Abstract
Objectives
Although liver metastasis has been known to be associated with poor prognosis, only a few studies have shown an association between liver metastasis and treatment outcomes with immune checkpoint inhibitors (ICI). Furthermore, factors associated with prognosis have remained unclear. The present study therefore evaluates the efficacy of nivolumab, pembrolizumab, and atezolizumab among patients with non-small cell lung cancer (NSCLC) who had liver metastasis and identifies factors correlated with prognosis.
Materials and methods
A total of 215 patients with advanced and recurrent NSCLC who received ICI therapy at a single center were retrospectively reviewed. A total of 41 patients (19.1%) had liver metastasis upon initiation of ICI therapy. Overall, 125, 64, and 26 patients were treated with nivolumab, pembrolizumab, and atezolizumab, respectively.
Results
Among the included patients, those with liver metastasis had shorter overall survival (OS) [hazard ratio (HR), 2.04; 95% CI 1.33–3.13] and progression-free survival (PFS) (HR, 1.89; 95% CI 1.29–1.71) compared to those without the same. Patients with liver metastasis had a response rate (RR) of 22.5%. Among patients with liver metastasis, inferior OS was associated with low albumin, poor Eastern Cooperative Oncology Group performance status, driver mutation, and number of liver metastasis (≥ 5). Moreover, patients with liver metastasis who had good Royal Marsden Hospital (0–1) and Gustave Roussy Immune (0–1) scores showed significantly longer OS and PFS.
Conclusion
Despite the poor outcomes with ICI treatment in patients with advanced and recurrent NSCLC who had liver metastasis, some characteristics among patients with liver metastasis may be associated with prognosis.
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Abbreviations
- ICI:
-
Immune checkpoint inhibitors
- NSCLC:
-
Non-small cell lung cancer
- OS:
-
Overall survival
- PFS:
-
Progression-free survival
- ECOG PS:
-
Eastern Cooperative Oncology Group performance status
- PD-1:
-
Programmed cell death protein-1
- PD-L1:
-
Programmed cell death-ligand-1
- RR:
-
Response rate
- DCR:
-
Disease control rate
- LDH:
-
Lactate dehydrogenase
- NLR:
-
Neutrophil-to-lymphocyte ratio
- RECIST:
-
Response evaluation criteria in solid tumors
- GRIm Score:
-
Gustave Roussy immune score
- RMH Score:
-
Royal Marsden Hospital Score
References
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
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(17):1627–1639. https://doi.org/10.1056/NEJMoa1507643
Brahmer JR, Drake CG, Wollner I et al (2010) Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 28(19):3167–3175. https://doi.org/10.1200/JCO.2009.26.7609
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(2):123–135. https://doi.org/10.1056/NEJMoa1504627
Brown K, Comisar C, Witjes H et al (2017) Population pharmacokinetics and exposure-response of osimertinib in patients with non-small cell lung cancer. Br J Clin Pharmacol 83(6):1216–1226. https://doi.org/10.1111/bcp.13223
Centanni M, Moes DJAR, Trocóniz IF, Ciccolini J, van Hasselt JGC (2019) Clinical pharmacokinetics and pharmacodynamics of immune checkpoint inhibitors. Clin Pharmacokinet 58(7):835–857. https://doi.org/10.1007/s40262-019-00748-2
Cibulskis K, Lawrence MS, Carter SL et al (2013) Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol 31(3):213–219. https://doi.org/10.1038/nbt.2514
Clark AM, Ma B, Taylor DL, Griffith L, Wells A (2016) Liver metastases: microenvironments and ex vivo models. Exp Biol Med (Maywood). 241(15):1639–1652. https://doi.org/10.1177/1535370216658144
Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. https://doi.org/10.1016/j.ejca.2008.10.026
Funazo T, Nomizo T, Kim YH (2017) Liver metastasis is associated with poor progression-free survival in patients with non-small cell lung cancer treated with nivolumab. J Thorac Oncol. 12(9):e140–e141. https://doi.org/10.1016/j.jtho.2017.04.027
Le DT, Uram JN, Wang H et al (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372(26):2509–2520. https://doi.org/10.1056/NEJMoa1500596
Mansfield AS, Murphy SJ, Peikert T et al (2016) Heterogeneity of programmed cell death ligand 1 expression in multifocal lung cancer. Clin Cancer Res 22(9):2177–2182. https://doi.org/10.1158/1078-0432.CCR-15-2246
