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Baseline Serum Interleukin-6 Levels Predict the Response of Patients with Advanced Non-small Cell Lung Cancer to PD-1/PD-L1 Inhibitors

  • Da Hyun Kang (Department of Internal Medicine, College of Medicine, Chungnam National University) ;
  • Cheol-Kyu Park (Lung Cancer Clinic, Chonnam National University Hwasun Hospital) ;
  • Chaeuk Chung (Department of Internal Medicine, College of Medicine, Chungnam National University) ;
  • In-Jae Oh (Lung Cancer Clinic, Chonnam National University Hwasun Hospital) ;
  • Young-Chul Kim (Lung Cancer Clinic, Chonnam National University Hwasun Hospital) ;
  • Dongil Park (Department of Internal Medicine, College of Medicine, Chungnam National University) ;
  • Jinhyun Kim (Department of Internal Medicine, College of Medicine, Chungnam National University) ;
  • Gye Cheol Kwon (Department of Laboratory Medicine, College of Medicine, Chungnam National University) ;
  • Insun Kwon (Clinical Trials Center, Chungnam National University Hospital) ;
  • Pureum Sun (Research Institute for Medical Sciences, College of Medicine, Chungnam National University) ;
  • Eui-Cheol Shin (Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • Jeong Eun Lee (Department of Internal Medicine, College of Medicine, Chungnam National University)
  • Received : 2020.02.18
  • Accepted : 2020.05.03
  • Published : 2020.06.30
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Abstract

Although various studies on predictive markers in the use of PD-1/PD-L1 inhibitors are in progress, only PD-L1 expression levels in tumor tissues are currently used. In the present study, we investigated whether baseline serum levels of IL-6 can predict the treatment response of patients with advanced non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 inhibitors. In our cohort of 125 NSCLC patients, the objective response rate (ORR) and disease control rate (DCR) were significantly higher in those with low IL-6 (<13.1 pg/ml) than those with high IL-6 (ORR 33.9% vs. 11.1%, p=0.003; DCR 80.6% vs. 34.9%, p<0.001). The median progression-free survival was 6.3 months (95% confidence interval [CI], 3.9-8.7) in the low IL-6 group, significantly longer than in the high IL-6 group (1.9 months, 95% CI, 1.6-2.2, p<0.001). The median overall survival in the low IL-6 group was significantly longer than in the high IL-6 group (not reached vs. 7.4 months, 95% CI, 4.8-10.0). Thus, baseline serum IL-6 levels could be a potential biomarker for predicting the efficacy and survival benefit of PD-1/PD-L1 inhibitors in NSCLC.

Keywords

Acknowledgement

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2018R1D1A1B07050870 and NRF-2019R1C1C1008864).

