On March 3, 2021, the U.S. Food and Drug Administration (FDA) granted regular approval to lorlatinib (Lorbrena®) for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive, as detected by an FDA-approved test. FDA also approved the Ventana ALK (D5F3) CDx Assay as a companion diagnostic for lorlatinib.
Lorlatinib received accelerated approval in November 2018 as a second- or third-line treatment for ALK-positive metastatic NSCLC. The current approval is based on data from a randomized, multicenter, open-label, active-controlled trial (Study B7461006; NCT03052608) of 296 patients with ALK-positive metastatic NSCLC who had not received prior systemic therapy for metastatic disease. Patients were required to have ALK-positive tumors detected by the Ventana ALK (D5F3) CDx assay and were randomized 1:1 to receive lorlatinib 100 mg orally once daily (n = 149) or crizotinib 250 mg orally twice daily (n = 147).
The trial demonstrated an improvement in progression-free survival (PFS) as assessed by blinded independent central review (BICR) (hazard ratio = 0.28; 95% CI = 0.19, 0.41; p < 0.0001). Median PFS was not estimable in the lorlatinib arm and was 9.3 months (95% CI = 7.6, 11.1) in the crizotinib arm. Overall survival data were immature at the PFS analysis.
Central nervous system (CNS) involvement was assessed in all patients. Among the 17 patients in the lorlatinib arm and 13 patients in the crizotinib arm with measurable CNS lesions based on baseline brain imaging, intracranial overall response rate, as assessed by BICR, was 82% (95% CI = 57, 96) and 23% (95% CI = 5, 54), respectively. The duration of intracranial response was greater than or equal to 12 months in 79% and 0% of patients in the lorlatinib and crizotinib arms, respectively.
The most common adverse reactions (≥ 20%), including grade 3–4 laboratory abnormalities, were edema, peripheral neuropathy, weight gain, cognitive effects, fatigue, dyspnea, arthralgia, diarrhea, mood effects, hypercholesterolemia, hypertriglyceridemia, and cough.
The recommended lorlatinib dose is 100 mg orally once daily.
The review was conducted under Project Orbis, an initiative of FDA’s Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For the review, FDA collaborated with the Australian Therapeutic Goods Administration, Brazilian Health Regulatory Agency, Health Canada, and United Kingdom’s Medicines and Healthcare products Regulatory Agency. The application reviews are ongoing at the other agencies.
The review used the Real Time Oncology Review, which streamlined data submission prior to the filing of the entire clinical application, and Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment. FDA approved the application eight weeks ahead of its goal date.
FDA granted the application priority review and orphan drug designations. A description of FDA expedited programs is in the Guidance for Industry—Expedited Programs for Serious Conditions—Drugs and Biologics.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.