CROWN: 1L lorlatinib improves PFS, reduces CNS progression in ALK-positive NSCLC ± brain metastases

First-line treatment of ALK-positive non-small-cell lung cancer (NSCLC) with lorlatinib improves progression-free survival (PFS) and reduces central nervous system (CNS) progression vs crizotinib, regardless of presence or absence of baseline brain metastases (BM), a post hoc analysis of the phase III CROWN trial has shown.

“For patients with advanced [ALK-positive] NSCLC, preventing or delaying CNS progression is often challenging,” said senior author Professor Tony Mok of the Department of Clinical Oncology, Chinese University of Hong Kong. “Therefore, we explored the efficacy [and safety] of lorlatinib, a third-generation anaplastic lymphoma kinase [ALK] inhibitor for managing the disease, especially CNS progression.”

In CROWN, 296 patients with previously untreated ALK-positive NSCLC were randomized 1:1 to receive lorlatinib 100 mg QD (n=149; median age, 61 years; female, 56 percent; BM, 26 percent; prior brain radiotherapy, 21 percent), or crizotinib 250 mg BID (n=147; median age, 56 years; female, 62 percent; BM, 27 percent; prior brain radiotherapy, 25 percent). Patients were stratified by presence of BM at baseline and ethnicity. The dose of lorlatinib (75 mg QD or 50 mg QD) could be reduced based on adverse event (AE) type and severity. [J Clin Oncol 2022;doi:10.1200/JCO.21.02278]

At the time of data cut-off (20 March 2020), PFS by blinded independent central review (BICR) was significantly longer with lorlatinib vs crizotinib in patients with or without baseline BM (with baseline BM: median, not reached [NR] vs 7.2 months; hazard ratio [HR], 0.20; 95 percent confidence interval [CI], 0.10–0.43; p<0.0001) (without baseline BM: median, NR vs 11.0 months; HR, 0.32; 95 percent CI, 0.20–0.49; p<0.0001). In lorlatinib-treated patients with baseline BM, median PFS was NR in those with or without prior brain radiotherapy.

The study also revealed higher intracranial complete response (CR) with lorlatinib vs crizotinib among patients with any baseline BM (61 percent vs 15 percent) or measurable baseline BM (71 percent vs 8 percent). “High intracranial CR with lorlatinib contributed to the improvement in PFS,” the researchers wrote.

Of note, the 12-month cumulative incidence of CNS progression was 7 percent with lorlatinib vs 72 percent with crizotinib in patients with baseline BM, and 1 percent vs 18 percent in those without baseline BM. “For most patients, lorlatinib is highly effective in preventing CNS progression,” the researchers highlighted.

CNS AEs occurred in 52 (35 percent) vs 15 (11 percent) patients treated with lorlatinib vs crizotinib, most of whom experienced grade 1 or 2 events (90 percent vs 100 percent). Grade 3 CNS AEs were reported in five lorlatinib-treated patients (10 percent). Of 86 CNS AEs in the lorlatinib group, 28 (33 percent) resolved spontaneously without interventions, while 15 of 20 events (17 percent) were managed with dose modification of lorlatinib and resulted in resolution.

“We are excited to discover the therapeutic potential of lorlatinib, which changes practice,” Mok commented. “Based on findings of the CROWN study, the US FDA has approved lorlatinib as first-line treatment for metastatic ALK-positive NSCLC.”