Lorlatinib/lorlatinib versus crizotinib in previously untreated advanced ALK-positive non-small cell lung cancer

An analysis of the 5-year results of the phase III CROWN trial showed that previously untreated patients who received lorlatinib did not reach median progression-free survival, while patients who received crizotinib for advanced ALK-positive non-small cell lung cancer (NSCLC) had a median progression-free survival of 9.1 months. The trial supports expanded approval of lorlatinib in this setting in March 2021 based on improved progression-free survival and intracranial activity compared with crizotinib and converts accelerated approval in 2018 to routine approval in this setting.

Study details

In this international open-label trial, 296 patients with ALK-positive NSCLC were randomly assigned to receive 28-day cycles of lorlatinib 100 mg once daily (n=149) or crizotinib 250 mg twice daily (n=147). The current analysis shows 5-year results.

Key points

At the data cutoff for the current analysis (October 2023), the median follow-up times for progression-free survival were 60.2 months in the lorlatinib group and 55.1 months in the crizotinib group. Median progression-free survival was not reached in the lorlatinib group (95% confidence interval [CI] = 64.3 months not reached) compared with 9.1 months (95% CI = 7.4-10.9 months) in the crizotinib group (hazard ratio [HR] = 0.19, 95% CI = 0.13-0.27). The 4-year and 5-year ratios are 63% vs. 10% and 60% vs. 8%, respectively.

Among 35 vs. 38 patients with measurable or non-measurable brain metastases at baseline, median progression-free survival was not reached in patients who received lotinib (95% CI = 32.9 months not reached) compared with 6.0 months (95% CI = 3.7-7.6 months) in patients who received crizotinib (HR = 0.08, 95% CI = 0.04-0.19).

Across all patients, the median time to intracranial progression was not reached in the lorlatinib group (95% CI = not reached or not reached) compared with 16.4 months (95% CI = 12.7-21.9 months) in the crizotinib group (HR = 0.06, 95% CI = 0.03-0.12). The likelihood of remaining free of intracranial disease progression over 5 years was 92% and 21%, respectively. Emerging ALK resistance mutations were detected at the end of crizotinib treatment; they were not detected in circulating tumor DNA at the end of lorlatinib treatment.

The safety profiles of lorlatinib and crizotinib were consistent with previous analyses. The researchers concluded that afterAfter 5 years of follow-up, the lorlatinib arm has not yet reached median progression-free survival, which is equivalent to the longest progression-free survival reported for any single-agent molecularly targeted therapy in advanced non-small cell lung cancer and all metastatic solid tumors. These results, coupled with the prolonged intracranial efficacy and lack of new safety signals, represent unprecedented results for patients with advanced ALK-positive non-small cell lung cancer and set a new benchmark for targeted therapies in cancer.