The priority review follows a breakthrough therapy designation awarded in April 2017. The FDA will make its final decision by August 2018.
In support of the 3 applications, Pfizer submitted data from the phase II part of a phase I/II trial in which the overall response rate (ORR) was 69% (41/59; 95% CI, 56-81) in ALK-positive patients previously treated with crizotinib (Xalkori) with or without chemotherapy, and the Intracranial ORR (IC-ORR) was 68% (25/37; 95% CI, 50-82).
ALK-positive patients previously treated with a non-crizotinib ALK inhibitor with or without chemotherapy had an ORR of 33% (9/27; 95% CI, 16-54) and the IC-ORR was 42% (5/12; 95% CI, 15-72). In ALK-positive patients previously treated with 2 or 3 ALK inhibitors with or without chemotherapy, ORR was 39% (43/111; 95% CI, 30-49) and IC-ORR was 48% (40/83; 95% CI, 37-59).
“Treatment resistance resulting in disease progression is a major challenge faced by patients with ALK-positive metastatic NSCLC. Lorlatinib was developed by Pfizer scientists with the specific goal of overcoming resistance to first- and second-generation ALK-targeted therapies,” Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development, said in a statement. “The encouraging results observed in a variety of patients previously treated with ALK inhibitors provides the basis for these applications.”
In the phase II study, 275 patients with or without asymptomatic, untreated or treated brain metastases were enrolled in 6 cohorts based on biomarker status, ALK-positivity, ROS1-positivity, and prior therapy.
Beyond the efficacy in pretreated patients, the results also showed that lorlatinib induced an ORR of 90% (27/30; 95% CI, 74-98) in treatment-naïve patients with ALK-positive NSCLC. The IC-ORR was 75% (6/8; 95% CI, 35-97) in this patient population.
Lorlatinib was generally tolerable. Most adverse events (AEs) were mild to moderate and managed with dose reductions, dose delays, or standard medical therapy. There were no treatment-related deaths and 3% of patients discontinued treatment due to drug-related AEs.
Hypercholesterolemia (81%) was the most common AE, followed by hypertriglyceridemia (60%), edema (43%), peripheral neuropathy (30%), weight increase (18%), cognitive effects (18%), mood effects (15%), fatigue (13%), diarrhea (11%), arthralgia (10%), and increased AST (10%).
Investigation into lorlatinib in NSCLC is continuing in the phase III CROWN trial. The open-label, randomized study is comparing lorlatinib to crizotinib in the first-line setting for patients with metastatic ALK-positive NSCLC. The targeted enrollment for the trial is 280 patients, and the study is being conducted at 221 locations.
No prior systemic treatment for NSCLC is allowed. Patients must have an ECOG performance status of 0, 1, or 2. Patients cannot enroll if they have had radiation therapy—including stereotactic or partial brain irradiation—within 2 weeks of randomization, or whole brain irradiation within 4 weeks of randomization. The primary outcome measure is progression-free survival. Secondary endpoints include overall survival, ORR, IC-ORR, time to tumor response, and safety.