CONFERENCE UPDATE: ASCO 2024

First-line lorlatinib continues to show PFS benefit over crizotinib in patients with advanced ALK+ NSCLC: 5-year follow-up of the CROWN study

RESPIROLOGY
12 Sep 2024

STUDY DESIGN

Lorlatinib is a brain-penetrant third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) which covers a broader ALK resistance profile than second-generation ALK TKIs.1 It has previously demonstrated improved progression-free survival (PFS) and intracranial (IC) activity compared to crizotinib in treatment-naïve patients with advanced ALK+ non-small cell lung cancer (NSCLC) in the ongoing randomized phase 3 CROWN study.1

In the CROWN study, a total of 296 treatment-naïve patients with advanced ALK+ NSCLC were randomized to receive lorlatinib 100mg once daily (QD) (n=149) or crizotinib 250mg twice daily (BID) (n=147).1 At approximately 3 years of follow-up, median PFS by blinded independent central review (BICR) was not reached (NR) in the lorlatinib arm and 0.3 months in the crizotinib arm (HR=0.27; 95% CI: 0.18-0.39).1

This post-hoc analysis evaluated the longer-term (5-year follow-up) efficacy and safety outcomes of lorlatinib versus crizotinib in the CROWN study.1 Key efficacy outcomes presented at the meeting included investigator-assessed PFS and time to IC tumor progression which were stratified by patients’ ethnicity (Asian or non-Asian) and the presence of brain metastases, gender, age (<65 or ≥65 years) and smoking status.1 Brain tumor assessments were conducted using brain magnetic resonance imaging (MRI) every 8 weeks.1 Biomarker analyses were also conducted by evaluating the circulating tumor deoxyribonucleic acid (ctDNA) to determine potential resistance mechanisms.1

FINDINGS

Efficacy outcomes

  • The key efficacy outcomes were investigator-assessed PFS and the time to IC progression1

  • The median duration of PFS follow-up was 60.2 months in the lorlatinib arm and 55.1 months in the crizotinib arm1

  • At 5 years, median PFS was NR in lorlatinib-treated patients compared with 9.1 months in crizotinib-treated patients (HR=0.19; 95% CI: 0.13-0.27)1
  • The 5-year PFS was 60% with lorlatinib compared to 8% with crizotinib1
  • Lorlatinib demonstrated superior PFS over crizotinib in treatment-naïve patients with advanced ALK+ NSCLC, regardless of the presence of baseline brain metastases, ethnic origin, gender, age and smoking status1
  • The median time to IC tumor progression was NR with lorlatinib while it was 16.4 months with crizotinib treatment (HR=0.06; 95% CI: 0.03-0.12)1
  • 92% of patients receiving lorlatinib and 21% of those receiving crizotinib were IC progression-free1
  • At the end of treatment, no new ALK mutations were detected in the lorlatinib arm while both single and compound ALK mutations were reported in the crizotinib arm1

Safety:
  • The safety profile was consistent with findings from earlier analyses, with no new safety signals observed1
  • Grade 3/4 AEs occurred in 77% of patients treated with lorlatinib compared with 57% of those treated with crizotinib1
  • The higher incidence of grade 3/4 observed in the lorlatinib arm was largely attributable to elevated levels of triglycerides (25%) and cholesterol (21%), weight gain (23%) and hypertension (12%)1

  • Treatment discontinuation due to treatment-related AEs occurred in 5% and 6% of patients in the lorlatinib arm and crizotinib arm, respectively1

 

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