Cancer is a global and growing problem imposing a tremendous burden on society. Lung carcinoma is the leading cause of cancer-related death worldwide. An estimated 2.1 million new lung cancer cases occurred in 2018, accounting for about 11.6% of total cancer diagnoses globally . The two main types of lung cancer are small-cell lung cancer and non–small-cell lung cancer (NSCLC). NSCLC accounts for approximately 85% of all cancer cases. Advanced NSCLC has a very low 5-year survival rate and poor prognosis, and nearly 70% of lung cancer patients present with locally advanced or metastatic disease at diagnosis [2–4].
Treatment options for lung cancer include surgery, radiation therapy, chemotherapy, targeted therapy, and immunotherapy. Surgery remains the preferred primary treatment for early and localized lesions, whereas standard combination therapy is typically used for locally advanced cancer. The choice of treatment for patients with stage IV NSCLC depends on many factors, including comorbidity, performance status, histology, and molecular genetic features [5,6]. Platinum-based chemotherapy has long been the standard first-line therapy for metastatic or recurrent NSCLC. Targeted therapeutic drugs like epidermal growth factor receptor-tyrosine kinase inhibitors and crizotinib for anaplastic lymphoma kinase-positive tumors have superior efficacy and lower toxicity than chemotherapy and have altered NSCLC treatment. However, these genetic mutations are rare, and the majority of patients may not be suitable for targeted therapies. Even those patients who have actionable mutations face the challenge of acquired drug resistance within a few years.
Therefore, there is an urgent demand for more effective and secure treatment methods. Programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) immune checkpoint suppression therapy has emerged as a new alternative treatment . In recent years, evidence concerning the antitumor activity of the immune system and an understanding of tumor immunosurveillance have made immunotherapy a promising therapeutic approach in lung cancer [8–13]. Immunotherapy combined with chemotherapy has far better efficacy than chemotherapy, especially for NSCLC without driver gene mutations for which targeted therapy is not effective. PD-1 was first identified in 1992 by Honjo and his colleagues as a gene which is activated in both stimulated murine T-cell hybridoma and interleukin-3 deprived murine hematopoietic progenitor cells . Generally, activated T cells express the PD-1 receptor, but it can also be found on natural killer cells and B cells. PD-L1 and PD-L2 are additional members of the B7 family, PD-L1 is expressed on various cell types, including hematopoietic cells like B cells, T cells, macrophages, dendritic cells, and bone marrow-derived mast cells; nonhematopoietic cells, including pneumocytes, vascular endothelial cells, liver nonparenchymal cells, mesenchymal stem cells, pancreatic islets, and keratinocytes; and malignant cells like melanoma, glioblastoma, and urothelial, lung, gastric, pancreatic, cervical, ovarian, and breast cancer cells. PD-L2 is restricted to macrophages and dendritic cells [15,16]. Tumors grow under immune surveillance and go through three stages: elimination, equilibrium, and escape. During the escape phase, cells that evade immune surveillance and continue to grow become cancers . PD-L1 expression, which has been correlated with poor prognosis, is one of the most important escape mechanisms of human cancers [18,19]. Cancer cells might use the PD-1/PD-L1 or PD-L2 pathway to escape antitumor immunity. Therefore, PD-1 blockade can restore immune surveillance in patients with cancer. To further clarify the issue, we performed a meta-analysis of clinical trials to examine the efficacy and safety of the PD-1/PD-L1 inhibitors in patients with advanced NSCLC.
We searched the PubMed, Embase, and Wiley Online Library databases using the following free language terms: ‘nonsmall cell lung cancer’ OR ‘NSCLC’ AND ‘PD-1’ OR ‘PD-L1’. In addition, the references and related reviews in the recovered studies were screened. Databases were searched starting from their inception until 26 August 2018. No language restrictions were applied.
