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.
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.
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%).
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.
Bayer HealthCare Pharmaceuticals.
Copyright © 2013 Elsevier Ltd. All rights reserved.