2024 World Conference on Lung Cancer (WCLC) - Posters-P1.12B.02 Mechanisms of Resistance to First-Line vs Later-Line Alectinib in ALK Fusion-Positive Non-Small Cell Lung Cancer

P1.12B.02 Mechanisms of Resistance to First-Line vs Later-Line Alectinib in ALK Fusion-Positive Non-Small Cell Lung Cancer

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This study examines resistance mechanisms in ALK fusion-positive advanced/metastatic non-small cell lung cancer (NSCLC) when treated with the next-generation ALK inhibitor alectinib, comparing its effectiveness as a first-line (1L) and later-line (2L) therapy. Research primarily shifted to focus on 1L alectinib after it and other next-generation inhibitors surpassed the first-generation TKI, crizotinib. The study involved 125 patients who received alectinib and underwent post-progression biopsies, with 66 receiving the drug as 1L therapy and 59 as 2L therapy. Both tissue and plasma biopsies were used to identify resistance mechanisms, such as ALK mutations, MET amplification, and histologic transformation.<br /><br />Key findings highlighted that on-target resistance (presence of ALK resistance mutations) was significantly lower when alectinib was used as a 1L therapy compared to 2L. This underscores the necessity for strategies to combat off-target resistance mechanisms. Tissue biopsies were more efficient in detecting MET amplification and identifying histologic transformation, whereas plasma biopsies were more adept at spotting multiple ALK mutations.<br /><br />The study suggests the complementary roles of tissue and plasma biopsies in understanding the resistance landscape, possibly impacting the choice of therapy post-progression. Detection of ALK mutations was generally higher in biopsies from patients on 2L alectinib. The results also indicated a potential correlation between biopsy type and the frequency of resistance mechanisms detected, suggesting that choice and sequencing of biopsies could be vital in guiding effective therapeutic strategies.<br /><br />Overall, this research contributes significantly to understanding how resistance mechanisms differ based on the alectinib treatment line in ALK fusion-positive NSCLC and the implications for treatment adjustments going forward.

Asset Subtitle

Sarah Waliany

Meta Tag

Speaker Sarah Waliany

Topic Metastatic NSCLC – Targeted Therapy

Keywords

ALK fusion-positive

non-small cell lung cancer

NSCLC

alectinib

resistance mechanisms

first-line therapy

second-line therapy

biopsies

ALK mutations

MET amplification