Skip to main content

Advertisement

SpringerLink
Log in

Efficacy and safety of immune checkpoint inhibitors plus anlotinib in small cell lung cancer with brain metastases: a retrospective, multicentre study

  • Research
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Background

Previous studies showed that both immune checkpoint inhibitors (ICIs) and anlotinib have central nervous system (CNS) efficacy. This study aimed to evaluate the efficacy and safety of ICIs combined with anlotinib in small cell lung cancer (SCLC) patients with brain metastases (BMs).

Methods

We retrospectively reviewed SCLC patients with CNS metastases confirmed by brain magnetic resonance imaging (MRI). Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and Response assessment in neuro-oncology brain metastases (RANO-BM) were used to evaluate treatment response to ICIs plus anlotinib. Kaplan–Meier analysis and Cox regression analysis were performed to determine patient’s prognosis.

Results

Sixty-six patients with baseline BMs were included. For patients with measurable intracranial lesions, the intracranial objective response rate (ORR) was 29.2% based on RECIST 1.1 criteria and was 27.1% based on RANO-BM criteria. The median intracranial progression-free survival (PFS) was 9.0 months (95% confidence interval [CI], 6.5–11.5 months). The median overall survival (OS) was 13.4 months (95% CI, 10.7–20.5 months). Multivariate Cox regression analysis showed that high disease burden (hazard ratio [HR] = 4.83, P < 0.001), multiple BMs (HR = 2.71, P = 0.036), and more than or equal to 3 prior lines of therapy (HR = 2.56, P = 0.023) were independent negative predictors of OS. The overall incidence of treatment-related adverse events (TRAEs) was 75.8%, and grade 3–4 TRAEs were reported in 19.7% of patients.

Conclusions

Our results suggested that ICIs plus anlotinib had potent CNS efficacy with tolerable toxicity and could be a promising treatment option for SCLC patients with BMs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

The datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

References

  1. Rudin CM, Brambilla E, Faivre-Finn C, Sage J (2021) Small-cell lung cancer. Nat Rev Dis Primers 7:3

    Article  Google Scholar 

  2. Rusthoven CG, Yamamoto M, Bernhardt D et al (2020) Evaluation of first-line radiosurgery vs whole-brain radiotherapy for small cell lung cancer brain metastases. JAMA ONCOL 6:1028

    Article  Google Scholar 

  3. Postmus PE, Haaxma-Reiche H, Smit EF et al (2000) Treatment of brain metastases of small-cell lung cancer: comparing teniposide and teniposide with whole-brain radiotherapy—A phase III study of the european organization for the research and treatment of cancer lung cancer cooperative group. J CLIN ONCOL 18:3400–3408

    Article  CAS  Google Scholar 

  4. Rittberg R, Banerji S, Kim JO, Rathod S, Dawe DE (2021) Treatment and prevention of brain metastases in small cell lung cancer. Am J Clin Oncol 44:629–638

    Article  CAS  Google Scholar 

  5. Liu SV, Reck M, Mansfield AS et al (2021) updated overall survival and pd-l1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). J Clin Oncol 39:619–630

    Article  CAS  Google Scholar 

  6. Goldman JW, Dvorkin M, Chen Y et al (2021) Durvalumab, with or without tremelimumab, plus platinum–etoposide versus platinum–etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 22:51–65

    Article  CAS  Google Scholar 

  7. Rudin CM, Awad MM, Navarro A et al (2020) Pembrolizumab or placebo plus etoposide and platinum as first-line therapy for extensive-stage small-cell lung cancer: randomized, double-blind, phase III KEYNOTE-604 study. J Clin Oncol 38:2369–2379

    Article  CAS  Google Scholar 

  8. Xie C, Wan X, Quan H et al (2018) Preclinical characterization of anlotinib, a highly potent and selective vascular endothelial growth factor receptor-2 inhibitor. Cancer Sci 109:1207–1219

    Article  CAS  Google Scholar 

  9. Cheng Y, Wang Q, Li K et al (2019) P2.12-26 the impact of anlotinib for relapsed sclc patients with brain metastases: a subgroup analysis of ALTER 1202. J Thorac Oncol 14:S823–S824

    Article  Google Scholar 

  10. Liu S, Qin T, Liu Z et al (2020) anlotinib alters tumor immune microenvironment by downregulating PD-L1 expression on vascular endothelial cells. CELL DEATH DIS 11:309

