WCLC 2025 - Posters & ePosters-P3.18.59 Resistance Mechanisms and Sequential Therapies Following 1St Line Lorlatinib in ALK+ NSCLC: A Real-World Study (LORES CTONG2501)

P3.18.59 Resistance Mechanisms and Sequential Therapies Following 1St Line Lorlatinib in ALK+ NSCLC: A Real-World Study (LORES CTONG2501)

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This multicenter, prospective real-world study (LORES, CTONG2501) investigates resistance mechanisms and sequential treatment strategies in patients with ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) who have progressed after first-line lorlatinib therapy. Lorlatinib, a third-generation ALK tyrosine kinase inhibitor (TKI), is noted for its superior progression-free survival and brain metastasis control. However, large-scale data on resistance mechanisms post-lorlatinib treatment and subsequent therapy options are limited, motivating this study.<br /><br />Approximately 100 patients aged 18 or older across about 10 sites in China will be enrolled from June 2025 to April 2027. Eligibility includes confirmed ALK rearrangement detected by approved tests (FISH, RT-PCR, IHC, or NGS), receipt of first-line lorlatinib without prior systemic therapy besides lorlatinib, and documented disease progression. Patients with prior ALK inhibitor treatments other than lorlatinib or involvement in other interventional studies will be excluded.<br /><br />The study aims primarily to characterize resistance patterns—classified as primary or acquired resistance—and their molecular underpinnings using comprehensive ctDNA and tissue next-generation sequencing. Secondary objectives include evaluating real-world sequential treatment approaches post-lorlatinib progression, stratified by resistance mechanisms (ALK-dependent or independent), and assessing their clinical effectiveness. Exploratory goals focus on identifying optimal sequential therapies tailored to specific resistance mechanisms and analyzing their impact on patient outcomes.<br /><br />Resistance assessment involves liquid biopsies (blood ctDNA NGS) and tissue biopsies, where feasible. The study's findings are expected to guide personalized sequential treatment strategies, enhancing management and overall survival in ALK-positive NSCLC patients after frontline lorlatinib failure. Funded by Pfizer, this investigation addresses critical gaps left by prior clinical trials, such as the CROWN study, by providing large-scale, real-world evidence on resistance evolution and treatment sequencing following lorlatinib therapy.

Asset Subtitle

ziming Li

Meta Tag

Speaker ziming Li

Topic Clinical Trials in Progress

Keywords

ALK-positive NSCLC

lorlatinib resistance

third-generation ALK TKI

progression after lorlatinib

ctDNA sequencing

next-generation sequencing

sequential treatment strategies

primary and acquired resistance

liquid biopsy

real-world study