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Cancer Immunology, Immunotherapy

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Open Access 01-09-2020 | NSCLC | Original Article

Peripheral blood markers predictive of outcome and immune-related adverse events in advanced non-small cell lung cancer treated with PD-1 inhibitors

Authors: Lihong Peng, Yong Wang, Fen Liu, Xiaotong Qiu, Xinwei Zhang, Chen Fang, Xiaoyin Qian, Yong Li

Published in: Cancer Immunology, Immunotherapy | Issue 9/2020

Abstract

Background

Selected patients with advanced non-small cell lung cancer (NSCLC) benefit from immunotherapy, especially immune checkpoint inhibitors such as PD-1 (programmed cell death protein 1) inhibitor. Peripheral blood biomarkers would be most convenient to predict treatment outcome and immune-related adverse events (irAEs) in candidate patients. This study explored associations between inflammation-related peripheral blood markers and onset of irAEs and outcome in patients with advanced NSCLC receiving PD-1 inhibitors.

Methods

A retrospective analysis was conducted of 102 patients with advanced NSCLC receiving PD-1 inhibitors from January 2017 to May 2019. Cox regression models were employed to assess the prognostic effect of low/high neutrophil/lymphocyte ratio (NLR), lactate dehydrogenase (LDH), and prognostic nutrition index (PNI) on overall survival (OS) and progression-free survival (PFS). Logistic regression models were used to analyze the correlation between peripheral blood markers and the onset of irAEs.

Result

NLR < 5, LDH < 240 U/L, or PNI ≥ 45 was favorably associated with significantly better outcomes compared with higher, higher, or lower values, respectively. The multivariate analysis determined that these parameters were independently associated with both better PFS (p = 0.049, 0.046, 0.014, respectively) and longer OS (p = 0.007, 0.031, < 0.001, respectively). Patients with three favorable factors among NLR, LDH, and PNI had better PFS and OS than did those with two, one, or none. PNI and NLR were associated with the onset of irAEs.

Conclusion

In patients with advanced NSCLC treated with PD-1 inhibitors, pretreatment NLR, LDH, and PNI may be useful predictive markers of clinical outcome and irAEs.

Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J (2016) Cancer statistics in China, 2015. CA Cancer J Clin 66:115–132. https://doi.org/10.3322/caac.21338 CrossRefPubMed

Gettinger SN, Horn L, Gandhi L et al (2015) Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 33:2004–2012. https://doi.org/10.1200/JCO.2014.58.3708 CrossRefPubMedPubMedCentral

Iwai Y, Hamanishi J, Chamoto K, Honjo T (2017) Cancer immunotherapies targeting the PD-1 signaling pathway. J Biomed Sci 24:26. https://doi.org/10.1186/s12929-017-0329-9 CrossRefPubMedPubMedCentral

Philip M, Rowley DA, Schreiber H (2004) Inflammation as a tumor promoter in cancer induction. Semin Cancer Biol 14:433–439. https://doi.org/10.1016/j.semcancer.2004.06.006 CrossRefPubMed

Ferrucci PF, Ascierto PA, Pigozzo J et al (2018) Baseline neutrophils and derived neutrophil-to-lymphocyte ratio: prognostic relevance in metastatic melanoma patients receiving ipilimumab. Ann Oncol 29:524. https://doi.org/10.1093/annonc/mdx059 CrossRefPubMed

Capone M, Giannarelli D, Mallardo D et al (2018) Baseline neutrophil-to-lymphocyte ratio (NLR) and derived NLR could predict overall survival in patients with advanced melanoma treated with nivolumab. J Immunother Cancer 6:74. https://doi.org/10.1186/s40425-018-0383-1 CrossRefPubMedPubMedCentral

Fujisawa Y, Yoshino K, Otsuka A et al (2018) Baseline neutrophil to lymphocyte ratio combined with serum lactate dehydrogenase level associated with outcome of nivolumab immunotherapy in a Japanese advanced melanoma population. Br J Dermatol 179:213–215. https://doi.org/10.1111/bjd.16427 CrossRefPubMed

Soyano AE, Dholaria B, Marin-Acevedo JA et al (2018) Peripheral blood biomarkers correlate with outcomes in advanced non-small cell lung cancer patients treated with anti-PD-1 antibodies. J Immunother Cancer 6:129. https://doi.org/10.1186/s40425-018-0447-2 CrossRefPubMedPubMedCentral

Diem S, Schmid S, Krapf M, Flatz L, Born D, Jochum W, Templeton AJ, Fruh M (2017) 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 111:176–181. https://doi.org/10.1016/j.lungcan.2017.07.024 CrossRefPubMed

10.

