Post Hoc Analysis of Lorlatinib Intracranial Efficacy and Safety in Patients With ALK-Positive Advanced Non-Small-Cell Lung Cancer From the Phase III CROWN Study

Abstract

Purpose: Lorlatinib significantly improved progression-free survival (PFS) versus crizotinib and showed robust intracranial activity in patients with previously untreated advanced ALK-positive non-small-cell lung cancer (NSCLC) in the phase III CROWN trial. Here, we report post hoc efficacy outcomes in patients with and without brain metastases at baseline, and present data on the incidence and management of CNS adverse events (AEs) in CROWN.

Methods: Eligible patients were randomly assigned 1:1 to first-line lorlatinib (100 mg once daily) or crizotinib (250 mg twice a day); no crossover between treatment arms was permitted. Tumor assessments, including CNS magnetic resonance imaging, were performed at screening and then at 8-week intervals. Regular assessments of patient-reported outcomes were conducted.

Results: PFS by blinded independent central review was improved with lorlatinib versus crizotinib in patients with and without brain metastases at baseline (12-month PFS rates: 78% v 22% and 78% v 45%, respectively). Lorlatinib was associated with lower 12-month cumulative incidence of CNS progression versus crizotinib in patients with (7% v 72%) and without (1% v 18%) brain metastases at baseline. In total, 35% of patients had CNS AEs with lorlatinib, most of grade 1 severity. Occurrence of CNS AEs did not result in a clinically meaningful difference in patient-reported quality of life. At analysis, 56% of CNS AEs had resolved (33% without intervention; 17% with lorlatinib dose modification), and 38% were unresolved; most required no intervention. Lorlatinib dose modification did not notably influence PFS.

Conclusion: First-line lorlatinib improved PFS outcomes and reduced CNS progression versus crizotinib in patients with advanced ALK-positive non-small-cell lung cancer with or without brain metastases at baseline. Half of all CNS AEs resolved without intervention or with lorlatinib dose modification.

Trial registration: ClinicalTrials.gov NCT03052608.

FIG 1.

Kaplan-Meier plot of PFS in patients from the intent-to-treat population (A) with and (B) without brain metastases at baseline per blinded independent central review. HR, hazard ratio; NR, not reached; PFS, progression-free survival.

FIG 2.

Cumulative incidence of CNS and non-CNS progression in CROWN: (A) CNS progression in patients with brain metastases at baseline and (B) CNS progression in patients without brain metastases at baseline. HR, hazard ratio.

FIG 3.

Best percentage change in intracranial tumor size per BICR in patients with at least one measurable brain metastases at baseline in the intent-to-treat population following treatments with (A) lorlatinib (n = 17) and (B) crizotinib (n = 11). Only included patients with target lesions at baseline and at least one adequate postbaseline assessment up to the time of PD or new anticancer therapy. Two patients from the crizotinib arm were excluded from the plot as they did not have any postbaseline tumor assessment. BICR, blinded independent central review; BOR, best overall response; PD, progressive disease.

FIG A1.

PFS by blinded independent central review assessment in patients with baseline brain metastases who received lorlatinib treatment by prior brain radiotherapy (intent-to-treat population). NR, not reported; PFS, progression-free survival; RT, radiotherapy.

FIG A2.

Cumulative incidence of non-CNS progression in CROWN: (A) non-CNS progression in patients with brain metastases at baseline and (B) non-CNS progression in patients without brain metastases at baseline. HR, hazard ratio.

FIG A3.

Swimmer plots of intracranial complete responses in the intent-to-treat population with lorlatinib over time (A) in patients with measurable or nonmeasurable brain metastases (n = 23) and (B) in patients with at least one measurable brain metastasis (n = 12). CR, complete response; EOT, end of treatment; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.

FIG A4.

Changes from baseline in EORTC QLQ-C30 Cognitive and Emotional Functioning scores with lorlatinib by (A and B) CNS adverse events; (C and D) cognitive effects; and (E and F) mood effects cluster terms (PRO population). The PRO population consisted of all randomly assigned patients who completed a baseline assessment and at least one postbaseline assessment. COGNITIVE EFFECTS were any events from HLGT Cognitive and attention disorders and disturbances, Deliria (including confusion) or Mental impairment disorders; MOOD EFFECTS were any events from HLGT Anxiety disorders and symptoms, Depressed mood disorders and disturbances, Manic and bipolar mood disorders and disturbances, Mood disorders and disturbances not elsewhere classified, or Personality disorders and disturbances in behavior. ^aBL was defined as the last assessment performed on or before the date of the first dose of study treatment. CNS effects defined as any event from the cognitive effects, mood effects, speech effects, or psychotic effects cluster terms. BL, baseline; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; HLGT, high-level group terms; PRO, patient-reported outcome.

FIG A5.

Landmark analysis of progression-free survival per BICR assessment (A) by first lorlatinib dose reduction within 16 weeks and (B) by mean relative lorlatinib dose intensity within 16 weeks (intent-to-treat population). Patients with PFS time ≤ 16 weeks were excluded. For patients included in the analysis, PFS time is recalculated starting at the landmark time. BICR, blinded independent central review; PFS, progression-free survival; RDI, relative dose intensity.