Your Health, We Care
Release date: 2026-01-23 15:07:59 Recommended: 14
On March 3, 2021, Pfizer announced that the U.S. Food and Drug Administration (FDA) had approved the supplemental New Drug Application (sNDA) for Lorbrena (lorlatinib), expanding its indications to include the first-line treatment of patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC).
Lorbrena had previously received accelerated approval in the United States in 2018 for the treatment of patients with ALK-positive metastatic NSCLC whose disease had progressed following treatment with certain ALK inhibitors. This sNDA was reviewed under the FDA’s Real-Time Oncology Review (RTOR) pilot program. The approval for the first-line indication also converted the 2018 accelerated approval to full approval.
The expanded indication for Lorbrena is based on results from the pivotal Phase 3 CROWN trial. As assessed by Blinded Independent Central Review (BICR), treatment with Lorbrena reduced the risk of disease progression or death by 72% compared with crizotinib in treatment-naive patients (hazard ratio [HR] = 0.28; 95% confidence interval [CI]: 0.19–0.41; p < 0.0001). The trial evaluated central nervous system (CNS) involvement in all patients. Based on baseline brain imaging, measurable brain metastases were present in 17 patients in the Lorbrena arm and 13 patients in the crizotinib arm.
Exploratory analyses showed that in these patients with measurable brain metastases, the intracranial objective response rate (IC-ORR) as assessed by BICR was 82% in the Lorbrena arm (95% CI: 57–96) versus 23% in the crizotinib arm (95% CI: 5–54). The intracranial duration of response (IC-DOR) was 12 months or longer in 79% of patients (n=11) in the Lorbrena arm, compared with 0% in the crizotinib arm. Detailed results from the CROWN study were published in The New England Journal of Medicine in November 2020.
In patients, the most common adverse reactions (≥20%) were edema (56%), weight gain (38%), peripheral neuropathy (35%), cognitive effects (21%), diarrhea (21%), dyspnea (20%), and hypertriglyceridemia (22%). The incidence of serious adverse reactions was 34%, with the most frequent being pneumonia (4.7%), dyspnea (2.7%), respiratory failure (2.7%), cognitive effects (2.0%), and pyrexia (2.0%). Fatal adverse reactions occurred in 3.4% of patients, including pneumonia (0.7%), respiratory failure (0.7%), acute heart failure (0.7%), pulmonary embolism (0.7%), and sudden death (0.7%). Permanent discontinuation of Lorbrena due to adverse reactions occurred in 6.7% of patients. Adverse reactions leading to dose interruption and dose reduction were reported in 49% and 21% of patients treated with Lorbrena, respectively.
Lorbrena is a third-generation ALK tyrosine kinase inhibitor (TKI) specifically designed to inhibit the most common tumor mutations that confer resistance to current therapies, and to address brain metastases—a common site of disease progression in ALK-positive NSCLC. Lorbrena has demonstrated high activity in preclinical lung cancer models harboring ALK chromosomal rearrangements.
Lung cancer is the leading cause of cancer-related deaths worldwide. NSCLC accounts for approximately 80–85% of all lung cancer cases, and ALK-positive tumors occur in roughly 3–5% of NSCLC cases. An estimated 228,820 new cases of lung cancer were diagnosed in the United States in 2020. Up to 40% of patients with ALK-positive metastatic NSCLC present with brain metastases at initial diagnosis. Although many patients with ALK-positive metastatic NSCLC respond to initial TKI therapy, their tumors typically progress over time. Furthermore, treatment options are very limited for patients whose disease progresses following treatment with second-generation ALK TKIs.
