FDA Grants Frontline Lorlatinib Priority Review for ALK+ NSCLC

The FDA has accepted a supplemental New Drug Application for lorlatinib as a first-line treatment of patients with ALK-positive metastatic non–small cell lung cancer and has granted the sNDA a Priority Review.

The FDA has accepted a supplemental New Drug Application (sNDA) for lorlatinib as a first-line treatment of patients with ALK-positive metastatic non–small cell lung cancer (NSCLC) and has granted the sNDA a Priority Review.1

The sNDA will be reviewed under the FDA’s Real-Time Oncology Review pilot program as well as the Project Orbis program, and has been given a Prescription Drug User Fee Act (PDUFA) goal date of April 2021 for a decision on the application.

Data supporting the sNDA come from the pivotal phase 3 CROWN trial, which established a high response rate an progression-free survival (PFS) rate for patients treated with lorlatinib in the frontline compared with crizotinib (Xalkori), the first-generation ALK inhibitor.

“The decision by the FDA to evaluate our application for Lorbrena under its innovative review pathways, which aim to speed up availability of potentially life-changing medicines, underscores the significance of the CROWN data and potential impact of Lorbrena as an initial therapy for people with ALK-positive advanced non–small cell lung cancer,” said Chris Boshoff, MD, PhD, FRCP, FMedSci, chief development officer, Oncology, Pfizer Global Product Development, in a statement. “We look forward to working with the FDA to bring this treatment option to patients as quickly as possible.”

CROWN was a global, randomized phase 3 trial that included 296 patients with advanced ALK-positive NSCLC who had not received any prior systemic therapy for metastatic disease. Patients were randomized 1:1 to receive either oral lorlatinib at 100 mg daily or oral crizotinib at 250 mg twice daily, both given continuously.2

Patients had a median age of 59.1 in the lorlatinib arm (range, 51-69) and 55.6 (range, 45-66) in the crizotinib arm. The majority of patients in both arms were female, either White or Asian, never smokers, had an ECOG performance status of 1, and had stage IV adenocarcinoma. Only about a quarter of patients (26.4%) had brain metastases at baseline.

At 1 year, 78% of patients in the lorlatinib arm (95% CI, 70%-84%) and 39% in the crizotinib arm (95% CI, 30%-48%) were alive without disease progression (HR< 0.28; 95% CI, 0.19-0.41; P <.001).

The 1-year PFS rates were 80% (95% CI, 73%-86%) with lorlatinib and 35% (95% CI, 27%-43%) with crizotinib (HR, 0.21; 95% CI, 0.14-0.31).

Objective responses were observed in 76% (95% CI, 68%-83%) of patients treated with lorlatinib and 58% (95% CI, 49%-66%) of those treated with crizotinib. Responses lasted at least 12 months in 70% of patients who received lorlatinib and 27% of those who received crizotinib.

In the central nervous system metastases (CNS) subgroup (n = 78), intracranial responses were reported in 66% (95% CI, 49%-80%) of the lorlatinib arm and 20% (95% CI, 9%-36%) in the crizotinib arm. Complete intracranial responses were reported in 61% and 15% of lorlatinib and crizotinib arms, respectively.

The time to CNS progression was longer with lorlatinib compared with crizotinib with 96% in the lorlatinib group alive without CNS progression at 1 year versus 60% in the crizotinib group (HR, 0.07; 95% CI, 0.03-0.17).The cumulative incidence of CNS progression at 12 months was 3% in the lorlatinib arm versus 33% in the crizotinib arm (HR, 0.06; 95% CI, 0.02-0.18).

Overall survival data were immature at the time of cutoff, but the hazard ratio for death was 0.72 (95% CI, 0.41-1.25).

The adverse events (AEs) that were observed more frequently with lorlatinib compared with crizotinib included hypercholesterolemia (70% vs 4%, respectively), hypertriglyceridemia (64% vs 6%), edema (55% vs 39%), increased weight (38% vs 13%), peripheral neuropathy (34% vs 15%), cognitive effects (21% vs 6%), anemia (19% vs 8%), hypertension (18% vs 2%), mood effects (16% vs 5%), and hyperlipidemia (11% vs 0%). Changes in cognition (such as memory impairment, disturbance in attention, and amnesia) and mood (including anxiety, depression, and affect lability) were typically of grade 1 in severity and reversible with dose interruption.

The most common grade 3/4 AEs in the lorlatinib arm were elevated triglyceride levels (20%), increased weight (17%), elevated cholesterol levels (16%), and hypertension (10%). Fatal AEs were reported in 7 patients in the lorlatinib arm and 7 in the crizotinib arm.

Lorlatinib was also granted prior accelerated approval from the FDA for the treatment of patients with ALK-positive metastatic NSCLC whose disease has progression on crizotinib and at least 1 other ALK inhibitor in the setting of metastatic disease, or for patients whose disease has progressed on alectinib (Alecensa) or ceritinib (Zykadia) as their frontline ALK inhibitor in the metastatic setting.

Data from the CROWN study will support the conversion to a full approval for lorlatinib for this indication.


LORBRENA® (lorlatinib) sNDA in Previously Untreated ALK-Positive Lung Cancer Accepted for Priority Review by U.S. FDA. News release. Pfizer. December 28, 2020. Accessed December 31, 2020. https://bwnews.pr/38R6jQ0

Shaw AT, Bauer TM, de Marinis F, et al; CROWN Trial Investigators. First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. N Engl J Med. 2020;383:2018-2029. doi:10.1056/NEJMoa2027187