JOURNAL of
ONCOLOGICAL
SCIENCES

ORIGINAL RESEARCH ARTICLE

Association of the Immune-Inflammation-Nutritional Parameters with Immune Checkpoint Inhibitor Outcomes in Patients with Advanced Non-Small Cell Lung Cancer
Received Date : 19 Dec 2021
Accepted Date : 14 Feb 2022
Available Online : 25 Feb 2022
Doi: 10.37047/jos.2021-87477 - Article's Language: EN
J Oncol Sci. 2022;8(1):43-53
This is an open access article under the CC BY-NC-ND license
ABSTRACT
Objective: Patient prognosis is determined not only based on tumor characteristics, host inflammation and the immune-nutritional index are also important. The aim of the study was to investigate the prognostic and predictive role of pretreatment immune-inflammation- nutritional biomarkers in patients with advanced non-small cell lung cancer who were treated with immune checkpoint inhibitors (ICIs). Material and Methods: All consecutive patients aged over 18 years who were treated with at least one cycle of ICIs at our centers were retrospectively reviewed. We evaluated modified Glasgow Prognostic Score (mGPS), Lung Immune Prognostic Index, serum C-reactive protein (CRP) and lactate dehydrogenase (LDH) as candidate predictors for response and survival. Results: A total of 102 patients who were treated with ICIs between March 2017 and October 2021 were reviewed. Among the patient cohort, 46.1% and 53.9% were treatmentnaive and platinum pretreated, respectively. Programmed death ligand-1 positivity (p=0.048), presence of bone metastasis (p=0.048), increasing serum CRP levels (p=0.018), and mGPS 1 (p=0.040) were independently associated with inferior progression-free survival. Presence of liver metastasis (p=0.036), serum LDH level>upper level of normal (p=0.048), Eastern Cooperative Oncology Group Performance Status (ECOG PS)2 (p=0.026), and increasing CRP levels (p<0.001) were independently associated with poorer overall survival. ECOG PS2 (p=0.001), the presence of bone metastasis (p=0.049), and mGPS 1 (p=0.016) were independently associated with poorer disease control rate. Conclusion: We found that immune-inflammation-nutritional parameters were reliable prognostic and predictive biomarkers to select patients with a greater likelihood of benefiting from ICIs.
KAYNAKLAR
  1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674. [Crossref]  [PubMed] 
  2. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627-1639. [Crossref]  [PubMed]  [PMC] 
  3. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123-135. [Crossref]  [PubMed]  [PMC] 
  4. Reck M, Rodríguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823-1833. [Crossref]  [PubMed] 
  5. Horn L, Spigel DR, Vokes EE, et al. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, Phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol. 2017;35(35):3924-3933. [Crossref]  [PubMed]  [PMC] 
  6. Rittmeyer A, Barlesi F, Waterkamp D, et al; OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389(10066):255-265. Erratum in: Lancet. 2017;389(10077):e5. [Crossref]  [PubMed]  [PMC] 
  7. West H, McCleod M, Hussein M, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(7):924-937. [Crossref]  [PubMed] 
  8. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. [Crossref]  [PubMed] 
  9. Paz-Ares L, Luft A, Vicente D, et al; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018;379(21):2040-2051. [Crossref]  [PubMed] 
  10. Hanna NH, Schneider BJ, Temin S, et al. Therapy for stage IV non-small-cell lung cancer without driver alterations: ASCO and OH (CCO) joint guideline update. J Clin Oncol. 2020;38(14):1608-1632. [Crossref]  [PubMed] 
  11. Mok TSK, Wu YL, Kudaba I, et al; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393(10183):1819-1830. [PubMed] 
  12. Sacher AG, Gandhi L. Biomarkers for the clinical use of PD-1/PD-L1 inhibitors in non-small-cell lung cancer: a review. JAMA Oncol. 2016;2(9):1217-1222. [Crossref]  [PubMed] 
  13. Lu S, Stein JE, Rimm DL, et al. Comparison of biomarker modalities for predicting response to PD-1/PD-L1 checkpoint blockade: a systematic review and meta-analysis. JAMA Oncol. 2019;5(8):1195-1204. [Crossref]  [PubMed]  [PMC] 
  14. Prelaj A, Tay R, Ferrara R, Chaput N, Besse B, Califano R. Predictive biomarkers of response for immune checkpoint inhibitors in non-small-cell lung cancer. Eur J Cancer. Jan 2019;106:144-159. [Crossref]  [PubMed] 
