The improvement in PFS with lorlatinib is statistically significant!

At the Presidential Symposium of the 2020 ESMO Annual Congress, results of a head-to-head study comparing lorlatinib versus crizotinib as first-line therapy for advanced ALK-positive non-small cell lung cancer (NSCLC) were presented. The findings demonstrated that lorlatinib yielded a statistically and clinically significant improvement in progression-free survival (PFS) compared with crizotinib.

Lorlatinib exerts potent activity against a broad spectrum of acquired ALK resistance mutations, and exhibits strong central nervous system (CNS) penetration, maintaining high drug concentrations in brain tissues.

The study enrolled 296 treatment-naive patients with stage IIIb/IV ALK-positive NSCLC. Eligible patients were randomized at a 1:1 ratio to receive either lorlatinib (100 mg once daily [QD]) or crizotinib (250 mg twice daily [BID]). Stratification was performed based on race and presence of CNS metastases.

Study Results: As of the data cutoff date of March 20, 2020, the median follow-up durations were 18.3 months for the lorlatinib group (n=149) and 14.8 months for the crizotinib group (n=147). According to assessments by the Blinded Independent Review Committee (BIRC), lorlatinib significantly prolonged median PFS—not reached (NR) in the lorlatinib group versus 9.3 months in the crizotinib group—reducing the risk of disease progression or death by 72% (hazard ratio [HR] = 0.28; 95% confidence interval [CI], 0.191–0.413; P < 0.001).

Investigator-assessed median PFS was NR in the lorlatinib group versus 9.1 months in the crizotinib group (HR = 0.21; 95% CI, 0.144–0.307). Subgroup analyses indicated that the PFS benefit of lorlatinib over crizotinib was consistent across all subgroups, regardless of baseline brain metastases, race, Eastern Cooperative Oncology Group Performance Status (ECOG PS) score, gender, age, or smoking status.

Regarding secondary endpoints, the objective response rates (ORR) were 76% in the lorlatinib group and 58% in the crizotinib group (odds ratio [OR] = 2.25; 95% CI, 1.35–3.89). Notably, the intracranial objective response rate (iORR) was as high as 82% in the lorlatinib group, far exceeding the 23% observed in the crizotinib group (OR = 16.83; 95% CI, 1.95–163.23). Among patients with baseline measurable brain metastases, 71% (12 cases) achieved intracranial complete response (CR) with lorlatinib, highlighting its remarkable CNS penetration efficacy.

Safety Analysis: The incidence of grade 3 or higher adverse events (AEs) was 72.5% in the lorlatinib group and 55.6% in the crizotinib group, leading to treatment discontinuation in 7% and 9% of patients, respectively. The most common grade 3–4 AEs in the lorlatinib group were laboratory abnormalities, including hypercholesterolemia and hypertriglyceridemia.