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Colon Cancer Patients With p.G13D KRAS Mutations See Better Survival With Cetuximab-Based Therapy

Colon Cancer Patients With p.G13D KRAS Mutations See Better Survival With Cetuximab-Based Therapy

Despite recommendations against using EGFR inhibitors in the presence of KRAS mutations, cetuximab therapy may be enhanced by the presence of the p.G13D KRAS mutation.

U.S. and European treatment guidelines discourage the use of cetuximab (Erbitux) or panitumumab (Vectibix) in patients with KRAS-mutated tumors (either condon 12 or codon 13 mutations). But not all KRAS mutations are created equal so an international group of researchers decided to determine if patients with p.G13D-mutated tumors responded to cetuximab any differently than patients with other KRAS mutations.

Wendy De Roock, MD, and colleagues, mined data from several major trials for their analysis, including EVEREST, BOND, SALVAGE, and CO.17 (see Table). The data set from CO.17 was specifically used to study the association of the p.G13D mutation with outcome in metastatic colon cancer.

For the current retrospective observational study, the main endpoint was overall survival (OS) with response rate (RR) and progression-free survival (PFS) as secondary endpoints. The differences in RR by KRAS status—p.G13D mutant, other KRAS mutation, or KRAS wild-type—were evaluated pairwise using the Fisher exact test.

“The effect of the different mutations was studied in vitro by constructing isogenic cell lines with wild-type KRAS, p.G12V, or p.G13D mutatant alleles and treating them with cetuximab,” the group wrote (JAMA 304:1812-1820, 2010).

In the pooled population of 579 patients, 40% demonstrated KRAS mutations of which 14.5% were p.G13D mutated, the authors reported. Patients with p.G13Dmutated tumors treated with cetuximab had longer OS (median of 7.6 months vs 5.7 months; P = .005) and longer PFS (median of four months vs 1.9 months; P = .004) compared with patients with other KRAS mutations. The investigators also found that patients with KRAS wildtype tumors who received cetuximab with chemotherapy had a significantly higher RR than patients with p.G13D-mutated tumors (P = .03). In general, there was a significant interaction between KRAS mutations status and OS benefit from cetuximab treatment (P = .003).

The in vitro analysis showed that p.G13D-mutated and KRAS wild-type cells were sensitive to cetuximab. “The improved survival observed in patients with p.G13D-mutated tumors in the cetuximab monotherapy group suggests that p.G13Dmutated tumors may be sensitive to cetuximab and precludes a chemotherapy-driven effect,” the authors wrote. However, in the 195 patients in the CO.17 trial who were randomized to best supportive care alone, patients with p.G13D-mutated tumors had a worse OS than those with KRAS wild-type tumors.

TABLE Colon cancer trials with cetuximab
 
• C0.17: N Engl J Med 357:2040-2048, 2007 and 359:1757-1765, 2008

• EVEREST: J Clin Oncol 25:4037, 2007

• BOND: N Engl J Med 351:337-345, 2007

• SALVAGE: J Clin Oncol 24:4914-4921, 2006

• MABEL: J Clin Oncol 24:3549, 2006

The authors cautioned that their study was retrospective in nature and that prospective randomized studies are needed before definitive conclusions can be drawn about the potential benefits of cetuximab in p.G13D-mutated colon cancer. Nonetheless, “our results indicate that patients with p.G13D-mutated tumors respond to cetuximab therapy, albeit with a lower response rate than those with KRAS wildtype tumors.”

 
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