Matsuda T, The Japan Cancer Surveillance Research Group (2011) Cancer incidence and incidence rates in Japan in 2005: based on data from 12 population-based cancer registries in the monitoring of cancer incidence in Japan (MCIJ) Project. Jpn J Clin Oncol. 41:139–147
Mok TSK, Wu Y-L, Kudaba I et al (2019) 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 393(10183):1819–1830. https://doi.org/10.1016/S0140-6736(18)32409-7
Nakamura Y, Kitano S, Takahashi A et al (2016) Nivolumab for advanced melanoma: pretreatment prognostic factors and early outcome markers during therapy. Oncotarget. 7(47):77404–77415. https://doi.org/10.18632/oncotarget.12677
Reck M, Rodríguez-Abreu D, Robinson AG et al (2016) Pembrolizumab versus chemotherapy for PD-L1—positive non–small-cell lung cancer. N Engl J Med 375(19):1823–1833. https://doi.org/10.1056/NEJMoa1606774
Reck M, Mok TSK, Nishio M et al (2019) Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with <em> EGFR</em> mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir Med. 7(5):387–401. https://doi.org/10.1016/S2213-2600(19)30084-0
Ren Y, Dai C, Zheng H et al (2016) Prognostic effect of liver metastasis in lung cancer patients with distant metastasis. Oncotarget. 7(33):53245–53253. https://doi.org/10.18632/oncotarget.10644
Rittmeyer A, Barlesi F, Waterkamp D et al (2017) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389(10066):255–265. https://doi.org/10.1016/S0140-6736(16)32517-X
Shiroyama T, Suzuki H, Tamiya M et al (2018) Clinical characteristics of liver metastasis in nivolumab-treated patients with non-small cell lung cancer. Anticancer Res 38(8):4723–4729. https://doi.org/10.21873/anticanres.12779
Sivan A, Corrales L, Hubert N et al (2015) Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350(6264):1084–1089. https://doi.org/10.1126/science.aac4255
Stroh M, Winter H, Marchand M et al (2017) Clinical pharmacokinetics and pharmacodynamics of atezolizumab in metastatic urothelial carcinoma. Clin Pharmacol Ther 102(2):305–312. https://doi.org/10.1002/cpt.587
Tamiya M, Tamiya A, Inoue T et al (2018) Metastatic site as a predictor of nivolumab efficacy in patients with advanced non-small cell lung cancer: a retrospective multicenter trial. PLoS ONE 13(2):1–10. https://doi.org/10.1371/journal.pone.0192227
Torimura T, Sata M, Ueno T et al (1998) Increased expression of vascular endothelial growth factor is associated with tumor progression in hepatocellular carcinoma. Hum Pathol 29(9):986–991. https://doi.org/10.1016/S0046-8177(98)90205-2
Tumeh PC, Hellmann MD, Hamid O et al (2017) Liver metastasis and treatment outcome with anti-PD-1 monoclonal antibody in patients with melanoma and NSCLC. Cancer Immunol Res 5(5):417–424. https://doi.org/10.1158/2326-6066.cir-16-0325
Vokes E, Ready N, Felip E et al (2018) 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 29(4):959–965. https://doi.org/10.1093/annonc/mdy041
Yamamoto N, Tamura T, Fukuoka M, Saijo N (1999) Survival and prognostic factors in lung cancer patients treated in phase I trials: Japanese experience. Int J Oncol 15(4):737–741
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We thank Enago (https://www.enago.jp/) for the English language review.
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YO has received honoraria from AstraZeneca Japan, Boehringer-Ingelheim Japan, Chugai Pharmaceutical Co. Ltd., Eli Lily Co. Ltd., MSD K. K., and Ono Pharmaceutical Co. The other authors have no conflicts of interest to disclose.
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This study protocol was approved by the Ethics Committee of the Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital (#2272) and was conducted in accordance with the tenets of the Declaration of Helsinki.
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Kitadai, R., Okuma, Y., Hakozaki, T. et al. The efficacy of immune checkpoint inhibitors in advanced non-small-cell lung cancer with liver metastases. J Cancer Res Clin Oncol 146, 777–785 (2020). https://doi.org/10.1007/s00432-019-03104-w
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DOI: https://doi.org/10.1007/s00432-019-03104-w