Regorafenib dosing strategies reduce adverse events among patients with colorectal cancer

Flexible dosing of regorafenib improved quality of life for patients with metastatic colorectal cancer without sacrificing efficacy, according to results from the randomized phase 2 REARRANGE trial presented at ESMO World Congress on Gastrointestinal Cancer.

However, the trial did not meet its primary endpoint of improving global tolerability of the multikinase inhibitor.
“Regorafenib (Stivarga, Bayer) has been approved since 2013 for patients with metastatic colorectal cancer who have progressed to standard treatments,” Guillem Argilés, MD, medical oncologist and clinical investigator in the gastrointestinal and endocrine tumors group at Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology in Barcelona, Spain, said in a press release. “Its adverse toxicity profile often limits its use in routine clinical practice. This clinical trial attempted to show the usefulness of different dose strategies in order to improve its tolerability and quality of life in patients who can benefit from the medicine in the context of advanced disease.”
REARRANGE study, Argilés and colleagues randomly assigned 299 patients (median age, 64 years) with refractory metastatic colorectal cancer in a 1:1:1 ratio to one of three regorafenib regimens: standard dose (160 mg per day in a 3-weeks-on, 1-week-off schedule, n = 100); reduced dose (120 mg per day in a 3-weeks-on, 1-week-off schedule, n = 98); or intermittent dose (160 mg per day in a 1-week-on, 1-week-off schedule, n = 99).

Patients had received a median four previous lines of treatment.

Those in the reduced- and intermittent-dose groups who experienced no dose-limiting toxicities after one cycle switched to standard-dose regorafenib.

The proportion of patients in each group with grade 3 to grade 4 treatment-related adverse events served as the primary endpoint. Secondary endpoints included OS, PFS, time to treatment failure, disease control rate, percentage of patients who initiated cycle 3, dose intensity and tolerability.

Median treatment duration was 3.2 months for the standard-dose group, 3.7 months for the reduced-dose group and 3.8 months for the intermittent-dose group.
The researchers set the threshold for trial positivity as a 20% decrease in the percentage of patients with grade 3 to grade 4 adverse events in the reduced- or intermittent-dose groups vs. the standard-dose group.

Grade 3 to grade 5 adverse events occurred among 61% of patients in the standard-dose group, 56% in the reduced-dose group and 55% in the intermittent-dose group.

These included: asthenia and fatigue (20% standard vs. 14% reduced vs. 15% intermittent); arterial hypertension (19% vs. 12% vs. 20%); hypokalemia (11% vs. 7% vs. 10%); increased gamma-glutamyltransferase (2% vs. 7% vs. 2%); increased aspartate aminotransferase (1% vs. 4% vs. 1%); decreased appetite (2% vs. 4% vs. 2%); proteinuria (6% vs. 3% vs. 1%); and hand-foot skin reaction (8% vs. 7% vs. 3%).

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Researchers escalated 45% of patients on a reduced dose and 64% of patients on an intermittent dose to the standard dose after the first cycle. Thirty-nine percent of patients in the standard-dose group, 44% in the reduced-dose group, and 35% in the intermittent-dose group began cycle 3.

The groups demonstrated similar rates of OS (7.4 months standard dose vs. 8.6 reduced dose vs. 7.1 months intermittent dose), PFS (1.94 months vs. 2 months vs. 2 months) and disease control (33% vs. 36% vs. 35%).
“Although statistical significance was not achieved, we did observe a numerical reduction in some side effects that can be very troublesome for the patients,” Argilés said in the press release. “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 colorectal cancer.”

– by Jennifer Byrne

Reference:

Argiles G, et al. Abstract O-026. Presented at: ESMO World Congress on Gastrointestinal Cancer; July 3-6, 2019; Barcelona, Spain.

Disclosure s : HemOnc Today could not confirm the authors’ relevant financial disclosures at the time of publication.

Photo of Guillem Argilés , MD, courtesy of VHIO.