Int J Clin Exp Med 2017;10(1):1529-1538www.ijcem.com /ISSN:1940-5901/IJCEM0040167

Review Article Therapeutic effects and associated adverse events of PD-1 and CTLA-4 pathway inhibitors in the treatment of non-small-cell lung cancer: meta-analyses of clinical phase II/III randomized controlled trials

Hui Zhan1, Yang Yang2, Bing Zhao1, Shuguang Hao1, Xiabao Hou1

1Department of Thoracic Oncology, Xinxiang Central Hospital, Affiliated Central Hospital of Xinxiang Medical Uni-versity, Xinxiang, China; 2Department of Clinical Laboratory, First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China

Received September 18, 2016; Accepted November 16, 2016; Epub January 15, 2017; Published January 30, 2017

Abstract: Objective: To summarize and compare the therapeutic efficacy of programmed death 1 (PD-1) and cyto-toxic T lymphocyte associated antigen 4 (CTLA-4) pathway inhibitors in the treatment of non-small-cell lung cancer (NSCLC). Methods: Traditional and network meta-analysis of clinical phase II/III randomized controlled trials of PD-1 and CTLA-4 pathway inhibitors vs. controls (general chemotherapy or best support therapy) in the treatment of NSCLC was performed by RevMan and ITC programs. The data of progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and grade 3/4 AE were extracted to evaluate the prognosis, tumor responses, and toxicity, respectively. Results: Among patients with NSCLC, when compared with controls, PD-1 pathway inhibi-tors had longer median OS, higher ORR, and lower incidence of grade 3 or 4 AE; further CTLA-4 pathway inhibitors had higher ORR. When compared with CTLA-4 pathway inhibitors, PD-1 pathway inhibitors had significant higher OS and lower incidence of grade 3 or 4 AE. Conclusion: Because the PD-1 pathway inhibitors have more advantages in patients’ survival, tumor response, and adverse events than CTLA-4 pathway inhibitors and traditional treatment, this agents could prioritize to use for the treatment of NSCLC.

Keywords: Programmed death 1 (PD-1), cytotoxic T lymphocyte associated antigen 4 (CTLA-4), non-small-cell lung cancer (NSCLC), meta-analysis

Introduction

Non-small-cell lung cancer (NSCLC) accounted for about 85% of all lung cancers [1]. As a class, NSCLCs are relatively insensitive to chemother-apy compared to small cell carcinoma [2]. However, the efficacy of traditional chemother-apy for advanced NSCLC over the last decade has been modest [3]. Molecularly targeted therapy, a major modalities of medical treat-ment, which developed in the recent years, has benefited to a small proportion of patients with NSCLC whose tumors contain anaplastic lym-phoma kinase (ALK) gene rearrangements or epidermal growth factor receptor (EGFR) muta-tions [4]. Unfortunately, the agents of molecu-larly targeted therapy have been evaluated in clinical trials with limited success, a large part of patients with advanced NSCLC still die within one year of diagnosis [5].

Recent cancer molecularly targeted therapy efforts have focused on immune checkpoint targeted inhibitors, which are considered as the “brakes” on immune system with the goal of inducing immune cell proliferation and activa-tion against cancer cells [6, 7]. Cytotoxic T lym-phocyte associated antigen 4 (CTLA-4) was the first immune checkpoint targeted therapeuti-cally [8]. Previous phase III trials have demon-strated that CTLA-4 antagonists have definite effects on improving the overall survival (OS) of patients with advanced melanoma [9, 10]. For NSCLC, CTLA-4 antagonists have shown mini-mal single-agent activity [11]; however, when combined with cytotoxic chemotherapy, these agents may have more promising results [12].

