Adverse effects (AEs) with regorafenib tend to occur early—during the first treatment cycle—and then quickly taper off. Although dose modification as a result of AEs will be required in about two-thirds of patients, most can be maintained on treatment, said Axel Grothey, MD, at the 2013 Gastrointestinal Cancers Symposium.
Regorafenib was approved as second-line therapy for the treatment of patients with metastatic colorectal cancer in Septem-ber 2012 on the basis of the phase 3 CORRECT (Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy) study, in which regorafenib improved overall and progression-free survival compared with placebo.
“As with other small-molecule kinase inhibitors, regorafenib has a toxicity profile that differs from those seen with cytotoxic chemotherapies,” said Grothey, a professor of oncology at the Mayo Clinic, Rochester, Minnesota.
The experience from the CORRECT trial was that when AEs occurred with regorafenib, they occurred early “and then got better, even if you kept the dose constant,” he said. “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.”
Close monitoring of AEs in the days immediately following the start of regorafenib treatment will allow prompt intervention. Grothey recommends patients be contacted or seen in the office 1 week after starting treatment at the full 160 mg/day dosage, to allow for early dosage adjustment if necessary. Per the package insert, patients should be seen 2 weeks into treatment, at which time lab tests, including measurement of liver enzymes, should be obtained.
"At that point, most of the time we can either continue the dose or make any dose adjustments,” he said.
In the CORRECT study, AEs led to dose modification in 66.6% of patients assigned to regorafenib, but treatment had to be discontinued permanently in only 17.6%. The most frequent grade 3 AEs were hand-foot skin reaction (HFSR), fatigue, diarrhea, hypertension, and rash/desquamation.
During cycle 1 of regorafenib, the incidence of fatigue was about 45% and the incidence of HFSR exceeded 30%. These incidence rates decreased to ≤25% during cycle 2 and remained relatively stable through cycle 6. The rates of fatigue and HFSR diminished 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.
On average, the dose intensity was highest in cycle 1 and reached a lower, relatively stable dose by cycle 3.
Because it works by blocking multiple protein kinases, identifying the actions of regorafenib that contribute to toxicity and efficacy is difficult, said Grothey. “There are so many different pathways that are being inhibited that it’s impossible to tease that out.”
“The critical issue now is no matter how thoughtfully and thoroughly we conduct a phase 3 trial, eventually when the drug is approved, it gets expanded to a larger patient population, sometimes patients that might not have met the eligibility criteria of a clinical trial,” he said. “As we get more experience, we will see side effects we have not seen before.” l
Grothey A, Van Cutsem E, Sobrero AF, et al. Time course of regorafenib-associated adverse events in the phase III CORRECT study. Presented at: 2013 Gastrointestinal Cancers Symposium; January 24-26, 2013; San Francisco, CA. Abstract 467/Poster C23.