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. 2024 Nov;19(11):1539-1549.
doi: 10.1016/j.jtho.2024.07.009. Epub 2024 Jul 15.

Impact of EML4-ALK Variants and Co-Occurring TP53 Mutations on Duration of First-Line ALK Tyrosine Kinase Inhibitor Treatment and Overall Survival in ALK Fusion-Positive NSCLC: Real-World Outcomes From the GuardantINFORM database

Kaushal Parikh  1 , Anastasios Dimou  2 , Konstantinos Leventakos  2 , Aaron S Mansfield  2 , Mohamed Shanshal  2 , Yin Wan  3 , Huamao M Lin  3 , Sylvie Vincent  3 , Jennifer Elliott  4 , Ioana R Bonta  5
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Free article

Impact of EML4-ALK Variants and Co-Occurring TP53 Mutations on Duration of First-Line ALK Tyrosine Kinase Inhibitor Treatment and Overall Survival in ALK Fusion-Positive NSCLC: Real-World Outcomes From the GuardantINFORM database

Kaushal Parikh et al. J Thorac Oncol. 2024 Nov.
Free article

Abstract

Introduction: Tyrosine kinase inhibitors (TKIs) are first-line treatment options for ALK-positive (ALK+) NSCLC. Factors such as variant allele frequencies (VAFs), EML4-ALK fusion variant, and concurrent TP53 mutations (TP53mt) in circulating tumor DNA (ctDNA) may affect treatment outcomes. We evaluated their effects on time to discontinuation (TTD) of first-line treatment with next-generation ALK TKIs in a real-world setting.

Methods: Adults with advanced or metastatic NSCLC and ctDNA-detected ALK fusion who received first-line next-generation ALK TKI monotherapy were identified in GuardantINFORM. Effects of ALK fusion VAF, EML4-ALK variants, and TP53mt detection on TTD were evaluated.

Results: A total of 307 patients with ALK fusion in baseline ctDNA received first-line alectinib (n = 280), brigatinib (n = 15), lorlatinib (n = 9), or ceritinib (n = 3); 150 patients (49%) had ALK-fusion VAF greater than or equal to 1%. Among 232 patients with EML4-ALK fusions (v1, 50%; v3, 36%), TP53mt co-occurred with v1 in 42 (18%) and v3 in 32 (14%). Patients with VAF less than 1% versus greater than or equal to 1% had a median TTD of 32.2 (95% confidence interval [CI]: 20.7-not estimable [NE]) versus 14.7 months (10.4-19.9; hazard ratio [HR] = 1.57 [95% CI: 1.09-2.26]; p = 0.0146). Median TTD was 13.1 (9.5-19.9) versus 27.6 months (17.3-NE) in patients with versus without TP53mt detected (HR = 1.53 [1.07-2.19]; p = 0.0202) and 20.3 (14.4-NE) versus 11.5 months (7.4-31.1) in patients with v1 versus v3 (HR = 1.29 [0.83-2.01]; p = 0.2641). Patients with TP53mt and v3 had a median TTD of 7.4 months (95% CI: 4.2-31.1).

Conclusion: High ctDNA VAF, EML4-ALK v3, and TP53mt were associated with early discontinuation of first-line ALK TKIs.

Keywords: Biomarkers; Carcinoma; Circulating Tumor DNA; EML4-ALK fusion protein; Non–Small-Cell Lung Cancer; Tumor Suppressor Protein p53.

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Conflict of interest statement

Disclosure Dr. Parikh holds consulting/advisory roles with AstraZeneca, Guardant Health (to institution) and receives honoraria from OncLive, MJH Life Sciences, and DAVA Oncology (to institution) and research funding from Verastem Oncology (to institution). Dr. Dimou holds consulting/advisory roles with TP Therapeutics, Guardant Health, Anheart Therapeutics, and ChromaCode and received travel, accommodations, and expenses from Guardant Health, honoraria from Roche/Genentech, Intellisphere, and (rest to institution) Intellisphere, research funding from Merck, Guardant Health, and (rest to institution) Syntrix Biosystems, Novartis, Sorrento Therapeutics, and AnHeart Therapeutics, and has other relationship (to institution) with Rising Tide Foundation. Dr. Leventakos holds consulting/advisory roles with (all to institution) AstraZeneca, Boehringer Ingelheim, Targeted Oncology, OncLive, Takeda, Jazz Pharmaceuticals, Mirati Therapeutics, Janssen Oncology, Regeneron, MJH Life Sciences, and Amgen and received research funding from (all to institution) AstraZeneca and Mirati Therapeutics. Dr. Mansfield was supported by a Mark Foundation ASPIRE award, NCI grant R21 CA251923, R33 CA272271, Department of Defense W81XWH-22-1-0021 Concept Award, received honoraria from advisory boards for (all to institution) AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Genentech, Janssen, and Sanofi), travel and honoraria from Shanghai Roche Pharmaceuticals, was a non-renumerated member of the Mesothelioma Applied Research Foundation and is member of the Friends of Patan Hospital Board of Directors. Dr. Wan holds employment with Takeda. Dr. Lin holds employment with Takeda. Dr. Vincent holds employment with Takeda. Dr. Elliott holds employment with Takeda. Dr. Bonta holds consulting roles with Roche and advisory board for Roche and Bayer. The remaining authors declare no conflict of interest.

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