Skip to main content

The efficacy of immune checkpoint inhibitors in advanced non-small-cell lung cancer with liver metastases

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.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

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

  1. 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

    Article  PubMed  Google Scholar 

  2. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 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

    Article  PubMed  PubMed Central  Google Scholar 

  7. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 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

    Article  PubMed  Google Scholar 

  11. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 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

    CAS  Article  PubMed  Google Scholar 

  13. 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

    Article  Google Scholar 

  14. 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

    CAS  Article  PubMed  Google Scholar 

  15. 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

    Article  PubMed  PubMed Central  Google Scholar 

  16. 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

    CAS  Article  PubMed  Google Scholar 

  17. 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

    CAS  Article  PubMed  Google Scholar 

  18. 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

    Article  PubMed  PubMed Central  Google Scholar 

  19. 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

    Article  PubMed  Google Scholar 

  20. 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

    CAS  Article  PubMed  Google Scholar 

  21. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 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

    CAS  Article  PubMed  Google Scholar 

  23. 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

    CAS  Article  Google Scholar 

  24. 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

    CAS  Article  PubMed  Google Scholar 

  25. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 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

    CAS  Article  PubMed  Google Scholar 

  27. 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

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Enago (https://www.enago.jp/) for the English language review.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Yusuke Okuma.

Ethics declarations

Conflict of interest

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.

Ethical approval

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.

Informed consent

Instead of obtaining informed consent from each patient, participants or their next of kin were given the opportunity to opt-out.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Keywords

  • Non-small-cell lung cancer
  • Liver metastasis
  • Nivolumab
  • Pembrolizumab
  • Atezolizumab
  • Overall survival