Regulatory Decision Summary for Lorbrena

Currently in Canada there are a few agents available for first- or second-line treatment of patients with ALK-positive non-small cell lung cancer (NSCLC). However, therapy is not currently available for Canadian patients who have progressed on crizotinib and another tyrosine kinase inhibitors (TKIs), or following ceritinib or alectinib therapies.

The efficacy and safety of lorlatinib are based on the data of the pivotal, ongoing Phase 1/2 clinical trial B7461001 (study 1001) in patients with ALK-positive or c-ros oncogene 1 (ROS1)-positive metastatic NSCLC. The Phase 2 portion of the study investigated the efficacy of lorlatinib in pre-specified cohorts of patients (expansion EXP-1 through EXP-6) defined primarily by type and line of prior treatment. The dose of 100 mg QD of lorlatinib identified in the Phase 1 dose-finding part was used in the Phase 2 portion of the study to evaluate the primary endpoint of objective response rate (ORR), based on independent committee review (ICR) assessment.

Lorlatinib following crizotinib and at least one other TKI was deemed as the therapeutic setting most representative of the benefit demonstrated with lorlatinib. Thus the pre-specified pooled data of the cohort EXP2-5 (n = 197) was considered to be clinically compelling and appropriate to represent the patient population. The pooled data also supported the benefit of using lorlatinib as second line treatment for patients who progressed on alectinib or ceritinib. The recommended indication was supported by an ORR of 47.2% where 93 patients with a confirmed objective response by ICR resulted in median time to response (TTR) of 1.4 months (range: 1.1 to 11.0 months). The median duration of response (DOR) was not reached with a lower boundary of the 95% CI of 11.1 months.

In the study, the most common (≥ 20%) adverse reactions were edema, peripheral neuropathy, cognitive effects, fatigue, weight increased, arthralgia, mood effects and diarrhea. The most common (≥ 20%) laboratory abnormalities were hypercholesterolemia, hypertriglyceridemia, anemia, creatinine increased, hyperglycemia, hypoalbuminemia, AST elevations, lymphopenia, ALP elevations, ALT elevations, lipase increased, amylase increased, hypomagnesemia, platelet count decreased, hypophosphatemia, hyponatremia, hyperkalemia. Serious adverse reactions were reported in 6.1% of patients. The most frequent serious adverse reactions reported were mental status changes in 1.4% and cognitive effects in 1.0% of patients.

Overall, study 1001 presented promising evidence to support a favorable benefit-risk profile for lorlatinib as a treatment of adult patients with ALK-positive metastatic NSCLC who have progressed on crizotinib and at least one other ALK inhibitor, or patients who have progressed on ceritinib or alectinib.

The sponsor will provide the results of the following confirmatory trial: B7461006 (study 1006), an ongoing, Phase 3, randomized, open-label trial comparing the safety and efficacy of lorlatinib to crizotinib in the first-line treatment of subjects with advanced ALK-positive NSCLC. The trial should confirm that lorlatinib is an active ALK TKI providing clinical benefit as a first-line therapeutic option or at a later-line treatment option with activity against ALK TKI resistance mutations.