Efficacy and safety of anti PD-1/PD-L1 antibodies in the treatment of advanced non-small cell lung cancer: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

FENG Haiming ¹ , ZHAO Ye ² , JING Tao ¹ , MA Jianxing ¹ ,  LI Bin ¹ , WANG Cheng ¹

1. Department of Thoracic Surgery, the Second Hospital of Lanzhou University, Lanzhou, 730000, P.R.China;
2. The Evidence Based Medicine Center of Lanzhou University, Lanzhou, 730000, P.R.China;

Corresponding author：

LI Bin, Email: dr.leebin@outlook.com

Keywords：

Non-small cell lung cancer (NSCLC); PD-1; PD-L1; Systematical review; Meta-analysis

DOI：

10.7507/1672-2531.201611027

Video：

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Objective To systematically evaluate the benefits and safety of anti-PD-1/PD-L1 antibody in the treatment of advanced non-small cell lung cancer (NSCLC). Methods Randomized controlled trials (RCTs) about anti-PD-1/PD-L1 antibody versus conventional-dose chemotherapy in the treatment of advanced NSCLC were searched in PubMed, EMbase, The Cochrane Library (Issue 8, 2016), Web of Science, CBM, CNKI, and VIP databases from inception to September 2016. Two reviewers independently screened literature, extracted data and evaluated the risk of bias of eligible studies, then meta-analysis was conducted by using RevMan 5.3 software. Results A total of five RCTs involving 2 580 patients were included. The results of meta-analysis showed that: the objective response rate (ORR) and one year overall survival rate (OSR_1y) in anti PD-1/PD-L1 monoclonal antibody group were higher than that of the conventional chemotherapy group (RR=1.86, 95%CI 1.37 to 2.52,P<0.001; RR=1.37, 95%CI 1.23 to 1.52,P<0.001, respectively). However, there were no significant differences between two groups in one-year progression-free survival rate (PFSR_1y) (RR=1.85, 95%CI 0.61 to 5.59,P=0.28) and disease control rate (DCR) (RR=1.13, 95%CI 0.76 to 1.68,P=0.55). With regard to untoward effect, rate of adverse effects (AEs) and AEs of 3-5 grade in anti PD-1/PD-L1 monoclonal antibody group were higher than those of the conventional chemotherapy group (RR=0.85, 95%CI 0.76 to 0.95,P=0.004; RR=0.28, 95%CI 0.18 to 0.43,P<0.001), the difference was statistically significant. But there was no significant difference in AEs to discontinuation between the two groups (RR=0.60, 95%CI 0.26 to 1.39,P=0.23). Conclusion Compared with conventional-dose chemotherapy, anti-PD-1/PD-L1 antibody has considerable current effect and safety in the treatment of advanced NSCLC.

Citation： FENG Haiming, ZHAO Ye, JING Tao, MA Jianxing, LI Bin, WANG Cheng. Efficacy and safety of anti PD-1/PD-L1 antibodies in the treatment of advanced non-small cell lung cancer: a meta-analysis. Chinese Journal of Evidence-Based Medicine, 2017, 17(2): 144-151. doi: 10.7507/1672-2531.201611027 Copy

