Nonetheless, Endurobol anticancer treatment discontinuation is usually mandated as part of the eligibility criteria for enrollment in clinical trials.We used this practice of a trialmandated erlotinib and gefitinib washout period as an opportunity to estimate the frequency of disease flare upon EGFR inhibitor discontinuation and to evaluate clinical and molecular characteristics that may be associated with disease flare.Trials were only included if they mandated discontinuation of the TKI for at least days.Patients were included in this analysis if their tumors harbored a sensitizing EGFR mutation and met the consensus criteria for acquired resistance. Patients who were enrolled in more than one such clinical trial were evaluated only during the initial washout period.Testing for EGFR mutations was as previously described. The primary endpoint of this analysis was frequency of disease flare after discontinuation of TKI, defined as hospitalization or death attributable to disease progression after stopping the TKI and before initiation of study therapy.Hospitalizations due to infection, venous thromboembolism and other nononcologic issues were not considered a disease flare.Time on TKI was calculated from date of first TKI until date of discontinuation for trial washout.For patients who had a disease flare, time to flare was calculated from date of TKI discontinuation to date of hospitalization or death.Of these, had EGFR exon deletions, had exon point mutations and had exon LR point mutations.EGFR TM results at the time of acquired resistance were available for patients including of the patients with disease flare.An EGFR TM was mutation found in patients who did not.We compared clinical characteristics in patients who did and did not develop a flare after TKI discontinuation.Patients with disease flare had a shorter time to progression on TKI treatment than patients who did not experience flare. The time from documentation of acquired resistance to trial enrollment for all patients was a median of months and was not different between the groups there were diseaserelated hospitalizations, in each group. Flare was associated with the presence of brain or pleural metastases before TKI discontinuation. Flare was not associated with type of EGFR sensitizing mutation, presenceabsence of TM, Letrozole performance status, sex, tobacco use, or specific TKI. After identifying the phenomenon of disease flare in a prior study, we had attempted to minimize harm by abbreviating the standard washout periods of to days to days in more recent trials.Despite this precaution, patients continued to experience flare after a median of only days off TKI.Characteristics associated with development of flare included a shorter time to progression on initial TKI, preceding symptoms of disease progression, and presence of CNS and pleural disease.We recently reported that when acquired resistance is attributable to a TM point mutation, disease may follow a more indolent course than clinical resistance without TM. We believe that the rate of rapid disease progression reported here is clinically significant and should alter the design of clinical trials in this patient population.This analysis has the inherent limitations of a retrospective study, which prevented us from identifying a matched comparison group to study the prevalence of disease flare in the absence of TKI discontinuation.

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