The programmed death 1 (PD-1) is an immune checkpoint receptor expressed on activated T

Meta-analyses of PD-1 and CTLA-4 inhibitors for NSCLC

1530 Int J Clin Exp Med 2017;10(1):1529-1538

cells [13]. Nivolumab and Pembrolizumab, fully human IgG4 PD-1 immune checkpoint inhibitor antibodies, were previously reported in the treatment of NSCLC [14, 15]. Clinical phase I and II trials of these agents suggest that sec-ond line treatment with these agents has clini-cally meaningful activity and a manageable safety profile in previously treatedpatients with advanced, refractory NSCLC [5, 16]. Moreover, the Atezolizumab, a fully humanized, engi-neered monoclonal antibody of IgG1 isotype against the protein PD-L1, is currently in clinical trials as an immunotherapy for several types of solid tumors [17, 18]. For NSCLC, a second line treatment prolonged the median overall survival for patients with locally advanced/met-astatic NSCLC to 16 months [19] safety and predictive biomarkers of the engineered anti-body MPDL3280A (anti-PDL1).

To date, the evidence of the efficacy of CTLA-4 inhibitors on NSCLC is still limited. Further, although the PD-1 and PD-L1 inhibitors, such as Nivolumab [20, 21], Pembrolizumab [22], and Atezolizumab [23], exhibited significant advantages on the tumor response and surviv-al for patients with NSCLC, the conclusions of these clinical trials were not entirely consis-tent. In addition, there is still lack of the direct evidence of the efficacy difference between CTLA-4 and PD-1 pathway inhibitors on NSCLC. In this scenario, two traditional meta-analyses of clinical phase II/III randomized controlled tri-als was performed to evaluate the therapeutic effect and associated adverse events of the CTLA-4 and PD-1 inhibitors for NSCLC, respec-tively. Furthermore, we conducted a network meta-analysis for detecting the efficacy and safety difference between these two agents.

Materials and methods

Study design

This study was meta-analyses based on data collected from previous clinical phase II/III ran-domized controlled trials (RCTs) of immunother-apy with PD-1 or CTLA-4 pathway inhibitors ver-sus traditional chemotherapies or conserva- tive treatments for patients with NSCLC. Two reviewers (HZ, YY) selected and reviewed the evidence respectively. Dilemmas were handled through group discussion.

Search strategy

Studies were search among PubMed/Medline, Embase, and Cochrane Central Register of

Controlled Trials (CENTRAL) by using the terms: “programmed death-1/PD-1 inhibitor” OR “pro-grammed death-1 ligand/PD-L1 inhibitor” OR “programmed death-1/PD-1 agent” OR “pro-grammed death-1 ligand/PD-L1 agent” OR “Ni- volumab” OR “Pembrolizumab” OR “Atezolizu- mab” OR “cytotoxic T lymphocyte associated antigen 4/CTLA-4 inhibitor” OR “cytotoxic T ly- mphocyte associated antigen 4/CTLA-4 inhibi-tor agent” OR “Tremelimumab” OR “Ipilimumab” AND “non-small-cell lung cancer/NSCLC” AND “randomized trials (random* trials)” in title and abstract. The databases were searched for studies published till July 2016. Only trails pub-lished in English were involved. Reference lists of related articles were manually checked to search for additional eligible publications. All references of relevant articles were scanned and all additional studies of potential interest were retrieved for further analysis.

Selection criteria

Eligible trails have to meet the following criteria: (1) patients involved were diagnosed with NSCLC through cytological diagnosis or patho-logical diagnosis; (2) clinical phase II/III ran-domized controlled trials using PD-1 or CTLA-4 pathway inhibitors versus traditional chemo-therapies or conservative treatment to treat NSCLC; (3) individual use traditional chemo-therapies or conservative treatment was used as control. The exclusion criteria is: (1) trails not in RCT or clinical phase II/III; (2) without ade-quate data for use; (3) the former paper of the duplicated studies.

The bias risk of included publications was eval-uated based on Cochrane handbook for sys-tematic reviews of interventions, version 5.1.0 [24]. The major quality components include “(1) sequence generation of the allocation; (2) allo-cation concealment; (3) blinding of partici-pants, personnel, and outcome assessors; (4) incomplete outcome data; (5) selective out-come reporting; and (6) other sources of bias” [24]. Trails were classified into three levels according to the bias risk. Trials with appropri-ate and sufficient support of index of outcome assessment that with minimal risk of bias are classified into A level; trials with one or more high or unclear risk for bias among the quality components and with middle level risk of bias are in B level; trails with three or more high or unclear risk for bias among the quality compo-

Meta-analyses of PD-1 and CTLA-4 inhibitors for NSCLC

1531 Int J Clin Exp Med 2017;10(1):1529-1538

nents and with the highest level of bias are in C level.

