Published Data Back Regorafenib Dose Escalation in Colorectal Cancer

Tanios Bekaii-Saab, MD

A weekly regorafenib (Stivarga) dose-escalation strategy beginning at 80 mg and ending at 160 mg is an appropriate and potentially optimal approach for previously treated patients with metastatic colorectal cancer (mCRC), according to data from the phase II ReDOS trial now published in the Lancet Oncology.

As opposed to the standard strategy of 160 mg/day of regorafenib throughout, the escalation approach explored in the ReDOS trial calls for a starting dose of 80 mg/daily on days 1 to 7, escalating to 120 mg/daily on days 8 to 14, and concluding with 160 mg/daily on days 15 to 21. For subsequent cycles, patients receive 160 mg of regorafenib on days 1 to 21 every 28 days.

The primary endpoint of the ReDOS trial was the percentage of patients who initiated cycle 3 of treatment. This endpoint was met, as 43% of patients in the dose-escalation group started cycle 3 compared with 26% of patients in the standard-dose group (P = .043). The median overall survival was 9.8 months in the dose-escalation arm versus 6.0 months in the standard arm (HR, 0.72; 95% CI, 0.47-1.10; log-rank P = .12). The median progression-free survival was 2.8 versus 2.0 months, respectively (HR, 0.84; 95% CI, 0.57-1.24; log-rank P = .38).

“Our study shows that a dose-escalation strategy for regorafenib is a feasible alternative to the standard regorafenib dosing strategy of 160 mg/day. The data presented herein show that the dose-escalation strategy does not negatively affect activity and is well tolerated,” lead investigator Tanios Bekaii-Saab, MD, professor of medicine, Mayo Clinic, and coinvestigators wrote.

In ReDOS, 54 patients assigned to dose escalation and 62 assigned to standard dosing were evaluable for the primary endpoint. In the dose-escalation group, the median age was 62, 67% of patients were male, and 81% were white. In the standard-dose group, the median age was 61, 56% were male, and 89% were white.

Across both groups, one-third of patients had an ECOG performance status of 0, and two-thirds had a performance status of 1. There were no BRAF-positive patients who received dose escalation compared with 2 BRAF-positive patients who received the standard dose. There were 21 and 34 KRAS-positive patients in the dose-escalation and standard-dose groups, respectively.

Investigators noted that toxicity was more favorable in the dose-escalation arm, and quality-of-life parameters were improved as well. The most frequently occurring grade 3/4 adverse events (AEs) included fatigue (7 patients in the dose-escalation arm vs 11 in the standard-dose arm), hand-foot skin reaction (8 vs 10 patients, respectively), abdominal pain (9 vs 4 patients), and hypertension (4 vs 9 patients). Six patients in the dose-escalation arm had at least 1 treatment-related serious AE compared with 8 patients in the standard-dose arm. There was 1 death of myocardial infarction in the standard-dose group categorized by the investigators as a “probable treatment-related death.”

In an interview with OncLive at the 2018 Gastrointestinal Cancers Symposium Bekaii-Saab discussed the significance of the ReDOS trial.

“The most important aspect of this study is that now we have another option, and I think it is a preferred option, of how to administer regorafenib,” said Bekaii-Saab. “As we get more confirmatory studies, [we might want] to consider regorafenib a little earlier if we want to get the full benefit of the agent rather than wait until the end when the patient is literally about to go to hospice. A dose-escalation strategy would make more sense now than the standard 160 mg. We have to become more proactive about how we place our drugs and how to optimize the dose-escalation strategy for regorafenib.”

Regorafenib is approved by the FDA for the treatment of patients with metastatic CRC who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type, an anti-EGFR therapy.

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:https://doi.org/10.1016/S1470-2045(19)30272-4.