The efficacy and safety of anti-PD-1/PD-L1 antibodies for treatment of advanced or refractory cancers: a meta-analysis

// Tengfei Zhang 1, 2, * , Jing Xie 3, * , Seiji Arai 2, 4 , Liping Wang 5 , Xuezhong Shi 6 , Ni Shi 7 , Fen Ma 2 , Sen Chen 2 , Lan Huang 1 , Li Yang 1 , Wang Ma 5 , Bin Zhang 8 , Weidong Han 9 , Jianchuan Xia 10 , Hu Chen 8 , Yi Zhang 1, 5, 11, 12 1 Biotherapy Center, Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China 2 Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States 3 School of Public Health, Xinxiang Medical University, Xinxiang, Henan, China 4 Department of Urology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Japan 5 Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China 6 Department of Epidemiology and Biostatistics, School of Public Health, Zhengzhou University, Zhengzhou, Henan, China 7 Comprehensive Cancer Center, the Ohio State University, Columbus, Ohio, United States 8 Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital to Academy of Military Medical Science (307 Hospital, PLA), Beijing, China 9 Molecular and Immunological/Bio-therapeutic Department, Institute of Basic Medicine, Chinese PLA General Hospital, Beijing China 10 Biotherapy Center, Cancer Center, Sun Yat-sen University, Guangzhou, Guangzhou, Guangdong, China 11 Henan Key Laboratory for Tumor Immunology and Biotherapy, Henan, China 12 School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China * These authors contributed equally to this work Correspondence to: Yi Zhang, email: yizhang@zzu.edu.cn Hu Chen, email: chenhu217@aliyun.com Keywords: PD-1, PD-L1, immunotherapy, advanced or refractory cancer, meta-analysis Received: May 27, 2016      Accepted: September 17, 2016      Published: September 24, 2016 ABSTRACT Purpose: To systematically evaluate the overall efficacy and safety of current anti-PD-1/PD-L1 antibodies for treatment of patients with advanced or refractory cancer. Results: Fifty-one trials including 6,800 patients were included. The overall response rates for melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC) were 29% (95% CI: 1.53−2.41), 21% (95% CI: 17%−25%) and 21% (95% CI: 16%−27%) respectively. While the overall adverse effects rate for melanoma, NSCLC, RCC were 16% (95% CI: 6%−28%), 11% (95% CI: 8%−14%) and 20% (95% CI: 11%−32%) respectively. Tumor PD-L1 expression and patient smoking status might serve as biomarkers to predict response of anti-PD-1/PD-L1 antibody treatment. Compared to tumors with negative PD-L1 expression, tumors with positive PD-L1 expression had a significantly higher clinical response rate (41.4% versus 26.5%) with RR = 1.92 (95% CI: 1.53−2.41, P < 0.001). Smoker patients also showed a significantly higher response rate (33.7%) than patients who never smoked (4.2%) with RR = 6.02 (95% CI: 1.22−29.75, P = 0.028). Nivolumab and Pembrolizumab were associated with significantly increased response rate (RR = 2.89, 95% CI: 2.46−3.40, P < 0.001), reduced death risk (HR= 0.53; 95% CI: 0.48−0.57; P < 0.001), and decreased adverse effect rate (RR = 0.49, 95% CI: 0.30−0.80, P = 0.004) compared with other therapies. Experimental Design: Clinical trials reporting response or safety of anti-PD-1/PD-L1 antibodies for advanced or refractory cancer patients published before January 31th 2016 were searched in PubMed and EMBASE database. Meta-analyses using random effects models were used to calculate the overall estimate. Conclusions: Anti-PD-1/PD-L1 antibodies have high response rates and low adverse effect rates for advanced or refractory cancers.