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Management strategies for intracranial progression in ALK-positive non-small cell lung cancer: a real-world cohort study

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Abstract

Purpose

ALK-positive NSCLC patients exhibit a particularly high propensity for the development of brain metastases. Current guidelines suggest transit to next-line therapy (SysTx) or local radiotherapy (RadTx) including whole-brain radiotherapy and radiosurgery. However, the clinical impact of these two strategies remains unclear.

Methods

We conducted a retrospective analysis focusing on patients with stage IV ALK-positive NSCLC who underwent first-line ALK TKI treatment. Patients with intracranial progression may receive two different treatment strategies: SysTx and RadTx. Our objective was to investigate the outcomes associated with these two distinct treatment pathways.

Results

A total 20 patients of ALK-positive NSCLC who received first-line ALK TKI therapy and subsequently developed intracranial progression were enrolled. About 55% of patients had brain metastasis initially. Nine patients (45%) were treated with crizotinib at first. Patients treated with crizotinib demonstrated a significantly shorter intracranial PFS1 (crizotinib: 8.27 months vs. others: 27.0 months, p = 0.006). Following intracranial progression, approximately 60% of patients transitioned to the next line of systemic treatment (SysTx), while the remaining 40% opted for local cranial radiotherapy (RadTx). Intriguingly, our analysis revealed no statistically significant difference in intracranial progression-free survival (PFS2) between these two distinct treatment strategies. (SysTx: 20.87 months vs. RadTx: 28.23 months, p = 0.461).

Conclusion

The intracranial progression-free survival showed no difference between the two strategies suggesting that both local radiotherapy and systemic therapy may be valid options. Individualized strategy, molecular analysis, and multidisciplinary conferences may all play a pivotal role in decision-making.

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References

  1. Ceddia S, Codacci-Pisanelli G (2021) Treatment of brain metastases in ALK-positive non-small cell lung cancer. Crit Rev Oncol Hematol 165:103400

    Article  PubMed  Google Scholar 

  2. Peters S, Bexelius C, Munk V, Leighl N (2016) The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small-cell lung cancer. Cancer Treat Rev 45:139–162

    Article  PubMed  Google Scholar 

  3. Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman JR, Bharat A et al (2023) NCCN guidelines insights: non-small cell lung cancer, version 2.2023. J Natl Compr Canc Netw 21(4):340–350

    Article  CAS  PubMed  Google Scholar 

  4. Nelson TA, Wang N (2023) Targeting lung cancer brain metastases: a narrative review of emerging insights for anaplastic Lymphoma kinase (ALK)-positive Disease. Transl Lung Cancer Res 12(2):379–392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Buss EJ, Wang TJC (2018) Treatment of lung adenocarcinoma brain metastases: what is the role of radiotherapy in the age of precision medicine? Transl Lung Cancer Res 7(Suppl 4):S318–S20

    Article  PubMed  PubMed Central  Google Scholar 

  6. Johung KL, Yeh N, Desai NB, Williams TM, Lautenschlaeger T, Arvold ND et al (2016) Extended survival and prognostic factors for patients with ALK-rearranged non-small-cell lung cancer and brain metastasis. J Clin Oncol 34(2):123–129

    Article  CAS  PubMed  Google Scholar 

  7. Dempke WC, Edvardsen K, Lu S, Reinmuth N, Reck M, Inoue A (2015) Brain metastases in NSCLC - are TKIs changing the treatment strategy? Anticancer Res 35(11):5797–5806

    CAS  PubMed  Google Scholar 

  8. Liao HR, Chiang CL, Shen CI, Chen CJ, Yang HC, Wu HM et al (2022) EGFR mutant status and tyrosine-kinase inhibitors affect the GKRS outcomes for NSCLC brain metastases. J Neurooncol 159(3):675–684

    Article  CAS  PubMed  Google Scholar 

  9. Matsunaga S, Shuto T (2021) Outcomes of gamma knife radiosurgery for brain metastases from anaplastic lymphoma kinase rearrangement-positive and EGFR mutation-positive non-small cell lung cancer. Cureus 13(12):e20398

