Solomon BJ, et al. - Researchers investigated the overall and intracranial antitumor activity of lorlatinib (a potent, brain-penetrant, third-generation inhibitor of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations) in patients with ALK-positive, advanced non-small-cell lung cancer. Findings revealed substantial overall and intracranial activity of lorlatinib, consistent with its broad ALK mutational coverage and CNS penetration, 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. Therefore, first-line or subsequent therapy with lorlatinib could be effective in patients with ALK-positive non-small-cell lung cancer.

Methods

• The subjects that were considered eligible for inclusion in this phase 2 study were 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.
• Based on ALK and ROS1 status and previous therapy, enrollment of patients into six different expansion cohorts (EXP1–6) was done.
• Lorlatinib 100 mg was administered orally to patients once daily continuously in 21-day cycles.
• In pooled subgroups of ALK-positive patients, independent central review assessing overall and intracranial tumor response was the primary endpoint.
• Independent central review assessed the safety analysis set (ie, all patients who received at least one dose of lorlatinib) on the basis of which analyses of activity and safety were performed.
• Intracranial activity analyses were performed including patients with measurable CNS metastases at baseline by independent central review.
• In this ongoing study, lorlatinib activity data and safety data were presented for the ALK-positive patients (EXP1–5 only) and for all treated patients (EXP1–6), respectively.

Results

• A total of 276 patients were enrolled between September 15, 2015, and October 3, 2016.
• Of those, 30 were ALK positive and treatment naive (EXP1); 59 were ALK positive and received previous crizotinib without (n=27; EXP2) or with (n=32; EXP3A) previous chemotherapy; 28 were ALK positive and received one previous non-crizotinib ALK tyrosine kinase inhibitor, with or without chemotherapy (EXP3B); 112 were ALK positive with two (n=66; EXP4) or three (n=46; EXP5) previous ALK tyrosine kinase inhibitors with or without chemotherapy; and 47 were ROS1positive with any previous treatment (EXP6).
• Before the receipt of lorlatinib, death of one patient in EXP4 was reported, who was excluded from the safety analysis set.
• Twenty-seven (90.0%; 95% CI 73.5–97.9) of 30 treatment-naive patients (EXP1) achieved an objective response.
• Per independent central review, measurable baseline CNS lesions were seen in three patients in EXP1, and two patients achieved objective intracranial responses (66.7%; 95% CI 9.4–99.2).
• In ALK-positive patients with at least one previous ALK tyrosine kinase inhibitor (EXP2–5), achievement of objective responses was documented in 93 (47.0%; 39.9–54.2) of 198 patients and objective intracranial response were achieved in those with measurable baseline CNS lesions in 51 (63.0%; 51.5–73.4) of 81 patients.
• In 41 of 59 patients who had only received previous crizotinib (EXP2–3A), 9 (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), achievement of objective response was reported.
• According to findings, 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, objective intracranial response was achieved.
• Hypercholesterolaemia (224 [81%] of 275 patients overall and 43 [16%] grade 3–4) and hypertriglyceridaemia (166 [60%] overall and 43 [16%] grade 3–4) were identified as most common treatment-related adverse events across all patients.
• The occurrence of serious treatment-related adverse events was reported in 19 (7%) of 275 patients and treatment-related adverse events led permanent treatment discontinuation in seven patients (3%).
• Findings revealed no treatment-related deaths.