Lorlatinib is a third generation ALK tyrosine kinase inhibitor. The phase 3 CROWN study shows superior efficacy of lorlatinib over crizotinib as a first-line treatment in patients with advanced ALK rearrangement-positive non-small cell lung cancer (NSCLC).

ALK rearrangements are found in 3-7% of NSCLC patients, typically non-smokers and adenocarcinoma histology, and result in sensitivity for small-molecule ALK tyrosine kinase inhibitors. Lorlatinib is a third generation ALK tyrosine kinase inhibitor that has shown overall and intracranial activity in advanced ALK rearrangement-positive NSCLC.

The CROWN study is a randomized phase 3 trial comparing lorlatinib versus the first generation ALK tyrosine kinase inhibitor crizotinib as first-line treatment of ALK rearrangement-positive NSCLC. A total of 296 patients were enrolled in the study and randomized 1:1 to receive lorlatinib (100 mg once daily) or crizotinib (250 mg twice daily). Patients had stage III/IV ALK rearrangement-positive NSCLC and no prior systemic therapy for metastatic disease; asymptomatic treated or untreated brain metastases were permitted. The primary endpoint of CROWN was progression-free survival (PFS) by blinded independent central review (BICR). PFS by investigator (INV), objective response (OR) and intracranial-OR by BICR, duration of response, intracranial duration of response, overall survival (OS), and safety were all assessed as secondary endpoints. Prof. Benjamin Solomon (Peter McCallum Cancer Center, Australia) presented results from the pre-planned interim analysis of CROWN [1]. This planned interim analysis was conducted at 72% of 177 expected PFS events.

Of 296 randomized patients, 291 received study treatment. At data cut-off, median follow-up for PFS by BICR was 18.3 months for lorlatinib (n=149) and 14.8 months for crizotinib (n=147). PFS by BICR was significantly prolonged with lorlatinib versus crizotinib: median PFS was not reached in the lorlatinib arm versus 9.3 months in the crizotinib arm (HR 0.28; P<0.001). 12-month PFS rate in the lorlatinib arm was 78% versus 39% in the crizotinib arm. Lorlatinib favoured PFS in all pre-specified subgroups. OR by BICR was improved by lorlatinib (76%) versus crizotinib (58%). The median duration of response was not reached in the lorlatinib arm versus 11.0 months in the crizotinib arm. In addition, median time to response was equal in both arms: 1.8 months. Intracranial response was superior for treatment with lorlatinib. In patients with measurable brain metastases at baseline (17 in the lorlatinib arm, 13 in the crizotinib arm), intracranial response rate was 82% for lorlatinib versus 23% for crizotinib (odds ratio 16.83); median duration of intracranial response was not reached in the lorlatinib arm versus 10.2 months in the crizotinib arm. Median time to intracranial progression was not reached in the lorlatinib arm versus 16.6 months in the crizotinib arm (HR 0.07; P<0.001). OS data are not yet mature.

Adverse events grade 3 or 4 were observed in 72% of the patients treated with lorlatinib versus 56% of the patients treated with crizotinib. Treatment discontinuation due to adverse events occurred in 7% of the lorlatinib arm and 9% of the crizotinib arm. Most common adverse events in the lorlatinib arm were hypercholesterolemia, hypertriglyceridemia, oedema, and weight increase. Most common adverse events in the crizotinib arm were diarrhea, nausea, vomiting, and oedema.

Based on these results, Prof. Solomon concluded that these results support the use of lorlatinib as a first-line treatment for patients with ALK rearrangement-positive NSCLC.

 

  1. Solomon B, et al. Lorlatinib vs crizotinib in the first-line treatment of patients (pts) with advanced ALK-positive non-small cell lung cancer (NSCLC): Results of the phase III CROWN study. ESMO 2020 Virtual Meeting, abstract LBA2.