BACKGROUND: Lorlatinib is a potent, brain-penetrant, third-generation inhibitor 
of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a 
phase 1 study, activity was seen in patients with ALK-positive non-small-cell 
lung cancer, most of whom had CNS metastases and progression after ALK-directed 
therapy. We aimed to analyse the overall and intracranial antitumour activity of 
lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer.
METHODS: In this phase 2 study, patients with histologically or cytologically 
ALK-positive or ROS1-positive, advanced, non-small-cell lung cancer, with or 
without CNS metastases, with an Eastern Cooperative Oncology Group performance 
status of 0, 1, or 2, and adequate end-organ function were eligible. Patients 
were enrolled into six different expansion cohorts (EXP1-6) on the basis of ALK 
and ROS1 status and previous therapy, and were given lorlatinib 100 mg orally 
once daily continuously in 21-day cycles. The primary endpoint was overall and 
intracranial tumour response by independent central review, assessed in pooled 
subgroups of ALK-positive patients. Analyses of activity and safety were based 
on the safety analysis set (ie, all patients who received at least one dose of 
lorlatinib) as assessed by independent central review. Patients with measurable 
CNS metastases at baseline by independent central review were included in the 
intracranial activity analyses. In this report, we present lorlatinib activity 
data for the ALK-positive patients (EXP1-5 only), and safety data for all 
treated patients (EXP1-6). This study is ongoing and is registered with 
ClinicalTrials.gov, number NCT01970865.
FINDINGS: Between Sept 15, 2015, and Oct 3, 2016, 276 patients were enrolled: 30 
who were ALK positive and treatment naive (EXP1); 59 who were ALK positive and 
received previous crizotinib without (n=27; EXP2) or with (n=32; EXP3A) previous 
chemotherapy; 28 who were ALK positive and received one previous non-crizotinib 
ALK tyrosine kinase inhibitor, with or without chemotherapy (EXP3B); 112 who 
were ALK positive with two (n=66; EXP4) or three (n=46; EXP5) previous ALK 
tyrosine kinase inhibitors with or without chemotherapy; and 47 who were ROS1 
positive with any previous treatment (EXP6). One patient in EXP4 died before 
receiving lorlatinib and was excluded from the safety analysis set. In 
treatment-naive patients (EXP1), an objective response was achieved in 27 
(90·0%; 95% CI 73·5-97·9) of 30 patients. Three patients in EXP1 had measurable 
baseline CNS lesions per independent central review, and objective intracranial 
responses were observed in two (66·7%; 95% CI 9·4-99·2). In ALK-positive 
patients with at least one previous ALK tyrosine kinase inhibitor (EXP2-5), 
objective responses were achieved in 93 (47·0%; 39·9-54·2) of 198 patients and 
objective intracranial response in those with measurable baseline CNS lesions in 
51 (63·0%; 51·5-73·4) of 81 patients. Objective response was achieved in 41 
(69·5%; 95% CI 56·1-80·8) of 59 patients who had only received previous 
crizotinib (EXP2-3A), nine (32·1%; 15·9-52·4) of 28 patients with one previous 
non-crizotinib ALK tyrosine kinase inhibitor (EXP3B), and 43 (38·7%; 29·6-48·5) 
of 111 patients with two or more previous ALK tyrosine kinase inhibitors 
(EXP4-5). Objective intracranial response was achieved in 20 (87·0%; 95% CI 
66·4-97·2) of 23 patients with measurable baseline CNS lesions in EXP2-3A, five 
(55·6%; 21·2-86·3) of nine patients in EXP3B, and 26 (53·1%; 38·3-67·5) of 49 
patients in EXP4-5. The most common treatment-related adverse events across all 
patients were hypercholesterolaemia (224 [81%] of 275 patients overall and 43 
[16%] grade 3-4) and hypertriglyceridaemia (166 [60%] overall and 43 [16%] grade 
3-4). Serious treatment-related adverse events occurred in 19 (7%) of 275 
patients and seven patients (3%) permanently discontinued treatment because of 
treatment-related adverse events. No treatment-related deaths were reported.
INTERPRETATION: Consistent with its broad ALK mutational coverage and CNS 
penetration, lorlatinib showed substantial overall and intracranial activity 
both in treatment-naive patients with ALK-positive non-small-cell lung cancer, 
and in those who had progressed on crizotinib, second-generation ALK tyrosine 
kinase inhibitors, or after up to three previous ALK tyrosine kinase inhibitors. 
Thus, lorlatinib could represent an effective treatment option for patients with 
ALK-positive non-small-cell lung cancer in first-line or subsequent therapy.
FUNDING: Pfizer.