Lorlatinib in ALK- or ROS1-rearranged non-small cell lung cancer: an international, multicenter, open-label phase 1 trial

BACKGROUND: Most patients with ALK- or ROS1-rearranged non-small cell lung cancer (NSCLC) are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops, commonly within the central nervous system (CNS). This study aimed to determine the safety, efficacy, and pharmacokinetic properties of lorlatinib, a novel, highly potent, selective, and brain-penetrant ALK/ROS1 TKI with preclinical activity against most known resistance mutations, in patients with advanced ALK- or ROS1-positive NSCLC. METHODS: In this ongoing, multicenter phase 1 study, eligible patients had advanced ALK- or ROS1-positive NSCLC. Lorlatinib was orally administered at doses ranging from 10–200 mg once daily or 35–100 mg twice daily. For some patients, tumor biopsy was performed before lorlatinib treatment to identify ALK resistance mutations. Safety was evaluated in patients who received ≥1 treatment; efficacy was evaluated in the intention-to-treat population (patients who received ≥1 dose of study treatment and were positive for either ALK or ROS1 rearrangement). The primary endpoint was dose-limiting toxicities (DLTs) during cycle 1; secondary endpoints included safety, pharmacokinetics, and overall response rate (ORR). This study is registered with ClinicalTrials.gov, NCT01970865. FINDINGS: Fifty-four patients were treated, including 41 with ALK-positive and 12 with ROS1-positive NSCLC. Twenty-eight patients had received ≥2 TKIs, and 39 patients had CNS metastases. The most common treatment-related adverse events among the 54 patients were hypercholesterolemia (39 [72%] of 54 patients), hypertriglyceridemia (21 [39%] of 54 patients), peripheral neuropathy (21 [39%] of 54 patients), and peripheral edema (21 [39%] of 54 patients). One DLT occurred at 200 mg (failure to deliver at least 16 of 21 prescribed total daily doses in cycle 1 because of toxicities attributable to study drug, in this case grade 2 neurocognitive adverse events comprising slowed speech and mentation and word-finding difficulty). No maximum tolerated dose was identified. The recommended phase 2 dose was selected to be 100 mg daily. Among ALK-positive patients, the ORR was 19 (46%) of 41 patients (95% CI, 31–63%); among those who had received ≥2 TKIs, the ORR was 11 (42%) of 26 patients (95% CI, 23–63%). Among ROS1-positive patients, including seven crizotinib-pretreated patients, ORR was 6 (50%) of 12 patients (95% CI, 21–79%). Responses were observed in the CNS and in patients with tumors harboring resistance mutations such as ALK G1202R. INTERPRETATION: In this phase 1, dose-escalation study, lorlatinib demonstrated both systemic and intracranial activity in patients with advanced ALK- or ROS1-positive NSCLC, most of whom had CNS metastases and had failed ≥2 TKIs. Therefore, lorlatinib may represent an effective therapeutic strategy for patients who have become resistant to currently available TKIs, including second-generation ALK TKIs in ALK-positive NSCLC. FUNDING: Pfizer