  15. Riedl JM, Barth DA, Brueckl WM, et al. C-reactive protein (CRP) levels in immune checkpoint inhibitor response and progression in advanced non-small cell lung cancer: a bi-center study. Cancers (Basel). 2020;12(8):2319. [Crossref]  [PubMed]  [PMC] 
  16. Mezquita L, Auclin E, Ferrara R, et al. Association of the lung immune prognostic index with immune checkpoint inhibitor outcomes in patients with advanced non-small cell lung cancer. JAMA Oncol. 2018;4(3):351-357. [Crossref]  [PubMed]  [PMC] 
  17. Sorich MJ, Rowland A, Karapetis CS, Hopkins AM. Evaluation of the lung immune prognostic index for prediction of survival and response in patients treated with atezolizumab for NSCLC: pooled analysis of clinical trials. J Thorac Oncol. 2019;14(8):1440-1446. [Crossref]  [PubMed] 
  18. Matsubara T, Takamori S, Haratake N, et al. The impact of immune-inflammation-nutritional parameters on the prognosis of non-small cell lung cancer patients treated with atezolizumab. J Thorac Dis. 2020;12(4):1520-1528. [Crossref]  [PubMed]  [PMC] 
  19. Oya Y, Yoshida T, Kuroda H, et al. Predictive clinical parameters for the response of nivolumab in pretreated advanced non-small-cell lung cancer. Oncotarget. 2017;8(61):103117-103128. [Crossref]  [PubMed]  [PMC] 
  20. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. [Crossref]  [PubMed] 
  21. Jin J, Hu K, Zhou Y, Li W. Clinical utility of the modified Glasgow prognostic score in lung cancer: A meta-analysis. PLoS One. 2017;12(9):e0184412. [Crossref]  [PubMed]  [PMC] 
  22. Hu Y, Shen J, Liu R, et al. Prognostic value of pretreatment prognostic nutritional index in non-small cell lung cancer: A systematic review and meta-analysis. Int J Biol Markers. 2018;33(4):372-378. [Crossref]  [PubMed] 
  23. Mandaliya H, Jones M, Oldmeadow C, Nordman II. Prognostic biomarkers in stage IV non-small cell lung cancer (NSCLC): neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), platelet to lymphocyte ratio (PLR) and advanced lung cancer inflammation index (ALI). Transl Lung Cancer Res. 2019;8(6):886-894. [Crossref]  [PubMed]  [PMC] 
  24. Fiala O, Hosek P, Pesek M, et al. Prognostic role of serum C-reactive protein in patients with advanced-stage NSCLC treated with pemetrexed. Neoplasma. 2017;64(4):605-610. [Crossref]  [PubMed] 
  25. Iivanainen S, Ahvonen J, Knuuttila A, Tiainen S, Koivunen JP. Elevated CRP levels indicate poor progression-free and overall survival on cancer patients treated with PD-1 inhibitors. ESMO Open. 2019;4(4):e000531. [Crossref]  [PubMed]  [PMC] 
  26. Demaria S, Pikarsky E, Karin M, et al. Cancer and inflammation: promise for biologic therapy. J Immunother. 2010;33(4):335-351. [Crossref]  [PubMed]  [PMC] 
  27. Damuzzo V, Solito S, Pinton L, et al. Clinical implication of tumor-associated and immunological parameters in melanoma patients treated with ipilimumab. Oncoimmunology. 2016;5(12):e1249559. [Crossref]  [PubMed]  [PMC] 
  28. Diakos CI, Charles KA, McMillan DC, Clarke SJ. Cancer-related inflammation and treatment effectiveness. Lancet Oncol. 2014;15(11):e493-503. [Crossref]  [PubMed] 
  29. Guthrie GJ, Roxburgh CS, Horgan PG, McMillan DC. Does interleukin-6 link explain the link between tumour necrosis, local and systemic inflammatory responses and outcome in patients with colorectal cancer? Cancer Treat Rev. 2013;39(1):89-96. [Crossref]  [PubMed] 
  30. Kumari N, Dwarakanath BS, Das A, Bhatt AN. Role of interleukin-6 in cancer progression and therapeutic resistance. Tumour Biol. 2016;37(9):11553-11572. [Crossref]  [PubMed] 
  31. Gervais C, Boudou-Rouquette P, Jouinot A, et al. Predictive and prognostic value of systemic inflammatory response biomarkers in patients receiving nivolumab for metastatic non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2017;35(15_suppl):3055. [Crossref] 
  32. Peng L, Wang Y, Liu F, et al. Peripheral blood markers predictive of outcome and immune-related adverse events in advanced non-small cell lung cancer treated with PD-1 inhibitors. Cancer Immunol Immunother. 2020;69(9):1813-1822. [Crossref]  [PubMed]  [PMC] 
  33. Banna GL, Signorelli D, Metro G, et al. Neutrophil-to-lymphocyte ratio in combination with PD-L1 or lactate dehydrogenase as biomarkers for high PD-L1 non-small cell lung cancer treated with first-line pembrolizumab. Transl Lung Cancer Res. 2020;9(4):1533-1542. [Crossref]  [PubMed]  [PMC] 
