Eric Van Cutsem, MD, PhD
Patients with heavily pretreated metastatic colorectal cancer (mCRC) who received the recently approved drug regorafenib experienced a sustained survival benefit, and the benefit of this multitargeted tyrosine kinase inhibitor (TKI) was observed across all prespecified subgroups, according to updated findings from the CORRECT clinical trial presented at the European Society for Medical Oncology (ESMO) 2012 congress in Vienna, Austria.
No new or unexpected safety findings emerged with longer-term follow-up.
At the first preplanned interim analysis of overall survival (OS), the study met the primary endpoint with a clear difference in favor of regorafenib. Median OS was 6.4 months for regorafenib versus 5 months for placebo (P
<.0052), and the study was halted early. These results were reported at the 2012 American Society of Clinical Oncology (ASCO) meeting earlier this year.
At the 2012 ESMO congress, the final updated analysis of OS confirmed the benefit of regorafenib. At 6 months, median overall survival was 6.4 months for regorafenib (95% CI, 5.8-7.0) versus 5 months for placebo (95% CI, 4.4-5.9), resulting in a 21% reduced risk of death for the newly approved agent (HR=0.79; 95% CI, 0.66-0.94; P
=.0038). At 6 months, 52.2% of the regorafenib-treated group were alive versus 43.1% of placebo patients; at 1 year, 24.1% and 17%, respectively, were alive.
“Regorafenib is the first oral multitargeted TKI with proven activity in metastatic colorectal cancer, improving overall survival in patients who progress on standard therapies,” said lead author Eric van Cutsem, MD, University Hospitals Gasthuisberg/Leuven, Leuven, Belgium. “The benefit is sustained over time, with manageable side effects. Regorafenib represents a new potential standard of care for patients with chemo refractory metastatic disease.”
Additionally, van Cutsem pointed out that the patients in this trial had good performance status despite disease progression and said that regorafenib was an option “as long as patients are in good condition.” He emphasized that many patients with mCRC fail standard treatments, and in this setting, there has been no salvage therapy available, “although many patients remain in good condition.”
Regorafenib recently gained FDA approval for mCRC in the salvage setting. The drug interferes with cell proliferation, inhibits the tumor microenvironment, cell signaling, and neoangiogenesis.
The phase III, randomized, placebo-controlled CORRECT trial was conducted at 114 centers in 16 countries in 760 patients with mCRC who progressed despite being treated with several lines of standard therapies. Patients were randomized in a 2:1 ratio to oral regorafenib 160 mg/day or placebo for 3 weeks on and 1 week off; both groups received best supportive care and were treated until disease progression, unacceptable toxicity, or investigator’s decision to withdraw treatment.
At baseline, demographics in both arms were well balanced. Median age was about 61 years and approximately 78% were Caucasian; 52.5% of patients who received regorafenib were ECOG Performance Status (PS) 0, and 47.5% were ECOG PS 1. The primary site of the cancer was the colon in 64%, the rectum in 29.9%, and a combination of the two sites in 5.9% of patients who received regorafenib. Slightly more patients with wild type KRAS were observed in the regorafenib group. Adenocarcinoma was observed in 98% of patients, and 100% received prior bevacizumab. No difference between treatment arms was observed for prior lines of chemotherapy for metastatic disease.
Dose reductions were initiated in 20% of regorafenib-treated patients. Although no difference in partial response was seen between groups, regorafenib was superior to placebo in achieving disease control (i.e., response plus stable disease): 41% versus 15% for placebo patients.
In the regorafenib group, drug-related adverse events included hand-foot syndrome in 46.6% (all grades, Grade 3, 16.6%); fatigue 47.4% (all grades; grade 3, 9.2%), hypertension 27.8% (all grades; grade 3, 7.2%); diarrhea 33.8% (all grades; grade 3, 7%); and rash or skin desquamation in 26% (all grades; grade 3, 5.8%). Rates for these events were considerably lower in the placebo group. Subgroup analysis of safety showed no difference in adverse events compared with the overall analysis, except slightly more hand-foot syndrome occurred in Asians than Caucasians and rash/desquamation was slightly more frequent in females than males.
At present, there is no biomarker to identify which subgroups have the most benefit from regorafenib. Translational research on serum and tissue samples from patients in the trial is planned.
Regorafenib is marketed by Bayer HealthCare Pharmaceuticals as Stivarga in the United States.