First-Line Lorlatinib Improves PFS Versus Crizotinib for ALK+ NSCLC

A randomized, phase 3 trial, comparing first-line lorlatinib to crizotinib found that lorlatinib demonstrated longer PFS and a higher frequency of intracranial response in previously treated patients with anaplastic lymphoma kinase (ALK)-positive non–small-cell lung cancer (NSCLC) (N Engl J Med. 2020 Nov 19;383(21):2018-2029.).

Alice T. Shaw, MD, PhD, Massachusetts General Hospital, Boston, and her team conducted this trial to see how lorlatinib, as first-line treatment, compared to crizotinib.

“Lorlatinib, a third-generation inhibitor of anaplastic lymphoma kinase (ALK), has antitumor activity in previously treated patients with ALK-positive non–small-cell lung cancer (NSCLC). The efficacy of lorlatinib, as compared with that of crizotinib, as first-line treatment for advanced ALK-positive NSCLC is unclear,” explained Dr Shaw et al.

The global trial included 296 patients with advanced ALK-positive NSCLC who had not received any prior systemic treatment for metastatic disease. Researchers planned interim analysis of efficacy after 133 of 177 (75%) expected events of disease progression or death occurred.

The primary endpoint of this study was progression-free survival (PFS) as assessed by blinded independent central review, while secondary endpoints included independently assessed objective response and intracranial response.

At 12 months, the percentage of patients who were alive without disease progression was 78% (95% confidence interval [CI], 70 to 84) in the lorlatinib group and 39% (95% CI, 30 to 48) in the crizotinib group (HR for disease progression or death, 0.28’ 95% CI, 0.19 to 0.41; P<0.001). In the lorlatinib arm, an objective response occurred in 76% of patients, compared to 58% in the crizotinib arm. 

Among patients with measurable brain metastases 82% (95% CI, 57 to 96) and 23% (95% CI, 5 to 54), respectively, had an intracranial response. Furthermore, 71% of patients who received lorlatinib had an intracranial complete response. 

Lorlatinib was associated with more grade 3 or 4 adverse events (AEs), with the most common being hyperlipidemia, edema, increased weight, peripheral neuropathy, and cognitive effects. The percentage of patients who discontinued treatment due to adverse events was 7% and 9% in the lorlatinib and crizotinib group, respectively.

“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,” concluded Dr Shaw and colleagues. —Alexandra Graziano

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