Optimizing The Administration Of Tyrosine Kinase Inhibitors With Chemoradiotherapy To Improve Outcomes In Locally Advanced, Egfr Plus Nsclc Using An Evolutionary Tumor Progression Model

It is currently unclear how to optimally combine tyrosine kinase inhibitors (TKIs) plus definitive chemoradiotherapy (CRT) for locally advanced non-small cell lung cancer (NSCLC) with a mutated epidermal growth factor receptor (EGFR+). Important questions regarding optimal scheduling and length of induction period remain unsolved and vary among clinical trial protocols. The purpose of this study is to develop and apply a model encompassing targeted drug resistance and radiobiology for quantitative, in-silico analyses of varying TKI + CRT treatment schedules to inform clinical trial design. Both local and distant tumor compartments were explicitly modeled, along with TKI sensitive, persistent, and resistant compartments to model acquired drug resistance. Deaths from comorbidities were modeled with a non-cancer death rate calculated from SEER data. The evolutionary resistance model was calibrated to the tumor volume trajectories of an internal institutional data set of n=17 Stage IV EGFR+ NSCLC patients receiving TKIs. Estimated freedom from distant and local failures (FFDF and FFLF) and progression free survival (PFS) were used as endpoints. The model’s accuracy was evaluated against CRT and TKI trial outcomes. The TKI induction optimization focused on the predicted impact of TKI induction lengths, the use of TKI maintenance, and omission of chemotherapy. Our population-based tumor progression model accurately predicts the reported PFS of a recent CRT trial in stage III NSCLC (predicted vs. reported 2/5 yr. PFS of 25/13% vs. 28/14%) and a TKI trial for EGFR+ stage IV NSCLC (predicted vs. reported 2 yr. PFS of 14% vs. 11%). For the stage III EGFR+ TKI induction optimization, model predicted PFS at 5 yrs. was 15%, 22%, 18%, 14% after 0, 2, 8, 16 weeks of induction, respectively. When adjuvant TKI maintenance was included, 5 yr. PFS increased to 31%, 28%, 24%, 20%. The predicted fraction of patients recurring during TKI induction is <1% at 4 weeks, but increases to 10% at 12 weeks, enabling an estimation of the longest but safe TKI induction length. Omitting chemotherapy from the treatment regimen led the predicted 5 yr. FFDF and PFS to decrease to 8% and 6%, because of uninhibited distant, TKI resistant cell growth. While TKI induction can stunt tumor growth and downstage large tumors, our model suggests that the proliferation of TKI resistant cells during longer (>16 weeks) induction periods decreases progression free survival and could lead to recurrences during induction. Our model also suggests a shorter induction period (2 weeks) increases the chance of controlling the TKI resistant compartment with CRT, with small tumors benefiting the most (12% change in 5 yr. PFS for tumors smaller than median). These data will inform the design of future TKI induction trials.Abstract 3856; Table 1TKI IndTKI Ind + MainTKI Ind + Main, No Chemo.0 wk2 wk8 wk16 wk0 wk2 wk8 wk16 wk0 wk2 wk8 wk16 wk5 yr FFLF6668676772717069474646455 yr FFDF253629234944373088885 yr PFS15221814312824206666 Open table in a new tab