Dose-Optimized Regorafenib Provides Comparable, Safe Option for mCRC


Patients with relapsed or refractory metastatic colorectal cancer who received dose-optimized regorafenib achieved superior survival outcomes than those who received best supportive care, fruquintinib, standard-dose regorafenib, and trifluridine/tipiracil.

In an updated network meta-analyses (NMA) of patients with relapsed or refractory metastatic colorectal cancer (mCRC), dose optimization of regorafenib (Stivarga) improved survival outcomes vs best supportive care, fruquintinib (Elunate), standard-dose regorafenib, and trifluridine/tipiracil (Lonsurf). Results from the updated NMA were presented at the 2022 European Society for Medical Oncology Congress.1

Regorafenib dose optimization was defined as 80 mg daily for week 1, 120 mg daily for week 2 and 160 mg daily for week 3 onward. The median overall survival (OS) for patients treated with on this schedule was 9.8 months (95% CI, 7.5-11.9). Comparatively, the median OS for patients who received best supportive care, regorafenib standard dosing (160 mg), trifluridine/tipiracil, and fruquintinib was 6.4 months (95% CI, 2.3-11.1), 7.5 months (95% CI, 4.6-11.9), 7.5 months (95% CI, 4.2-12.6), and 7.7 months (95% CI, 4.2-13.5), respectively.

Regorafenib dose optimization provided a reduction in the risk of death of 52% (HR, 0.48; 95% CI, 0.28-0.82), 28% (HR, 0.72; 95% CI, 0.41-1.27), 31% (HR, 0.69; 95% CI, 0.40-1.20), and 26% (HR, 0.74; 95% CI, 0.41-1.33) vs each comparator, respectively.

Regorafenib dose optimization also led to an improvement in progression-free survival (PFS) in all groups except fruquintinib. The median PFS among patients treated with regorafenib dose optimization was 2.8 months (95% CI, 2.0-2.5). Patients who received best supportive care, regorafenib standard dosing, and trifluridine/tipiracil achieved a median PFS of 1.9 months (95% CI, 1.0-2.5), 2.1 months (95% CI, 1.7-5.9), and 2.0 months (95% CI, 1.8-5.8), respectively.

The hazard ratios compared with regorafenib dose optimization, were 0.34 with best supportive care (95% CI, 0.19-0.61), 0.84 with regorafenib standard dosing (95% CI, 0.47-1.48), and 0.74 with trifluridine/tipiracil (95% CI, 0.40-1.35) all did not lead to a PFS benefit.

The median PFS in the fruquintinib was 3.9 months (95% CI, 2.0-10.3), surpassing that achieved with regorafenib dose optimization (HR, 1.29; 95% CI, 0.68-2.45).

Investigators concluded that regorafenib dose optimization may represent a favorable treatment option for patients with mCRC.

In February 2022, investigators conducted a systematic literature review which identified randomized controlled trials to include in the NMA and a feasibility assessment was conducted. The NMA included 3 global or US-only trials—ReDOS (NCT02368886), CORRECT (NCT01103323), and RECOURSE (NCT01607957—and 4 Asia-only trials (TERRA (NCT01955837), a phase 2 trial (JapicCTI-090880), CONCUR (NCT01584830), and FRESCO (NCT02314819).

The standard dosing for oral regorafenib is 160 mg daily for the first 21 days of each 28-day cycle. The label notes that dose modifications should occur in 40 mg increments, with the lowest recommended daily dose being 80 mg. Reductions to 120 mg are included for the following occurrences: grade 2 hand-foot skin reaction, after recovery of any grade 3/4 adverse reaction except infection, for grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation. Reductions to 80 mg are recommended for the following: re-occurrence of grade 2 hand-foot skin reaction at the 120-mg dose, or after recovery of any grade 3/4 adverse reaction at the 120 mg dose (except hepatotoxicity or infection).2

At the optimized-dose level, the agent displayed no significant drug-related adverse events (AEs) over a standard-dose strategy of 21 days per 28-day cycle.1 The dose optimization strategy aims to lower incidences of AEs and allow patients to receive comparable treatment with the agent.3

In the NMA, the most common grade 3 or greater AEs were neutropenia, leukopenia, anemia, hand-foot skin reaction, fatigue, and hypertension.1 Regorafenib dose optimization led to lower hematological toxicities vs trifluridine/tipiracil. The lowest number of grade 3 or higher drug-related AEs were in the best supportive care group; however, safety events varied significantly as some studies reported AEs as drug-related while others reported them as treatment-emergent.

Significant AEs included increased aspartate transaminase, diarrhea, febrile neutropenia, and death.

Additionally, findings were consistent across fixed effect (FE) and random effect (RE) Bayesian and FE and RE frequentist Bucher NMAs which were used to synthesize the HRs for OS and PFS. The Bucher RE NMAs HRs were applied to the regorafenib dose optimization Kaplan-Meier curves from the ReDOS trial to approximate the predicted median OS and PFS of each treatment.


  1. Burnett H, Proskorovsky I, Yoon S, et al. Impact of regorafenib dose optimization on comparative outcomes in the treatment of relapsed/refractory metastatic colorectal cancer. Poster presented at: 2022 European Society for Medical Oncology; September 9-13, 2022; Paris, France. Accessed September 12, 2022.
  2. Stivarga. Prescribing information. Bayer HealthCare Pharmaceuticals Inc; 2020. Accessed September 13, 2022.
  3. Bekaii-Saab TS, Ou FS, Ahn DH, et al. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019;20(8):1070-1082. doi:10.1016/S1470-2045(19)30272-4
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