As reported in The New England Journal of Medicine by Alice T. Shaw, MD, PhD, and colleagues, an interim analysis of the phase III CROWN trial has shown that first-line lorlatinib significantly improved progression-free survival and intracranial response rate vs crizotinib in patients with advanced ALK-positive non–small cell lung cancer (NSCLC).

As stated by the investigators, “Lorlatinib, a third-generation inhibitor of ALK, has antitumor activity in previously treated patients with ALK-positive NSCLC. The efficacy of lorlatinib, as compared with that of crizotinib, as first-line treatment for advanced ALK-positive NSCLC is unclear.”

Alice T. Shaw, MD, PhD

Study Details

In the open-label trial, 296 patients from sites in 23 countries who had received no prior systemic treatment for metastatic disease were randomly assigned between May 2017 and February 2019 to receive lorlatinib at 100 mg daily (n = 149) or crizotinib at 250 mg twice daily (n = 147) continuously in 28-day cycles. Stage IV disease was present in 91% vs 95% of patients, and 44% of patients in each group were Asian.

The primary endpoint was progression-free survival on blinded independent central review. The current planned interim analysis occurred after 75% of expected progression-free survival events had occurred.

Progression-Free Survival

The median follow-up for progression-free survival was 18.3 months in the lorlatinib group and 14.8 months in the crizotinib group. Progression-free survival at 12 months was 78% (95% confidence interval [CI] = 70%–84%) in the lorlatinib group vs 39% (95% CI = 30%–48%) in the crizotinib group (hazard ratio [HR] = 0.28, 95% CI = 0.19–0.41, P < .001). Median progression-free survival was not reached (95% CI = not reached–not reached) vs 9.3 months (95% CI = 7.6–11.1 months).

Objective response was observed in 76% of patients in the lorlatinib group vs 58% in the crizotinib group (odds ratio [OR] = 2.25, 95% CI = 1.35–3.89), including complete response in four vs no patients. Median duration of response was not reached vs 11.0 months. Among 17 vs 13 patients with measurable brain metastases at baseline, an intracranial objective response was observed in 14 (82%) vs 3 patients (23%; OR = 16.83, 95% CI = 1.95–163.23), with complete response in 12 vs 1; the median duration of response was not reached vs 10.2 months.

Overall survival data were not mature at data cutoff. Death had occurred in 23 patients (15%) in the lorlatinib group and 28 patients (19%) in the crizotinib group (HR = 0.72, 95% CI = 0.41–1.25).  

Adverse Events

The most common adverse events of any grade occurring with > 10% greater incidence in either group were hypercholesterolemia (70%), hypertriglyceridemia (64%), and edema (55%) in the lorlatinib group, and diarrhea (52%), nausea (52%), vision disorder (39%), and vomiting (39%) in the crizotinib group. Grade 3 or 4 adverse events occurred in 72% vs 56% of patients; the most common were elevated triglycerides (20%), increased weight (17%), elevated cholesterol (16%), and hypertension (10%) in the lorlatinib group, and laboratory abnormalities in the crizotinib group.

Serious adverse events occurred in 34% vs 27%. Adverse events led to discontinuation of treatment in 7% vs 9%. Adverse events led to death in seven patients in each group.

The investigators concluded, “In an interim analysis of results among patients with previously untreated advanced ALK-positive NSCLC, those who received lorlatinib had significantly longer progression-free survival and a higher frequency of intracranial response than those who received crizotinib. The incidence of grade 3 or 4 adverse events was higher with lorlatinib than with crizotinib because of the frequent occurrence of altered lipid levels.”

Disclosure: The study was funded by Pfizer. For full disclosures of the study authors, visit nejm.org.