Data extraction

Two reviewers (HZ, BZ) separately and inde- pendently exacted data from the trials. Disa- greements were handled with consensus. All data were checked for internal consistency. The trails were identified with the first author and the year of publication. For the trials that did not report the required data to determine the outcomes, the reviewers contacted the authors to obtain required information. The baseline information of patients and details of intervention of each trial were extracted to assess the heterogeneity. The prognosis data including progression free survival (PFS) and overall survival (OS) were evaluated in the meta-analysis. The tumor responses assess- ed by overall response rate (ORR). In addition, toxicity data, typically the number of patients who suffered grade 3/4 adverse events (AE) were retrieved and extracted to assess the adverse effect of treatments.

Statistical analysis

Traditional meta-analysis was conducted with Review Manager5.3 (RevMan5.3; The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). Odds ratio (OR) or Hazard ratio (HR) was used for evaluation and 95% confidence intervals (CI) was calculated for each estimate. P≤0.05 was used to denote statistical significance. Heterogeneity of the

results of the trials was assessed with the I2 statistic by using the chi-square (X2) test at α=0.1 [25]. Primary assessment was done with a fixed model. When P≥0.05 and I2≤50%, it was considered the trials are without heterogeneity and a fixed effect model was used to perform meta-analysis. When P<0.05 and I2>50%, it was considered that the trials are with signifi-cant heterogeneity [26]. The source of the het-erogeneity was further analyzed. If there was no significant clinical heterogeneity, a second-ary confirmatory analysis was done with a ran-dom effects model. Otherwise, descriptive an- alysis was performed. Where necessary, sensi-tivity analyses were performed to test the sta-bility of identified outcomes. The network me- ta-analysis was conducted with Indirect Treat- ment Comparison (ITC) software (https://www.cadth.ca/resources/itc-user-guide/). Funnel pl- ots were performed to evaluate the possibility of publications bias.

Results

Literature search

The whole search process is as described in the QUOROM-type flowchart (Figure 1). Overall six studies [11, 12, 20-23] with 2466 patients were included. The trials were all multicenter, randomized, controlled and phase II or III trails. Four studies [20-23] assessed the PD-1 path-way inhibitors (Nivolumab, Pembrolizumab, or Atezolizumab) versus Controls (Docetaxel), and two studies [11, 12] evaluated CTLA-4 pathway inhibitors (Tremelimumab or Ipilimumab plus general chemotherapy) versus Controls (best supportive care or general chemotherapy). The methodological details relevant to bias and characteristics of the selected studies are described in Table 1.

Progression free survival

Four studies [20-23] evaluated the median PFS of patients underwent PD-1 pathway inhibitor treatment, and only one [12] assessed the median PFS of patients underwent CLTA-4 pathway inhibitor treatment. According to the traditional meta-analysis, when compared with controls, both the PD-1 pathway inhibitors (HR=0.98, 95% CI: 0.77 to 1.25, P=0.87, Figure 2) and CTLA-4 pathway inhibitors (HR=1.28, 95% CI: 0.99 to 1.67, P=0.06, Figure 2) had the similar median PFS among patients with

Figure 1. Searching pro-cesses of meta-analy-sis.

Meta-analyses of PD-1 and CTLA-4 inhibitors for NSCLC

1532 Int J Clin Exp Med 2017;10(1):1529-1538

Table 1. Patients’ characteristics of four clinical trials included

Reference Trial name Phase Line of treatment Group Drugs and dose Patients

(n)Sex

(M; n)

Median age

(years)

Median OS

(months)

Median PFS

(months)

Quality level

Borghaei 2015 CheckMate 057 III Second/Third Experimental Nivolumab 3 mg/kg 292 151 61 12.2 2.3 B

Control Docetaxel 75 mg/m2 290 168 64 9.4 4.2

Brahmer 2015 CheckMate 017 III Second Experimental Nivolumab 3 mg/kg 135 111 62 9.2 3.5 B

