Disease flare after tyrosine kinase inhibitor (TKI) discontinuation in patients with EGFR-mutant lung cancer and acquired resistance.

Abstract

e18001 Background: Treatment of oncogene-addicted malignant neoplasms with targeted kinase inhibitors is biologically and clinically different than treatment with cytotoxic chemotherapy. We have observed that some patients (pts) with acquired resistance to EGFR TKI (initial response followed by RECIST disease progression) have accelerated progression of disease after discontinuation of EGFR TKI. The risk of a serious disease flare after discontinuing erlotinib or gefitinib in EGFR-mutant lung cancer despite acquired resistance has not been systematically evaluated. Methods: We identified pts with EGFR-mutant lung adenocarcinoma enrolled in 6 trials for treatment of acquired resistance which mandated TKI discontinuation prior to treatment. Disease flare was defined as symptomatic progression of disease leading to hospitalization or death during the washout period. All pts met consensus criteria for acquired resistance (Jackman, JCO, 2010). Results: 55 pts were eligible, (age range: 27-82, women: 76%). Baseline EGFR mutations were exon 19 deletions (36) and L858R (19). The median time on TKI before discontinuation was 19 months (range 7-78). 12 pts (22%; 95% CI 13-35%) experienced a disease flare after discontinuation of EGFR TKI. The median time to disease flare from discontinuation of TKI was 8 days (range 3-21). Of these 12, all were hospitalized and 3 died. Flare was associated with a preceding shorter initial time to progression on TKI, median 9 vs. 13 months, p=0.015 (Wilcoxon). There was no association between disease flare and EGFR sensitizing mutation, presence of secondary T790M mutation, sites of disease, or performance status. Conclusions: In pts with EGFR-mutant lung cancer with acquired resistance to EGFR TKI, discontinuation of erlotinib or gefitinib prior to initiation of an alternative treatment is associated with a clinically significant risk of accelerated disease progression. There is a need to identify clinical and molecular characteristics that predict this phenomenon. Future clinical trials targeting this patient population should eliminate or minimize protocol-mandated washout periods. Funded by NIH T32 CA009207, P01 CA129243.