Similarly the

CRYSTAL trial showed a modest increase in rates of surgery and R0 resection in the KRAS wild-type patients who received Alvocidib solubility dmso FOLFIRI with cetuximab versus FOLFIRI alone (surgery rate 7.9% vs. 4.6% P=0.0633; R0 resections 5.1% vs. 2.0%, P=0.0265, respectively) (25). A phase II trial reported at the annual European Society Inhibitors,research,lifescience,medical of Medical Oncology (ESMO) meeting in 2012 randomized 116 patients with KRAS wild-type tumors to mFOLFOX6 or FOLFIRI with or without cetuximab. Response rates were 66% vs. 33% in the 2 arms with improved R0 resection rates (31% vs. 9%) and a median OS of 46.6 months in the resected cetuximab arm (57). Are all KRAS mutations equal? Recent controversial findings suggest that not all KRAS mutations will confer resistance to EGFR inhibitor therapy. A recent retrospective study combining findings

from the CRYSTAL and OPUS studies showed improved RR and PFS in patients with tumors exhibiting a codon 13 glycine to aspartate mutation (G13D) who received cetuximab compared to those who did not Inhibitors,research,lifescience,medical receive cetuximab (58). Another recent retrospective review of randomized studies with panitumumab in patients with KRAS mutated tumors did not Inhibitors,research,lifescience,medical reveal a similar benefit for adding panitumumab when looking at individual mutations in codons 12 or 13 (59). A meta-analysis looking at 7 studies with anti-EGFR agents found overall response rates to be 25.2%, 17.6% and 42.6% in codon 13 mutations vs. any other KRAS mutations vs. KRAS wild-type tumors (59). PFS was 6.4, 4.1 and 6.6 mo and OS 14.6, 11.8 and 17.3 mo for the three groups, Inhibitors,research,lifescience,medical respectively. The incidence of codon 13 mutations was 6.6% in the entire study cohort. Patients with codon 13 mutated tumors receiving EGFR inhibitor as second-line seemed to

benefit more than patients receiving it in the first-line (60). It is therefore Inhibitors,research,lifescience,medical possible that tumors with G13D KRAS mutations may respond better than tumors with other KRAS mutations, although the magnitude of the benefit is small at the risk of added toxicities and cost. The NCCN guidelines do not recommend administering EGFR inhibitors to patients with codon 13D mutation based on these concerns (19). Further results from genomic analysis of the PRIME study will be presented at ASCO 2013, included analysis DNA ligase of KRAS exon 3, exon 4; NRAS exon 2, exon 3, exon 4; and BRAF exon 15. Findings from this study suggest that panitumumab is unlikely to benefit patients with any RAS mutations and that BRAF mutations had no predictive value (46). Can patients who progress on one EGFR inhibitor benefit from another? It is unclear whether panitumumab has activity in patients who have previously progressed on cetuximab (or vice versa) as two prospective studies have had discrepant results. The most important determinant for responses to subsequent panitumumab therapy from these small studies may be prior benefit from cetuximab therapy. Metges et al.