ArticlesRegorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial
Introduction
Worldwide, nearly 1·25 million patients are diagnosed with and more than 600 000 patients die from colorectal cancer each year.1 At least 50% of patients develop metastases,2 and most of these patients have unresectable tumours.2, 3 Standard treatment for these patients involves chemotherapy based on fluoropyrimidines, oxaliplatin, and irinotecan (used in combination and sequentially); and monoclonal antibodies targeting vascular endothelial growth factor (VEGF; bevacizumab). In patients with KRAS wild-type tumours, monoclonal antibodies targeting epidermal growth factor receptor (EGFR; cetuximab and panitumumab) are also used.2, 3 Additional options are needed for patients who have disease progression despite all currently available standard therapies, because many patients maintain good performance status and might be candidates for further therapy.
Various signalling pathways have been implicated in the development and progression of colorectal cancer, involving receptor tyrosine kinases (eg, EGFR, VEGF receptor, platelet-derived growth factor receptor [PDGFR], and fibroblast growth factor receptor [FGFR]) and downstream signalling cascades (RAS-RAF-MEK-ERK and PI3K-PTEN-AKT-mTOR).4 Regorafenib is a novel oral multikinase inhibitor that blocks the activity of several protein kinases, including kinases involved in the regulation of tumour angiogenesis (VEGFR1 [also known as FLT1], VEGFR2 [KDR], VEGFR3 [FLT4], TIE2 [TEK]), oncogenesis (KIT, RET, RAF1, BRAF, and BRAFV600E), and the tumour microenvironment (PDGFR and FGFR).5 In preclinical studies, regorafenib has shown antitumour activity, including in colorectal cancer models.5
In a phase 1b study, oral regorafenib, given at a dose of 160 mg once daily for the first 3 weeks of each 4 week cycle, showed a tolerable toxicity profile and preliminary evidence of antitumour activity in 38 patients with progressive colorectal cancer who had received previous therapy for metastatic disease (median four lines).6 The disease control rate (partial response plus stable disease) was 74% (20 of 27 assessable patients). On the basis of these results and the high unmet need in this population of patients, the decision was made to proceed to a randomised phase 3 trial. We did the CORRECT trial (patients with metastatic colorectal cancer treated with regorafenib or placebo after failure of standard therapy) to assess efficacy and safety of regorafenib in patients with metastatic colorectal cancer, progressing after all approved standard therapies.
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Study design and participants
CORRECT was a randomised, placebo-controlled, phase 3 study involving 114 centres in 16 countries in North America, Europe, Asia, and Australia. Patients were eligible to participate when they had histological or cytological documentation of adenocarcinoma of the colon or rectum. They had to have received locally and currently approved standard therapies and to have disease progression during or within 3 months after the last administration of the last standard therapy or to have stopped
Results
Between April 30, 2010, and March 22, 2011, 1052 patients were screened and 760 patients were randomised to receive regorafenib (n=505) or placebo (n=255; population for efficacy analyses; figure 1). 753 patients initiated treatment (regorafenib n=500, placebo n=253; population for safety analyses; four patients, two in each group, did not receive treatment because of an adverse event associated with clinical disease progression; additionally in the regorafenib group, one patient had an adverse
Discussion
We showed that the addition of regorafenib to best supportive care increases overall survival, compared with best supportive care only, in patients with metastatic colorectal cancer who have received all currently approved standard therapies. The trial met its primary endpoint of overall survival at the second planned interim analysis. Although the recorded difference in median overall survival was modest at 1·4 months, the HR of 0·77 translates into a 23% reduction in risk of death during the
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These authors contributed equally
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Primary investigators from the participating centres are listed in the appendix