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7.	Hamanishi J, Mandai M, Konishi I. Immune checkpoint inhibition in ovarian cancer. Int Immunol, 2016, 28(7): 339-348.
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12.	Ribas A, Kefford R, Marshall MA,et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. In J Clin Oncol, 2013, 31(5): 616-622.
13.	Zatloukal P, Heo DS, Park K,et al. Randomized phase II clinical trial comparing tremelimumab with best supportive care following first-line platinum-based therapy in patients with advanced non-small cell lung cancer. Asco Meeting Abstracts, 2009, 27: 15S.
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15.	李然, 王睿, 汤建华, 等. 紫杉醇治疗小细胞肺癌的系统评价. 中国循证医学杂志, 2008, 8(10): 851-860.
16.	Ishida Y, Agata Y, Shibahara K,et al. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. Embo J, 1992, 11(11): 3887-3895.
17.	Okazaki T, Maeda A, Nishimura H,et al. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA, 2001, 98(24): 13866-13871.
18.	Moreno BH, Parisi G, Robert L,et al. Anti-PD-1 Therapy in Melanoma. Semin Oncol, 2015, 42(3): 466-473.
19.	Zimmerman MP, Mehr SR. Targeted programmed cell death in lung cancer treatment. Am J Manag Care, 2014, 20(5): 3.
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21.	Calles A, Liao X, Sholl LM,et al. Expression of PD-1 and Its Ligands, PD-L1 and PD-L2, in Smokers and Never Smokers with KRAS-Mutant Lung Cancer. J Thorac Oncol, 2015, 10(12): 1726-1735.
22.	Zhu L, Jing S, Wang B,et al. Anti-PD-1/PD-L1 Therapy as a Promising Option for Non-Small Cell Lung Cancer: a Single arm Meta-Analysis. POR, 2016, 22(2): 331-339.
23.	Carbognin L, Pilotto S, Milella M,et al. Differential Activity of Nivolumab, Pembrolizumab and MPDL3280A according to the Tumor Expression of Programmed Death-Ligand-1 (PD-L1): Sensitivity Analysis of Trials in Melanoma, Lung and Genitourinary Cancers. PLoS One, 2015, 10(6): e0130142.
24.	Zhang T, Xie J, Arai S,et al. The efficacy and safety of anti-PD-1/PD-L1 antibodies for treatment of advanced or refractory cancers: a meta-analysis. Oncotarget, 2016, 7(45): 73068-73079.
25.	Rossi A, Pasquale R, Esposito C,et al. Should epidermal growth factor receptor tyrosine kinase inhibitors be considered ideal drugs for the treatment of selected advanced non-small cell lung cancer patients? Cancer Treat Rev, 2013, 39(5): 489-497.
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27.	Lynch TJ, Bell DW, Sordella R,et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med, 2004, 350(350): 2129-2139.
28.	Borghaei H, Paz-Ares L, Horn L,et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med, 2015, 373(17): 1627-1639.
29.	Brahmer J, Reckamp KL, Baas P,et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med, 2015, 373(2): 123-135.
30.	Weber JS, Minor DR, D'Angelo SP,et al. A phase 3 randomized, open-label study of nivolumab (anti-pd-1; bms-936558; ono-4538) versus investigator's choice chemotherapy (icc) in patients with advanced melanoma after prior anti-ctla-4 therapy. Ann Oncol, 2014, 25(suppl 4): 1210.
31.	Fehrenbacher L, Spira A, Ballinger M,et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet, 2016, 387(10030): 1837-1846.
32.	Herbst RS, Baas P, Kim DW,et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet, 2015, 387(10027): 1540-1550.