Control Docetaxel 75 mg/m2 137 97 64 6.0 2.8

Herbst 2016 Keynote 010 II/III Second Experimental Pembrolizumab 2 mg/kg 345 212 63 10.4 3.9 B

Experimental Pembrolizumab 10 mg/kg 346 213 63 12.7 4.0

Control Docetaxel 75 mg/m2 343 209 62 8.5 4.0

Fehrenbacher 2016 POPLAR II Second Experimental Atezolizumab 1200 mg 144 93 62 12.6 2.7 B

Control Docetaxel 75 mg/m2 143 76 62 9.7 3.0

Zatloukal 2009 - II Second Experimental Tremelimumab 15 mg/kg 44 Not state Not state Not state Not state B

Control Best supportive care 43 Not state Not state Not state Not state

Lynch 2012 - II First Experimental Concurrent Ipilimumab 10 mg/kg + Paclitaxel 175 mg/m2 + Carboplatin AUC 6

70 53 59 9.7 4.1 B

Experimental Phased Ipilimumab 10 mg/kg + Paclitaxel 175 mg/m2 + Carboplatin AUC 6

68 49 61 12.2 5.1

Control Paclitaxel 175 mg/m2 + Carboplatin AUC 6 + Placebo 66 49 62 8.3 4.2

Meta-analyses of PD-1 and CTLA-4 inhibitors for NSCLC

1533 Int J Clin Exp Med 2017;10(1):1529-1538

NSCLC. Furthermore, according to the network meta-analysis, the PD-1 and CTLA-4 pathway inhibitors had similar median PFS (HR=0.77, 95% CI: 0.54 to 1.09, P=0.14, Table 2). The symmetric funnel plots suggested the non-exis-tence of publication bias.

Overall survival

Four studies [20-23] evaluated the median OS of patients underwent PD-1 pathway inhibitor treatment, and only one [12] assessed the median OS of patients underwent CLTA-4 path-

Figure 2. Meta-analysis of effect in median PFS.

Table 2. Network meta-analysis of PFS, OS, ORR, and 3/4 AE for PD-1 compared with CTLA-4 pathway inhibitors

VariablePD-1 pathway inhibitors CTLA-4 pathway inhibitors

Pooled HR/OR 95% CI P-value AssociationNo. of

events/deathsTotal No. of

patientsNo. of

events/deathsTotal No.

of patientsPFS 1069* 1262 114 138 0.766 0.536-1.093 0.143 0.872OS 787* 1262 102 138 0.620 0.458-0.839 0.002 0.812ORR 233 1262 39 182 0.756 0.336-1.702 0.499 0.6053/4 AE 111 903 85 182 0.033 0.003-0.443 0.005 0.989*acquired from Kaplan-Meier curves.

Figure 3. Meta-analysis of effect in median OS.

Meta-analyses of PD-1 and CTLA-4 inhibitors for NSCLC

1534 Int J Clin Exp Med 2017;10(1):1529-1538

way inhibitor treatment. According to the tradi-tional meta-analysis, when compared with con-trols, the PD-1 pathway inhibitors had longer median OS among patients with NSCLC (HR=0.67, 95% CI: 0.61 to 0.75, P<0.01, Figure 3), however, the CTLA-4 pathway inhibitors had the similar median OS among patients with NSCLC (HR=1.08, 95% CI: 0.81 to 1.43, P=0.62, Figure 3). Furthermore, according to the network meta-analysis, the PD-1 pathway

inhibitors had significantly longer median OS among patients with NSCLC than CTLA-4 path-way inhibitors (HR=0.62, 95% CI: 0.46 to 0.84, P<0.01, Table 2). Publication bias did not exist.

Overall response rate

Four studies [20-23] evaluated the overall response rate of patients underwent PD-1 pathway inhibitor treatment, and two [11, 12]

Figure 4. Meta-analysis of effect in ORR.

Figure 5. Meta-analysis of grade 3/4 AE.

