Abstract
Introduction
Alectinib is an effective second-generation ALK tyrosine kinase inhibitor (TKI) used in the first-line treatment of patients with advanced ALK-positive NSCLC. Recent studies demonstrated that the percentage of ALK-positive tumor cells in patient groups receiving crizotinib might affect outcomes. This study aimed to investigate whether the percentage of ALK-positive cells had a predictive effect in patients with advanced NSCLC who received first-line Alectinib as ALK-TKI.
Materials and methods
This retrospective study included patients with advanced-stage NSCLC who received alectinib as a first-line ALK-TKI and whose percentage of ALK-positive cells was determined by FISH at 27 different centers. Patients who received any ALK-TKI before alectinib were not included in the study. Patients were separated into two groups according to the median (40%) value of the percentage of ALK-positive cells (high-positive group ≥ 40% and low-positive group < 40%). The primary endpoint was PFS, and the secondary endpoints were OS, ORR, and PFS of the subgroups based on different threshold values for the percentage of ALK-positive cells.
Results
211 patients were enrolled (48.3% female, 51.7% male) to study. 37% (n = 78) of the patients had received chemotherapy previously. After a median of 19.4 months of follow-up, the median PFS was not reached in the high-positive group (n = 113), but it was 10.8 months in the low-positive group (n = 98) (HR 0.39; 95% CI 0.25–0.60, p < 0.001). The median OS in the high-positive group was not reached, whereas it was 22.8 months in the low-positive group (HR 0.37; 95% CI 0.22–0.63, p < 0.001). ORR was significantly higher in the high-positive group (87.2 vs. 68.5%; p = 0.002). According to the cut-off values of < 20%, 20–39%, 40–59%, and ≥ 60%, the median PFS was 4.5, 17.1, and 26 months, respectively, and could not be reached in the ≥ 60% group.
Conclusion
Our study demonstrated that the efficacy of alectinib varies significantly across patient subgroups with different percentages of ALK-positive cells. If these findings are prospectively validated, the percentage of ALK-positive cells may be used as a stratification factor in randomized trials comparing different ALK-TKIs.
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References
Bilgin B, Şendur MAN, Yücel Ş, Hizal M, Güner G, Akyürek N et al (2021) The effect of EML4-ALK break-apart ratio on crizotinib outcomes in non-small cell lung cancer harboring EML4-ALK rearrangement. J Cancer Res Clin Oncol 147(9):2637–2643
He Y, Gong R, Sun LY, Zhang ZC, Liu XY, Shao Q et al (2019) The percentage of anaplastic lymphoma kinase-positive tumor cells has clinical implications for patients with non-small cell lung cancer. Genet Test Mol Biomark 23(8):589–597
Jiang F, Wang C, Yang P, Sun P, Liu J (2021) Pathological cytomorphologic features and the percentage of ALK FISH-positive cells predict pulmonary adenocarcinoma prognosis: a prospective cohort study. World J Surg Oncol 19(1):278
Koh Y, Kim DW, Kim TM, Lee SH, Jeon YK, Chung DH et al (2011) Clinicopathologic characteristics and outcomes of patients with anaplastic lymphoma kinase-positive advanced pulmonary adenocarcinoma: suggestion for an effective screening strategy for these tumors. J Thorac Oncol 6(5):905–912
Kwak EL, Bang Y-J, Camidge DR, Shaw AT, Solomon B, Maki RG et al (2010) Anaplastic lymphoma kinase inhibition in non–small-cell lung cancer. N Engl J Med 363(18):1693–1703
Lei YY, Yang JJ, Zhang XC, Zhong WZ, Zhou Q, Tu HY et al (2016) Anaplastic lymphoma kinase variants and the percentage of ALK-positive tumor cells and the efficacy of crizotinib in advanced NSCLC. Clin Lung Cancer 17(3):223–231
Mok T, Camidge DR, Gadgeel SM, Rosell R, Dziadziuszko R, Kim DW et al (2020) Updated overall survival and final progression-free survival data for patients with treatment-naive advanced <em>ALK</em>-positive non-small-cell lung cancer in the ALEX study. Ann Oncol 31(8):1056–1064
Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW et al (2017) Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med 377(9):829–838
Rodig SJ, Mino-Kenudson M, Dacic S, Yeap BY, Shaw A, Barletta JA et al (2009) Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res 15(16):5216–5223
Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS et al (2009) Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 27(26):4247–4253
Shaw AT, Kim D-W, Nakagawa K, Seto T, Crinó L, Ahn M-J et al (2013) Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368(25):2385–2394
Solomon BJ, Mok T, Kim D-W, Wu Y-L, Nakagawa K, Mekhail T et al (2014) First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 371(23):2167–2177
Soria JC, Ho SN, Varella-Garcia M, Iafrate AJ, Solomon BJ, Shaw AT et al (2018) Correlation of extent of ALK FISH positivity and crizotinib efficacy in three prospective studies of ALK-positive patients with non-small-cell lung cancer. Ann Oncol 29(9):1964–1971
Toruner GA, Tang Z, Tang G, Medeiros LJ, Hu S (2020) Low ALK FISH positive metastatic non-small cell lung cancer (NSCLC) patients have shorter progression-free survival after treatment with ALK inhibitors. Cancer Genet 241:57–60
Zito Marino F, Liguori G, Aquino G, La Mantia E, Bosari S, Ferrero S et al (2015) Intratumor heterogeneity of ALK-rearrangements and homogeneity of EGFR-mutations in mixed lung adenocarcinoma. PLoS One 10(9):e0139264
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MH, BB, MANS, SK: contributed to the study conception and design. Material preparation, data collection were performed by all authors. Analysis were performed by MH, BB and SK. The first draft of the manuscript was written by MH and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Hizal, M., Bilgin, B., Paksoy, N. et al. The percentage of ALK-positive cells and the efficacy of first-line alectinib in advanced non-small cell lung cancer: is it a novel factor for stratification? (Turkish Oncology Group Study). J Cancer Res Clin Oncol 149, 4141–4148 (2023). https://doi.org/10.1007/s00432-022-04252-2
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DOI: https://doi.org/10.1007/s00432-022-04252-2