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To be or not to be: whether anti-angiogenic agent combined with immune checkpoint inhibitoris necessary in the treatment of advanced or metastatic renal cell carcinoma

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Although it’s widely known that targeted therapy against angiogenesis and immunotherapy agents showed survival benefit over chemoradiotherapy in advanced or metastatic renal cell carcinoma, some patients still cannot receive a satisfied prognosis. We performed a systematic review and meta-analysis to explore the efficacy and safety of anti-angiogenic agents combined with immune checkpoint inhibitors. We conducted a search for randomized controlled trials in Pubmed, Embase, Cochrane, and major conference. Enrolled eligible studies and extracted data were completed by two investigators to compare OS, PFS, and ORR both in PD-L1 and ITT subset. Then, we calculated the pooled RR and 95% CI of all-grade and high-grade adverse effects to study its safety. Besides, we assessed the heterogeneity through subgroup and sensitivity analysis. A total of three RCTs covering 2662 patients were enrolled. In PFS analysis, the estimated HR for ITT subset was 0.74 with 95% CI of 0.65 to 0.84 and for PD-L1 subset was 0.65 with 95% CI of 0.56 to 0.76. And in OS analysis, the result was 0.74 with 95% CI of 0.53 to 1.03 in ITT subset and 0.74 with 95% CI of 0.56 to 0.96 in PD-L1 subset. As for ORR analysis, combination therapy showed advantage rather than monotherapy in ITT subset (RR 1.54; 95% CI 1.11 to 2.14), but conversely in PD-L1 positive subset (RR 1.64; 95% CI 0.94 to 2.84). Additionally, combination therapy failed to show obvious safety in most immune-related adverse events, whatever in all-grade or high grade.

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All data generated or analyzed during this study are included in this article and its Supplementary Information files.


  1. 1.

    Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32.

  2. 2.

    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018.

  3. 3.

    Allemani C, Matsuda T, Di Carlo V, Harewood R, Matz M, Niksic M, et al. Global surveillance of trends in cancer survival 2000–14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet. 2018;391(10125):1023–75.

  4. 4.

    Barata PC, Rini BI. Treatment of renal cell carcinoma: Current status and future directions. CA Cancer J Clin. 2017;67(6):507–24.

  5. 5.

    Escudier B, Porta C, Schmidinger M, Rioux-Leclercq N, Bex A, Khoo V, et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-updagger. Ann Oncol. 2019;30(5):706–20.

  6. 6.

    Nuti M, Zizzari IG, Botticelli A, Rughetti A, Marchetti P. The ambitious role of anti angiogenesis molecules: Turning a cold tumor into a hot one. Cancer Treat Rev. 2018;70:41–6.

  7. 7.

    Lanitis E, Irving M, Coukos G. Targeting the tumor vasculature to enhance T cell activity. Curr Opin Immunol. 2015;33:55–63.

  8. 8.

    Ramjiawan RR, Griffioen AW, Duda DG. Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy? Angiogenesis. 2017;20(2):185–204.

  9. 9.

    Tsukita Y, Okazaki T, Ebihara S, Komatsu R, Nihei M, Kobayashi M, et al. Beneficial effects of sunitinib on tumor microenvironment and immunotherapy targeting death receptor5. Oncoimmunology. 2019;8(2):e1543526.

  10. 10.

    Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, Nezivar J, et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci USA. 2012;109(43):17561–6.

  11. 11.

    Kloepper J, Riedemann L, Amoozgar Z, Seano G, Susek K, Yu V, et al. Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proc Natl Acad Sci USA. 2016;113(16):4476–81.

  12. 12.

    Peterson TE, Kirkpatrick ND, Huang Y, Farrar CT, Marijt KA, Kloepper J, et al. Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages. Proc Natl Acad Sci USA. 2016;113(16):4470–5.

  13. 13.

    Schmittnaegel M, Rigamonti N, Kadioglu E, Cassara A, Wyser Rmili C, Kiialainen A, et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci Transl Med. 2017.