Meta-analyses of PD-1 and CTLA-4 inhibitors for NSCLC

1535 Int J Clin Exp Med 2017;10(1):1529-1538

assessed the overall response rate of patients underwent CLTA-4 pathway inhibitor treatment. According to the traditional meta-analysis, both PD-1 (OR=1.86, 95% CI: 1.44 to 2.40, P<0.01, Figure 4) and CTLA-4 (OR=2.46, 95% CI: 1.14 to 5.32, P=0.02, Figure 4) pathway inhibitors had a significantly higher ORR than controls. However, according to network meta-analysis, the PD-1 and CTLA-4 pathway inhibitors had similar ORR (OR=0.76, 95% CI: 0.34 to 1.70, P=0.50, Table 2). Publication bias did not exist.

Adverse effect

Four studies [20-23] evaluated the adverse events of patients underwent PD-1 pathway inhibitor treatment, and two [11, 12] assessed the adverse events of patients underwent CLTA-4 pathway inhibitor treatment. According to the traditional meta-analysis, compared with controls, the PD-1 pathway inhibitors had sig-nificantly lower incidence of grade 3 or 4 adverse events among patients with NSCLC (OR=0.15, 95% CI: 0.07 to 0.32, P<0.01, Figure 5), however, the CTLA-4 pathway inhibitors had a similar incidence of grade 3 or 4 adverse events (OR=4.50, 95% CI: 0.38 to 53.33, P=0.23, Figure 5). Furthermore, according to the network meta-analysis, the PD-1 pathway inhibitors had significantly lower incidence of grade 3 or 4 adverse events among patients with NSCLC than CTLA-4 pathway inhibitors (OR=0.03, 95% CI: 0.01 to 0.44, P<0.01, Table 2). Publication bias did not exist.

Discussion

This meta-analysis aimed to summarize and compare the therapeutic effects and associat-ed adverse events of PD-1 and CTLA-4 pathway inhibitors in the treatment of NSCLC by system-ic evaluation of six clinical phase II/III random-ized controlled trials. We demonstrates that patients use of PD-1 pathway inhibitors have the advantages in the OS, tumor response and grade 3 or 4 AE when compared with traditional chemotherapy; however, patients use of CTLA-4 pathway inhibitors only have a significant advantage on tumor response when compared with traditional therapy. In addition, our net-work meta-analysis further revealed that patients use of PD-1 pathway inhibitors have more advantages in OS and 3 or 4 AE than patients use of CTLA-4 pathway inhibitors.

Although the treatment options for NSCLC are increasing year by year, the improvement of patients’ survival is still negligible, except among patients with EGFR, ALK, BRAF or KRAS mutations [27]. Docetaxel is considered to be the standard agent for the second or later lines to treat the patients with NSCLC, but the overall efficiency and safety are far from satisfactory [28]. During recent years, scholars are consid-ering immune checkpoint inhibitors including the CTLA-4 and PD-1 pathway inhibitors to treat NSCLC [29]. In various clinical trials of CTLA-4 and PD-1 pathway inhibitors, the later agents may have gained more remarkable attentions due to their impressive efficacy and safety in the clinical trials [30], yet the direct or indirect evidences were still absence. To our knowledg-es, the present study provides the first evi-dence regarding the efficacy and safety of PD-1 versus CTLA-4 pathway inhibitors.

In our traditional meta-analyses, the therapeu-tic effects of PD-1 pathway inhibitors for NSCLC are mainly reflected in terms of prolonged OS, increased ORR, and decreased grade 3/4 AE, which are mainly consistent with the results of previously clinical phase II/III randomized con-trolled trials [20-23]. In the same time, the het-erogeneities also exists in this meta-analysis. It is known, PD-L1 is regarded as the logical bio-marker on which to guide molecular selection for NSCLC receiving agents of PD-1/PD-L1 inhibitors that because the individuals with high PD-L1 expression have higher sensitivity to these agents [31]. Hence, we inferred that the heterogeneity may result from the different proportions of patients with high PD-L1 expres-sion during the including studies. In addition, we should note that the meta-analytic results of CTLA-4 pathway inhibitors are consistent with the outcomes of the study by Lynch et al. [12]. This is because the weight of this study was 64.8% to 100% in the meta-analysis.