Two authors examined studies that evaluated PD-1/PD-L1 inhibitors in the management of patients with NSCLC. Inclusion criteria for trials included in this meta-analysis were as follows: involved human subjects, pathologically confirmed NSCLC, PD-L1 expression in specimens of patients with NSCLC was detected by immunohistochemistry, and patients received either chemotherapy or anti-PD-1/PD-L1 immunotherapy. The studies examined one or more of the following outcomes: overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse effects. We excluded reviews, commentaries, studies published only in abstract form, retrospective studies, letters, editorials, expert opinions, quality of life research, cost-benefit analysis, and studies that were unable to determine drug effects. We screened all the titles and abstracts for full-text review and discussed the full-text articles. Disagreements were resolved through consensus. All included studies represent unique trials.
Data extraction and outcomes of interest
Data were independently extracted from the complete publications of the prospective clinical trials and related appendices by two authors, guided by the extraction form (Table 1). Differences were resolved through consensus.
Hazard ratios for PFS and OS and odds ratios (ORs) for the ORR were collected or computed for all included studies. We adhered to the definition of progression used by each trial and evaluated the methodological quality of the included articles to guarantee consistency with the Cochrane Collaboration’s bias tool Review Manager 5.3 (RevMan 5.3; Nordic Cochrane Center, Copenhagen, Denmark).
Data synthesis and statistical analysis
Statistical analyses were carried out using RevMan 5.3). Using the extracted data, we calculated the OR and 95% confidence interval (CI) for the ORR and the hazard ratios and corresponding 95% CIs for PFS and OS. We extracted relevant data from each study and estimated the combined ORs and hazard ratios by meta-analysis.
Statistical heterogeneity among trials was evaluated using the Cochran Q statistic , and inconsistency was measured using the I2 statistic, indicating that the percentage of total variation in the study can be attributed to heterogeneity rather than opportunity. Heterogeneity was quantified using χ2 and I2 values. Values of P < 0.05 and I2 ≤ 50% indicated that no heterogeneity existed. A random effect model was used when statistical heterogeneity was identified, otherwise we chose a fixed effect model . Finally, publication bias was graphically evaluated through funnel plots.
A flow diagram of the selection process is displayed in Fig. 1. A total of 1383 studies were retrieved during the literature search. We identified 925 duplicate studies, which were discarded. The remaining 458 abstracts were screened further, and 402 studies were excluded because they were unrelated, irrelevant, or review articles, comments, letters, editorials, expert opinions, or quality of life studies. Among the remaining 56 full-text articles that were assessed for eligibility, 30 retrospective studies were excluded. Initially, 26 studies were classified as potentially relevant and included in a qualitative synthesis. Of the 26 articles, 9 potentially relevant studies were excluded because of a lack of necessary data. Finally, 17 studies were included in this meta-analysis [22–38].
Description of the studies
Seventeen full-text articles were included in our analysis, including seven phase III trials [24–28,33,35], five phase II trials [22,23,34,36,38]and five phase I trials [29–32,37]. The included articles were published between 2015 and 2018. Eight studies [22–28, 33] were multicenter randomized controlled clinical trials, three [31,32,37]were dose-escalation studies and three [29,34,36]were single-arm trials. Two studies evaluated nivolumab monotherapy versus docetaxel [25,26], two studies evaluated atezolizumab monotherapy versus docetaxel [22,33], one study evaluated durvalumab monotherapy versus placebo , three studies evaluated pembrolizumab monotherapy versus chemotherapy [23,27,28], and one study evaluated nivolumab and ipilimumab combinations every 12 weeks versus every 6 weeks . Nivolumab, pembrolizumab, atezolizumab, and durvalumab were administered intravenously at different doses with varying frequencies in patients with advanced NSCLC. All patients had undergone one or more previous therapies, such as surgery, radiotherapy, chemotherapy, and biological therapy. Table 1 shows the baseline characteristics of the included studies.
OS data were available for 7 (of 17) studies including 3452 patients, and PFS and ORR data were available for 8 (of 17) studies including 4161 patients, all comparing PD-1/PD-L1 inhibitors to chemotherapy. The combined hazard ratios for OS and PFS were 0.69 (95% CI 0.63–0.75, I2 = 0%, P < 0.00001) and 0.74 (95% CI, 0.63–0.87, I2 = 80%, P = 0.0003), respectively. The combined OR for the ORR was 1.78 (95% CI 1.36–2.32, I2 = 55%, P < 0.0001; supporting information Fig. 2). For PFS and the ORR, a P-value <0.05 and an I2 value >50% indicated that there was statistical heterogeneity, so we used a random effect model. For OS, P = 0.75 and I2 = 0% suggested that no significant heterogeneity existed, so we selected a fixed effect model. These results indicated that anti-PD-1/PD-L1 therapy improved survival and led to a higher overall response compared with chemotherapy.
