The development and grade of rash had been associated with an improved OS

in both cetuximab and panitumumab studies. For example, Peeters et al. found patients with grade 2-4 skin toxicities to have a significantly longer OS (7.9 vs. 5.6 mo; hazard ratio 0.60, P=0.0033) compared to patients with grade 1 skin toxicities. In this study 91% of patients had grade 1 or higher skin toxicity with 69% having grade 2-4 (66). The EVEREST phase I/II study randomized irinotecan-refractory patients who had not developed a rash > grade 1 after 21 days of standard-dose cetuximab (400 mg/m2 Inhibitors,research,lifescience,medical initial dose, then 250 mg/m2 per week) plus irinotecan, to dose escalations versus continuing the same dose. Of 157 patients, 89 patients were randomized after 21 days. The dose escalation was consistent with Inhibitors,research,lifescience,medical higher drug pharmacokinetics [Cmax and area under curve (AUC)] and was associated with an increase in skin reactions ≥ grade 2. In the KRAS-wild-type population, response rates were 43% in the

dose escalation vs. 30% in the same dose population (compared to 42% in the patients who had a rash with the initial dosing) but PFS and OS were not markedly different. Grade 2/3 skin reactions, diarrhea, hypomagnesemia and dry Inhibitors,research,lifescience,medical skin were more frequent in the dose escalation group but infusion reactions were not increased (67). Cetuximab is associated with infusion reactions, particularly in North Carolina and Tennessee where grade 3-4 hypersensitivity reactions were reported in up to 22%, all of them occurring during the first infusion (63). This is thought to be linked to IgE specific for galactose-alpha-1.3-galactose in these individuals and may be caused by a crossreaction Inhibitors,research,lifescience,medical with a specific antigen, possibly related to animals or plants, found in those regions (68). Other areas have found a lower learn more incidence with grade Inhibitors,research,lifescience,medical 3 or 4 infusion reactions being reported in 2.3% of patients in the CRYSTAL trial (25). Panitumumab, being a fully humanized monoclonal antibody, causes infusion reactions in <1% (30).

Mechanisms of resistance Mutations in the KRAS gene cause resistance to EGFR inhibition, as the MAPK pathway remains constitutively active even in the presence of an EGFR inhibitor. It is not clear why only 40-60% (10-20% response rate, 30-40% stable disease) of patients with KRAS wild-type tumors benefit from EGFR isothipendyl inhibition. Furthermore, even in the presence of a response, progression eventually occurs. Several mechanisms of resistance have been proposed (see Figure 2). Figure 2 Potential mechanisms of resistance to EGFR inhibitors Several investigators have looked at predictive factors for EGFR inhibitor responses. PIK3CA mutations and PTEN loss occur in ~15% and 20% of mCRC tumors and result in constitutive activation of the PIK3/Akt/mTor pathway which is an important anti-apoptotic and pro-survival tumor cell pathway (69).