Bagley SJ, Kothari S, Aggarwal C et al (2017) Pretreatment neutrophil-to-lymphocyte ratio as a marker of outcomes in nivolumab-treated patients with advanced non-small-cell lung cancer. Lung Cancer 106:1–7. https://doi.org/10.1016/j.lungcan.2017.01.013 CrossRefPubMed

11.

Mezquita L, Auclin E, Ferrara R et al (2018) Association of the lung immune prognostic index with immune checkpoint inhibitor outcomes in patients with advanced non-small cell lung cancer. JAMA Oncol 4:351–357. https://doi.org/10.1001/jamaoncol.2017.4771 CrossRefPubMedPubMedCentral

12.

Taniguchi Y, Tamiya A, Isa SI et al (2017) Predictive factors for poor progression-free survival in patients with non-small cell lung cancer treated with nivolumab. Anticancer Res 37:5857–5862. https://doi.org/10.21873/anticanres.12030 CrossRefPubMed

13.

Kataoka Y, Hirano K, Narabayashi T, Hara S, Fujimoto D, Tanaka T, Ebi N, Tomii K, Yoshioka H (2018) Carcinoembryonic antigen as a predictive biomarker of response to nivolumab in non-small cell lung cancer. Anticancer Res 38:559–563. https://doi.org/10.21873/anticanres.12259 CrossRefPubMed

14.

Buzby GP, Mullen JL, Matthews DC, Hobbs CL, Rosato EF (1980) Prognostic nutritional index in gastrointestinal surgery. Am J Surg 139:160–167CrossRefPubMed

15.

Hong S, Zhou T, Fang W et al (2015) The prognostic nutritional index (PNI) predicts overall survival of small-cell lung cancer patients. Tumour Biol 36:3389–3397. https://doi.org/10.1007/s13277-014-2973-y CrossRefPubMed

16.

Okada S, Shimada J, Kato D, Tsunezuka H, Teramukai S, Inoue M (2017) Clinical significance of prognostic nutritional index after surgical treatment in lung cancer. Ann Thorac Surg 104:296–302. https://doi.org/10.1016/j.athoracsur.2017.01.085 CrossRefPubMed

17.

Eo WK, Chang HJ, Suh J et al (2015) The prognostic nutritional index predicts survival and identifies aggressiveness of gastric cancer. Nutr Cancer 67:1260–1267. https://doi.org/10.1080/01635581.2015.1082112 CrossRefPubMed

18.

Tokunaga R, Sakamoto Y, Nakagawa S, Miyamoto Y, Yoshida N, Oki E, Watanabe M, Baba H (2015) Prognostic nutritional index predicts severe complications, recurrence, and poor prognosis in patients with colorectal cancer undergoing primary tumor resection. Dis Colon Rectum 58:1048–1057. https://doi.org/10.1097/DCR.0000000000000458 CrossRefPubMed

19.

Rigamonti A, Imbesi F, Silvani A et al (2019) Prognostic nutritional index as a prognostic marker in glioblastoma: data from a cohort of 282 Italian patients. J Neurol Sci 400:175–179. https://doi.org/10.1016/j.jns.2019.04.002 CrossRefPubMed

20.

Haanen J, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, Jordan K, Committee EG (2017) Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 28:iv119-iv42. https://doi.org/10.1093/annonc/mdx225 CrossRef

21.

Watanabe I, Kanauchi N, Watanabe H (2018) Preoperative prognostic nutritional index as a predictor of outcomes in elderly patients after surgery for lung cancer. Jpn J Clin Oncol 48:382–387. https://doi.org/10.1093/jjco/hyy014 CrossRefPubMed

22.

Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264. https://doi.org/10.1038/nrc3239 CrossRefPubMedPubMedCentral

23.

Graves M, CelliMarchett G, van Zyl B, Tang D, Vilain RE, van der Westhuizen A, Bowden NA (2019) Monitoring patient response to pembrolizumab with peripheral blood exhaustion marker profiles. Front Med (Lausanne) 6:113. https://doi.org/10.3389/fmed.2019.00113 CrossRef

24.

Borghaei H, Paz-Ares L, Horn L et al (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373:1627–1639. https://doi.org/10.1056/NEJMoa1507643 CrossRefPubMedPubMedCentral

25.

Herbst RS, Baas P, Kim DW et al (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387:1540–1550. https://doi.org/10.1016/S0140-6736(15)01281-7 CrossRefPubMed

26.

