Your Health, We Care
Release date: 2026-01-23 15:13:35 Recommended: 11
Pfizer recently announced that the U.S. Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) for the targeted anticancer therapy Lorbrena (lorlatinib), expanding its indication to include the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). The approval was granted under the FDA’s Real-Time Oncology Review (RTOR) pilot program, and it also converts the accelerated approval granted in 2018 to a full approval.
Lorbrena is a third-generation ALK inhibitor specifically developed to inhibit the most common tumor mutations that drive resistance to current therapies, and to address brain metastases—the most frequent site of disease progression in ALK-positive NSCLC. Up to 40% of patients with ALK-positive lung cancer present with brain metastases at initial diagnosis.
The expanded indication approval is based on data from the pivotal Phase 3 CROWN study, a head-to-head trial evaluating the efficacy and safety of two ALK-targeted anticancer agents, Lorbrena and Xalkori (crizotinib), as first-line treatments for advanced ALK-positive NSCLC. Data demonstrated that treatment with Lorbrena significantly reduced the risk of disease progression or death by 72% compared with Xalkori (hazard ratio [HR] = 0.28; p < 0.001). Additionally, Lorbrena achieved substantially higher intracranial response rates (objective response rate [ORR]: 82% vs. 23%; complete response rate [CR]: 71% vs. 8%) and a notably higher proportion of patients with an intracranial duration of response (IC-DOR) of ≥12 months (79% vs. 0%).
Biomarker-driven therapies have improved outcomes for patients with ALK-positive NSCLC, yet innovative treatments are still needed to delay disease progression. Findings from the CROWN study indicate that Lorbrena has the potential to become a practice-changing first-line treatment option for ALK-positive NSCLC. Relevant data have been published in the New England Journal of Medicine (NEJM), a top-tier international medical journal.
Lorbrena initially received accelerated FDA approval for the aforementioned indication based on tumor response rate and duration of response. The CROWN study, a confirmatory Phase 3 trial, was designed to convert this accelerated approval to full approval. Based on the positive results of the CROWN study, these data were reviewed under the FDA’s RTOR pilot program and will be shared with other regulatory authorities to support full approval and the application for Lorbrena’s first-line indication in the treatment of treatment-naïve adult patients with ALK-positive metastatic NSCLC.
CROWN is a global, randomized, open-label, parallel, two-arm, Phase 3 trial that enrolled a total of 296 treatment-naïve patients with advanced ALK-positive NSCLC. Patients were randomized 1:1 to receive either Lorbrena monotherapy (n=149) or Xalkori monotherapy (n=147). The primary endpoint was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Secondary endpoints included investigator-assessed PFS, overall survival (OS), ORR, intracranial ORR, and safety.
Results showed that at the prespecified interim analysis, the study met its primary endpoint: Lorbrena treatment yielded a statistically and clinically significant improvement in PFS compared with Xalkori, as evaluated by BICR (HR = 0.28; 95% confidence interval [CI]: 0.19–0.41; p < 0.001), representing a 72% reduction in the risk of disease progression or death.
Regarding secondary endpoints, OS data were immature at the time of the interim analysis. In terms of ORR, the Lorbrena arm achieved 76% (95% CI: 68–83) versus 58% (95% CI: 49–66) in the Xalkori arm. Furthermore, Lorbrena exhibited enhanced intracranial activity: at 12 months, 96% (95% CI: 91–98) of patients in the Lorbrena arm were free of central nervous system (CNS) progression, compared with 60% (95% CI: 49–69) in the Xalkori arm. Among patients with brain metastases (n=30), the intracranial ORR was 82% (95% CI: 57–96; n=14) in the Lorbrena arm versus 23% (95% CI: 5–54; n=3) in the Xalkori arm, with intracranial complete response rates (CRR) of 71% and 8%, respectively.
In this study, adverse events (AEs) occurring in ≥20% of patients in the Lorbrena arm included hypercholesterolemia (70%), hypertriglyceridemia (64%), edema (55%), weight gain (38%), peripheral neuropathy (34%), cognitive effects (21%), and diarrhea (21%). Grade 3 or 4 AEs were reported in 72% of patients in the Lorbrena arm and 56% in the Xalkori arm. The most common Grade 3 or 4 AEs in the Lorbrena arm were hypertriglyceridemia (20%), weight gain (17%), hypercholesterolemia (16%), and hypertension (10%). Permanent treatment discontinuation due to AEs occurred in 7% of patients in the Lorbrena arm and 9% in the Xalkori arm.
