Nivolumab ile tedavi edilen ileri evre küçük hücreli dışı akciğer kanserinde tedavi sırasındaki dNLR ve metastatik yük sağkalımı öngörür

Öz

Amaç: İleri evre küçük hücreli dışı akciğer kanserinde (KHDAK) immün kontrol noktası inhibitörleri ile sağkalım avantajı elde edilmesine rağmen, sonuçlar heterojen kalmaktadır. PD-L1 ekspresyonu yerleşik bir biyobelirteç olsa da, tedavi sırasındaki sistemik inflamatuar dinamiklerin prognostik önemi ve immünoterapi alan hastalarda Endotel Aktivasyon ve Stres İndeksi (EASIX) gibi endotel stres tabanlı indekslerin kullanımı hakkında daha az bilgi mevcuttur. Gereç ve Yöntemler: Nivolumab ile tedavi edilen ileri evre KHDAK'li hastalar retrospektif olarak değerlendirildi. PD-L1 ekspresyonu, metastatik yük, bazal inflamatuar parametreler ve bazal EASIX kaydedildi. 3. aydaki türetilmiş nötrofil-lenfosit oranı (dNLR) ve NLR'deki boylamsal değişimler (ΔNLR) dahil olmak üzere tedavi sırasındaki inflamatuar belirteçler analiz edildi. Genel sağkalım (OS) ve progresyonsuz sağkalım (PFS), Kaplan–Meier ve Cox regresyon modelleri kullanılarak değerlendirildi. Zaman bağımlı yanlılığı (time-dependent bias) önlemek amacıyla 3. ay landmark (sınır değer) analizleri yapıldı. Bulgular: Çalışmaya 81 hasta dahil edildi. Yüksek PD-L1 ekspresyonu (≥%50), OS'de anlamlı iyileşme ile ilişkili bulundu ancak PFS için bağımsız prognostik önemi korunmadı. Özellikle dört veya daha fazla metastatik organ tutulumu başta olmak üzere yüksek metastatik yük, daha kötü OS ile ilişkilendirildi. Landmark düzeltmeli analizlerde, 3. aydaki dNLR hem OS hem de PFS ile bağımsız olarak ilişkili bulunurken; ΔNLR'nin OS ile ilişkili olması, tedavi sırasındaki olumlu immün-inflamatuar değişikliklerin sağkalım iyileşmesiyle korele olduğunu gösterdi. Bazal EASIX skorunun ise OS veya PFS ile ilişkisi saptanmadı. Sonuç: Nivolumab alan ileri evre KHDAK'de sağkalım sonuçları; temel olarak tümör biyolojisi, hastalık yükü ve tedavi sırasında gelişen immün-inflamatuar dinamikler tarafından yönlendirilmektedir. Tedavi sırasındaki inflamatuar belirteçler, özellikle dNLR ve ΔNLR, bazal indekslerden daha klinik olarak ilgili prognostik bilgiler sağlarken; bazal EASIX'in bu ortamda sınırlı kullanışlılığa sahip olduğu görülmektedir. Bu bulgular, immünoterapide biyobelirteç temelli risk sınıflamasında tedaviye özgü ve zamana bağımlı bir yaklaşımı desteklemektedir.

Anahtar Kelimeler

• nivolumab
• türetilmiş nötrofil/lenfosit oranı(dNLR)
• küçük hücreli dışı akciğer kanseri
• sistemik inflamasyon

On-treatment dNLR and metastatic burden predict survival in advanced non-small-cell lung cancer treated with nivolumab

Öz

Aim: Despite the survival benefit achieved with immune checkpoint inhibitors in advanced non–small-cell lung cancer (NSCLC), outcomes remain heterogeneous. While PD-L1 expression is an established biomarker, less is known about the prognostic relevance of on-treatment systemic inflammatory dynamics and the utility of endothelial stress–based indices such as the Endothelial Activation and Stress Index (EASIX) in patients receiving immunotherapy. Material and Methods: We retrospectively evaluated patients with advanced NSCLC treated with nivolumab. PD-L1 expression, metastatic burden, baseline inflammatory parameters, and baseline EASIX were recorded. On-treatment inflammatory markers, including derived neutrophil-to-lymphocyte ratio (dNLR) at 3 months and longitudinal changes in NLR (ΔNLR), were analyzed. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan–Meier and Cox regression models. To account for time-dependent bias, 3-month landmark analyses were performed. Results: Eighty-one patients were included. High PD-L1 expression (≥50%) was associated with significantly improved OS but did not retain independent prognostic significance for PFS. A high metastatic burden, particularly involvement of four or more metastatic organs, was associated with inferior OS. In landmark-adjusted analyses, dNLR at 3 months was independently associated with both OS and PFS, while ΔNLR was associated with OS, indicating that favorable on-treatment immune–inflammatory changes correlated with improved survival. Baseline EASIX was not associated with either OS or PFS. Conclusion: In nivolumab-treated advanced NSCLC, survival outcomes are primarily driven by tumor biology, disease burden, and immune–inflammatory dynamics evolving during therapy. On-treatment inflammatory markers, particularly dNLR and ΔNLR, provide more clinically relevant prognostic information than baseline indices, whereas baseline EASIX appears to have limited utility in this setting. These findings support a treatment-specific, time-dependent approach to biomarker-based risk stratification in immunotherapy.