    PubMed  PubMed Central  Google Scholar 

  10. Weber B, Winterdahl M, Memon A, Sorensen BS, Keiding S, Sorensen L et al (2011) Erlotinib accumulation in brain metastases from non-small cell lung cancer: visualization by positron emission tomography in a patient harboring a mutation in the epidermal growth factor receptor. J Thorac Oncol 6(7):1287–1289

    Article  PubMed  Google Scholar 

  11. Togashi Y, Masago K, Masuda S, Mizuno T, Fukudo M, Ikemi Y et al (2012) Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharmacol 70(3):399–405

    Article  CAS  PubMed  Google Scholar 

  12. Chen YC, Lee CC, Chiang CL, Yang HC, Wu HM, Chen CJ et al Combined BBB-penetrant tyrosine kinase inhibitor and intracranial radiotherapy versus BBB-penetrant tyrosine kinase inhibitor alone for the treatment of EGFR-mutated non-small cell lung cancer patients with brain metastases. https://doi.org/10.21203/rs.3.rs-2960400/v1

  13. Cho A, Untersteiner H, Hirschmann D, Shaltout A, Gobl P, Dorfer C et al (2020) Gamma knife radiosurgery for brain metastases in non-small cell lung cancer patients treated with immunotherapy or targeted therapy. Cancers (Basel). 12(12)

  14. Vogelbaum MA, Brown PD, Messersmith H, Brastianos PK, Burri S, Cahill D et al (2022) Treatment for brain metastases: ASCO-SNO-ASTRO guideline. J Clin Oncol 40(5):492–516

    Article  CAS  PubMed  Google Scholar 

  15. Thomas NJ, Myall NJ, Sun F, Patil T, Mushtaq R, Yu C et al (2022) Brain metastases in EGFR- and ALK-Positive NSCLC: outcomes of central nervous system-penetrant tyrosine kinase inhibitors alone versus in combination with radiation. J Thorac Oncol 17(1):116–129

    Article  CAS  PubMed  Google Scholar 

  16. Zhang Z, Guo H, Lu Y, Hao W, Han L (2019) Anaplastic lymphoma kinase inhibitors in non-small cell Lung cancer patients with brain metastases: a meta-analysis. J Thorac Dis 11(4):1397–1409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Costa DB, Kobayashi S, Pandya SS, Yeo WL, Shen Z, Tan W et al (2011) CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol 29(15):e443–e445

    Article  PubMed  Google Scholar 

  18. Kim DW, Mehra R, Tan DSW, Felip E, Chow LQM, Camidge DR et al (2016) Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol 17(4):452–463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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

    Article  CAS  PubMed  Google Scholar 

  20. Camidge DR, Kim HR, Ahn MJ, Yang JC, Han JY, Lee JS et al (2018) Brigatinib versus crizotinib in ALK-positive non-small-cell Lung cancer. N Engl J Med 379(21):2027–2039

    Article  CAS  PubMed  Google Scholar 

  21. Kodama T, Hasegawa M, Takanashi K, Sakurai Y, Kondoh O, Sakamoto H (2014) Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases. Cancer Chemother Pharmacol 74(5):1023–1028

    Article  CAS  PubMed  Google Scholar 

  22. Shaw AT, Bauer TM, de Marinis F, Felip E, Goto Y, Liu G et al (2020) First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med 383(21):2018–2029

    Article  CAS  PubMed  Google Scholar 

  23. Felip E, Shaw AT, Bearz A, Camidge DR, Solomon BJ, Bauman JR et al (2021) Intracranial and extracranial efficacy of lorlatinib in patients with ALK-positive non-small-cell lung cancer previously treated with second-generation ALK TKIs. Ann Oncol 32(5):620–630

    Article  CAS  PubMed  Google Scholar 

  24. Tan AC, Itchins M, Khasraw M (2020) Brain metastases in lung cancers with emerging targetable fusion drivers. Int J Mol Sci 21(4)

