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.