#VisualAbstract: Effectiveness of lorlatinib in advanced anaplastic lymphoma kinase-positive lung cancer

1. In this randomized, double-blind, phase three trial, progression-free survival was higher in patients treated with lorlatinib compared with crizotinib.

2. Lorlatinib treated patients had improved overall cancer response including greater intracranial response.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Anaplastic lymphoma kinase (ALK) chromosome rearrangement is a target for anti-cancer treatment in advanced non-small cell lung cancer (NSCLC). Crizotinib was one of the first agents targeting ALK-positive tumors. Lorlatinib is a 3^rd generation ALK targeting agent with previous data suggesting improved blood-brain barrier penetration and improved durability against drug-resistant mechanisms. This was a randomized, double-blind, placebo-controlled trial of untreated advanced ALK-positive NSCLC patients comparing lorlatinib vs. crizotinib and this article detailed the results of the interim analysis. Progression-free survival (PFS) and the objective response rate (ORR) favored the lorlatinib group compared to crizotinib. Of those with CNS metastases, lorlatinib induced a higher intracranial response and the time to CNS progression was longer. Hypercholesteremia, hypertriglyceridemia, hypertension, and weight gain were noted to be higher in the lorlatinib group while diarrhea, nausea, and vomiting were higher in the crizotinib group. There should be caution for the interpretation of this paper as overall survival data had not matured enough to detect a difference. As well, 2^nd generation ALK inhibitors have been demonstrated to be superior to crizotinib which makes it unclear what is the more optimal 1^st line therapy. Overall, this interim analysis of a phase 3 trial comparing lorlatinib and crizotinib showed promising results, specifically the improvement in CNS metastases; however, more data will be needed to determine which is more appropriate therapy to replace crizotinib as 1^st line therapy for untreated ALK-positive NSCLC.

Click here to read the study in the NEJM

Relevant Reading: ALK Resistance Mutations and Efficacy of Lorlatinib in Advanced Anaplastic Lymphoma Kinase-Positive Non–Small-Cell Lung Cancer

In-Depth [randomized controlled trial]: This was a phase three, double-blind, placebo-controlled, randomized trial of 296 persons with untreated advanced ALK-positive NSCLC. The primary endpoint for this interim analysis was PFS and analyzed in the intention-to-treat population. PFS was longer in the lorlatinib group compared with crizotinib (hazard ratio (HR) 0.21; 95% confidence interval (CI), 0.14 to 0.31). At the 12-month mark, 78% were alive in the lorlatinib group and 39% in the crizotinib group. ORR was 76% in lorlatinib treated patients compared to 27% in crizotinib treated patients. Among those with brain metastases at baseline, an intracranial response was found in 66% (95% CI, 49 to 80%) of the lorlatinib group compared to 20% (95% CI, 9 to 36%) in the crizotinib group. Patients without CNS progression at the time of analysis were 96% (95% CI, 91 to 98%) in the lorlatinib group and 60% (95% CI, 49 to 69%) in the crizotinib group (HR, 0.07; 95% CI, 0.03 to 0.17). The most common grade 3-4 adverse events in the lorlatinib group were hypertriglyceridemia (20%), weight gain (17%) and hypercholesteremia (16%) and hypertension (10%). Adverse events leading to treatment discontinuation occurred in 7% of the lorlatinib group and 9% for the crizotinib group.

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