Efficacy and safety exposure–response analyses of entrectinib in patients with advanced or metastatic solid tumors

Purpose Entrectinib is an anti-cancer agent that inhibits TRKA/B/C, ROS1, and ALK. Secondary pharmacokinetic (PK) exposure parameters for entrectinib derived from a previously described population PK model were used to characterize exposure–response relationships in patients treated with entrectinib. Methods Data were pooled from Phase 1 and 2 studies of entrectinib (600–800 mg/day in adults, 250–750 mg/m 2 /day in children) in 293 patients with NTRK -, ROS1 -, or ALK -positive, locally advanced or metastatic tumors. Efficacy was evaluated by the changes in sum of target lesion diameters and best overall response defined by RECIST1.1. A longitudinal nonlinear mixed-effect model described the relationship between entrectinib exposure and tumor size data in patients with ROS1 -positive non-small-cell lung cancer (NSCLC) or NTRK fusion-positive solid tumors. The relationship between exposure and treatment-emergent (TEAEs) or serious (SAEs) adverse events was assessed by logistic regression in all patients for whom secondary PK parameter estimates were derived. Results Among the 89 patients with evaluable efficacy data included in the exposure-efficacy analysis, 73% (65/89) achieved a complete or partial response. Entrectinib exposure distribution was similar in responders and non-responders. Model-described tumor shrinkage rates were 8–12 times greater than growth rates in both ROS-1-positive NSCLC patients and NTRK fusion-positive solid tumor patients, with no relationship between exposure and these rates. The probability of experiencing a Grade ≥ 3 TEAE or SAE increased with exposure, primarily at doses > 600 mg/day. Conclusion These analyses supported that entrectinib at 600 mg/day provides an acceptable benefit–risk ratio in adults with NTRK- , ROS1- , or ALK -positive tumors, considered as rare disease.