Flexible Regorafenib Dosing Has Benefits for Patients With mCRC

Liam Davenport

July 10, 2019

BARCELONA, Spain — Taking a flexible approach to the dosing of the oral multikinase inhibitor regorafenib (Stivarga, Bayer) in patients with colorectal cancer has the potential to reduce adverse effects, suggests the largest study to date to examine the concept.

The REARRANGE study compared standard regorafenib dosing with an initially reduced dosing or intermittent regimen in almost 300 patients with chemorefractory metastatic colorectal cancer in Spain, Italy, and France.

Guillem Argilés, MD, medical oncologist and clinical investigator, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain, presented the findings here at the 2019 World Congress on Gastrointestinal Cancer.

He showed that there was no significant difference in overall survival and progression-free survival (PFS) between the three approaches, and indeed no overall difference in toxicity.

However, the rate of some adverse effects, such as asthenia/fatigue and also hypertension, were reduced by taking a more flexible approach to how regorafenib was dosed at the start of treatment.

These results complement those of another study, the recently published ReDOS trial, in which two different regorafenib regimens were assessed in 123 patients with chemorefractory metastatic colorectal cancer.

This study also found no differences in overall survival or PFS between the treatment groups, but also showed a reduction in adverse events at the start of treatment, so that more patients were likely to start cycle 3 than those in the standard treatment group.

Argilés said results from the REARRANGE study, when viewed in the context of the ReDOS findings, "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."

"This is an important study," commented Eric Van Cutsem, MD, PhD, from University Hospital Gasthuisberg, Leuven, Belgium and co-chair of the Congress. Speaking at a press conference, he said that, considering the results from both studies together, "it is clear that we are going away from the initial approved dose of regorafenib, so that the drug is more easily manageable and there is less toxicity".

He added that the studies "confirm what many oncologists do already: starting regorafenib at a lower dose, because of toxicity."

The new results mean that "now we are confident that we really can do that without losing activity in this setting," Van Cutsem said.

Now we are confident that we really can do that. Dr Eric Van Cutsem

Study coauthor Josep Tabernero, MD, PhD, also from Vall d'Hebron University Hospital and co-chair of the Congress, told Medscape Medical News that there also shouldn't be any implications for patient compliance in using a reduced or intermittent regimen.

"Honestly, I don't think that, in the end, it will make a difference when you go to a clinical setting," he said. "The important thing is that you provide clear instructions to the patients and there are several formulas for that."

A similar approach has been taken with other drugs, said Tabernero, and thus patients are "knowledgeable and flexible" when it comes to dosing, "provided you have a clear strategy."

Regarding longer-term outcomes, Tabernero commented that the data are "quite mature," adding that more extended follow-up is nevertheless important "not only for toxicity but of course for PFS and overall survival."

High Rate of Adverse Events

Argilés began his presentation by noting that, while regorafenib has been shown to improve survival in chemorefractory metastatic colorectal cancer, the high rate of severe adverse events has limited its use in clinical practice.

Detailed analysis of the safety profile revealed that the highest incidence of adverse events was seen during the first and second cycles, leading to several groups exploring dose reduction strategies.

To date, REARRANGE is the largest such study, involving 299 patients with metastatic colorectal cancer who had progressed on standard of care and had measurable disease.

They were randomly assigned in a 1:1:1 fashion to a standard therapy control group or one of two experimental groups:

  • Control: regorafenib 160 mg/day at 3 weeks on, 1 week off

  • Reduced: 120 mg/day at 3 weeks on, 1 week off for the first cycle, followed by the standard regimen for subsequent cycles

  • Intermittent: 160 mg/day at 1 week on, 1 week off, followed by the standard regimen for subsequent cycles

The median age of the patients was 63–65 years, and between 52% and 59% were male.

Approximately 75% of patients had liver metastases, and the average number of prior treatment lines was about four.

Argilés noted that the groups were well balanced in terms of baseline characteristics.

Less Toxicity With Dose Reduction

In terms of the primary endpoint, there was no significant difference between the three treatment groups in the proportion of patients who had grade 3/4 adverse events during treatment.

The rate was 60% in the control group, 54% in the reduced dose group, and 55% in the patients given the intermittent regimen.

Notably, however, patients in the reduced and intermittent groups were less likely to experience asthenia/fatigue than those in the control group (14% and 15%, respectively) vs 20% in the control group. In addition, proteinuria occurred less often in the reduced and intermittent groups (3% and 1%, respectively) vs 6% in the control group.

Patients in the reduced dosing group also had lower rates of hypertension (12%) vs those in the control group (19%), whereas those given the intermittent regimen were less likely to have a hand–foot skin reaction than those in the control group (3% vs 8%) .

In all cases, the tolerability of the cycles improved dramatically at cycle 3, in line with previous findings.

There was no difference in the proportion of patients who started cycle 3: 39% of patients in the control group, 43% in the reduced dose group and 45% in the intermittent group.

No Difference in Efficacy

Concerning overall survival, there were no significant differences between the treatment approaches, with 12-month survival rates of 32.4% for control patients vs 32.3% with the reduced dosage regimen and 27.8% for the intermittent approach.

Similarly, 6-month PFS rates were comparable across the groups, at 13.6% for control patients, 20.5% for reduced dosage patients, and 14.5% with the intermittent regimen.

Concluding, Argilés said that the numerical improvement in relevant adverse events in the experimental groups, achieved "without jeopardizing efficacy," supports the use of an initial reduced regorafenib dose during the first cycle.

The study was sponsored by the Spanish Cooperative Group for the Treatment of Digestive Tumours, in collaboration with Bayer. Argilés reports honoraria from Hoffmann La-Roche, Bristol-Myers Squibb, Bayer, Servier, Amgen, Merck, and Serono. He also reports institutional honoraria from Bayer, Servier, Novartis, Boehringer Ingelheim, Boston Pharmaceuticals, Hoffmann La-Roche, and Genentech. Tabernero has disclosed no relevant financial relationships.

World Congress on Gastrointestinal Cancer (WCGC) 2019: Abstract O-026. Presented July 6, 2019.

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