Shaw AT, et al. - Researchers performed this phase 1, dose-escalation study to assess the safety, efficacy, and pharmacokinetic properties of lorlatinib, in patients with advanced anaplastic lymphoma kinase (ALK)-positive or ROS proto-oncogene 1 (ROS1)-positive non-small-cell lung cancer (NSCLC). Findings demonstrated that lorlatinib has both systemic and intracranial activity in these patients. Most of these patients had CNS metastases and had previously had two or more tyrosine kinase inhibitor (TKI) treatments fail. For patients with ALK-positive NSCLC who have become resistant to currently available TKIs, including second-generation ALK TKIs, findings thus suggested lorlatinib as an effective therapeutic strategy. It is being investigated in a phase 3 randomised controlled trial comparing lorlatinib to crizotinib.

Methods

• In this study, eligible patients had advanced ALK-positive or ROS1-positive NSCLC and were older than 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate end-organ function.
• At doses ranging from 10 mg to 200 mg once daily or 35 mg to 100 mg twice daily, patients received lorlatinib orally, with a minimum of three patients receiving each dose.
• Tumour biopsy was performed before lorlatinib treatment in some patients to identify ALK resistance mutations.
• In patients who received at least one dose of lorlatinib, researchers assessed safety; in the intention-to-treat population (patients who received at least one dose of study treatment and had either ALK or ROS1 rearrangement), they assessed efficacy.
• For this study, the primary endpoint was dose-limiting toxicities during cycle 1 according to investigator assessment; secondary endpoints included safety, pharmacokinetics, and overall response.

Results

• Fifty four patients received at least one dose of lorlatinib from Jan 22, 2014, to July 10, 2015.
• These included 41 (77%) with ALK-positive and 12 (23%) with ROS1-positive NSCLC; one patient had unconfirmed ALK and ROS1 status. 28 (52%) patients had received two or more TKIs, and 39 (72%) patients had CNS metastases.
• Among the 54 patients, the most common treatment-related adverse events were hypercholesterolaemia (39 [72%] of 54 patients), hypertriglyceridaemia (21 [39%] of 54 patients), peripheral neuropathy (21 [39%] of 54 patients), and peripheral oedema (21 [39%] of 54 patients).
• At 200 mg, researchers noticed one dose-limiting toxicity (the patient did not take at least 16 of 21 prescribed total daily doses in cycle 1 because of toxicities attributable to study drug, which were grade 2 neurocognitive adverse events comprising slowed speech and mentation and word-finding difficulty).
• They identified no maximum tolerated dose.
• They selected 100 mg once daily as the recommended phase 2 dose.
• The proportion of patients who achieved an objective response was 19 (46%) of 41 patients (95% CI 31–63) for ALK-positive patients; the proportion of patients with an objective response was 11 (42%) of 26 patients (23–63) for those who had received two or more TKIs.
• Including seven crizotinib-pretreated patients, an objective response was achieved by six (50%) of 12 patients (95% CI 21–79) in ROS1-positive patients .