1. Ferlay J, Shin HR, Bray F,et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN2008. Int J Cancer, 2010, 127(12): 2893-2917.
2. Miller KD, Siegel RL, Lin CC,et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin, 2016, 66(4): 271-289.
3. Parums DV. Current status of targeted therapy in non-small cell lung cancer. Drugs Today (Barc), 2014, 50(7): 503-525.
4. Jackman DM, Miller VA, Cioffredi LA,et al. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin Cancer Res, 2009, 15(16): 5267-5273.
5. Cufer T, Ovcaricek T, O'Brien ME. Systemic therapy of advanced non-small cell lung cancer: major-developments of the last 5-years. Eur J Cancer, 2013, 49(6): 1216-1225.
6. 秦虹, 曾川, 范卫东, 等. 2016 年 ASCO 会议非小细胞肺癌免疫治疗的相关进展. 中华肺部疾病杂志(电子版), 2016, 9(4): 464-466.
7. Hamanishi J, Mandai M, Konishi I. Immune checkpoint inhibition in ovarian cancer. Int Immunol, 2016, 28(7): 339-348.
8. Gettinger SN, Horn L, Gandhi L,et al. Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer. J of Clin Oncol, 2015, 33(18): 2004-2012.
9. Zhu L, Jing S, Bing W,et al. Anti-PD-1/PD-L1 Therapy as a Promising Option for Non-Small Cell Lung Cancer: a Single arm Meta-Analysis. POR, 2016, 22(2): 1-9.
10. Hodi FS, O'Day SJ, McDermott DF,et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med, 2010, 363(8): 711-723.
11. Topalian SL, Hodi FS, Brahmer JR,et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med, 2012, 366(26): 2443-2454.
12. Ribas A, Kefford R, Marshall MA,et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. In J Clin Oncol, 2013, 31(5): 616-622.
13. Zatloukal P, Heo DS, Park K,et al. Randomized phase II clinical trial comparing tremelimumab with best supportive care following first-line platinum-based therapy in patients with advanced non-small cell lung cancer. Asco Meeting Abstracts, 2009, 27: 15S.
14. Dizon DS, Krilov L, Cohen E,et al. Clinical Cancer Advances 2016: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology. J Clin Oncol, 2016, 34(9): 987-1011.
15. 李然, 王睿, 汤建华, 等. 紫杉醇治疗小细胞肺癌的系统评价. 中国循证医学杂志, 2008, 8(10): 851-860.
16. Ishida Y, Agata Y, Shibahara K,et al. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. Embo J, 1992, 11(11): 3887-3895.
17. Okazaki T, Maeda A, Nishimura H,et al. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA, 2001, 98(24): 13866-13871.
18. Moreno BH, Parisi G, Robert L,et al. Anti-PD-1 Therapy in Melanoma. Semin Oncol, 2015, 42(3): 466-473.
19. Zimmerman MP, Mehr SR. Targeted programmed cell death in lung cancer treatment. Am J Manag Care, 2014, 20(5): 3.
20. Wolchok JD. PD-1 Blockers. Cell, 2015, 162(5): 937.
21. Calles A, Liao X, Sholl LM,et al. Expression of PD-1 and Its Ligands, PD-L1 and PD-L2, in Smokers and Never Smokers with KRAS-Mutant Lung Cancer. J Thorac Oncol, 2015, 10(12): 1726-1735.
22. Zhu L, Jing S, Wang B,et al. Anti-PD-1/PD-L1 Therapy as a Promising Option for Non-Small Cell Lung Cancer: a Single arm Meta-Analysis. POR, 2016, 22(2): 331-339.
23. Carbognin L, Pilotto S, Milella M,et al. Differential Activity of Nivolumab, Pembrolizumab and MPDL3280A according to the Tumor Expression of Programmed Death-Ligand-1 (PD-L1): Sensitivity Analysis of Trials in Melanoma, Lung and Genitourinary Cancers. PLoS One, 2015, 10(6): e0130142.
24. Zhang T, Xie J, Arai S,et al. The efficacy and safety of anti-PD-1/PD-L1 antibodies for treatment of advanced or refractory cancers: a meta-analysis. Oncotarget, 2016, 7(45): 73068-73079.
25. Rossi A, Pasquale R, Esposito C,et al. Should epidermal growth factor receptor tyrosine kinase inhibitors be considered ideal drugs for the treatment of selected advanced non-small cell lung cancer patients? Cancer Treat Rev, 2013, 39(5): 489-497.
26. Zhou C, Wu YL, Chen G,et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol, 2011, 12(8): 735-742.
27. Lynch TJ, Bell DW, Sordella R,et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med, 2004, 350(350): 2129-2139.
28. Borghaei H, Paz-Ares L, Horn L,et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med, 2015, 373(17): 1627-1639.
29. Brahmer J, Reckamp KL, Baas P,et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med, 2015, 373(2): 123-135.
30. Weber JS, Minor DR, D'Angelo SP,et al. A phase 3 randomized, open-label study of nivolumab (anti-pd-1; bms-936558; ono-4538) versus investigator's choice chemotherapy (icc) in patients with advanced melanoma after prior anti-ctla-4 therapy. Ann Oncol, 2014, 25(suppl 4): 1210.
31. Fehrenbacher L, Spira A, Ballinger M,et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet, 2016, 387(10030): 1837-1846.
32. Herbst RS, Baas P, Kim DW,et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet, 2015, 387(10027): 1540-1550.

Chinese Journal of Evidence-Based Medicine

Efficacy and safety of anti PD-1/PD-L1 antibodies in the treatment of advanced non-small cell lung cancer: a meta-analysis

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