In clinical practice, the balance between thera-peutic effect and associated adverse events should be carefully evaluated before final selec-tion. In our meta-analyses, due to the impres-sive efficacy and safety of PD-1 pathway inhibi-tors, this agents rather than CLTA-4 pathway inhibitors could prioritize to use for the treat-ment of NSCLC. The major limitation of this study is the small number of studies involved and the inconsideration of PD-L1 expression.

Meta-analyses of PD-1 and CTLA-4 inhibitors for NSCLC

1536 Int J Clin Exp Med 2017;10(1):1529-1538

Therefore, more studies with stratified analysis of PD-L1 expression and large sample size or update data are required to further identify the clinical values of PD-1 pathway inhibitors in the treatment of NSCLC.

Acknowledgements

The authors thank Yi Wang and Lei Wang (Xinxiang medical University), who assisted with the preparation and proof reading of data and the manuscript.

Disclosure of conflict of interest

None.

Authors’ contribution

Author HZ and XH designed the study. HZ wrote the protocol and the first draft of the manu-script. Author HZ, YY managed the literature searches. Author HZ and BZ finished the data extraction. Author YY and SH undertook the statistical analysis. All authors contributed to and have approved the final manuscript.

Address correspondence to: Dr. Xiabao Hou, De- partment of Thoracic Oncology, Xinxiang Central Hospital, Affiliated Central Hospital of Xinxiang Medical University, No. 56, Jinsui Road, Xinxiang 453000, China. Tel: +86 373 2022155; E-mail: chengdufx2014@tom.com

References

[1] Chan BA and Coward JI. Chemotherapy ad-vances in small-cell lung cancer. J Thorac Dis 2013; 5 Suppl 5: S565-578.

[2] Herbst RS, Heymach JV and Lippman SM. Lung cancer. N Engl J Med 2008; 359: 1367-1380.

[3] Gettinger S and Lynch T. A decade of advances in treatment for advanced non-small cell lung cancer. Clin Chest Med 2011; 32: 839-851.

[4] Reungwetwattana T, Weroha SJ and Molina JR. Oncogenic pathways, molecularly targeted therapies, and highlighted clinical trials in non-small-cell lung cancer (NSCLC). Clin Lung Can-cer 2012; 13: 252-266.

[5] Gettinger SN, Horn L, Gandhi L, Spigel DR, An-tonia SJ, Rizvi NA, Powderly JD, Heist RS, Car-vajal RD, Jackman DM, Sequist LV, Smith DC, Leming P, Carbone DP, Pinder-Schenck MC, Topalian SL, Hodi FS, Sosman JA, Sznol M, Mc-Dermott DF, Pardoll DM, Sankar V, Ahlers CM,

Salvati M, Wigginton JM, Hellmann MD, Kollia GD, Gupta AK and Brahmer JR. Overall survival and long-term safety of nivolumab (Anti-Pro-grammed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J Clin On-col 2015; 33: 2004-2012.

[6] Postow MA, Callahan MK and Wolchok JD. Im-mune checkpoint blockade in cancer therapy. J Clin Oncol 2015; 33: 1974-1982.

[7] Herzberg B, Campo MJ and Gainor JF. Immune checkpoint inhibitors in non-small cell lung cancer. Oncologist 2016; [Epub ahead of print].

[8] El-Osta H, Shahid K, Mills GM and Peddi P. Im-mune checkpoint inhibitors: the new frontier in non-small-cell lung cancer treatment. Onco Targets Ther 2016; 9: 5101-5116.

[9] Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A and Wolchok JD. Ipilim-umab plus dacarbazine for previously untreat-ed metastatic melanoma. N Engl J Med 2011; 364: 2517-2526.

[10] Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A and Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711-723.

[11] Zatloukal P, Heo DS, Park K, Kang J, Butts C, Bradford D, Graziano S, Huang B and Healey D. Randomized phase II clinical trial comparing tremelimumab (CP-675,206) with best sup-portive care (BSC) following first-line platinum-based therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC). J Clin On-col 2009; 27: 8071.

[12] Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu HL, Cuillerot JM and Reck M. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol 2012; 30: 2046-2054.

[13] Butte MJ, Keir ME, Phamduy TB, Sharpe AH and Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimu-latory molecule to inhibit T cell responses. Im-munity 2007; 27: 111-122.

