Results of irreversible inhibitors in erlotinib- or gefitinibresistant, mutant EGFR NSCLCs have been disappointing to date and suggest that the ability of irreversible inhibitors to overcome acquired resistance may have limitations that were not predicted in preclinical studies. This may be a result of AZD6244 Selumetinib an inability to attain the drug concentrations in humans that were effective in preclinical studies. In the case of neratinib, grade 3 diarrhea in half of the patients necessitated a dose reduction in the three-arm phase II trial.               

            Although not measured, it was proposed that dose reduction of neratinib to 240 mg daily resulted in steady-state neratinib concentrations that may have been insufficient to inhibit exon 19 deletions or T790M mutations based on the concentrations required for inhibition in preclinical models (60 nmol/L for exon 19 AZD6244 606143-52-6 deletion and 90–800 nmol/L for T790M mutation). In contrast, the much lower dose of neratinib required to inhibit the G719S mutation may have been achievable, leading to the PRs observed in that small subgroup of patients refractory to reversible TKIs. Similar to neratinib, the half-maximal inhibitory concentration of PF00299804 required for growth inhibition in NSCLC cell lines with the T790M resistance mutation is 100– 900 nM. The inability to achieve these concentrations with doses administered clinically may explain the lack of efficacy in tumors with a T790M mutation .Because T790M-mutant EGFR has an affinity for ATP that is similar to the affinity of wild-type EGFR for ATP.

            concentrations of irreversible inhibitors that overcome the resistance mutation in vitro are not clinically achievable because of AZD6244 MEK inhibitor toxicities related to systemic wild-type EGFR inhibition, such as diarrhea and rash. EGFR T790M mutations notwithstanding, there are glimpses into the potential for irreversible inhibitors in gefitinib- or erlotinib-refractory disease. The PRs and SD seen in PF00299804-treated NSCLC patients with exon 20 insertions (typically resistant to reversible EGFR TKIs) and the PRs seen in neratinib-treated NSCLC patients with exon BIBF1120 18 G719X-mutant tumors previously treated with a reversible EGFR TKI suggest that specific EGFR.