EGFR tyrosine kinase inhibitors gefitinib and erlotinib induce preferential responses in patients with mutations1,5,6. patients13. The most common etiologies of resistance are the development of the T790M missense mutation14, amplification of mutant lung cancers treated with EGFR TKI therapy typically have a longer clinical course than wild type disease treated with cytotoxic chemotherapy, suggesting that these patients may be an appropriate group of patients to study the power of local therapy. We chose to investigate the efficacy of local therapy with AZD8329 continued EGFR TKI therapy specifically in patients with acquired resistance to EGFR TKIs. We hypothesized AZD8329 that local therapy is usually associated with improved outcomes in patients with mutant lung cancers with acquired resistance to EGFR TKI therapy. Methods Design To be included in this analysis, patients had to have mutation as well as the mechanism of acquired resistance if identified. Both the clinical course on EGFR directed therapy and treatment regimens after progression on EGFR TKI were documented. Local interventions including surgical resection, radiofrequency ablation, stereotactic radiosurgery, and conventional radiation therapy were recorded. As local therapy for brain metastases is considered standard of care, brain metastases treated with local therapy were not included in this analysis. Outcomes of interest were time to progression, time until change in systemic therapy and overall survival from time of local therapy. The date of progression was defined based on routine surveillance imaging and/or symptomatic progression that prompted earlier radiographic evaluation with routine CTMP imaging every 2C3 months for most patients. Time until change in systemic therapy was noted when a change in therapy occurred which included the addition of cytotoxic chemotherapy or enrollment on to a clinical trial. Statistical Analysis Patients who did not receive local therapy but signed consent AZD8329 for a prospective study of patients with acquired resistance were used as a comparison group. Distribution of clinical variables was compared across patients with EGFR-mutant lung cancers with acquired resistance who had and did not have local therapy using Wilcoxon rank-sum test (for continuous variables) and Fisher exact test (for categorical variables). Time to progression and overall survival were measured starting from the time of local therapy until progression and death, respectively, using Kaplan Meier method. Patients who did not experience progression or death during the study time were censored at the time of the last available follow-up. Results Intra-cranial procedures Of 184 patients identified with acquired resistance to EGFR TKI, 42 patients developed brain metastases during their treatment course that required one or more central nervous system-directed interventions. Eight patients underwent craniotomy for surgical resection of solitary or oligometastatic brain metastases. Ten patients had stereotactic radiosurgery and 28 patients had whole brain radiation therapy. As local therapy for brain metastases is considered standard of care, treatment of brain metastases with local therapy was not included in this analysis. Two of the 42 patients who had CNS interventions also had local therapy to a non-CNS site; these non-CNS procedures were included in this analysis. Clinical and Molecular Characteristics Eighteen patients had one or more local therapies, excluding intracranial treatments, for advanced amplification and small cell histologic transformation. One patient in the local therapy group had an acquired mutation. Table 1 Patient Characteristics mutation type- (%)??Exon 19 deletion14 (78)109 (66)0.63??Exon 21 L858R4 (22)53 (32)??Other04 (2)Best response to TKI??Complete response120.70??Partial response13130??Stable disease119??Adjuvant therapy313??Progression disease02Initial EGFR TKI TTP (months)??Median19120.089??Range5C 332 C 73Resistance mechanism-no (%)??T790M11 (61%)84 (51%)**0.63??amplification15??Small cell histology13??Unknown675 Open in a separate window *P value for white vs all others is 0.99 **P value for T790M group vs. all others is usually 0.63 Procedures and post-procedure course The local therapies are detailed in Table 2. Most patients had surgical resections of pulmonary metastases. Fifteen of 18. AZD8329 AZD8329