  25. Ou SH, Klempner SJ, Azada MC, Rausei-Mills V, Duma C (2015) Radiation necrosis presenting as pseudoprogression (PsP) during alectinib treatment of previously radiated brain metastases in ALK-positive NSCLC: implications for Disease assessment and management. Lung Cancer 88(3):355–359

    Article  PubMed  Google Scholar 

  26. Miller JA, Bennett EE, Xiao R, Kotecha R, Chao ST, Vogelbaum MA et al (2016) Association between radiation necrosis and tumor biology after stereotactic radiosurgery for brain metastasis. Int J Radiat Oncol Biol Phys 96(5):1060–1069

    Article  PubMed  Google Scholar 

  27. Gondi V, Pugh SL, Tome WA, Caine C, Corn B, Kanner A et al (2014) Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol 32(34):3810–3816

    Article  PubMed  PubMed Central  Google Scholar 

  28. Tsao MN, Xu W, Wong RK, Lloyd N, Laperriere N, Sahgal A et al (2018) Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev 1(1):CD003869

    PubMed  Google Scholar 

  29. Zhang I, Zaorsky NG, Palmer JD, Mehra R, Lu B (2015) Targeting brain metastases in ALK-rearranged non-small-cell lung cancer. Lancet Oncol 16(13):e510–e521

    Article  CAS  PubMed  Google Scholar 

  30. Solomon BJ, Cappuzzo F, Felip E, Blackhall FH, Costa DB, Kim DW et al (2016) Intracranial efficacy of crizotinib versus chemotherapy in patients with advanced ALK-positive non-small-cell lung cancer: results from PROFILE 1014. J Clin Oncol 34(24):2858–2865

    Article  CAS  PubMed  Google Scholar 

  31. Costa DB, Shaw AT, Ou SH, Solomon BJ, Riely GJ, Ahn MJ et al (2015) Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases. J Clin Oncol 33(17):1881–1888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. McCoach CE, Blakely CM, Banks KC, Levy B, Chue BM, Raymond VM et al (2018) Clinical utility of cell-free DNA for the detection of ALK fusions and genomic mechanisms of ALK inhibitor resistance in non-small cell lung cancer. Clin Cancer Res 24(12):2758–2770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sanchez-Herrero E, Serna-Blasco R, Ivanchuk V, Garcia-Campelo R, Domine Gomez M, Sanchez JM et al (2021) NGS-based liquid biopsy profiling identifies mechanisms of resistance to ALK inhibitors: a step toward personalized NSCLC treatment. Mol Oncol 15(9):2363–2376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Dagogo-Jack I, Yoda S, Lennerz JK, Langenbucher A, Lin JJ, Rooney MM et al (2020) MET alterations are a recurring and actionable resistance mechanism in ALK-positive lung cancer. Clin Cancer Res 26(11):2535–2545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Chest Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei, 11217, Taiwan

    Chia-I Shen, Chi-Lu Chiang, Hsu-Ching Huang, Yen-Han Tseng, Yung-Hung Luo & Yuh-Min Chen

  2. School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Chia-I Shen, Chi-Lu Chiang, Hsu-Ching Huang, Yen-Han Tseng, Yung-Hung Luo, Huai-Che Yang & Yuh-Min Chen

  3. Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Chia-I Shen & Chi-Lu Chiang

  4. Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan

    Huai-Che Yang

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Contributions

The study conception and design were done by CIS. Data acquisition and analysis were done by CIS, CLC, HSC and YHT. The manuscript writing was done by CIS. Critical revision and final approval of the manuscript were done by all authors. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yuh-Min Chen.

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Competing interests

CIS, CLC, HSC, YHT and YMC has received honoraria from Pfizer, Takeda, Chugai Pharmaceutical.

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The authors declare they have no non-financial interests.

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Shen, CI., Chiang, CL., Huang, HC. et al. Management strategies for intracranial progression in ALK-positive non-small cell lung cancer: a real-world cohort study. J Neurooncol 165, 459–465 (2023). https://doi.org/10.1007/s11060-023-04497-y

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  • DOI: https://doi.org/10.1007/s11060-023-04497-y

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