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Release date: 2026-01-23 13:09:56 Recommended: 13
Pfizer recently announced that the U.S. Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) for its 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 sNDA was approved under the FDA’s Real-Time Oncology Review (RTOR) pilot program, and this approval also converts the therapy’s 2018 accelerated approval to full approval.
As a third-generation ALK inhibitor, Lorbrena is 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 approval for expanded indication 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 compared with Xalkori, Lorbrena treatment significantly reduced the risk of disease progression or death by 72% (HR=0.28, p<0.001). It also achieved substantial improvements in 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 intracranial duration of response (IC-DOR) ≥12 months (79% vs 0%).
Biomarker-driven therapies have improved outcomes for patients with ALK-positive NSCLC, but there remains an unmet need for innovative treatments 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 international medical journal.
Lorbrena initially received accelerated approval for the aforementioned indication from the FDA based on tumor response rate and duration of response. The CROWN study, as a confirmatory Phase 3 trial, was designed to convert this accelerated approval to full approval. Leveraging the positive results from 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-naive adult patients with ALK-positive metastatic NSCLC.
The CROWN study is a global, randomized, open-label, parallel, two-arm Phase 3 trial that enrolled a total of 296 treatment-naive patients with advanced ALK-positive NSCLC. In the study, 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), objective response rate (ORR), intracranial ORR, and safety.
Results showed that at the prespecified interim analysis, the study met its primary endpoint: Lorbrena treatment yielded statistically and clinically significant improvements in PFS compared with Xalkori (crizotinib) (HR=0.28; 95% 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 interim analysis. In terms of ORR, the Lorbrena group achieved 76% (95% CI: 68–83) versus 58% (95% CI: 49–66) in the Xalkori group. Furthermore, Lorbrena exhibited enhanced intracranial activity compared with Xalkori: at 12 months, 96% of patients in the Lorbrena group (95% CI: 91–98) were free from central nervous system (CNS) progression, compared with 60% in the Xalkori group (95% CI: 0.49–0.69). Among patients with brain metastases (n=30), the intracranial ORR was 82% in the Lorbrena group (95% CI: 0.57–0.96; n=14) versus 23% in the Xalkori group (95% CI: 0.05–0.54; n=3), with intracranial complete response rates (CRR) of 71% and 8%, respectively.
In this study, adverse events (AEs) occurring in more than 20% of patients in the Lorbrena group 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 group and 56% in the Xalkori group. The most common Grade 3 or 4 AEs in the Lorbrena group were hypertriglyceridemia (20%), weight gain (17%), hypercholesterolemia (16%), and hypertension (10%). Adverse events leading to permanent discontinuation occurred in 7% of patients in the Lorbrena group and 9% in the Xalkori group.
