Elsevier

The Lancet

Volume 381, Issue 9863, 26 January–1 February 2013, Pages 303-312
The Lancet

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

https://doi.org/10.1016/S0140-6736(12)61900-XGet rights and content

Summary

Background

No treatment options are available for patients with metastatic colorectal cancer that progresses after all approved standard therapies, but many patients maintain a good performance status and could be candidates for further therapy. An international phase 3 trial was done to assess the multikinase inhibitor regorafenib in these patients.

Methods

We did this trial at 114 centres in 16 countries. Patients with documented metastatic colorectal cancer and progression during or within 3 months after the last standard therapy were randomised (in a 2:1 ratio; by computer-generated randomisation list and interactive voice response system; preallocated block design (block size six); stratified by previous treatment with VEGF-targeting drugs, time from diagnosis of metastatic disease, and geographical region) to receive best supportive care plus oral regorafenib 160 mg or placebo once daily, for the first 3 weeks of each 4 week cycle. The primary endpoint was overall survival. The study sponsor, participants, and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01103323.

Findings

Between April 30, 2010, and March 22, 2011, 1052 patients were screened, 760 patients were randomised to receive regorafenib (n=505) or placebo (n=255), and 753 patients initiated treatment (regorafenib n=500; placebo n=253; population for safety analyses). The primary endpoint of overall survival was met at a preplanned interim analysis; data cutoff was on July 21, 2011. Median overall survival was 6·4 months in the regorafenib group versus 5·0 months in the placebo group (hazard ratio 0·77; 95% CI 0·64–0·94; one-sided p=0·0052). Treatment-related adverse events occurred in 465 (93%) patients assigned regorafenib and in 154 (61%) of those assigned placebo. The most common adverse events of grade three or higher related to regorafenib were hand-foot skin reaction (83 patients, 17%), fatigue (48, 10%), diarrhoea (36, 7%), hypertension (36, 7%), and rash or desquamation (29, 6%).

Interpretation

Regorafenib is the first small-molecule multikinase inhibitor with survival benefits in metastatic colorectal cancer which has progressed after all standard therapies. The present study provides evidence for a continuing role of targeted treatment after disease progression, with regorafenib offering a potential new line of therapy in this treatment-refractory population.

Funding

Bayer HealthCare Pharmaceuticals.

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.

Section snippets

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

Primary investigators from the participating centres are listed in the appendix

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