Dose reduction has little impact on regorafenib tolerability, efficacy not compromised
Reducing the dose of regorafenib did little to affect the overall tolerability of the drug in patients with metastatic colorectal cancer (mCRC), according to the phase II REARRANGE* trial presented at ESMO GI 2019.
“REARRANGE did not meet its primary endpoint of improving regorafenib global tolerability in either [reduced dose or intermittent dose] arms … [however], flexible dosing showed numerical improvement on relevant [adverse events (AEs)] like fatigue, hand-foot skin reactions (HFSR), and hypertension, without jeopardizing efficacy,” said the study authors led by Dr Guillem Argilés, from the Gastrointestinal & Endocrine Tumors Group, Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain.
Study participants were 299 patients (median age 64 years) with refractory mCRC who were randomized 1:1:1 to receive regorafenib at the standard dose of 160 mg/day on a 3-weeks-on, 1-week-off schedule, at a reduced dose of 120 mg/day on a 3-weeks-on, 1-week-off schedule, or at an intermittent dose of 160 mg/day on a 1-week-on, 1-week-off schedule. Patients who were assigned the reduced or intermittent dose were escalated to the standard dose from the second cycle onwards if they did not experience limiting toxicities. Patients had received a median four treatment lines prior to inclusion in this trial.
Patients on the standard, reduced, and intermittent dose of regorafenib received treatment for a median 3.2, 3.7, and 3.8 months, respectively. The safety population comprised 100, 98, and 99 patients in the standard, reduced, and intermittent dose arms, respectively.
The overall incidence of grade 3–4 AEs did not differ between patients who received the standard, reduced, and intermittent doses of regorafenib (60, 56, and 55 percent, respectively). [ESMO GI 2019, abstract O-026]
However, certain grade ≥3 AEs occurred at a lower rate among patients who received the reduced and intermittent doses compared with the standard dose. These included HFSR (which occurred in 3 percent of patients on the intermittent dose compared with 8 and 7 percent of patients who received the standard and reduced doses, respectively), arterial hypertension (12 percent in the reduced dose arm compared with 19 and 20 percent in the standard and intermittent dose arms, respectively), and asthenia and fatigue (14 and 15 percent in the reduced and intermittent dose arms compared with 20 percent in the standard arm).
Forty-five percent of patients assigned to the reduced dose were escalated to the standard dose for cycle 2, as were 64 percent of patients initially assigned the intermittent dose. Thirty-nine percent of patients on the standard dose initiated cycle 3 compared with 44 and 35 percent of patients in the reduced and intermittent dose arms, respectively.
Overall survival (OS) did not differ between patients who received the standard, reduced, and intermittent doses of regorafenib (7.4, 8.6, and 7.1 months, respectively), nor did progression-free survival (1.94, 2.0, and 2.0 months, respectively).
“Regorafenib improves OS compared with placebo in patients with refractory mCRC … [however], its adverse toxicity profile often limits its use in routine clinical practice,” said Argilés.
“[The numerical reduction in certain side effects, as seen in this trial] 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,” he added.