References

  1. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373:1627-1639. https://doi.org/10.1056/NEJMoa1507643
  2. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123-135. https://doi.org/10.1056/NEJMoa1504627
  3. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016;387:1540-1550. https://doi.org/10.1016/S0140-6736(15)01281-7
  4. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, et al. 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;389:255-265. https://doi.org/10.1016/S0140-6736(16)32517-X
  5. Topalian SL, Taube JM, Anders RA, Pardoll DM. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 2016;16:275-287. https://doi.org/10.1038/nrc.2016.36
  6. Mitsuhashi A, Okuma Y. Perspective on immune oncology with liquid biopsy, peripheral blood mononuclear cells, and microbiome with non-invasive biomarkers in cancer patients. Clin Transl Oncol 2018;20:966-974. https://doi.org/10.1007/s12094-017-1827-7
  7. Kim KH, Cho J, Ku BM, Koh J, Sun JM, Lee SH, Ahn JS, Cheon J, Min YJ, Park SH, et al. The first-week proliferative response of peripheral blood PD-1+ CD8+ T cells predicts the response to anti-PD-1 therapy in solid tumors. Clin Cancer Res 2019;25:2144-2154.  https://doi.org/10.1158/1078-0432.CCR-18-1449
  8. Kang DH, Chung C, Kim JO, Jung SS, Park HS, Park DI, Jung SY, Park M, Lee JE. Pleural or pericardial metastasis: a significant factor affecting efficacy and adverse events in lung cancer patients treated with PD-1/PD-L1 inhibitors. Thorac Cancer 2018;9:1500-1508. https://doi.org/10.1111/1759-7714.12877
  9. Kurman JS, Murgu SD. Hyperprogressive disease in patients with non-small cell lung cancer on immunotherapy. J Thorac Dis 2018;10:1124-1128. https://doi.org/10.21037/jtd.2018.01.79
  10. Valpione S, Pasquali S, Campana LG, Piccin L, Mocellin S, Pigozzo J, Chiarion-Sileni V. Sex and interleukin-6 are prognostic factors for autoimmune toxicity following treatment with anti-CTLA4 blockade. J Transl Med 2018;16:94.
  11. Hodge DR, Hurt EM, Farrar WL. The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer 2005;41:2502-2512. https://doi.org/10.1016/j.ejca.2005.08.016
  12. Kitamura H, Ohno Y, Toyoshima Y, Ohtake J, Homma S, Kawamura H, Takahashi N, Taketomi A. Interleukin-6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy. Cancer Sci 2017;108:1947-1952. https://doi.org/10.1111/cas.13332
  13. Chung YC, Chang YF. Serum interleukin-6 levels reflect the disease status of colorectal cancer. J Surg Oncol 2003;83:222-226. https://doi.org/10.1002/jso.10269
  14. Nakashima J, Tachibana M, Horiguchi Y, Oya M, Ohigashi T, Asakura H, Murai M. Serum interleukin 6 as a prognostic factor in patients with prostate cancer. Clin Cancer Res 2000;6:2702-2706.
  15. Zhang GJ, Adachi I. Serum interleukin-6 levels correlate to tumor progression and prognosis in metastatic breast carcinoma. Anticancer Res 1999;19:1427-1432.
  16. Silva EM, Mariano VS, Pastrez PR, Pinto MC, Castro AG, Syrjanen KJ, Longatto-Filho A. High systemic IL-6 is associated with worse prognosis in patients with non-small cell lung cancer. PLoS One 2017;12:e0181125.
  17. Chang CH, Hsiao CF, Yeh YM, Chang GC, Tsai YH, Chen YM, Huang MS, Chen HL, Li YJ, Yang PC, et al. Circulating interleukin-6 level is a prognostic marker for survival in advanced nonsmall cell lung cancer patients treated with chemotherapy. Int J Cancer 2013;132:1977-1985. https://doi.org/10.1002/ijc.27892
  18. Park HY, Oh IJ, Kho BG, Kim TO, Shin HJ, Park CK, Kwon YS, Kim YI, Lim SC, Kim YC, et al. Clinical characteristics of Korean patients with lung cancer who have programmed death-ligand 1 expression. Tuberc Respir Dis 2019;82:227-233. https://doi.org/10.4046/trd.2018.0070
  19. Madore J, Vilain RE, Menzies AM, Kakavand H, Wilmott JS, Hyman J, Yearley JH, Kefford RF, Thompson JF, Long GV, et al. PD-L1 expression in melanoma shows marked heterogeneity within and between patients: implications for anti-PD-1/PD-L1 clinical trials. Pigment Cell Melanoma Res 2015;28:245-253. https://doi.org/10.1111/pcmr.12340