    Article  Google Scholar 

  11. Yang Y, Li L, Jiang Z, Wang B, Pan Z (2020) Anlotinib optimizes anti-tumor innate immunity to potentiate the therapeutic effect of PD-1 blockade in lung cancer. Cancer Immunol Immunother 69:2523–2532

    Article  CAS  Google Scholar 

  12. Berghoff AS, Ricken G, Wilhelm D et al (2016) Tumor infiltrating lymphocytes and PD-L1 expression in brain metastases of small cell lung cancer (SCLC). J Neuro-Oncol 130:19–29

    Article  CAS  Google Scholar 

  13. Louveau A, Smirnov I, Keyes TJ et al (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523:337–341

    Article  CAS  Google Scholar 

  14. Louveau A, Harris TH, Kipnis J (2015) Revisiting the mechanisms of CNS immune privilege. Trends Immunol 36:569–577

    Article  CAS  Google Scholar 

  15. Goldberg SB, Schalper KA, Gettinger SN et al (2020) Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. Lancet Oncol 21:655–663

    Article  CAS  Google Scholar 

  16. Kluger HM, Chiang V, Mahajan A et al (2019) Long-term survival of patients with melanoma with active brain metastases treated with pembrolizumab on a phase II trial. J Clin Oncol 37:52–60

    Article  CAS  Google Scholar 

  17. Powell SF, Abreu DR, Langer CJ et al (2019) 1483PD - Pembrolizumab (pembro) plus platinum-based chemotherapy (chemo) in NSCLC with brain metastases: Pooled analysis of KEYNOTE-021, 189, and 407. Ann Oncol 30:v606–v607

    Article  Google Scholar 

  18. Mansfield AS, Herbst RS, Castro G et al (2019) 1482O - Outcomes with pembrolizumab (pembro) monotherapy in patients (pts) with PD-L1–positive NSCLC with brain metastases: Pooled analysis of KEYNOTE-001, -010, -024, and -042. Ann Oncol 30:v604–v606

    Article  Google Scholar 

  19. Gadgeel SM, Lukas RV, Goldschmidt J et al (2019) Atezolizumab in patients with advanced non-small cell lung cancer and history of asymptomatic, treated brain metastases: exploratory analyses of the phase III OAK study. Lung Cancer 128:105–112

    Article  Google Scholar 

  20. Lukas RV, Gandhi M, O’hear C, Hu S, Lai C, Patel JD (2017) Safety and efficacy analyses of atezolizumab in advanced non-small cell lung cancer (NSCLC) patients with or without baseline brain metastases. Ann Oncol 28:ii25

    Article  Google Scholar 

  21. Tawbi HA, Forsyth PA, Algazi A et al (2018) Combined nivolumab and ipilimumab in melanoma metastatic to the brain. New Engl J Med 379:722–730

    Article  CAS  Google Scholar 

  22. Watanabe H, Kubo T, Ninomiya T et al (2017) The effect of nivolumab treatment for central nervous system metastases in non-small cell lung cancer. J Clin Oncol 35:e20601

    Article  Google Scholar 

  23. Zhou S, Xie J, Huang Z et al (2021) Anti-PD-(L)1 immunotherapy for brain metastases in non-small cell lung cancer: mechanisms, advances, and challenges. Cancer Lett 502:166–179

    Article  CAS  Google Scholar 

  24. Cheng Y, Han L, Wu L et al (2022) Serplulimab, a novel anti-PD-1 antibody, plus chemotherapy versus chemotherapy alone as first-line treatment for extensive-stage small-cell lung cancer: An international randomized phase 3 study. J Clin Oncol 40:8505

    Article  Google Scholar 

  25. Wu Y, Zhang T, Liu Y, Wang J, Bi N (2021) Anlotinib combined with durvalumab in a patient with recurrent multifocal brain metastases of small cell lung cancer after definitive concurrent chemoradiotherapy and palliative radiotherapy of the lung and brain: a case report. Ann Palliat Med 10:2379–2386

    Article  Google Scholar 

  26. Skribek M, Rounis K, Makrakis D et al (2020) Outcome of patients with NSCLC and brain metastases treated with immune checkpoint inhibitors in a “real-life” setting. Cancers. https://doi.org/10.3390/cancers12123707

