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First-line lorlatinib provides unprecedented improvement for patients with advanced ALK+ NSCLC

Presented by
Prof. Benjamin Solomon, Peter MacCallum Cancer Center, Australia
ASCO 2024
Phase 3, CROWN
Even after 5 years of treatment with lorlatinib, median progression-free survival (mPFS) was not reached in patients with ALK+ non-small cell lung cancer (NSCLC), a post hoc analysis of CROWN trial showed.

Lorlatinib is a third-generation ALK inhibitor that is more potent than second-generation inhibitors and was designed to cross the blood‚Äďbrain barrier to achieve high exposures in the central nervous system. Previously, interim analyses of phase 3 CROWN trial (NCT03052608) showed a significantly improved mPFS in patients with advanced ALK+ NSCLC of first-line treatment with lorlatinib versus crizotinib after 18 and 36 months of follow-up (HR 0.28 and HR 0.27, respectively). After 36 months of follow-up, PFS rate in the lorlatinib arm was 63% [1,2]. ¬†Now, Prof. Benjamin Solomon (Peter MacCallum Cancer Center, Australia) presented results of a 5-years analysis [3].

In CROWN, 296 patients with treatment-na√Įve, advanced ALK+ NSCLC were 1:1 randomised to receive lorlatinib (100 mg QD) or crizotinib (250 mg BID). At 60.2 months of median follow-up, mPFS was still not reached with lorlatinib versus 9.1 months with crizotinib (HR 0.19 [95%CI 0.13-0.27]). PFS rates at 60 months were 60% versus 8%. Lorlatinib showed superior PFS benefit irrespective of the presence or absence of baseline brain metastases (HR 0.08 vs HR 0.24). Time to intracranial progression was longer with lorlatinib. At 60 months, 92% of lorlatinib-treated patients were without intracranial progression versus 21% of patients treated with crizotinib. Intracranial progression benefit with lorlatinib was observed in patients with or without baseline brain metastases.

In addition, the efficacy benefit of lorlatinib was also observed in patients with poor prognostic biomarkers (ELM4:ALK variant3, TPP53 mut). Unlike treatment with crizotinib, treatment with lorlatinib was not associated with emerging of new ALK mutations during follow-up.

No new safety signals were observed.

Based on these results, Prof Salomon concluded that ‚Äúthe PSF observed with lorlatinib corresponds to the longest PSF ever reported with a single-agent molecular targeted treatment in advanced NSCLC ever. Therefore, first-line lorlatinib provides an unprecedented improvement in outcomes for patients with advanced ALK+ NSCLC.‚ÄĚ

  1. Shaw T, et al. N Engl J Med. 2020; 383: 2018-2029.
  2. Solomon BJ, et al. Lancet Respir Med. 2023; 11: 354-366.
  3. Solomon BJ, et al. Loralatinib vs crizotinib in treatment-na√Įve patients with advanced ALK+ non-small cell lung cancer: 5-year progression-free survival and safety in the CROWN study. Abstract LBA8503. ASCO Annual Meeting 2024, May 31-June 4, Chicago, IL, USA.

Medical writing support was provided by Marten Dooper, PhD.

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