Brahmer J, Reckamp KL, Baas P et al (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373:123–135. https://doi.org/10.1056/NEJMoa1504627 CrossRefPubMedPubMedCentral

27.

Kos FT, Hocazade C, Kos M, Uncu D, Karakas E, Dogan M, Uncu HG, Ozdemir N, Zengin N (2015) Assessment of prognostic value of “neutrophil to lymphocyte ratio” and “prognostic nutritional index” as a sytemic inflammatory marker in non-small cell lung cancer. Asian Pac J Cancer Prev 16:3997–4002. https://doi.org/10.7314/apjcp.2015.16.9.3997 CrossRefPubMed

28.

Miyazaki T, Sakai M, Sohda M et al (2016) Prognostic significance of inflammatory and nutritional parameters in patients with esophageal cancer. Anticancer Res 36:6557–6562. https://doi.org/10.21873/anticanres.11259 CrossRefPubMed

29.

Ferrucci PF, Gandini S, Battaglia A et al (2015) Baseline neutrophil-to-lymphocyte ratio is associated with outcome of ipilimumab-treated metastatic melanoma patients. Br J Cancer 112:1904–1910. https://doi.org/10.1038/bjc.2015.180 CrossRefPubMedPubMedCentral

30.

Zaragoza J, Caille A, Beneton N, Bens G, Christiann F, Maillard H, Machet L (2016) High neutrophil to lymphocyte ratio measured before starting ipilimumab treatment is associated with reduced overall survival in patients with melanoma. Br J Dermatol 174:146–151. https://doi.org/10.1111/bjd.14155 CrossRefPubMed

31.

Kiriu T, Yamamoto M, Nagano T et al (2018) The time-series behavior of neutrophil-to-lymphocyte ratio is useful as a predictive marker in non-small cell lung cancer. PLoS ONE 13:e0193018. https://doi.org/10.1371/journal.pone.0193018 CrossRefPubMedPubMedCentral

32.

Kelderman S, Heemskerk B, van Tinteren H et al (2014) Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. Cancer Immunol Immunother 63:449–458. https://doi.org/10.1007/s00262-014-1528-9 CrossRefPubMed

33.

Diem S, Kasenda B, Spain L, Martin-Liberal J, Marconcini R, Gore M, Larkin J (2016) Serum lactate dehydrogenase as an early marker for outcome in patients treated with anti-PD-1 therapy in metastatic melanoma. Br J Cancer 114:256–261. https://doi.org/10.1038/bjc.2015.467 CrossRefPubMedPubMedCentral

34.

Oya Y, Yoshida T, Kuroda H et al (2017) Predictive clinical parameters for the response of nivolumab in pretreated advanced non-small-cell lung cancer. Oncotarget. 8:103117–103128. https://doi.org/10.18632/oncotarget.21602 CrossRefPubMedPubMedCentral

35.

Onodera T, Goseki N, Kosaki G (1984) Prognostic nutritional index in gastrointestinal surgery of malnourished cancer patients. Nihon Geka Gakkai Zasshi 85:1001–1005PubMed

36.

Lee YJ, Kim WR, Han J, Han YD, Cho MS, Hur H, Lee KY, Kim NK, Min BS (2016) Prognostic impact of immunonutritional status changes during preoperative chemoradiation in patients with rectal cancer. Ann Coloproctol 32:208–214. https://doi.org/10.3393/ac.2016.32.6.208 CrossRefPubMedPubMedCentral

37.

Michot JM, Bigenwald C, Champiat S et al (2016) Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 54:139–148. https://doi.org/10.1016/j.ejca.2015.11.016 CrossRefPubMed

38.

Nakaya A, Kurata T, Yoshioka H et al (2018) 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 23:634–640. https://doi.org/10.1007/s10147-018-1250-2 CrossRefPubMedPubMedCentral

Title: Peripheral blood markers predictive of outcome and immune-related adverse events in advanced non-small cell lung cancer treated with PD-1 inhibitors
Authors: Lihong Peng
Yong Wang
Fen Liu
Xiaotong Qiu
Xinwei Zhang
Chen Fang
Xiaoyin Qian
Yong Li
Publication date: 01-09-2020
Publisher: Springer Berlin Heidelberg
Keywords: NSCLC
Lung Cancer
Lung Cancer
Nutrition
NSCLC
Lung Cancer
Checkpoint Inhibitors
Published in: Cancer Immunology, Immunotherapy / Issue 9/2020
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-020-02585-w

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