medwireNews: Patients with advanced ALK-positive non-small-cell lung cancer (NSCLC) derive prolonged progression-free survival (PFS) from first-line treatment with lorlatinib regardless of the presence of brain metastases, post-hoc analyses indicate.
The phase 3 CROWN trial showed that lorlatinib significantly improves PFS in patients with advanced ALK-positive NSCLC compared with crizotinib. Following these trial results, the FDA and EMA extended the indication of lorlatinib to previously untreated patients.
Noting that “[b]rain metastases develop in more than half of patients with ALK-positive [NSCLC],” Benjamin Solomon (Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia) and team investigated the intracranial efficacy of lorlatinib among the CROWN participants.
In total 149 patients were randomly assigned to receive first-line lorlatinib 100 mg daily, of whom 38 (26%) had brain metastases at baseline. The remaining 147 patients received crizotinib, including 40 (27%) people with brain metastases at baseline.
Median progression-free survival (PFS) was not reached in patients with or without brain metastases who received lorlatinib, but was a corresponding median 7.2 and 11.0 months among those given crizotinib.
Lorlatinib achieved a significantly higher 12-month PFS rate than crizotinib among those who had brain metastases (78 vs 22%; hazard ratio [HR]=0.2) and those without brain metastases (78 vs 45%; HR=0.32).
In addition, the lorlatinib group had a significantly lower incidence of central nervous system (CNS) progression than crizotinib for patients with and without brain metastases, at corresponding rates of 7% versus 72% (HR=0.07) and 1% versus 18% (HR=0.05).
CNS adverse events (AEs) resulted in dose modifications in 17% of those in the lorlatinib arm and the study authors say that these “did not notably influence PFS.”
Over a third (35%) of patients given lorlatinib had a CNS AE compared with 11% of those given lorlatinib, of whom 10% and 0%, respectively, had a maximum AE severity of grade 3. Of the patients with a brain metastasis at baseline who were given lorlatinib, 42% had a CNS AE compared with 32% of those without baseline brain involvement.
Of note, CNS AEs associated with lorlatinib did not “result in a clinically meaningful difference in patient-reported quality of life,” according to Solomon et al.
Writing in the Journal of Clinical Oncology, the study investigators conclude: “Our data support lorlatinib as first-line treatment in patients with advanced ALK-positive NSCLC with/without brain metastases.”
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