Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial

Summary\r\nBackground No treatment options are available for patients with metastatic colorectal cancer that progresses after all\r\napproved standard therapies, but many patients maintain a good performance status and could be candidates for further\r\ntherapy. An international phase 3 trial was done to assess the multikinase inhibitor regorafenib in these patients.\r\nMethods We did this trial at 114 centres in 16 countries. Patients with documented metastatic colorectal cancer and\r\nprogression during or within 3 months after the last standard therapy were randomised (in a 2:1 ratio; by computergenerated\r\nrandomisation list and interactive voice response system; preallocated block design (block size six);\r\nstratifi ed by previous treatment with VEGF-targeting drugs, time from diagnosis of metastatic disease, and\r\ngeographical region) to receive best supportive care plus oral regorafenib 160 mg or placebo once daily, for the fi rst\r\n3 week s of each 4 week cycle. The primary endpoint was overall survival. The study sponsor, participants, and\r\ninvestigators were masked to treatment assignment. Effi cacy analyses were by intention to treat. This trial is registered\r\nat ClinicalTrials.gov, number NCT01103323.\r\nFindings Between April 30, 2010, and March 22, 2011, 1052 patients were screened, 760 patients were randomised to\r\nreceive regorafenib (n=505) or placebo (n=255), and 753 patients initiated treatment (regorafenib n=500; placebo\r\nn=253; population for safety analyses). The primary endpoint of overall survival was met at a preplanned interim\r\nanalysis; data cutoff was on July 21, 2011. Median overall survival was 6·4 months in the regorafenib group versus\r\n5·0 months in the placebo group (hazard ratio 0·77; 95% CI 0·64–0·94; one-sided p=0·0052). Treatment-related\r\nadverse events occurred in 465 (93%) patients assigned regorafenib and in 154 (61%) of those assigned placebo. The\r\nmost common adverse events of grade three or higher related to regorafenib were hand-foot skin reaction (83 patients,\r\n17%), fatigue (48, 10%), diarrhoea (36, 7%), hypertension (36, 7%), and rash or desquamation (29, 6%).\r\nInterpretation Regorafenib is the fi rst small-molecule multikinase inhibitor with survival benefi ts in metastatic\r\ncolorectal cancer which has progressed after all standard therapies. The present study provides evidence for a\r\ncontinuing role of targeted treatment after disease progression, with regorafenib off ering a potential new line of\r\ntherapy in this treatment-refractory population.