Dose-Optimization Strategies Continue for Regorafenib in Colorectal Cancer With ReDOS Success

A dose-escalation strategy for giving regorafenib improved the frequency of adverse events while still demonstrating similar efficacy to a standard-dose strategy in patients with metastatic colorectal cancer.

Tanios S. Bekaii-Saab, MD

A dose-escalation strategy for giving regorafenib (Stivarga) improved the frequency of adverse events (AEs) while still demonstrating similar efficacy to a standard-dose strategy in patients with metastatic colorectal cancer (CRC). Findings from the phase II ReDOS trial were recently published in theLancet Oncology.1

More patients who started at 80 mg of regorafenib and escalated up to 160 mg were able to complete 2 cycles of therapy and initiate the third cycle compared with those who received the standard dose of 160 mg from the start (43% vs 26%; one-sidedP= .043).

“This study provides the clinical data to potentially establish a new approach for optimizing regorafenib dosing through a dose-escalation strategy. The study met its prespecified primary endpoint. The results suggest that an increase of the dose of regorafenib from 80 to 160 mg/day via 40 mg increments over 3 weeks is a viable regimen, compared with the standard starting dose of 160 mg/day,” the study authors, led by Tanios S. Bekaii-Saab, MD, wrote in their published report.

Regorafenib was approved for the treatment of patients with metastatic CRC whose disease had progressed after prior therapy in 2012. The standard dosing regimen is 160 mg/day of regorafenib for 3 weeks of treatment followed by 1 week off in each cycle.

However, the toxicities associated with regorafenib, such as hand-foot skin reaction (HFSR) and fatigue, have often limited its use. The ReDOS trial aimed to improve the tolerability of regorafenib for patients by finding an optimal dose strategy for administering the multikinase inhibitor.

The randomized, open-label trial enrolled 123 patients between June 2, 2015 and June 22, 2017, who had advanced or metastatic CRC that was refractory to previous standard therapy, including irinotecan, oxaliplatin, fluoropyrimidines, and VEGF inhibition. Those who were eligible for EGFR inhibition were required to have progressed on anti-EGFR therapy before entering the trial. Participants were also required to have an ECOG performance status of 0 or 1 and adequate organ and bone marrow function.

Patients were randomized into 1 of 4 preplanned groups of 2 dose strategies for receiving regorafenib with either pre-emptive or reactive clobetasol cream for HFSR. When the investigators tested the interaction between the 2 interventions being tested, they noted that there was no significant interaction (P= .74) and decided to pool the data for the clobetasol approaches, instead just comparing the 2 dosing strategies.

In the dose-escalation group (n = 54 evaluable), patients started at 80 mg/day in the first week, 120 mg/day in the second week, and 160 mg/day in the third week, all within the first cycle. Incremental escalations occurred as long as no significant drug-related toxicities were seen. If a significant toxicity was observed, patients could reduce the dose to the preceding level until the event resolved. Treatment was permanently discontinued for a patient if more than 2 dose-level reductions were needed.

The primary endpoint was the proportion of patients in each arm that completed the second cycle of treatment and initiated the third. Secondary endpoints included progression-free survival (PFS), overall survival (OS), time to progression, the rate of grade 3 HFSR events, and quality of life (QOL). Response and progression were evaluated by investigator assessment using RECIST 1.1 criteria, and QOL measurements were assessed with self-assessment questionnaires.

Baseline characteristics were relatively similar between the 2 dose-strategy groups. The median age was 61.5 years (range, 53-68) between the 2 arms. The primary tumor had been resected in 70% of patients, and almost half of the patients (47%) hadKRAS-mutant metastatic disease.

As of the data cutoff of July 24, 2018, 43% of patients (95% CI, 29%-56%) in the dose-escalation group compared with 26% (95% CI, 15%-37%) in the standard-dose arm were able to complete 2 cycles of therapy and initiate the third cycle. Thirty-seven percent of patients in the dose-escalation group had discontinued treatment prior to the third cycle due to progressive disease versus 47% in the standard-dose group. Among all patients who did not receive a third cycle of therapy, 69% and 33%, respectively, went on to receive subsequent therapy.

The study authors noted that “although more patients in the dose-escalation group received subsequent therapy overall, a similar proportion of patients who continued onto cycle 3 received subsequent therapy in both groups. These findings suggest that a dose-escalation strategy that allows more patients to initiate cycle 3 might lead to improved outcomes.”

After a median follow-up of 1.18 years (range, 0.98-1.57), the median OS was 9.8 months (95% CI, 7.5-11.9) for those who received the dose-escalation strategy compared with 6.0 months (95% CI, 4.9-10.2) for those who received the standard regorafenib dose (HR, 0.72; 95% CI, 0.47-1.10; log-rankP= .12). A post-hoc analysis found that there was no significant difference in OS found between those in either arm that reached the third cycle.

The median PFS was 2.8 months (95% CI, 2.0-5.0) with dose-escalated regorafenib versus 2.0 months (95% CI, 1.8-2.8) with standard regorafenib (HR, 0.84; 95% CI, 0.57-1.24; log-rankP= .38).

The 2 patients withBRAF-mutated disease, who were both treated in the standard-dose group, were observed to have a longer OS than the median survival time for patients in their group at 7.0 and 11.5 months.KRASmutations did not have a significant impact on OS (P= .95).

