Clinical trialPhase 3Lung cancer

Lorlatinib Versus Crizotinib in Patients With Advanced ALK-Positive Non–Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study

J Clin Oncol · 2024296 patients

Solomon BJ, Liu G, Felip E, Mok TSK, Soo RA, Mazieres J, et al. J Clin Oncol. 2024. 42:3400-3409

Study type: Clinical trial
Study name: CROWN
Phase: Phase 3
Design: Randomised, open-label trial (1:1); this paper is a 5-year post hoc analysis
Sample size: 296 patients
Source: J Clin Oncol · 2024
Trial registration: NCT03052608

In plain words

In advanced lung cancer with an ALK gene change, the tablet lorlatinib kept the disease under control much longer than the older drug crizotinib: after 5 years, 60% of patients in the lorlatinib group still had no worsening of their disease, and the drug was very good at preventing the cancer from spreading to the brain. Its common side effects are raised blood fats and weight gain and sometimes changes in mood or memory, which can be managed with monitoring and dose adjustment.

Key results

Not reached vs 9.1 months

Median progression-free survival

HR 0.19; 95% CI 0.13–0.27

60% vs 8%

5-year progression-free survival

Not reached vs 16.4 months

Time to intracranial progression

HR 0.06; 95% CI 0.03–0.12

Drugs in this study:Alectinib (Alecensa)

Dose and schedule cards

ALK inhibitors (a single drug)

Metastatic ALK-positive NSCLC; first-lineCycle length: ContinuousOn the page “Lung cancer” · Advanced NSCLC with an EGFR mutation or ALK rearrangement

Metastatic ALK-positive NSCLC; first-line

Drug	Dose	Route	Schedule
One of the following drugs, continuous
Alectinib	600 mg	Oral, with food	Twice daily
Lorlatinib	100 mg	Oral, with or without food	Once daily
Brigatinib	90 mg for 7 days, then 180 mg	Oral, with or without food	Once daily
Ensartinib	225 mg	Oral, with or without food	Once daily

Cycle length: Continuous
Duration: Until disease progression or intolerable toxicity

Sources: FDA labels; CROWN. Alectinib: liver tests every 2 weeks for the first 3 months, CPK every 2 weeks during the first month, monitoring for bradycardia. Lorlatinib: cholesterol and triglycerides before starting and at months 1 and 2; monitor for neuropsychiatric effects, atrioventricular block and blood pressure; CrCl 15 to below 30: 75 mg; severe hepatic impairment (Child-Pugh C): 50 mg; concomitant use of a strong CYP3A inducer carries a risk of severe hepatotoxicity. Brigatinib: monitor respiratory symptoms, especially during the first week (the reason for the 90-mg starting dose); if treatment is interrupted for ≥14 days, restart at 90 mg for 7 days. Ensartinib: liver tests and fasting glucose before starting.

On the page “Lung cancer” · Advanced NSCLC with an EGFR mutation or ALK rearrangement

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Lorlatinib

Lorlatinib 100 mg (four 25 mg tablets) orally once daily, continuously in 28-day cycles (149 patients). Median duration of treatment 57.0 months; 33% had at least one dose reduction, and dose reduction in the first 16 weeks did not reduce efficacy.

FDA label notes (Lorbrena): 100 mg once daily with or without food until progression or unacceptable toxicity. Dose reduction: 75 mg, then 50 mg; if 50 mg is not tolerated, discontinue permanently. Creatinine clearance 15 to less than 30 mL per minute: 75 mg; severe hepatic impairment (Child-Pugh C): 50 mg. Avoid concomitant use with strong CYP3A inhibitors (and fluconazole); if unavoidable, starting dose 75 mg. Monitor cholesterol and triglycerides before starting, 1 and 2 months after starting and then periodically; start or increase lipid-lowering therapy as needed.

2Crizotinib

Crizotinib 250 mg (one 250 mg capsule) orally twice daily, continuously in 28-day cycles (147 patients; median duration of treatment 9.6 months).

Source of the regimen details: Full text of the paper (PMC11458101), ClinicalTrials.gov NCT03052608 and the FDA label for Lorbrena (DailyMed, 2026 version)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with histologically or cytologically confirmed locally advanced or metastatic ALK-positive NSCLC, with no previous systemic therapy for NSCLC; at least one measurable extracranial lesion not previously irradiated; ECOG 0 to 2; adequate bone marrow, liver, kidney and pancreatic function. Asymptomatic CNS metastases not currently requiring corticosteroids were allowed.

Important exclusion criteria: active or recent (past 3 months) significant cardiovascular disease, arrhythmia, bradycardia or congenital long QT syndrome; predisposition to acute pancreatitis in the past month; grade 3 or 4 or extensive ILD; radiotherapy in the past 2 weeks (whole-brain in the past 4 weeks); use of strong CYP3A inhibitors or inducers; severe psychiatric illness including recent or active suicidal ideation.

Endpoints

Primary endpoint of the study: progression-free survival by blinded independent central review. In this 5-year analysis: investigator-assessed PFS, time to intracranial progression, safety and biomarkers (ctDNA).

Safety and side effects

Grade 3 or 4 adverse events of any cause: 77% with lorlatinib versus 57% with crizotinib, mainly due to hypertriglyceridaemia (25% versus 0%), hypercholesterolaemia (21% versus 0%), weight gain (23% versus 2%) and hypertension (12% versus 1%). Grade 5 adverse events of any cause 9% versus 5% (treatment-related 1% versus 0%) and serious adverse events 44% versus 32%.

With lorlatinib: temporary interruption 62%, dose reduction 23% and permanent discontinuation 11% (discontinuation because of a treatment-related adverse event 5%); with crizotinib 48%, 15% and 11%, respectively. Cardiovascular adverse events 28% in both groups.

Central nervous system adverse events with lorlatinib: 42% (86% grade 1 or 2), including cognitive effects 28%, mood effects 21%, speech effects 6% and psychotic effects 5%; they were more common in patients with previous brain radiotherapy (6 of 9 patients versus 41%). Only 3 patients stopped the drug because of treatment-related CNS adverse events.

Clinical significance and place in guidelines

CROWN led to FDA approval of lorlatinib for first-line treatment of advanced ALK-positive NSCLC (2021). The 5-year data have made lorlatinib the preferred option of many specialists, especially in patients with brain metastases; alectinib and brigatinib are also standard first-line options in the ESMO and NCCN guidelines.

Limitations

The 5-year analysis is post hoc and investigator-assessed; the comparison was with crizotinib (not alectinib or brigatinib, which are the current standards); overall survival data are still immature; metabolic and neuropsychiatric adverse events require close monitoring.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.