CONFERENCE UPDATE: ESMO 2024

First-line lorlatinib shows 5-year benefits in Asian patients with ALK+ NSCLC: Post-hoc analysis from the CROWN trial

ONCOLOGY
20 Feb 2025

Dr. Wu, Yi-Long

Guangdong Lung Cancer Institute,
Guangdong Provincial People’s Hospital,
Guangdong Academy of Medical Sciences,
Southern Medical University, Guangzhou, China

STUDY DESIGN

Lorlatinib, a third-generation, brain-penetrant anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor, demonstrates potent antitumor activity in patients with ALK-positive (ALK+) non-small cell lung carcinoma (NSCLC) and is approved as a first-line treatment in many countries.1 This post-hoc analysis presents long-term outcomes in the Asian subgroup of the CROWN study, following a 5-year observation period.1

The CROWN study is an ongoing, international, randomized, phase 3 trial comparing lorlatinib with crizotinib in patients with previously untreated, advanced (stage IIIB or IV) ALK+ NSCLC (n=296).1 In the Asian subgroup, 120 patients (40.5% of the overall intention-to-treat [ITT] population) were randomized in a 1:1 ratio to receive either oral lorlatinib 100mg once daily (n=59) or crizotinib 250mg twice daily (n=61), with stratification by the presence of brain metastases.1 Patient demographics and baseline clinical characteristics were well-balanced between both treatment arms.1 Efficacy endpoints of the post-hoc analysis included progression-free survival (PFS), objective response rate (ORR), intracranial objective response rate (IC ORR), and intracranial time to progression (IC TTP), all assessed by investigator evaluation, along with safety and biomarker analyses.1

PFS was defined as the time from randomization to either disease progression or death from any cause, whichever occurred first.1 In the current post-hoc analyses, efficacy endpoints were analyzed using unstratified methods, with both efficacy and safety data summarized descriptively.1

FINDINGS

Efficacy endpoints:
  • The efficacy endpoints assessed in this post-hoc analysis in the Asian subgroup were PFS, ORR, IC ORR and IC TTP (all by investigator assessment)1
  • After a median duration of follow-up of 62.4 months in the lorlatinib arm and 55.1 months in the crizotinib arm, the median PFS was not reached (95% CI: 64.3-not estimable) with lorlatinib, and was 9.2 months (95% CI: 7.2-12.7) with crizotinib (HR=0.22; 95% CI: 0.13-0.37)1
  • Median PFS was not reached in the lorlatinib arm regardless of EML4-ALK variant subtype v1 or v3 or TP53 mutation status1
  • Clinically meaningful improvements in ORR (81.4% vs. 59.0%), and IC ORR in patients with baseline brain metastases (69.2% vs. 6.3%) were also observed with lorlatinib vs. crizotinib1
  • Additionally, the median IC TTP was not reached in the lorlatinib arm and was 14.6 months (95% CI: 9.2-27.4) in the crizotinib arm (HR=0.01; 95% CI: 0.01-0.11)1
Safety:
  • No new safety signals were observed in the CROWN Asian subgroup with extended follow-up, and the safety profile was consistent with that observed in the overall ITT population1
  • However, there was a higher incidence of grade 3/4 adverse events (AEs) with lorlatinib, primarily attributed to hypertriglyceridemia (33.9%), hypercholesterolemia (22.0%), and weight gain (22.0%)1
  • Overall treatment-related AEs leading to permanent treatment discontinuation were generally infrequent at <10%, with 5.1% reported with lorlatinib and 8.3% with crizotinib1
Dr. Wu, Yi-Long
Guangdong Lung Cancer Institute,
Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences,
Southern Medical University, Guangzhou, China

"These data support the use of first-line lorlatinib in Asian patients with advanced ALK+ NSCLC

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