Lorlatinib Versus Crizotinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study

Abstract

Purpose: Lorlatinib improved progression-free survival (PFS) and intracranial activity versus crizotinib in patients with previously untreated, advanced, ALK-positive non-small cell lung cancer (NSCLC) in the phase III CROWN study. Here, we report long-term outcomes from CROWN after 5 years of follow-up.

Methods: Two hundred ninety-six patients with ALK-positive NSCLC were randomly assigned 1:1 to receive lorlatinib 100 mg once daily (n = 149) or crizotinib 250 mg twice daily (n = 147). This post hoc analysis presents updated investigator-assessed efficacy outcomes, safety, and biomarker analyses.

Results: With a median follow-up for PFS of 60.2 and 55.1 months, respectively, median PFS was not reached (NR [95% CI, 64.3 to NR]) with lorlatinib and 9.1 months (95% CI, 7.4 to 10.9) with crizotinib (hazard ratio [HR], 0.19 [95% CI, 0.13 to 0.27]); 5-year PFS was 60% (95% CI, 51 to 68) and 8% (95% CI, 3 to 14), respectively. Median time to intracranial progression was NR (95% CI, NR to NR) with lorlatinib and 16.4 months (95% CI, 12.7 to 21.9) with crizotinib (HR, 0.06 [95% CI, 0.03 to 0.12]). Safety profile was consistent with that in prior analyses. Emerging new ALK resistance mutations were not detected in circulating tumor DNA collected at the end of lorlatinib treatment.

Conclusion: After 5 years of follow-up, median PFS has yet to be reached in the lorlatinib group, corresponding to the longest PFS ever reported with any single-agent molecular targeted treatment in advanced NSCLC and across all metastatic solid tumors. These results coupled with prolonged intracranial efficacy and absence of new safety signals represent an unprecedented outcome for patients with advanced ALK-positive NSCLC and set a new benchmark for targeted therapies in cancer.

Trial registration: ClinicalTrials.gov NCT03052608.

FIG 1.

CONSORT diagram for the CROWN study. AE, adverse event.

FIG 2.

PFS by investigator assessment in the intention-to-treat population. HR, hazard ratio; NR, not reached; PFS, progression-free survival.

FIG 3.

Time to intracranial progression by investigator assessment using modified RECIST, version 1.1, in (A) the intention-to-treat population, (B) patients with baseline brain metastases, and (C) patients without baseline brain metastases. HR, hazard ratio; IC, intracranial; NR, not reached.

FIG 4.

Outcomes in patients who had first lorlatinib dose reduction within 16 weeks. (A) PFS by investigator assessment and (B) time to intracranial progression by investigator assessment. PFS and time to intracranial progression were recalculated starting at the landmark time. Patients with event/censor time within the landmark time were excluded from the analysis. HR, hazard ratio; IC, intracranial; NR, not reached; PFS, progression-free survival.

FIG A1.

PFS by investigator assessment in patients with baseline brain metastases. HR, hazard ratio; NR, not reached; PFS, progression-free survival.

FIG A2.

PFS by investigator assessment in patients without baseline brain metastases. HR, hazard ratio; NR, not reached; PFS, progression-free survival.

FIG A3.

Cumulative incidence of progression of brain metastases as first event in (A) the intention-to-treat population, (B) patients with baseline brain metastases, and (C) patients without baseline brain metastases.

FIG A4.

Baseline plasma ctDNA samples available in the lorlatinib and crizotinib groups. ctDNA, circulating tumor DNA.

FIG A5.

Mutational landscape in (A) lorlatinib and (B) crizotinib patients at screening and EOT. None indicates no mutation, which includes no ctDNA samples and failed samples. If all mutations detected are SILENT, the column corresponding to the sample is blank. One crizotinib patient had no screening visit sample and was not included in the plot for screening. EOT, end of treatment; NoRearr, no rearrangement; OthRearr, other rearrangement.