Lorlatinib is a potent, brain-penetrant, 3rd-generation anaplastic lymphoma kinase (ALK)/ROS proto-oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) active against most known resistance mutations. This is an ongoing phase 1/2, multinational study (NCT01970865) investigating the efficacy, safety, and pharmacokinetics of lorlatinib in ALK-rearranged/ROS1-rearranged advanced non-small cell lung cancer (NSCLC) with or without intracranial (IC) metastases. Because patterns of ALK TKI use in Japan differ from other regions, we present a subgroup analysis among Japanese patients. Patients were enrolled into 6 expansion (EXP) cohorts based on ALK/ROS1 mutation status and treatment history. Primary endpoint was objective response rate (ORR) and IC-ORR by independent central review. Secondary endpoints included pharmacokinetic evaluations. At data cutoff, 39 ALK-rearranged /ROS1-rearranged Japanese patients were enrolled across the 6 expansion cohorts; all received lorlatinib 100 mg once daily. Thirty-one ALK-rearranged patients previously treated with ≥1 ALK TKI (EXP2 through EXP5) were evaluable for ORR and 15 were evaluable for IC-ORR. ORR and IC-ORR for Japanese in EXP2-5 were 54.8% (95% Confidence Interval [CI]: 36.0-72.7) and 46.7% (95% CI: 21.3-73.4), respectively. Among patients who had received prior alectinib only (EXP3B), ORR was 42.9%; 95% CI: 9.9-81.6). The most common treatment-related AEs (TRAE) was hypercholesterolemia (79.5%). Hyper-triglyceridemia was the most common Grade 3/4 TRAE (25.6%). Single- and multiple-dose pharmacokinetic profiles among Japanese patients were similar to those in non-Japanese patients. Lorlatinib showed clinically meaningful responses and IC-responses among ALK-rearranged Japanese patients with NSCLC who received ≥1 prior ALK TKI, including meaningful responses among those receiving prior alectinib only. Lorlatinib was generally well tolerated.
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