Analysis Confirms Safety of Regorafenib in mCRC Among Best Responders

Adverse events among patients with metastatic colorectal cancer who responded best to regorafenib in the phase III CORRECT trial were "broadly similar" to the overall study population.

Axel Grothey, MD

Toxicities among patients with metastatic colorectal cancer (mCRC) who responded best to regorafenib were“broadly similar” to the overall study population, according to a posthoc analysis of the pivotal phase III CORRECT trial presented at the 2015 Gastrointestinal (GI) Cancers Symposium.

“The results of this exploratory subgroup analysis support the clinical benefit and tolerability of regorafenib as a treatment option for patients with metastatic colorectal cancer,” said lead investigator Axel Grothey, MD, a professor in the Division of Medical Oncology at Mayo Clinic in Rochester, Minnesota.

CORRECT randomized 760 patients with mCRC in a 2:1 ratio to the oral multikinase inhibitor regorafenib (n = 505) or placebo (n = 255). Overall, treatment with regorafenib improved overall survival (OS) by 1.4 months (6.4 vs 5.0 months; HR = 0.77; P = .0052) and progression-free survival (PFS) by 0.2 months (1.9 vs 1.7 months; HR = 0.49; P <.000001). Based on these data, the FDA approved regorafenib in September 2012 for use in patients with previously treated mCRC.

The subgroup analysis presented at the GI Symposium included 98 patients (19.4%) treated with regorafenib who had PFS >4 months. Forty-seven percent of these patients were KRAS-mutation positive and 44% were KRAS wild-type.

Patients in this best responder subgroup received a median of 6 cycles of regorafenib, with 92% receiving ≥5 cycles and 20% receiving >8 cycles. Overall, 34% of patients had their regorafenib dose reduced and 87% had dose interruptions. The resulting mean daily dose was 139 mg, or 81% of the planned dose.

The review of toxicities in the subgroup found that these patients mostly experienced adverse events (AEs) at comparable rates to those in the overall trial population, despite exposure to regorafenib for over twice as long as the overall group.

All patients with longer PFS experienced AEs; the most common grade ≥3 AEs were hand-foot skin reaction (20%), hypertension (17%), diarrhea (17%), and fatigue (16%).

Although the AE profile of regorafenib was similar in both populations, some AEs did occur more frequently in patients treated with regorafenib for >4 months. Rates of all-grade diarrhea, hand-foot skin reaction, and weight loss were ≥15% higher in the subgroup with longer PFS than in the overall CORRECT population.

Rates of grade ≥3 diarrhea and hypertension (17% each) in the longer PFS population were twice as high as in the overall population.

According to Grothey, prospective validation of these AE findings among the best responders is needed, in conjunction with biomarker analysis from real-life clinical experience.

"While adverse events across both populations were broadly similar, some did occur more frequently in patients with longer exposure, an observation that is possibly related to the longer duration in this subgroup. Analyses to identify clinical and molecular markers in these patients are ongoing.”

CORRECT was an international trial involving 114 centers across 16 countries in North America, Europe, Asia, and Australia. Patients had to have an ECOG PS of 0 or 1 and had to have progressed within 3 months of receiving standard treatments, including chemotherapy, bevacizumab (Avastin), cetuximab (Erbitux), and panitumumab (Vectibix).

Patients received either 160 mg of oral regorafenib or placebo once daily on a 3-weeks-on/1-week off basis. All patients in the trial also received best supportive care. Radiologic evaluation was done every 8 weeks, with treatment continuing in the absence of progression, unacceptable toxicity, or death.

The primary endpoint was OS, defined as the time from randomization to death from any cause. Secondary endpoint was PFS, defined as the time to disease progression (radiological or clinical) or death from any cause. Patients were permitted dose interruptions or dose reductions for management of treatment-related AEs.

Regorafenib blocks the activity of multiple protein kinases involved in oncogenesis (KIT, RET, RAF-1, BRAF, and BRAF V600E), tumor angiogenesis, (VEGFR 1-3 and TIE2), and the tumor microenvironment (PDGFR and FGFR).

Approximately 50% to 60% of patients diagnosed with CRC develop metastases, and the majority of these patients have unresectable disease.The standard of care for unresectable mCRC is chemotherapy with or without the VEGF inhibitor bevacizumab, but few options are available for patients whose disease progresses after standard therapies.


Grothey A, Falcone A, Humblet Y, et al. Subgroup analysis of patients with metastatic colorectal cancer (mCRC) treated with regorafenib (REG) in the CORRECT trial who had progression-free survival (PFS) longer than 4 months. J Clin Oncol 33, 2015 (suppl 3; abstr 710).