Lorlatinib Exposure-Response Analyses for Safety and Efficacy in a Phase 1/2 Trial to Support Benefit-Risk Assessment in Non-Small Cell Lung Cancer.

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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 1/2 study (NCT01970865), potential exposure-response (E-R) relationships between lorlatinib and selected safety and efficacy endpoints were evaluated in patients with NSCLC. E-R relationships were assessed for safety endpoints with incidence >10% in all treated patients (n=328). In total, four safety endpoints 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 endpoint. 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.

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Authors: Joseph Chen, Ana Ruiz-Garcia, Leonard P James, Gerson Peltz, Holger Thurm, Jill Clancy, Jennifer Hibma