Background: Despite advancement of 2^nd generation (gen) ALK tyrosine kinase inhibitors (TKIs), ALK⁺ NSCLC pts continue to develop resistance and CNS metastases (mets) become more difficult to manage. Lorlatinib, a potent brain-penetrant 3^rd gen ALK/ROS1 TKI, has shown robust clinical activity in ALK⁺ or ROS1⁺ NSCLC pts, most of whom had CNS mets and failed ≥1 ALK TKI. Methods: This ongoing ph 2 study (NCT01970865) enrolled 275 pts with ALK⁺ or ROS1⁺ advanced NSCLC ± CNS mets in cohorts (ALK: EXP 1–5; ROS1: EXP 6) based on prior treatment; starting dose was lorlatinib 100 mg QD. Antitumor activity (by independent central review per RECIST 1.1), safety and biomarkers were evaluated. Results: In 198 ALK⁺ pts assessed for antitumor activity (ITT population) in pooled subgroups (EXP 2–3A [only prior crizotinib ± chemotherapy (CT)], EXP 3B [only 1 prior 2^nd gen ALK TKI ± CT], and EXP 4–5 [2 or 3 prior ALK TKIs ± CT]), lorlatinib led to rapid (median time to response 1.4 mo) deep and durable systemic and intracranial (IC) responses (Table). Of a total 139 pts in EXP 3B + EXP 4–5, 62, 47 and 8 received alectinib, ceritinib and brigatinib, respectively, as last ALK TKI prior to lorlatinib. Additional efficacy, including PFS, in all cohorts will be presented. The most common treatment-related AEs (TRAEs) and grade 3/4 TRAEs across all cohorts (N = 275) were hypercholesterolemia (84%/16%) and hypertriglyceridemia (66%/16%); 32% and 24% of pts had TRAEs that led to dose delays and reductions, respectively. No treatment-related deaths occurred; TRAEs led to permanent discontinuation in 8 pts. Antitumor activity was seen across a range of ALK resistance mutations, eg G1202R and G1202del. Clinical trial information: NCT01970865Conclusions: Lorlatinib showed clinically meaningful benefit in ALK⁺ NSCLC pts with ≥1 prior ALK TKI and was generally tolerable with AEs managed by dose modification or supportive therapy.

^a≥1 measurable brain lesion at baseline

DOR, duration of response; NR, not reached