Abstract 4720: Evaluation of lorlatinib efficacy using plasma DNA

Abstract Background: Lorlatinib is approved globally as a second-line treatment for ALK-positive NSCLC following resistance to alectinib, with Japan being the first country to approve its use. This study is the first to analyze lorlatinib’s efficacy in such patients by integrating ctDNA analysis to explore predictive markers and resistance mechanisms. Methods: This multi-center prospective study enrolled patients with ALK-rearranged NSCLC resistant to alectinib, with no prior exposure to ALK-TKIs other than alectinib and brigatinib. Patient eligibility required documented ALK translocations, CT imaging within 56 days, and written consent. Blood and pathology samples were collected pre- and post-treatment. Clinical data were integrated using an Electronic Data Capture (EDC) system. ctDNA analysis was conducted via Guardant Health, focusing on mutation emergence, persistence, and correlation with treatment outcomes. Results: Among 27 evaluable patients, partial response (PR) was observed in 37% of cases, while stable disease (SD) was noted in 14.8%. The median progression-free survival (PFS) was 6.5 months (95% CI: 1.8-23.5), consistent with previously reported outcomes for lorlatinib-treated patients. Disease progression commonly involved the CNS (18.5% of cases). Genetic analysis of ctDNA revealed that patients with TP53 mutations had a reduced PFS of 2.9 months compared to 6.7 months in wild-type TP53 cases, suggesting a potential role as a poor prognostic marker. Additionally, persistent ALK fusions or new rearrangements were observed and correlated with reduced efficacy, indicating coactivation of other oncogenic pathways. Notably, two patients exhibited ALK secondary mutations (L1196M) following alectinib treatment, both of whom responded with a partial response (PR) to lorlatinib. Conclusions: This exploratory study highlights the complexity of resistance mechanisms in ALK-rearranged NSCLC treated with lorlatinib, demonstrating ctDNA’s potential as a predictive biomarker for treatment outcomes. The persistence and emergence of specific mutations, such as in TP53 and ALK, underscore the need for further investigation into combination or personalized therapeutic strategies. Despite the study’s limited sample size, these findings offer critical insights into the genomic landscape influencing lorlatinib efficacy following alectinib resistance. Citation Format: Yasushi Goto, Tadaaki Yamada, Akehiro Nishiyama, Naoko Aragane, Minehiko Inomata, Hiroki Nagai, Satoshi Takahashi, Kazuhito Miyazaki, Yukari Tsubata, Hiroaki Akamatsu, Tetsuya Mitsudomi. Evaluation of lorlatinib efficacy using plasma DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4720.