Meta-analyses of PD-1 and CTLA-4 inhibitors for NSCLC

1537 Int J Clin Exp Med 2017;10(1):1529-1538

[14] Garon EB, Rizvi NA, Hui R, Leighl N, Balma-noukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K and Gandhi L. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015; 372: 2018-2028.

[15] Rajan A and Gulley JL. Nivolumab (anti-PD-1, BMS-936558, ONO-4538) in patients with ad-vanced non-small cell lung cancer. Transl Lung Cancer Res 2014; 3: 403-405.

[16] Melosky B, Chu Q, Juergens R, Leighl N, McLeod D and Hirsh V. Pointed progress in second-line advanced non-small-cell lung can-cer: the rapidly evolving field of checkpoint in-hibition. J Clin Oncol 2016; 34: 1676-1688.

[17] Adams S, Diamond J, Hamilton E, Pohlmann P, Tolaney S, Molinero L, Zou W, Liu B, Water-kamp D, Funke R and Powderly J. Abstract P2-11-06: safety and clinical activity of atezoli-zumab (anti-PDL1) in combination with nab- paclitaxel in patients with metastatic triple-negative breast cancer. Cancer Research 2016; 76: P2-11-06.

[18] Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Daw-son N, O’Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Gal-sky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD and Dreicer R. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016; 387: 1909-1920.

[19] Horn L, Spigel DR, Gettinger SN, Antonia SJ, Gordon MS, Herbst RS, Sequist LV, Chappey C, Kowanetz M, Sandler A and Soria JC. Clinical activity, safety and predictive biomarkers of the engineered antibody MPDL3280A (anti-PDL1) in non-small cell lung cancer (NSCLC): update from a phase Ia study. J Clin Oncol (Meeting Abstracts) 2015; 33: 8029.

[20] Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crino L, Blumenschein GR Jr, Antonia SJ, Dor-ange C, Harbison CT, Graf Finckenstein F and Brahmer JR. Nivolumab versus docetaxel in

advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015; 373: 1627-1639.

[21] Brahmer J, Reckamp KL, Baas P, Crino L, Eber-hardt WE, Poddubskaya E, Antonia S, Pluzans-ki A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Aren Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B and Spigel DR. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373: 123-135.

[22] Herbst RS, Baas P, Kim DW, Felip E, Perez-Gra-cia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Fil-hart M and Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-posi-tive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016; 387: 1540-1550.

[23] Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Water-kamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A; POPLAR Study Group. Atezolizum-ab versus docetaxel for patients with previ-ously treated non-small-cell lung cancer (POP-LAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 2016; 387: 1837-46.

[24] Higgins J, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0. The Cochrane Collaboration 2011; 2013.

[25] Higgins JP and Green S. Cochrane handbook for systematic reviews of interventions. Wiley Online Library 2008.

[26] Higgins JP, Thompson SG, Deeks JJ and Altman DG. Measuring inconsistency in meta-analy-ses. BMJ 2003; 327: 557-560.

[27] Pao W and Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol 2011; 12: 175-180.

[28] Gandara DR, Chansky K, Albain KS, Leigh BR, Gaspar LE, Lara PN Jr, Burris H, Gumerlock P, Kuebler JP, Bearden JD 3rd, Crowley J and Liv-ingston R. Consolidation docetaxel after con-current chemoradiotherapy in stage IIIB non-small-cell lung cancer: phase II southwest oncology group study S9504. J Clin Oncol 2003; 21: 2004-2010.

[29] Ott PA, Hodi FS and Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeu-tic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res 2013; 19: 5300-5309.

Meta-analyses of PD-1 and CTLA-4 inhibitors for NSCLC

1538 Int J Clin Exp Med 2017;10(1):1529-1538

[30] Topalian SL, Drake CG and Pardoll DM. Target-ing the PD-1/B7-H1 (PD-L1) pathway to acti-vate anti-tumor immunity. Curr Opin Immunol 2012; 24: 207-212.

[31] Abdel-Rahman O. Correlation between PD-L1 expression and outcome of NSCLC patients

treated with anti-PD-1/PD-L1 agents: a meta-analysis. Crit Rev Oncol Hematol 2016; 101: 75-85.