Identified EGFR TKI-resistant mutation (insertion in exon 20, D770GY), who hadIdentified EGFR TKI-resistant mutation (insertion

Identified EGFR TKI-resistant mutation (insertion in exon 20, D770GY), who had
Identified EGFR TKI-resistant 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 with the molecular mechanisms that underlie the 12-LOX Inhibitor site resistance patterns of those mutations (33). It has been reported that EGFR, via its kinase-independent XIAP drug 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 really is hence conceivable that the effect of an antibody which include cetuximab could enable to overcome this pathway of resistance. In preclinical models of EGFR TKI-resistant tumors (exon 20 insertions), exposure to dual EGFR inhibitors resulted in considerably more substantial levels of apoptosis than that observed with single sorts of EGFR inhibitors (15, 16, 34), suggesting synergy. This may possibly possibly clarify the response observed in some of our sufferers such as those with primary resistance to EGFR TKI’s. We also observed a response inside a patient (case #17, Table two; EGFR TKI-sensitive mutation (L858R) in codon 21) who had progressed on prior erlotinib (35). This patient now has SD for 7.7 months (prior TTF = six.1 months). Whether or not synergy with cetuximab or retreatment with erlotinib led to response is unclear (36, 37), but the reality that the TTF around the combination is longer than the prior TTF on single-agent erlotinib suggests that the cetuximab plays a role within the activity observed. There are lots of clinical studies which can be underway targeting other pathways of EGFR resistance which includes HER2ERBB2 amplifications or mutations, MET amplifications, and, notch dysregulation in NSCLC individuals (38, 39). Encouraging clinical results have also been reported with use of irreversible EGFR tyrosine kinases in NSCLC sufferers. Not too long ago, Janjigian et al had reported of confirmed objective response in 40 of your 60 evaluable EGFR-mutant NSCLC patients with acquired resistance to erlotinib or gefitinib (which includes individuals with T790M mutation) when treated on a mixture with cetuximab and afatinib(40). This study isn’t devoid of limitations. The sample size is modest (20 sufferers) and much more so when we take into consideration every single particular subtype. On top of that, individuals were treated at two different dose levels. Additionally, it’s unclear if the antitumor activity (SD for 7.7 months) observed inMol Cancer Ther. Author manuscript; available in PMC 2014 August 19.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptWheler et al.Pagea patient who had progressed on prior treatment with erlotinib (case #17, Table three) is as a result of re-treatment impact that occurs with reintroduction of an EGFR TKI after a drug holiday (41). In conclusion, this study demonstrated that remedy with erlotinib plus cetuximab is feasible in NSCLC sufferers. It truly is a protected mixture with all the primary toxicity being rash. Though not conclusive as a result of little sample size in this study, it truly is noteworthy that SD6 monthsPR was observed in two of 3 individuals (66 ) with EGFR wild-type squamous cell carcinoma; a single patient with an EGFR TKI-resistant mutation; and, two of eight individuals with EGFR TKI-sensitive mutations which includes one particular patient who had progressed on prior erlotinib therapy after initial response. The combination of erlotinib plus cetuximab, either alone or with chemotherapy, warrants additional exploration in pick populations of NSCLC.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptAck.