Safety of Regorafenib Confirmed in Patients With mCRC and High PFS

Axel Grothey, MD

A post-hoc analysis of the CORRECT trial showed that patients with metastatic colorectal cancer (mCRC) who had progression-free survival (PFS) >4 months, experienced AEs at rates broadly similar to those in the overall trial population, despite exposure to regorafenib (Stivarga) for over twice as long as the overall group.

“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, Mayo Clinic, Rochester, Minnesota, at the 2015 Gastrointestinal Symposium. “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.”

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 (Avastin), but few options are available for patients whose disease progresses after standard therapies. Regorafenib is an oral multikinase inhibitor that 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).

CORRECT was a randomized, placebo-controlled, phase III trial involving 760 patients in 114 centers across 16 countries in North America, Europe, Asia, and Australia. Key inclusion criteria were an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, plus previous treatment with chemotherapy and bevacizumab. Patients were randomized 2:1 to receive 160 mg oral regorafenib (n = 505) or placebo (n = 255) once daily, in combination with best supportive care (BSC) and a radiologic evaluation every 8 weeks. Treatment continued until progression, death, unacceptable toxicity, or patient/investigator decision to withdraw.

The primary endpoint was overall survival (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 was approved after meeting the primary (OS: HR = 0.77 [95% CI, 0.64-0.94; one-sided P = .0052]) and secondary (PFS: HR = 0.49 [95% CI, 0.42-0.58; one-sided P <.0001]) endpoints of the trial.¹

Median duration of PFS in CORRECT was 1.9 months (interquartile range [IQR] 1.6-3.9) in the regorafenib group and 1.7 months (IQR 1.4-1.9) in the placebo group. A subset of 98 (19.4%) patients treated with regorafenib had a PFS >4 months. These patients with longer PFS received a median of 6 cycles of regorafenib, with 92% receiving &ge;5 cycles and 20% receiving >8 cycles of the drug. Overall, 34% of patients had their regorafenib dose reduced and 87% underwent dose interruptions. The resulting mean daily dose was 139 mg, or 81% of the planned dose.

All patients with longer PFS experienced AEs; the most common grade &ge;3 AEs were hand-foot skin reaction (20%), hypertension (17%), diarrhea (17%), and fatigue (16%). Although the AE profile of regorafenib was broadly 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 &ge;15% higher in the subgroup with longer PFS than in the overall CORRECT population. Rates of grade &ge;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 findings in conjunction with biomarker analysis from real-life clinical experience is needed.

Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.Lancet.