    Article  Google Scholar 

  27. Hendriks L, Henon C, Auclin E et al (2019) Outcome of patients with non-small cell lung cancer and brain metastases treated with checkpoint inhibitors. J Thorac Oncol 14:1244–1254

    Article  CAS  Google Scholar 

  28. Hazuka MB, Burleson WD, Stroud DN, Leonard CE, Lillehei KO, Kinzie JJ (1993) Multiple brain metastases are associated with poor survival in patients treated with surgery and radiotherapy. J CLIN ONCOL 11:369–373

    Article  CAS  Google Scholar 

  29. Ding J, Karp JE, Emadi A (2017) Elevated lactate dehydrogenase (LDH) can be a marker of immune suppression in cancer: interplay between hematologic and solid neoplastic clones and their microenvironments. Cancer Biomark 19:353–363

    Article  CAS  Google Scholar 

  30. Seth P, Csizmadia E, Hedblom A et al (2017) Deletion of lactate dehydrogenase-a in myeloid cells triggers antitumor immunity. Cancer Res 77:3632–3643

    Article  CAS  Google Scholar 

  31. 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

    Article  Google Scholar 

  32. Luke JJ, Lemons JM, Karrison TG et al (2018) Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J CLIN ONCOL 36:1611–1618

    Article  CAS  Google Scholar 

  33. Deng L, Liang H, Burnette B et al (2014) Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 124:687–695

    Article  CAS  Google Scholar 

  34. Dovedi SJ, Cheadle EJ, Popple AL et al (2017) Fractionated radiation therapy stimulates antitumor immunity mediated by both resident and infiltrating polyclonal t-cell populations when combined with PD-1 blockade. Clin Cancer Res 23:5514–5526

    Article  CAS  Google Scholar 

  35. Feng Y, Tang L, Wang H et al (2022) Immune checkpoint inhibitors combined with angiogenic inhibitors in the treatment of locally advanced or metastatic lung adenocarcinoma patients. Cancer Immunol Immunother. https://doi.org/10.1007/s00262-022-03251-z

    Article  Google Scholar 

  36. Shi Y, Ji M, Jiang Y et al (2022) A cohort study of the efficacy and safety of immune checkpoint inhibitors plus anlotinib versus immune checkpoint inhibitors alone as the treatment of advanced non-small cell lung cancer in the real world. Transl Lung Cancer Res 11:1051–1068

    Article  CAS  Google Scholar 

Download references

Funding

The study was funded by National Natural Science Foundation of China (81972796 and 82272845), Natural Science Foundation of Shandong Province (ZR2019MH010 and ZR2019MH289), Beijing Bethune Charitable Foundation (flzh202107), Wu Jieping Medical Foundation (320.6750.2020-12-10), CSCO-Haosen Foundation (Y-HS202102-0089), and CSCO-Xinda Foundation (Y-XD202001-0008).

Author information

Author notes

  1. Shujie Zhou and Fei Ren have contributed equally to this work.

Authors and Affiliations

  1. Shandong University Cancer Center, Jinan, Shandong, China

    Shujie Zhou, Xiangjiao Meng & Zhaoqin Huang

  2. Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China

    Shujie Zhou, Fei Ren, Xiangjiao Meng & Zhaoqin Huang

  3. Department of Medical Oncology, Weifang Medical University, Shandong Cancer Hospital and Institute, Weifang, Shandong, China

    Chaozhuo Li & Liyang Jiang

  4. Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China

    Zhaoqin Huang

Authors
  1. Shujie Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fei Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chaozhuo Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liyang Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiangjiao Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhaoqin Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XJ M and ZQ H conceived of the review and edited the manuscript. FR collected the data. CZ L and LY J analyzed the data. SJ Z analyzed the data and drafted the article.

Corresponding authors

Correspondence to Xiangjiao Meng or Zhaoqin Huang.

Ethics declarations

Competing interests

The authors have stated that they have no conflicts of interest.

Ethical approval

This retrospective study has been approved by the Ethics Review Board of Shandong Cancer Hospital and it conforms to the provisions of the Declaration of Helsinki.

Consent to participate

Not required.

Consent for publication

Not required.

Additional information

Publisher's Note

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, S., Ren, F., Li, C. et al. Efficacy and safety of immune checkpoint inhibitors plus anlotinib in small cell lung cancer with brain metastases: a retrospective, multicentre study. J Neurooncol 160, 631–642 (2022). https://doi.org/10.1007/s11060-022-04182-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-022-04182-6

Keywords

Search

Navigation