We conducted further analyses to assess the efficacy of varying doses of anti-PD-1/PD-L1 agent monotherapy. The combined OR for the ORR was 0.99 (95% CI 0.76–1.29, I2 = 4%, P = 0.94; supporting information Fig. 3), suggesting that there was no significant difference in efficacy based on dose of pembrolizumab or nivolumab (between 1 and 10 mg/kg). Considering that the PD-L1 expression level in tumor cells may influence the efficacy of anti-PD-1/PD-L1 therapies, we conducted a subgroup analysis to elucidate the treatment efficacy in patients with NSCLC with varying PD-L1 expression levels. The ORR data and PD-L1 expression levels were examined in nine studies. PD-L1 positivity was defined using an expression threshold of 1% (7/9 studies) or 5% (2/9 studies). As shown in Fig. 3, the OR of PD-L1 positivity versus PD-L1 negativity was 2.48 (I2 = 29%, P < 0.00001), reflecting a better effectiveness in the PD-L1-positive group.
Data concerning total adverse effects and grades 3–5 adverse effects were used to assess the safety and side effects of anti-PD-1/PD-L1 monoclonal antibodies in patients with advanced NSCLC. Seven studies [22,23,25–28,33] were included in the any grade adverse effect analysis and eight [22–28,33] were included in the grades 3–5 adverse effects analysis. A random effect model was used for the grades 3–5 adverse effects because of the existence of significant heterogeneity (P < 0.05, I2 > 50%). The ORs of total adverse effects and grades 3–5 adverse effects for patients receiving PD-1/PD-L1 agents versus chemotherapy were 0.33 (I2 = 39%, P < 0.00001, 95% CI 0.28–0.39) and 0.30 (I2 = 94%, P < 0.0003, 95% CI 0.16–0.57), respectively (Fig. 4), demonstrating a manageable safety profile compared with chemotherapy.
The results of the funnel plot were symmetrical, indicating that no explicit publication bias existed in this work (Fig. 5).
Antitumor immunity depends on the capability of the body’s immune system to recognize tumor cells and eliminate them as foreign objects, a process involving adaptive immunity and T cells. PD-L1 is ubiquitous in NSCLC, and the interaction between PD-1 and its ligands-PD-L1 and PD-L2 promotes tumor immune escape by inhibiting the activation of T cells. By blocking the PD-1 semaphore, PD-1/PD-L1 monoclonal antibodies such as pembrolizumab and nivolumab activate T cells and restore their antitumor functionality. Immunotherapy, specifically PD-1/PD-L1 monoclonal antibodies, offers a new treatment strategy with controlled toxicity and promising antitumor activity for patients with advanced NSCLC. It has revolutionized the treatment of NSCLC and has progressed to adjuvant therapy and neoadjuvant therapy. Still, there are many unknowns, requiring further exploration on the strategy of maximizing the efficacy and minimizing toxicity when immune monotherapy as a first-line treatment. Recently, the FDA approved durvalumab for patients with stage III unresectable NSCLC with stable disease after chemoradiotherapy. To further assess the safety and efficacy of immunotherapy, we took advantage of online databases and conducted qualitative analyses of 17 prospective trials studying PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab) in patients with NSCLC.
