Elsevier

The Lancet Oncology

Volume 16, Issue 6, June 2015, Pages 619-629
The Lancet Oncology

Articles
Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S1470-2045(15)70156-7Get rights and content

Summary

Background

In the international randomised phase 3 CORRECT trial (NCT01103323), regorafenib significantly improved overall survival versus placebo in patients with treatment-refractory metastatic colorectal cancer. Of the 760 patients in CORRECT, 111 were Asian (mostly Japanese). This phase 3 trial was done to assess regorafenib in a broader population of Asian patients with refractory metastatic colorectal cancer than was studied in CORRECT.

Methods

In this randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done in 25 hospitals in mainland China, Hong Kong, South Korea, Taiwan, and Vietnam, we recruited Asian patients aged 18 years or older with progressive metastatic colorectal cancer who had received at least two previous treatment lines or were unable to tolerate standard treatments. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and adequate bone marrow, liver, and renal function, without other uncontrolled medical disorders. We randomly allocated patients (2:1; with a computer-generated unicentric randomisation list [prepared by the study funder] and interactive voice response system; block size of six; stratified by metastatic site [single vs multiple organs] and time from diagnosis of metastatic disease [<18 months vs ≥18 months]) to receive oral regorafenib 160 mg once daily or placebo on days 1–21 of each 28 day cycle; patients in both groups were also to receive best supportive care. Participants, investigators, and the study funder were masked to treatment assignment. The primary endpoint was overall survival, and we analysed data on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01584830.

Findings

Between April 29, 2012, and Feb 6, 2013, we screened 243 patients and randomly assigned 204 patients to receive either regorafenib (136 [67%]) or placebo (68 [33%]). After a median follow-up of 7·4 months (IQR 4·3–12·2), overall survival was significantly better with regorafenib than it was with placebo (hazard ratio 0·55, 95% CI 0·40–0·77, one-sided p=0·00016; median overall survival 8·8 months [95% CI 7·3–9·8] in the regorafenib group vs 6·3 months [4·8–7·6] in the placebo group). Drug-related adverse events occurred in 132 (97%) of 136 regorafenib recipients and 31 (46%) of 68 placebo recipients. The most frequent grade 3 or higher regorafenib-related adverse events were hand–foot skin reaction (22 [16%] of 136 patients in the regorafenib group vs none in the placebo group), hypertension (15 [11%] vs two [3%] of 68 patients in the placebo group), hyperbilirubinaemia (nine [7%] vs one [1%]), hypophosphataemia (nine [7%] vs none), alanine aminotransferase concentration increases (nine [7%] vs none), aspartate aminotransferase concentration increases (eight [6%] vs none), lipase concentration increases (six [4%] vs one [1%]), and maculopapular rash (six [4%] vs none). Drug-related serious adverse events occurred in 12 (9%) patients in the regorafenib group and three (4%) in the placebo group.

Interpretation

This phase 3 trial is the second to show an overall survival benefit with regorafenib compared with placebo in patients with treatment-refractory metastatic colorectal cancer, substantiating the role of regorafenib as an important treatment option for patients whose disease has progressed after standard treatments. In this trial, preceding standard treatments did not necessarily include targeted treatments. Adverse events were generally consistent with the known safety profile of regorafenib in this setting.

Funding

Bayer HealthCare Pharmaceuticals.

Introduction

During the past few decades, the incidence of colorectal cancer has increased around the world, including in Asia.1, 2, 3 Although isolated metastases might be resectable with potentially curative outcomes,4 around 25% of patients with colorectal cancer have metastatic disease that has a clinically significant detrimental effect on prognosis.5, 6 Consensus guidelines for treatment of Asian patients with metastatic colorectal cancer are mostly similar to other international guidelines, with adaptations to account for differences in clinical practice and local availability of approved drugs.2, 4 Patients with metastatic colorectal cancer are typically offered chemotherapy (fluoropyrimidines plus either oxaliplatin or irinotecan) and might also receive biological drugs targeting VEGF (bevacizumab) and, if they have RAS wild-type tumours, EGFR (cetuximab or panitumumab).4, 7

