Lorlatinib Exposure-Response Analyses for Safety and Efficacy in a Phase I/II Trial to Support Benefit-Risk Assessment in Non-Small Cell Lung Cancer.

Lorlatinib is a small molecule inhibitor of anaplastic lymphoma kinase (ALK) and c-ROS oncogene 1 (ROS1) tyrosine kinases and is approved for the treatment of patients with ALK-positive advanced non-small cell lung cancer (NSCLC). In the phase I/II study (NCT01970865), potential exposure-response (E-R) relationships between lorlatinib and selected safety and efficacy end points were evaluated in patients with NSCLC. E-R relationships were assessed for safety end points with incidence > 10% in all treated patients (n = 328). In total, 4 safety end points were assessed: hypercholesterolemia grade ≥ 3, hypertriglyceridemia grade ≥ 3, weight gain grade ≥ 2, and treatment-emergent adverse events (TEAEs) grade ≥ 3. Using logistic regression, significant relationships were identified between lorlatinib plasma exposure and risk of hypercholesterolemia grade ≥ 3 (odds ratio (OR) 5.256) and risk of TEAE grade ≥ 3 (OR 3.214). The covariates baseline cholesterol and time on study prior to the event (TE) were associated with the probability of hypercholesterolemia grade ≥ 3. Baseline cholesterol and TE were found to have a statistically significant correlation with TEAE grade ≥ 3. Exposure-efficacy relationships were assessed for objective response rate (ORR; n = 197) and intracranial objective response rate (IC-ORR; n = 132). Lorlatinib plasma exposure was not identified as a statistically significant factor related to either efficacy end point. The only significant E-R relationships identified for efficacy were between baseline alkaline phosphatase and baseline amylase with IC-ORR (ORs 0.363 and 1.015, respectively). These findings support the lorlatinib indicated dose and dose modification guidelines regarding the management of lorlatinib-related AEs.