FDA Approves Expanded Indication for Lorlatinib for Frontline ALK+ NSCLC

The FDA has expanded the approval for lorlatinib to include an indication for the first-line treatment of patients with ALK-positive non–small cell lung cancer.

The FDA has expanded the approval for lorlatinib (Lorbrena) to include an indication for the first-line treatment of patients with ALK-positive non–small cell lung cancer (NSCLC).1

Lorlatinib is now indicated for the treatment of adult patients with metastatic NSCLC whose tumors harbor ALK alterations, as detected by an FDA-approved test. In addition, the FDA’s accelerated approval for the agent from November 2018 has been converted to a full approval.2 The application was reviewed through the FDA’s Real-Time Oncology Review Program as well as through the Project Orbis Program.

The FDA simultaneously approved the Ventana ALK (D5F3) CDx Assay as a companion diagnostic for lorlatinib.

The new indication for the ALK inhibitor was supported by findings from the phase 3 CROWN study, which demonstrated a significant reduction in the risk of progression or death for patients with previously untreated ALK-positive NSCLC with lorlatinib compared with crizotinib (Xalkori).

“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,” said Benjamin Solomon, MD, of the Department of Medical Oncology, Peter MacCallum Cancer Centre, Australia, in a statement. “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.”

The global, randomized CROWN trial enrolled 296 patients with advanced ALK-positive NSCLC who had not received any prior systemic therapies in the metastatic setting. Patients were randomized 1:1 to receive either oral lorlatinib, a third-generation ALK inhibitor, at 100 mg daily or oral crizotinib, the first-generation ALK inhibitor, at 250 mg twice daily given continuously until disease progression, unacceptable toxicity, or death. Treatment was allowed to continue even after disease progression.3

The primary end point was progression-free survival (PFS) by RECIST criteria as assessed by a blinded independent central review and secondary end points were investigator’s assessment of PFS, overall survival (OS), objective response rate (ORR), objective intracranial response rate, and safety.

In the lorlatinib arm, patients had a median age of 61 (range, 51-69), 56% were female, 48% were White, 53% had an ECOG performance status of 1, 54% were never smokers, 91% had stage IV disease, 94% had adenocarcinoma, and 26% had brain metastases. Only 8% had previously received anticancer therapy and 6% had received brain radiotherapy.

In the control arm, patients had a median age of 56 (range, 45-66), 62% were female, 49% were White, 55% had an ECOG performance status of 1, 64% were never smokers, 95% had stage IV disease, 95% had adenocarcinoma, and 27% had brain metastases. Only 6% had previously received anticancer therapy and 7% had received brain radiotherapy.

At 12 months, 78% of patients in the lorlatinib arm (95% CI, 70%-84%) were alive without disease progression versus 39% (95% CI, 30%-48%) in the crizotinib arm (HR, 0.28; 95% CI, 0.19-0.41; P < .001). By investigator assessment, the 1-year PFS rate was 80% (95% CI, 73%-86%) with lorlatinib and 35% (95% CI, 27%-43%) with crizotinib (HR, 0.21; 95% CI, 0.14-0.31).

ORR was 76% (95% CI, 68%-83%) and 58% (95% CI, 49%-66%) with lorlatinib and crizotinib, respectively. Seventy percent of the patients who received lorlatinib and 27% of those who received crizotinib had a response lasting at least a year.

In the patients with baseline central nervous system (CNS) metastases, the intracranial response rate was 66% (95% CI, 49%-80%) with lorlatinib and 20% (95% CI, 9%-36%) with crizotinib.Seventy-two percent of those with CNS metastases who received crizotinib had a response lasting more than a year.

Data for OS were still immature at the time of data cutoff, but the HR for OS was 0.72 (95% CI, 0.41-1.25).

Adverse events (AEs) the occurred more frequently in the lorlatinib arm than the crizotinib arm were 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%). Cognitive and mood changes were usually grade 1 and reversible with dose interruption, which was consistent with prior reports of lorlatinib.

The most common grade 3/4 events in the lorlatinib arm (72%) were elevated triglyceride levels (20%), increased weight (17%), elevated cholesterol levels (16%), and hypertension (10%), whereas the most common grade 3/4 events in the crizotinib arm (56%) were laboratory abnormalities. Serious AEs occurred in 34% of patients in the lorlatinib arm and in 27% of the crizotinib arm. Fatal AEs were reported in 5% of patients in each arm. AEs led to treatment discontinuation for 7% of patients in the lorlatinib and for 9% in the crizotinib arm.

Patients in the lorlatinib arm also had a significantly greater improvement overall from baseline in quality of life, as calculated from patient-reported outcomes, than those who received crizotinib (estimated mean difference, 4.65; 95% CI, 1.14 to 8.16), although the difference was not found to be clinically meaningful.

“Lorbrena has been a transformative medicine for people with ALK-positive advanced NSCLC, and this FDA approval in the first-line setting means that we can now extend hope to even more people,” said Andy Schmeltz, global president, Pfizer Oncology, in a statement.

The FDA first approved lorlatinib in November 2018 as a treatment for patients with ALK-positive NSCLC whose disease has progressed on crizotinib and at least one other ALK inhibitor for metastatic disease or whose disease has progressed on alectinib (Alecensa) or ceritinib (Zykadia) as the first ALK inhibitor therapy for metastatic disease.4


1. U.S. FDA expands approval of Pfizer’s Lorbrena® as first-line treatment for ALK-positive metastatic lung cancer. News release. Pfizer. March 3, 2021. Accessed March 4, 2021. https://bit.ly/2PnGbpF

2. FDA approves lorlatinib for metastatic ALK-positive NSCLC. FDA. March 3, 2021. Accessed March 4, 2021. https://bit.ly/3qh6U4f

3. 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

4. FDA approves lorlatinib for second- or third-line treatment of ALK-positive metastatic NSCLC. FDA. Updated December 14, 2018. Accessed March 4, 2021. https://bit.ly/2OnGW1G