ArticlesAnalysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial
Introduction
Standard treatment for metastatic colorectal cancer includes drugs that target the molecular drivers of colorectal cancer pathogenesis, such as VEGF and EGFR. These drugs have improved overall survival, progression-free survival, and response in metastatic colorectal cancer.1, 2, 3, 4, 5, 6, 7, 8, 9
Tumour genotype plays an important part in drug resistance in patients with metastatic colorectal cancer. For example, use of anti-EGFR-antibody treatment is restricted to patients with RAS-wild-type tumours, some of whom acquire RAS mutations during treatment as a mechanism of drug resistance.10, 11 Genotyping of tumour tissue can help with the selection of patients with tumours amenable to treatment; however, the value of testing a tumour sample is limited by intertumour and intratumour heterogeneity. Moreover, archival tissue will not show genotypic changes that have occurred since the sample was obtained.
Regorafenib is a multikinase inhibitor that inhibits various protein kinases implicated in oncogenesis, angiogenesis, and the tumour microenvironment.12 Treatment with regorafenib has shown significant benefits for overall survival and progression-free survival in patients with previously treated metastatic colorectal cancer in two placebo-controlled phase 3 trials, CORRECT13 and CONCUR.14
Investigation of the effect of genotype on treatment outcomes in patients treated with regorafenib is important in view of the association between tumour genotype and response to treatment that exists with other drugs used for metastatic colorectal cancer. In this retrospective exploratory analysis, we investigated the clinical activity of regorafenib in biomarker subgroups of the study population of CORRECT, as defined by tumour mutation status, plasma DNA concentration, or plasma protein concentrations.
Section snippets
Study design and participants
CORRECT13 was an international, multicentre, randomised, placebo-controlled phase 3 study in patients with histologically or cytologically documented metastatic adenocarcinoma of the colon or rectum who had received all approved standard therapies available locally (including a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and, if appropriate, cetuximab or panitumumab), with disease progression during, or within 3 months after the last administration of the last standard therapy. 760
Results
In CORRECT, 760 patients were randomly assigned (2:1) to receive treatment with regorafenib (505 patients) or placebo (255 patients) between April 30, 2010, and March 22, 2011. The trial was stopped by the data monitoring committee at the second planned interim analysis on Oct 22, 2011, after 432 deaths, because the hazard ratio (HR) for overall survival for regorafenib versus placebo crossed the prespecified overall survival efficacy boundary (HR 0·77, 95% CI 0·64–0·94, one-sided p=0·0052).
Discussion
Our analysis shows that regorafenib provides a consistent overall and progression-free survival benefit in a range of subgroups of patients with metastatic colorectal cancer based on tumour mutation status and plasma protein biomarker concentrations. Furthermore, our results support the use of circulating tumour DNA to establish tumour genotype at the time of treatment.
To our knowledge, this is the largest study published so far to address the genetic evolution of metastatic colorectal cancer
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Authors contributed equally