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

After 5 years of treatment with lorlatinib, median progression-free survival (PFS) was not reached in patients with ALK-positive non-small cell lung cancer (NSCLC), a post-hoc analysis of the CROWN trial revealed.

Lorlatinib is a third-generation ALK inhibitor that is more potent than second-generation inhibitors and was designed to cross the blood-brain barrier to achieve high exposure in the CNS. In the phase 3 CROWN trial (NCT03052608), 296 participants with treatment-naïve, advanced ALK-positive NSCLC were 1:1 randomised to receive lorlatinib (100 mg once daily) or crizotinib (250 mg twice daily).

Previous interim analyses of CROWN showed a significantly improved median PFS in patients with advanced ALK-positive NSCLC who received 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, the PFS rate in the lorlatinib arm was 63% [1,2]. Now, Prof. Benjamin Solomon (Peter MacCallum Cancer Centre, Australia) presented the results of a 5-year analysis [3].

At a median follow-up of 60.2 months, the median PFS was still not reached in participants treated with lorlatinib versus 9.1 months in those treated with crizotinib (HR 0.19; 95% CI 0.13–0.27). The PFS rates at 60 months were 60% and 8%, respectively. Lorlatinib showed superior PFS irrespective of the presence or absence of brain metastases at baseline (HR 0.08 vs HR 0.24). The time to intracranial progression was also longer with lorlatinib. At 60 months, 92% of lorlatinib-treated participants did not have intracranial progression, versus 21% of those treated with crizotinib. The intracranial progression benefit of lorlatinib was observed both in participants with or without brain metastases at baseline.

In addition, the efficacy benefit of lorlatinib was also observed in participants with poor prognostic biomarkers (i.e. ELM4:ALK variant3, TP53 mutation). Unlike crizotinib, lorlatinib was not associated with the emergence of new ALK mutations during follow-up. No new safety signals were observed.

Based on these results, Prof. Solomon concluded that “the PFS observed with lorlatinib corresponds to the longest PFS ever reported with a single-agent targeted treatment for advanced NSCLC. Therefore, first-line lorlatinib provides an unprecedented improvement in outcomes for patients with advanced ALK-positive NSCLC.”

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. Lorlatinib vs crizotinib in treatment-naïve 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, 31 May–4 June, Chicago, IL, USA.

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Posted on 18 July 202418 July 2024