Side Effects With Regorafenib Occur Early and Tend to Taper

Axel Grothey, MD

The incidence of adverse effects with regorafenib is highest during the first treatment cycle and then diminishes over time. This time course of regorafenib-associated adverse events was evident in a subanalysis of the phase III CORRECT study conducted in patients with metastatic colorectal cancer (mCRC). In the trial, drug-related side effects tapered off starting with cycle 2, said Axel Grothey, MD, during a poster presentation at the 2013 Gastrointestinal Cancers Symposium.

“The side effects, if at all, came early and then got better even if you kept the dose constant,” said Grothey, professor of Oncology and consultant in the Division of Medical Oncology in the Department of Oncology, Mayo Clinic, Rochester, Minnesota. “This is not necessarily a given. When you look at some chemotherapy drugs—for instance, neuropathy or neurotoxicity on oxaliplatin gets worse over time. Often, the impact on neutrophils accumulates over time, so it is not a given that side effects are strongest in the first cycle and then abate over time, but this is exactly what we saw in the study.”

Regorafenib is an oral multikinase inhibitor that blocks the activity of several protein kinases. On the basis of the CORRECT study, it was approved by the FDA in September 2012 for the treatment of patients with mCRC whose disease has progressed after prior treatment with chemotherapy, an anti-VEGF therapy, and an anti-EGFR therapy if KRAS wild type.

Five hundred five patients were randomized to regorafenib in CORRECT, at a dosage of 160 mg for the first 3 weeks of each 4-week cycle. Two hundred fifty-five patients were assigned to placebo. Adverse events led to dose modification in 66.6% of the regorafenib recipients and 22.5% of the placebo recipients. Treatment was discontinued permanently in 17.6% of the regorafenib group and 12.6% of the placebo group because of adverse events.

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Dr. Grothey on the Time Course of Regorafenib-Associated AEs

During cycle 1 of regorafenib, the incidence of fatigue was about 45% and the incidence of hand-foot skin reaction (HFSR) exceeded 30%. These incidence rates dropped to 23% and 26%, respectively, during cycle 2 and remained relatively stable until cycle 6. The rates of fatigue and HFSR decreased further in cycles 7 and 8.

The incidences of hypertension and rash/desquamation were highest in cycle 1, at 20% to 25%, “and tapered to low or no incidence over cycles 2 to 8,” said Grothey.

The incidence of diarrhea remained relatively constant from cycles 1 to 6, but was lower in cycles 7 and 8.

“The time course suggested an initial flare-up of key side effects, in particular fatigue and HFSR, and then over time these side effects decreased in incidence but also in severity,” he said. “There were a higher number of early grade 3 adverse events but over time, even if you keep the same dose, these side effects fade away a little bit.”

As a result, the proportion of regorafenib received was highest in cycle 1 and decreased over cycles 2 and 3 as the dosage was adjusted to manage adverse events. The dose density remained relatively stable over cycles 3 through 8. “The dose that people could be maintained on over a longer term was about three quarters of the dose—instead of 160 mg, it was 120 mg,” he said. “The way adverse events were handled with dose modification was the basis for the positive survival results observed in this study.”

There was no evidence of cumulative toxicity with regorafenib.

Grothey A, Van Cutsem E, Sobrero AF, et al. Time course of regorafenib-associated adverse events in the phase III CORRECT study. J Clin Oncol 30: 2012 (suppl 34; abstr 467).

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