QOL scores were similar at baseline between the 2 groups, but by week 2, mean QOL scores were significantly better in terms of fatigue (5.30 vs 4.25;P= .046), activity interference (5.59 vs 4.31;P= .032), mood interference (6.22 vs 4.92;P= .038), walking ability (5.96 vs 4.50;P =.019), and work interference (5.48 vs 4.17;P= .039) in patients receiving the dose-escalation strategy compared with those who received the standard dose. The QOL score were not significantly different at weeks 4, 6, and 8. However, patients receiving the dose-escalation strategy had slightly high QOL scores than in the standard-dose group, although the overall difference was not significant.

In the first cycle, dose modifications occurred in 24% of patients in the dose-escalation group and in 21% of the standard-dose group; dose delays occurred in 9% and 2% of patients, respectively. In the second cycle, dose modifications were needed in 22% and 32% of patients in the dose-escalation and standard-groups, respectively, and dose delays in 0% and 15%.

Grade 3 AEs were reported less frequently in the dose-escalation group compared with the standard-dose group. Common grade 3/4 AEs included fatigue (13% with dose-escalation vs 18% with standard-dose), HFSR (15% vs 16%, respectively), abdominal pain (17% vs 6%), and hypertension (7% vs 15%). These findings were consistent with previous reports of regorafenib.

At least 1 serious AE was noted in 26% of patients in the dose-escalation group compared with 34% in the standard-dose group, most frequently being abdominal pain. A total of 14 patients had serious regorafenib-related AEs, including 6 patients in the dose-escalation arm and 8 in the standard-dose arm. Fatigue was the most common serious drug-related AE.

Further Optimization Research

Three patients died on the study, 1 of which was considered to be possibly due to treatment. This patient, who was treated with the standard dose of regorafenib, developed a myocardial infarction.The study authors noted that 2 ongoing phase II trials (REGOCC and RE-ARRANGE) are looking at different dose-escalation and scheduling approaches for administering regorafenib to patients with metastatic CRC.

REGOCC is a single-arm, multicenter phase II dose-titration trial exploring an initial dose of 120 mg/day of regorafenib for 21 days followed by a 7-day break in patients with metastatic CRC who have progressed after chemotherapy. In the second cycle, patients were escalated to the standard 160 mg/day dose.

Initial results from the Japanese study were presented at the 2018 Gastrointestinal Cancers Symposium.2Sixty patients were enrolled with a median age of 68.5 years (range, 47-80).

The disease control rate (DCR) was 38.3%, consisting entirely of stable disease. The median PFS was 2.45 months (95% CI, 1.9-3.7).

Forty percent of patients required dose reduction to 80 mg due to AEs, and 10% overall required this in the first cycle. Grade 3/4 AEs were noted in 52% of patients, which were generally consistent with the known safety profile of regorafenib.

The 120-mg starting dose was considered comparable to the 160-mg dose in terms of efficacy.

The international, randomized RE-ARRANGE trial (NCT02835924) considered different dose approaches to initial regorafenib treatment. Patients in the trial were randomized 1:1:1 to receive either the standard schedule for regorafenib of 160 mg/day for 3 weeks on followed by 1 week off, a reduced dose of 120 mg/day for 3 weeks on followed by 1 week off, or 160 mg/day on an intermittent schedule of 1 week on and 1 week off.

Results from the trial were presented at the 2019 European Society of Medical Oncology World Congress on Gastrointestinal Cancer.3The median age of the 299 randomized patients was 64 years. Patients had received a median of 4 prior lines of therapy.

The median OS was 7.4 months in the standard-dose arm, 8.6 months in the reduced-dose arm, and 7.1 months in the intermittent-dosing arm. Median PFS was 1.94, 2.0, and 2.0 months in the standard-, reduced-, and intermittent-dose arms, respectively.

The DCR was 33% in patients who received the standard dose and schedule of regorafenib, 36% with the reduced dose, and 35% with the intermittent schedule. The median duration of treatment was 3.2 months, 3.7 months, and 3.8 months, respectively.

Forty-five percent of patients in the reduced-dose arm and 64% in the intermittent-dosing arm were escalated to receive the standard dose after the first cycle.

The rate of grade 3/4 AEs was 60% in the standard-dose arm, 56% in the reduced-dose arm, and 55% in the intermittent-dosing arm. In the standard-dose arm, 39% of patients initiated the third cycle of treatment compared with 44% in the reduced-dose arm and 35% in the intermittent-dosing arm.

The trial did not meet its primary endpoint of improving global tolerability of regorafenib in the reduced-dose and intermittent-dosing arms, but improvements were seen in the frequency of regorafenib-related AEs such as fatigue, HFSR, and hypertension.

“These results, interpreted in the context of other trials, like the American study ReDOS, tell us that the more flexible doses of regorafenib are an effective alternative in order to improve quality of life in patients with metastatic refractory CRC,” study author Guillem Argilés, MD, said in a statement ahead of the presentation.


  1. Bekaii-Saab TS, Ou F-S, Ahn DH, et al. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study [published online June 28, 2019].Lancet Oncol. doi: 10.1016/S1470-2045(19)30272-4.
  2. Kudo T, Kato T, Kagawa Y, et al. Phase II dose titration study of regorafenib for patients with unresectable metastatic colorectal cancer that progressed after standard chemotherapy.J Clin Oncol. 2018;36(suppl 4; abstr 821). doi: 10.1200/JCO.2018.36.4_suppl.821.
  3. Argiles G, Margalef NM, Valladares-Ayerbes M, et al. Results of REARRANGE trial: a randomized phase 2 study comparing different dosing approaches for regorafenib (REG) during the first cycle of treatment in patients (pts) with metastatic colorectal cancer (mCRC). Presented at: European Society for Medical Oncology World Congress on Gastrointestinal Cancer 2019; July 3-6, 2019; Barcelona, Spain. Abstract O-026.