  20. McLaughlin J, Han G, Schalper KA, Carvajal-Hausdorf D, Pelekanou V, Rehman J, Velcheti V, Herbst R, LoRusso P, Rimm DL. Quantitative assessment of the heterogeneity of pd-l1 expression in non-small-cell lung cancer. JAMA Oncol 2016;2:46-54. https://doi.org/10.1001/jamaoncol.2015.3638
  21. Xing X, Guo J, Ding G, Li B, Dong B, Feng Q, Li S, Zhang J, Ying X, Cheng X, et al. Analysis of PD1, PDL1, PDL2 expression and T cells infiltration in 1014 gastric cancer patients. OncoImmunology 2017;7:e1356144.
  22. Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM, Miller V, Stephens PJ, Daniels GA, Kurzrock R. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther 2017;16:2598-2608. https://doi.org/10.1158/1535-7163.MCT-17-0386
  23. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to pd-1 inhibition. N Engl J Med 2017;377:2500-2501. https://doi.org/10.1056/NEJMc1713444
  24. McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, Jamal-Hanjani M, Wilson GA, Birkbak NJ, Hiley CT, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016;351:1463-1469. https://doi.org/10.1126/science.aaf1490
  25. Voong KR, Feliciano J, Becker D, Levy B. Beyond PD-L1 testing-emerging biomarkers for immunotherapy in non-small cell lung cancer. Ann Transl Med 2017;5:376.
  26. Teng F, Meng X, Kong L, Yu J. Progress and challenges of predictive biomarkers of anti PD-1/PD-L1 immunotherapy: a systematic review. Cancer Lett 2018;414:166-173. https://doi.org/10.1016/j.canlet.2017.11.014
  27. Yi M, Jiao D, Xu H, Liu Q, Zhao W, Han X, Wu K. Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors. Mol Cancer 2018;17:129.
  28. Yamazaki N, Kiyohara Y, Uhara H, Iizuka H, Uehara J, Otsuka F, Fujisawa Y, Takenouchi T, Isei T, Iwatsuki K, et al. Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a phase 2 study for advanced melanoma. Cancer Sci 2017;108:1022-1031. https://doi.org/10.1111/cas.13226
  29. Kauffmann-Guerrero D, Kahnert K, Syunyaeva Z, Kiefel R, Tufman A, Huber RM. Pretherapeutic inflammation status and cytokine profile may predict response to immunotherapy in NSCLC patients. Ann Oncol 2017;28:xi12.
  30. Hardy-Werbin M, Rocha P, Arpi O, Taus A, Nonell L, Duran X, Villanueva X, Joseph-Pietras D, Nolan L, Danson S, et al. Serum cytokine levels as predictive biomarkers of benefit from ipilimumab in small cell lung cancer. OncoImmunology 2019;8:e1593810.
  31. Sanmamed MF, Perez-Gracia JL, Schalper KA, Fusco JP, Gonzalez A, Rodriguez-Ruiz ME, Onate C, Perez G, Alfaro C, Martin-Algarra S, et al. Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients. Ann Oncol 2017;28:1988-1995. https://doi.org/10.1093/annonc/mdx190
  32. Ohno Y, Toyoshima Y, Yurino H, Monma N, Xiang H, Sumida K, Kaneumi S, Terada S, Hashimoto S, Ikeo K, et al. Lack of interleukin-6 in the tumor microenvironment augments type-1 immunity and increases the efficacy of cancer immunotherapy. Cancer Sci 2017;108:1959-1966. https://doi.org/10.1111/cas.13330
  33. Kitamura H, Kamon H, Sawa S, Park SJ, Katunuma N, Ishihara K, Murakami M, Hirano T. IL-6-STAT3 controls intracellular MHC class II αβ dimer level through cathepsin S activity in dendritic cells. Immunity 2005;23:491-502. https://doi.org/10.1016/j.immuni.2005.09.010
  34. Park SJ, Nakagawa T, Kitamura H, Atsumi T, Kamon H, Sawa S, Kamimura D, Ueda N, Iwakura Y, Ishihara K, et al. IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation. J Immunol 2004;173:3844-3854. https://doi.org/10.4049/jimmunol.173.6.3844
  35. Liu H, Shen J, Lu K. IL-6 and PD-L1 blockade combination inhibits hepatocellular carcinoma cancer development in mouse model. Biochem Biophys Res Commun 2017;486:239-244. https://doi.org/10.1016/j.bbrc.2017.02.128
  36. Mace TA, Shakya R, Pitarresi JR, Swanson B, McQuinn CW, Loftus S, Nordquist E, Cruz-Monserrate Z, Yu L, Young G, et al. IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut 2018;67:320-332. https://doi.org/10.1136/gutjnl-2016-311585