FDA Grants Full, Expanded Approval to Lorlatinib in ALK-Positive NSCLC

The FDA has granted full approval to lorlatinib, expanding its indication to include frontline treatment for patients with anaplastic lymphoma kinase (ALK)-positive metastatic NSCLC.

The FDA has granted full approval to lorlatinib (sold as Lorbrena by Pfizer, Inc.), expanding its indication to include frontline treatment for patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as determined by an FDA-approved assay.1 The Ventana ALK (D5F3) CDx Assay (Ventana Medical Systems, Inc.) was also approved as a companion diagnostic.

The full approval of lorlatinib follows its accelerated approval for the second- or third-line treatment of ALK-positive metastatic NSCLC in November 2018.

The approval was based on data from the phase 3, multicenter, open-label, active-controlled CROWN study (NCT03052608), which assessed lorlatinib monotherapy versus crizotinib in 296 patients with metastatic NSCLC whose tumors were ALK-positive.2 Patients who had not received prior systemic therapy for metastatic disease and whose tumors tested positive with the Ventana ALK (D5F3) CDx Assay were recruited for the study.

Participants were randomized 1:1 to receive either 100 mg of oral lorlatinib once per day or 250 mg of crizotinib orally twice per day. Those on the lorlatinib regimen showed improved progression-free survival (PFS) by 72% compared with the crizotinib cohort, with a hazard ratio of 0.28 (95% CI: 0.19, 0.41; P < 0.0001) as assessed by a blinded independent central review.

Overall survival data were not yet mature at the PFS analysis, and median PFS was not estimable in the lorlatinib arm. In patients given crizotinib, median PFS was 9.3 months (95% CI: 7.6, 11.1). Researchers also assessed central nervous system (CNS) involvement in the overall study population, conducting baseline brain imaging to detect measurable CNS lesions. The lorlatinib arm had 17 patients with CNS lesions, and the crizotinib arm had 13. The intracranial overall response rate (ORR) was 82% in the lorlatinib group and 23% in the crizotinib group, with intracranial responses lasting at least 12 months in 79% of the lorlatinib cohort and 0% of the crizotinib cohort.

Grade 3 or 4 adverse reactions that occurred in at least 20% of patients given lorlatinib were edema, peripheral neuropathy, weight gain, cognitive effects, fatigue, dyspnea, arthralgia, diarrhea, mood effects, hypercholesterolemia, hypertriglyceridemia, and cough.

The FDA review was conducted under the FDA Oncology Center of Excellence’s Project Orbis initiative, which allows for the submission and review of oncology drugs concurrently among international partners. The application was approved 8 weeks ahead of the FDA’s goal date.

“The CROWN data have shown Lorbrena can significantly improve outcomes in the first-line treatment of ALK-positive non-small cell lung cancer, including those that present with brain metastases,” Benjamin Solomon, MD, Department of Medical Oncology, Peter MacCallum Cancer Centre, said in a press release.3 “This approval is meaningful for my patients because we now have a highly effective treatment option that can delay the progression of a typically aggressive disease.”


1. FDA approves lorlatinib for metastatic ALK-positive NSCLC. News release. FDA; March 3, 2021. Accessed March 4, 2021. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-lorlatinib-metastatic-alk-positive-nsclc

2. Shaw AT, Bauer TM, Marinis F, et al. First-Line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med. 2020;383(9):2018-2029. doi:10.1056/NEJMoa2027187

3. US FDA expands approval of Pfizer's Lorbrena as first-line treatment for ALK-positive metastatic lung cancer. News release. March 3, 2021. Accessed March 5, 2021. https://investors.pfizer.com/investor-news/press-release-details/2021/U.S.-FDA-Expands-Approval-of-Pfizers-LORBRENA-as-First-Line-Treatment-for-ALK-Positive-Metastatic-Lung-Cancer/default.aspx