Anahtar Kelimeler

• non-small-cell lung cancer
• nivolumab
• dnlr
• immune checkpoint inhibitors
• metastatic burden
• easix
• systemic inflammation
• survival analysis
• immunotherapy

Kaynakça

1. Zimmermann S, Peters S, Owinokoko T, Gadgeel SM. Immune checkpoint inhibitors in the management of lung cancer. Am Soc Clin Oncol Educ Book 2018; 38: 682-95.
2. Borghaei H, Gettinger S, Vokes EE, Chow LQM, Burgio MA, de Castro Carpeno J et al. Five-Year Outcomes From the Randomized, Phase III Trials CheckMate 017 and 057: Nivolumab Versus Docetaxel in Previously Treated Non-Small-Cell Lung Cancer. J Clin Oncol 2021; 39: 723-33.
3. Schoenfeld AJ, Hellmann MD. Acquired resistance to immune checkpoint inhibitors. Cancer Cell 2020; 37: 443-55.
4. Havel JJ, Chowell D, Chan TA. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer 2019; 19: 133-50.
5. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010; 140: 883-99.
6. Nakaya A, Kurata T, Yoshioka H, Takeyasu Y, Niki M, Kibata K et al. Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with advanced non-small-cell lung cancer treated with nivolumab. Int J Clin Oncol 2018; 23: 634-40.
7. Takeda T, Takeuchi M, Saitoh M, Takeda S. Neutrophil-to-lymphocyte ratio after four weeks of nivolumab administration as a predictive marker in patients with pretreated non-small-cell lung cancer. Thorac Cancer 2018; 9: 1291-9.
8. Liu D, Schilling B, Liu D, Sucker A, Livingstone E, Jerby-Arnon L et al. Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma. Nat Med 2019; 25: 1916-27.

9. Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015; 373: 123-35.
10. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015; 373: 1627-39.
11. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016; 375: 1823-33.
12. Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 2017; 18: e143-52.
13. Gettinger S, Horn L, Jackman D, Spigel D, Antonia S, Hellmann M et al. Five-Year Follow-Up of Nivolumab in Previously Treated Advanced Non-Small-Cell Lung Cancer: Results From the CA209-003 Study. J Clin Oncol 2018; 36: 1675-84.
14. Bagley SJ, Kothari S, Aggarwal C, Bauml JM, Alley EW, Evans TL et al. Pretreatment neutrophil-to-lymphocyte ratio as a marker of outcomes in nivolumab-treated patients with advanced non-small-cell lung cancer. Lung Cancer 2017; 106: 1-7.
15. Dudnik E, Moskovitz M, Daher S, Shamai S, Hanovich E, Grubstein A et al. Effectiveness and safety of nivolumab in advanced non-small cell lung cancer: The real-life data. Lung Cancer 2018; 126: 217-23.
16. Vokes EE, Ready N, Felip E, Horn L, Burgio MA, Antonia SJ et al. Nivolumab versus docetaxel in previously treated advanced non-small-cell lung cancer (CheckMate 017 and CheckMate 057): 3-year update and outcomes in patients with liver metastases. Ann Oncol 2018; 29: 959-65.
17. Park S, Go SI, Lee GW. The Endothelial Activation and Stress Index (EASIX) score is an independent prognostic factor in patients with diffuse large B-cell lymphoma. BMC Cancer 2022; 22: 816.
18. Go SI, Park S, Kang MH, Kim HG, Kang JH, Kim JH et al. Endothelial activation and stress index (EASIX) as a predictive biomarker in small cell lung cancer. Cancer Biomark 2022; 35: 217-25.
19. Cavdar VC, Gokmen Y, Aric M, Altunkaya T, Erdem CG, Gulturk I et al. The Prognostic Value of the EASIX Score in Patients with Metastatic Pancreatic Cancer. Diagnostics (Basel) 2025; 15: 1740.
20. Gu JS, Ryu JW, Yu SH, Chung HS, Hwang JE, Bae WK et al. Prognostic value of the endothelial activation and stress index in patients with upper tract urothelial cancer undergoing radical nephroureterectomy. Investig Clin Urol 2022; 63: 623-30.
21. Anderson JR, Cain KC, Gelber RD. Analysis of survival by tumor response. J Clin Oncol 1983; 1: 710-19.
22. Suissa S. Immortal time bias in pharmacoepidemiology. Am J Epidemiol 2008; 167: 492-9.