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What healthcare professionals should do to treat side effects of multikinase inhibitor treatment – flexible dosing strategies

Management of MKI skin toxicities may involve dose adjustments as defined in each drug's SPC or US Prescribing Information, which are in turn largely based on Phase III data and standard dosing. Considering that toxicities, including skin toxicities, are both time and dose dependent, alternative dosing schedules (flexible dosing) have been investigated for some MKIs and shown to alleviate toxicities and improving quality of life in patients, without jeopardizing efficacy. While some studies have assessed different schedules, most have focused on optimizing the dose, i.e. different dosing strategies instead of alternative dosing schedules. 1-6  The ReDOS and REARRANGE trials, for example, have evaluated a flexible dosing strategy in the first treatment cycle. 1-2

The ReDOS, regorafenib dose optimization, randomized, open-label, phase 2 trial in patients with refractory metastatic colorectal cancer, compared the standard-dose of 160 mg/day oral regorafenib for 21 days over a 28-day cycle, to a dose-escalation strategy of a starting dose of 80 mg/day orally with weekly escalation, per 40 mg increment, to 160 mg/day regorafenib, provided no significant drug-related adverse events occurred.1 The study met its primary endpoint demonstrating that a significantly higher proportion of patients from the dose-escalation group initiated cycle 3 of treatment compared with the standard-dose group (43% of patients in the dose-escalation group initiated Cycle 3 vs 26% in the standard dose group; P=0.043). Importantly the results suggested that the dose escalation strategy did not jeopardize efficacy, especially considering that there was no difference in overall survival between the groups for patients who initiated Cycle 3. In addition, the investigators remarked that although adverse events were similar between the two groups, the severity of some toxicities, including hand-foot skin reaction, might be slightly lower in the dose-escalation group than in the standard dose group during the first 2 cycles and in addition that a weekly dose-escalation strategy was associated with improved patient Quality of Life after week 2 of the first cycle compared with the standard dose

These finding were corroborated in the REARRANGE randomized phase 2 trial  (N = 299) of regorafenib in patients with metastatic colorectal cancer, that investigated different dosing approaches during the first cycle of treatment.2 In this trial patients were enrolled in a standard dose group (160 mg/day 3 weeks on/1 week off), reduced dose group (120 mg/day 3 weeks on/1 week off) or an intermittent dosing group (160 mg/day 1 week on/1 week off), with patients in the latter two groups escalating to the standard dose after the first cycle if no limiting toxicity occurred. Although there was no difference in survival outcomes and the trial did not meet its primary endpoint of improving global tolerability in the reduced and intermittent dose groups, flexible dosing showed a numerical improvement in relevant adverse events including fatigue, hand-foot skin reaction, and hypertension.


  1. Bekaii-Saab TS, et al. Lancet Oncol 2019;20:1070–1082
  2. Argilés G, et al. Ann Oncol 2019;30(Suppl_4):O-026
  3. Kudo T, et al. J Clin Oncol 2018;36(Suppl_4S):821
  4. Maráz A, et al. BMC Cancer 201818(1):296
  5. Bjarnason GA, et al. Eur J Cancer 2019108:69–77
  6. Petrioli R, et al. Clin Colorectal Cancer 2018;17(4):307–312

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