  14. 14.

    Jain RK. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell. 2014;26(5):605–22.

  15. 15.

    Missiaen R, Mazzone M, Bergers G. The reciprocal function and regulation of tumor vessels and immune cells offers new therapeutic opportunities in cancer. Semin Cancer Biol. 2018;52(Pt 2):107–16.

  16. 16.

    Huang Y, Kim BYS, Chan CK, Hahn SM, Weissman IL, Jiang W. Improving immune-vascular crosstalk for cancer immunotherapy. Nat Rev Immunol. 2018;18(3):195–203.

  17. 17.

    Network NCC. (NCCN) Clinical Practice Guidelines in Oncology. Kidney Cancer, Version 2. 2020. https://www.nccnorg/professionals/physician_gls/f_guidelinesasp. Accessed 5 Aug 2019.

  18. 18.

    Oncology CSoC. Guidelines of Chinese Society of Clinical Oncology (CSCO). Kidney Cancer, Version 2019.

  19. 19.

    Atkins MB, Plimack ER, Puzanov I, Fishman MN, McDermott DF, Cho DC, et al. Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. Lancet Oncol. 2018;19(3):405–15.

  20. 20.

    Choueiri TK, Larkin J, Oya M, Thistlethwaite F, Martignoni M, Nathan P, et al. Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial. Lancet Oncol. 2018;19(4):451–60.

  21. 21.

    Dudek AZ, Sica RA, Sidani A, Jha GG, Xie H, Alva AS, et al. Phase Ib study of pembrolizumab in combination with bevacizumab for the treatment of metastatic renal cell carcinoma: Big Ten Cancer Research Consortium BTCRC-GU14–003. J Clin Oncol. 2016;34:559.

  22. 22.

    Chowdhury S, McDermott DF, Voss MH, Hawkins RE, Aimone P, Voi M, et al. A phase I/II study to assess the safety and efficacy of pazopanib (PAZ) and pembrolizumab (PEM) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 2017;35:4506.

  23. 23.

    Hammers HJ, Plimack ER, Infante JR, Rini BI, McDermott DF, Lewis LD, et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 Study. J Clin Oncol. 2017;35(34):3851–8.

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This study was financially supported by National Natural Science Foundation of China (Minhe Shen, No. 81573902); Natural Science Foundation of Zhejiang Province (Shanming Ruan, No. LY17H270007); China Postdoctoral Science Foundation (Shanming Ruan, No. 2017M612040/2018T110610); Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents (Shanming Ruan, No. 2015-43); Program for the Cultivation of Youth talents in China Association of Chinese Medicine (Shanming Ruan, No. QNRC2-C08); Zhejiang Provincial Program for the Cultivation of the Young and Middle-Aged Academic Leaders in Colleges and Universities (Shanming Ruan, No. 2017-248); Zhejiang Provincial Project for the key discipline of Traditional Chinese Medicine (Yong Guo, No. 2017-XK-A09).

Author information

SR, HSW, and DH contributed to the design and conception of the study. YZ and JY carried out the collection and assembly of data. LZ and CS performed the data analysis and interpretation. LS and LZ wrote the manuscript, SR revised the manuscript, then SR and DH gave the final approval of manuscript.

Correspondence to Shanming Ruan or Dawei Huang.

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We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and company that could be construed as influencing the position presented in, or the review of, the manuscript entitled.

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Dawei Huang and Shanming Ruan are co-corresponding author in this work.

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Sun, L., Zhang, L., Yu, J. et al. To be or not to be: whether anti-angiogenic agent combined with immune checkpoint inhibitoris necessary in the treatment of advanced or metastatic renal cell carcinoma. Med Oncol 37, 15 (2020).

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  • Combination therapy
  • Anti-angiogenic agent
  • Immune checkpoint inhibitor
  • Renal cell carcinoma
  • Meta-analysis