Phase II Feasibility Study Tests Four Molecular-Based Hypotheses in Advanced Colorectal Cancer
In a phase II feasibility study (MRC FOCUS3) reported in British Journal of Cancer, Maughan et al used KRAS and BRAF mutation status and topoisomerase-1 expression status to randomly assign patients with advanced colorectal cancer to molecular hypothesis–driven treatment or control treatment. They found that patient samples can be collected and analyzed in a timely fashion with reproducible mutation results and that the complex design was acceptable to patients provided with good information regarding study conduct and treatments.
Study Details
In the study, patients with advanced colorectal cancer had tumor samples analyzed for KRAS/BRAF oncogene mutation status and topoisomerase-1 immunohistochemistry status. Patients were then classified into one of four molecular strata: (1) low topoisomerase-1 expression levels and both KRAS and BRAF wild-type; (2) low topoisomerase-1 and either KRAS- or BRAF-activating mutations; (3) high topoisomease-1 and both KRAS and BRAF wild-type; and (4) high topoisomerase-1 and either KRAS or BRAF mutations.
Within each stratum, patients were randomly assigned to control therapy consisting of FOLFIRI (leucovorin, fluorouracil [5-FU], irinotecan) and to one of two hypothesis-driven experimental therapies:
- In stratum 1, patients were randomly assigned to FOLFIRI plus cetuximab (Erbitux) to test the addition of cetuximab in KRAS and BRAF wild-type disease or 5-FU/leucovorin to test the omission of irinotecan.
- In stratum 2, patients were randomly assigned to FOLFIRI plus bevacizumab (Avastin) in order to test the addition of bevacizumab in KRAS- or BRAF-mutant disease or 5-FU/leucovorin to test the omission of irinotecan.
- In stratum 3, patients were randomly assigned to FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, irinotecan) to test the addition of oxaliplatin in disease with high topoisomerase-1 expression or FOLFIRI plus cetuximab to test cetuximab in KRAS and BRAF wild-type disease
- In stratum 4, patients were randomly assigned to FOLFOXIRI to test the addition of oxaliplatin in disease with high topoisomerase-1 expression or FOLFIRI plus bevacizumab to test the addition of bevacizumab in KRAS- or BRAF-mutant disease.
A four-stage suite of patient information sheets was developed to avoid patient overload.
Biomarker Availability and Patient Understanding
A total of 244 patients were randomized. Biomarker results were provided within 10 working days in 71% of patients, 15 days in 91%, and 20 days in 99%. DNA mutation analysis was 100% concordant between two laboratories. More than 90% of patients reported excellent understanding of all aspects of the trial.
Efficacy Outcomes
In patients with low topoisomerase-1, 12-week response rate was 60% with leucovorin/5-FU alone and 47% with FOLFIRI, supporting the hypothesis that irinotecan does not add benefit, and there was no evidence of difference in progression-free survival (hazard ratio [HR] = 2.18, 95% confidence interval [CI] = 0.56–8.51). Response rates were 40% with FOLFIRI plus oxaliplatin and 45% with FOLFIRI alone, and no difference in progression-free survival was observed (HR = 1.08, 95% CI = 0.67–1.76).
In patients with wild-type KRAS and BRAF, the addition of cetuximab was associated with improved response rate (66% vs 44%) and progression-free survival (HR = 0.44, 95% CI = 0.23–0.82). In patients with mutant KRAS or BRAF, the addition of bevacizumab was associated with increased response rate (47% vs 33%) but no progression-free survival benefit (HR = 0.84, 95% CI = 0.43–1.64).
The investigators concluded, “Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-group designs are acceptable to patients with good patient information sheets. Randomisation within each cohort provides outcome data that can inform clinical practice.”
Angela M. Meade, DPhil, of the MRC Clinical Trials Unit at University College London, is the corresponding author for the British Journal of Cancer article.
The study was sponsored by the Medical Research Council. Additional support was provided by Merck KGaA, Pfizer, and Roche.
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