Research in context

Evidence before this study

We searched for articles published up to Jan 31, 2012, reporting on treatment of metastatic colorectal cancer in Asian patients using the search terms “colorectal cancer” AND (“treatment” OR “therapy”) AND “Asian”, with no language restrictions, retrieving 211 articles. Of these, 11 were clinical studies of treatments for advanced colorectal cancer, consisting of fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, and panitumumab. More than half of the studies were in the first-line setting, with only one (of panitumumab) focusing exclusively on pretreated patients. Thus, evidence is scarce for continuing treatment of patients with metastatic colorectal cancer that has progressed on standard treatment. At the time of the search, the international, randomised, phase 3 CORRECT trial, which included patients from Asia (mostly Japan), was in progress.

Added value of this study

Although CORRECT provided evidence of a significant overall survival benefit of regorafenib versus placebo in patients with pretreated metastatic colorectal cancer, only a low proportion of patients were Asian (mostly Japanese). This trial was designed specifically to assess regorafenib in a broader population of Asian patients with metastatic colorectal cancer than was studied in CORRECT.

Implications of all the available evidence

This phase 3 trial is the second to show an overall survival benefit with regorafenib compared with placebo in patients with treatment-refractory metastatic colorectal cancer, substantiating the additional clinical benefit of regorafenib monotherapy in these patients.

Regorafenib is an orally available, small-molecule multikinase inhibitor that targets signalling pathways implicated in tumour angiogenesis (VEGF receptors 1–3 and TIE2), oncogenesis (KIT, RET, RAF1, and BRAF), and the tumour microenvironment (platelet-derived growth factor receptor and fibroblast growth factor receptor).8 Evidence of the activity of regorafenib in preclinical models of colorectal cancer8, 9 and a phase 1 trial of patients with advanced colorectal cancer10 prompted an international, randomised, phase 3 trial (CORRECT, NCT01103323), in which regorafenib monotherapy added to best supportive care improved overall survival versus placebo plus best supportive care in patients with disease progression after standard treatments (hazard ratio [HR] 0·77, 95% CI 0·64–0·94; one-sided p=0·0052).11

For any new drug, confirmation that activity and toxicity profiles noted in non-Asian patients are similar in Asian patients is important in view of evidence of differences in treatment effects between populations with some drugs (eg, S-1, which has a different toxicity profile in Japanese populations compared with European or US populations).12, 13 Of the 760 patients enrolled in CORRECT, 111 (15%) were Asian, and, of those, 100 (90%) were Japanese.11, 13 We did this phase 3 CONCUR trial to allow robust assessment of the efficacy and safety of regorafenib in a broader population of Asian patients with metastatic colorectal cancer than that in CORRECT. Although similar to CORRECT in design, our protocol allowed inclusion of patients who had not been given targeted biological drugs because, when CONCUR was initiated, these drugs were not widely available in some Asian countries.

Section snippets

Study design and patients

CONCUR was a randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done in 25 hospitals in mainland China, Hong Kong, South Korea, Taiwan, and Vietnam. Each centre's institutional review board approved the protocol. The trial adhered to the guiding principles of the Declaration of Helsinki and Good Clinical Practice, and complied with local laws and regulations.

Eligible patients had histologically or cytologically confirmed adenocarcinoma of the colon or rectum, with

Results

Of the 243 patients screened between April 29, 2012, and Jan 19, 2013, we randomly allocated 204 (84%) patients to receive either regorafenib (136 [67%]) or placebo (68 [33%]; figure 1); we randomly allocated and began treating the last patient on Feb 6, 2013. At the cutoff date for analysis of the primary endpoint (Nov 29, 2013), 155 (76%) deaths had occurred (95 [70%] in the regorafenib group and 60 [88%] in the placebo group). Median follow-up for the overall survival analysis was 7·4 months

Discussion

This study is the second phase 3 trial to show an overall survival benefit from the addition of regorafenib to best supportive care in patients with metastatic colorectal cancer in whom standard treatments have failed. Few treatment options exist for this population of patients. Although this trial had a smaller number of patients than the international CORRECT trial did, the sample size calculation and statistical power were appropriate for a confirmatory trial of this type, and the benefit of

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    Primary investigators from the participating centres are listed in the appendix

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