T dual EGFR therapy may perhaps assist to overcome some instances of primary EGFR TKI resistance. Indeed, a single patient (case #2, Table three) using a recognized EGFR TKIresistant mutation (insertion in exon 20, D770GY), who had not received prior EGFR therapy, has an ongoing PR at 24.two months (Figure two). There is a lack of understanding of the molecular mechanisms that underlie the resistance patterns of these mutations (33). It has been reported that EGFR, via its kinaseindependent activity is in a position to retain basal intracellular glucose levels that enhances the survival capacity of tumor cells even in the presence of EGFR TKI’s (25). It is therefore conceivable that the impact of an antibody such as cetuximab might assist to overcome this pathway of resistance. In preclinical models of EGFR TKIresistant tumors (exon 20 insertions), exposure to dual EGFR inhibitors resulted in far more substantial levels of apoptosis than that noticed with single kinds of EGFR inhibitors (15, 16, 34), suggesting synergy. This might possibly clarify the response noticed in a number of our sufferers like those with main resistance to EGFR TKI’s. We also observed a response within a patient (case #17, Table two; EGFR TKIsensitive mutation (L858R) in codon 21) who had progressed on prior erlotinib (35). This patient now has SD for 7.7 months (prior TTF = 6.1 months). Regardless of whether synergy with cetuximab or retreatment with erlotinib led to response is unclear (36, 37), but the fact that the TTF on the mixture is longer than the prior TTF on singleagent erlotinib suggests that the cetuximab plays a function inside the activity observed. There are several clinical research that happen to be underway targeting other pathways of EGFR resistance such as HER2/ERBB2 amplifications or mutations, MET amplifications, and, notch dysregulation in NSCLC individuals (38, 39). Encouraging clinical outcomes have also been reported with use of irreversible EGFR tyrosine kinases in NSCLC patients. Recently, Janjigian et al had reported of confirmed objective response in 40 on the 60 evaluable EGFRmutant NSCLC patients with acquired resistance to erlotinib or gefitinib (such as patients with T790M mutation) when treated on a combination with cetuximab and afatinib(40). This study isn’t devoid of limitations. The sample size is small (20 patients) and much more so when we think about every distinct subtype. Also, individuals were treated at two distinctive dose levels. Moreover, it can be unclear if the antitumor activity (SD for 7.7 months) observed inMol Cancer Ther. Author manuscript; obtainable in PMC 2014 August 19.1363404-84-5 site NIHPA Author Manuscript NIHPA Author Manuscript NIHPA Author ManuscriptWheler et al.1780038-41-6 web Pagea patient who had progressed on prior remedy with erlotinib (case #17, Table three) is as a result of retreatment impact that happens with reintroduction of an EGFR TKI soon after a drug holiday (41).PMID:24377291 In conclusion, this study demonstrated that therapy with erlotinib plus cetuximab is feasible in NSCLC individuals. It truly is a protected combination with the most important toxicity being rash. Even though not conclusive due to the little sample size within this study, it truly is noteworthy that SD6 months/PR was observed in two of 3 individuals (66 ) with EGFR wildtype squamous cell carcinoma; one particular patient with an EGFR TKIresistant mutation; and, two of eight patients with EGFR TKIsensitive mutations which includes a single patient who had progressed on prior erlotinib therapy following initial response. The mixture of erlotinib plus cetuximab, either alone or with chemotherapy, warrants further ex.
