CHICAGO, IL—Data showing that patients with metastatic colorectal cancer (mCRC) who had RAS wild-type (wt) tumors derived marked benefit when cetuximab was added to FOLFIRI—while those with RAS tumor mutations did not—means cetuximab can be furthered tailored to maximize patient response, a retrospective subgroup analysis concluded at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting.
Previously, the CRYSTAL study found adding cetuximab to FOLFIRI significantly improved progression-free survival, overall survival, and response in the first-line treatment of patients with KRAS codon 12/13 (hereinafter exon 2) wt mCRC, said Eric Van Cutsem, MD, PhD, of University Hospitals Leuven and KU Leuven, Leuven, Belgium.. Conversely, those with KRAS exon 2 tumor mutations showed no benefit when treated with cetuximab.
In this analysis of the CRYSTAL population, the investigators screened patients for 26 mutations (new RAS) in four additional KRAS codons (exons 3 and 4) and six NRAS codons (exons 2, 3 and 4) using BEAMing technology, with a 5% sensitivity cutoff selected for analysis. Outcome was assessed by RAS mutation status (KRAS exon 2 + new RAS).
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In 430 (65%) of 666 patients with KRAS exon 2 wt tumors, mutation status was evaluable and new RAS mutations were detected in 63 (14.7%).
Eric Van Cutsem, MD, PhDThis included a response rate of 66.3% in the FOLFIRI plus cetuximab arm (n=178) versus 38.6% in the FOLFIRI-alone arm (n=189; odds ratio [OR, 3.11; 95% CI: 2.03-4.78; P < 0.0001). In the new RAS mutation patients, response rate was 34.4% in the FOLFIRI plus cetuximab arm (n=32) versus 35.5% in the FOLFIRI arm (n=31; OR 1.02; 95% CI: 0.33-3.15; P = 0.97). Among those with RAS mutation (any locus), a subset of the CRYSTAL KRAS evaluable population (n=1,063), response rate was 31.7% in the FOLFIRI plus cetuximab arm (n=246) versus 36.0% in the FOLFIRI-alone arm (n=214; OR, 0.85; 95% CI: 0.58-1.25; P = 0.40).
In the FOLFIRI plus cetuximab versus FOLFIRI-alone arm, median PFS was 11.4 months versus 8.4 months, respectively, in RAS wt patients (hazard ratio [HR], 0.56; 95% CI: 0.41-0.76; P < 0.00002). This is in comparison to those with new RAS mutation (7.2 vs. 6.9 months; HR, 0.81; 95% CI: 0.39-1.67; P = 0.56) and RAS mutation (7.4 vs. 7.5 months; HR, 1.10; 95% CI: 0.85-1.42; P = 0.47).
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In those with RAS wt tumors, a significant benefit across all endpoints was associated with the addition of cetuximab to FOLFIRI.
Median OS was 28.4 months in the FOLFIRI plus cetuximab arm versus 20.2 months in the FOLFIRI-alone arm (HR, 0.69; 95% CI: 0.54-0.88; P < 0.0024) compared with 18.2 versus 20.7 months in the new RAS mutations (HR, 1.22; 95% CI: 0.69-2.16; P = 0.50) and 16.4 versus 17.7 months in the RAS mutation groups (HR, 1.05; 95% CI: 0.86-1.28; P = 0.64), respectively.
These data support use of FOLFIRI plus cetuximab as first-line treatment in patients with RAS wt mCRC. “Molecular testing of tumors for all activating mutations of KRAS and NRAS is therefore essential in selecting the most appropriate first-line treatment for patients with mCRC,” Dr. Van Cutsem concluded.
Reference
- Ciardiello F, Lenz HJ, Kohne CH et al. Abstract 3506. Presented at: 2014 American Society of Clinical Oncology (ASCO) Annual Meeting; May 30-June 3, 2014; Chicago, IL.
