cycles.

In ReDOS, the median OS was 9.0 months with the dose escalation regimen versus 5.9 months for the standard dose of 160 mg of regorafenib daily (P = .0943). The 6-month OS rate was 66.5% (95% CI, 53.8-82.2) in the escalation arm versus 49.8% (95% CI, 37.2-66.8) in the standard arm. The 12-month OS rate also favored the dose escalation arm, at 34.4% versus 26.7%, respectively.


  1. Van Custem E, Martinelli E, Cascinu S, et al. Regorafenib for patients with metastatic colorectal cancer who progressed after standard therapy: results of the large, single-arm, open-label phase IIIb CONSIGN study [published online September 6, 2018]. Oncologist. doi: 10.1634/theoncologist.2018-0072.
  2. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312. doi: 10.1016/S0140-6736(12)61900-X.
  3. Li J, Qin S, Xu R, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16(6):619-629. doi: 10.1016/S1470-2045(15)70156-7.
  4. Bekaii-Saab TS, Ou FS, Anderson DM, et al. Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)—an ACCRU Network study. J Clin Oncol. 2018;36(suppl 4S; abstr 611).
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