• Oncology Clinical Trials
• Gastrointestinal Cancers

• Oncology Clinical Trials
• Gastrointestinal Cancers

The randomized Phase 3 Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer trial [CRYSTAL; Van Cutsem E et al. N Engl J Med 2009] investigated the efficacy and safety of cetuximab combined with a simplified regimen of leucovorin–5-flourouracil—irinotecan (FOLFIRI) for the initial treatment of metastatic colorectal cancer. The study found that cetuximab (CET) added to FOLFIRI improved progression-free survival (PFS), overall survival (OS), and response in patients with KRAS 12/13 (exon 2) wild-type disease [Van Cutsem E et al. N Engl J Med 2009; Van Cutsem E et al. J Clin Oncol 2011]. Patients with KRAS exon 2 mutations did not benefit from treatment.

The aim of this analysis of the CRYSTAL study [Ann Oncol 2014 (abstr O-0020); Ciardello F et al. J Clin Oncol 2014 (abstr 3506)], presented by Eric Van Cutsem, MD, Department of Clinical Digestive Oncology, Leuven Cancer Institute, UZ Leuven, Leuven, Belgium, was to assess the efficacy of CET added to FOLFIRI in patients who had metastatic colorectal cancer with new RAS mutations.

KRAS exon 2 wild-type tumor samples from CRYSTAL study patients were screened for 26 new RAS mutations in 4 additional KRAS codons (exons 3 and 4) and 6 NRAS codons (exons 2, 3, and 4) using a technique based on polymerase chain reaction (PCR) amplification of single target DNA molecules. Flow cytometry and fluorescent probes were used to identify wild-type and mutant sequences. The ratio of mutant to wild-type RAS DNA molecules in the original tumor DNA sample was determined for patients in whom mutations were identified. A 5% cutoff was selected for the analysis. Treatment outcomes were evaluated according to whether the patients had RAS wild-type, new RAS mutations, or RAS mutations (KRAS exon 2 or new RAS).

Mutation status was evaluated in 430 of 666 patients (65%) with KRAS exon 2 wild-type tumors. Using the 5% cutoff, new RAS mutations were identified in 63 of the 430 patients (15%). Comparison of outcomes with mutation status showed that patients with RAS wild-type (all loci) tumors treated with CET plus FOLFIRI versus FOLFIRI alone had significantly better response rates (66.3% vs 38.6%; odds ratio, 3.11; 95% CI, 2.03 to 4.78; p < .0001), median PFS (11.4 vs 8.4 months; HR, 0.56; 95% CI, 0.41 to 0.76; p = .0002), and median OS (28.4 vs 20.2 months; HR, 0.69; 95% CI, 0.54 to 0.88; p = .0024). The subgroup with new RAS mutations and those with RAS mutations at any locus derived no benefit from the addition of CET to FOLFIRI with respect to response rate, PFS, and OS (Table 1).

Analysis of treatment outcomes in subgroups with new RAS mutations defined according to a range of sensitivity cutoffs from 20% to .1% supported the use of 5% as a clinically appropriate cutoff point for defining a subgroup of patients most likely to benefit from the addition of CET to FOLFIRI.

Dr. Van Cutsem concluded that in the first-line treatment of metastatic colorectal cancer, patients with RAS wild-type tumors derived a marked benefit throughout all efficacy end points with the addition of CET to FOLFIRI. Patients with RAS tumor mutations did not benefit from treatment with CET. These results support patient selection according to RAS mutation status to maximize benefit from CET therapy.

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