  34. Koukourakis MI, Giatromanolaki A, Sivridis E, et al; Tumour and Angiogenesis Research Group. Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis. Br J Cancer. 2003;89(5):877-885. [Crossref]  [PubMed]  [PMC] 
  35. Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC, Harris AL; Tumour Angiogenesis Research Group. Lactate dehydrogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway--a report of the Tumour Angiogenesis Research Group. J Clin Oncol. 2006;24(26):4301-4308. [Crossref]  [PubMed] 
  36. Hirschhaeuser F, Sattler UG, Mueller-Klieser W. Lactate: a metabolic key player in cancer. Cancer Res. 2011;71(22):6921-6925. [Crossref]  [PubMed] 
  37. Fischer K, Hoffmann P, Voelkl S, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood. 2007;109(9):3812-3819. [Crossref]  [PubMed] 
  38. Morita R, Okishio K, Shimizu J, et al. Real-world effectiveness and safety of nivolumab in patients with non-small cell lung cancer: A multicenter retrospective observational study in Japan. Lung Cancer. Feb 2020;140:8-18. [Crossref]  [PubMed] 
  39. Lin SY, Yang CY, Liao BC, et al. Tumor PD-L1 expression and clinical outcomes in advanced-stage non-small cell lung cancer patients treated with nivolumab or pembrolizumab: real-world data in Taiwan. J Cancer. 2018;9(10):1813-1820. [Crossref]  [PubMed]  [PMC] 
  40. Weis TM, Hough S, Reddy HG, Daignault-Newton S, Kalemkerian GP. Real-world comparison of immune checkpoint inhibitors in non-small cell lung cancer following platinum-based chemotherapy. J Oncol Pharm Pract. 2020;26(3):564-571. [Crossref]  [PubMed] 
  41. Schmid S, Diem S, Li Q, et al. Organ-specific response to nivolumab in patients with non-small cell lung cancer (NSCLC). Cancer Immunol Immunother. 2018;67(12):1825-1832. [Crossref]  [PubMed] 
  42. Li X, Wang L, Chen S, et al. Adverse impact of bone metastases on clinical outcomes of patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors. Thorac Cancer. 2020;11(10):2812-2819. [Crossref]  [PubMed]  [PMC] 
  43. Tournoy KG, Thomeer M, Germonpré P, et al. Does nivolumab for progressed metastatic lung cancer fulfill its promises? An efficacy and safety analysis in 20 general hospitals. Lung Cancer. Jan 2018;115:49-55. [Crossref]  [PubMed] 
  44. Landi L, D'Incà F, Gelibter A, et al. Bone metastases and immunotherapy in patients with advanced non-small-cell lung cancer. J Immunother Cancer. 2019;7(1):316. [Crossref]  [PubMed]  [PMC] 
  45. Shiroyama T, Suzuki H, Tamiya M, et al. Clinical characteristics of liver metastasis in nivolumab-treated patients with non-small cell lung cancer. Anticancer Res. 2018;38(8):4723-4729. [Crossref]  [PubMed] 
  46. Li F, Tian Z. The liver works as a school to educate regulatory immune cells. Cell Mol Immunol. 2013;10(4):292-302. [Crossref]  [PubMed]  [PMC] 
  47. Li J, Zhu H, Sun L, Xu W, Wang X. Prognostic value of site-specific metastases in lung cancer: A population based study. J Cancer. 2019;10(14):3079-3086. [Crossref]  [PubMed]  [PMC] 
  48. Vokes EE, Ready N, Felip E, 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(4):959-965. [Crossref]  [PubMed] 
  49. Gadgeel S, Rodríguez-Abreu D, Speranza G, et al. Updated Analysis From KEYNOTE-189: Pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer. J Clin Oncol. 2020;38(14):1505-1517. [Crossref]  [PubMed] 
  50. Kazandjian D, Gong Y, Keegan P, Pazdur R, Blumenthal GM. Prognostic value of the lung immune prognostic index for patients treated for metastatic non-small cell lung cancer. JAMA Oncol. 2019;5(10):1481-1485. [Crossref]  [PubMed]  [PMC] 
  51. Diem S, Schmid S, Krapf M, et al. Neutrophil-to-Lymphocyte ratio (NLR) and Platelet-to-Lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. Lung Cancer. Sep 2017;111:176-181. [Crossref]  [PubMed] 
  52. Bagley SJ, Kothari S, Aggarwal C, 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. Apr 2017;106:1-7. [Crossref]  [PubMed] 
  53. Russo A, Franchina T, Ricciardi GRR, et al. Baseline neutrophilia, derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), and outcome in non small cell lung cancer (NSCLC) treated with Nivolumab or Docetaxel. J Cell Physiol. 2018;233(10):6337-6343. [Crossref]  [PubMed]  [PMC] 
  54. Mezquita L, Preeshagul I, Auclin E, et al. Predicting immunotherapy outcomes under therapy in patients with advanced NSCLC using dNLR and its early dynamics. Eur J Cancer. Jul 2021;151:211-220. [Crossref]  [PubMed]