We first assessed the efficacy of anti-PD-1/PD-L1 immunotherapy compared with conventional chemotherapy in patients with metastatic NSCLC. The overall ORR, OS, and PFS data of 4161 patients were extracted for this evaluation. PD-1/PD-L1 inhibitors improved OS, PFS, and ORR when compared with standard chemotherapy (pooled hazard ratio of OS = 0.69, pooled hazard ratio of PFS = 0.74, and pooled OR of ORR = 1.78, all P ≤ 0.05). We performed further analyses to assess the effectiveness of different doses and treatment schedules for PD-1/PD-L1 inhibitors in patients with metastatic NSCLC. The results of our subgroup analysis were close to the overall results of the randomized Phase 3 KEYNOTE-010 study (NCT01905657) . The response rates of PD-1/PD-L1 agents were similar among most patients in the subgroups, despite dose differences and treatment schedules. Therefore, a 3-week treatment schedule is preferable as it requires less frequent patient visits and lower hospitalization costs than a 2-week treatment schedule.
Immune monotherapy has become the standard second-line treatment for NSCLC, but the effective rate is only approximately 14–20%, which cannot adequately meet treatment needs. Determining ways to further maximize the efficacy of single-agent treatment and identify patients in whom it will be most effective is important. We conducted subgroup analysis and assessed the value of PD-L1 expression as a promising biomarker for anti-PD-1/PD-L1 therapeutic response in metastatic NSCLC. The OR between PD-L1-positive and PD-L1-negative tumors was 2.48 (P < 0.00001), indicating that advanced NSCLC patients with PD-L1 positivity were more likely to benefit from treatment with anti-PD-1/PD-L1 therapy. Therefore, PD-L1 may be an important biomarker to help identify patients who are more likely to derive benefit from anti-PD-1/PD-L1 treatment. However, PD-L1 expression varies, and the immunohistochemistry staining platform, antibodies used, method of result evaluation, and previous treatments such as radiotherapy, chemotherapy, or immunotherapy may all affect the PD-L1 immunohistochemistry results . Therefore, it is best for oncologists to be prudent in choosing appropriate treatment options for patients with NSCLC.
Although the incidence of serious adverse reactions and treatment-related deaths is extremely low, other side effects of immune checkpoint inhibitors also exist. Treatment-related adverse effects include fatigue, rash, pruritus, diarrhea, nausea, asthenia, pneumonitis, colitis, neutropenia, thrombocytopenia, hyperthyroidism, hypothyroidism, and other rare toxicities [31–33,40]. Fatigue and rash are the most common adverse effects. In this analysis, patients receiving PD-1/PD-L1 inhibitor monotherapy had a lower risk of most adverse effects than those receiving chemotherapy. The pooled ORs for any grade adverse effects and grades 3–5 adverse effects for patients receiving anti-PD-1/PD-L1 agents versus chemotherapy were 0.33 and 0.30, respectively, demonstrating that PD1/PD-L1 inhibitors are better tolerated than chemotherapy. With conventional chemotherapy, many patients stop treatment or even die because of gastrointestinal symptoms, leukopenia, liver dysfunction, and renal insufficiency. The low quality of life of these patients and the psychological burden of such side effects may increase their fear of further treatment. In contrast, the hypotoxicity of PD1/PD-L1 inhibitors makes treatment more acceptable for cancer patients. However, clinicians need to have intensive discussions with their patients on the risks and benefits of the treatment options for advanced malignant disease.
Our work has several limitations. First, there was statistical heterogeneity when we pooled the ORs for the ORR. Because of the heterogeneity of participation, we chose a random effect model to combine studies and conducted a subgroup analysis. Second, as some included trials used an open label design, these trials were prone to ascertainment bias. Finally, the patients in the included studies who were enrolled in academic centers had good PS, and their OS was expected to be longer. In clinical practice, the actual treatment toxicity may be higher in patients with impaired organ function.
In summary, our meta-analysis analyzed 17 prospective clinical trials and demonstrated the effectiveness and safety of PD-1/PD-L1 monoclonal antibodies compared with chemotherapy in metastatic NSCLC. In addition, the outcomes of this study support the concept that PD-L1 positivity results in better objective responses to PD-1/PD-L1 therapy than PD-L1 negativity. In 2017, Wang et al.  also conducted a meta-analysis of the efficacy and safety of PD-1 inhibitors in the treatment of solid tumors. The following year, Shen et al.  analyzed the efficacy and safety of PD-1/PD-L1 or CTLA4 inhibitors combined with chemotherapy as first-line treatment for lung cancer. Their conclusions were inconsistent in terms of disease control rate (DCR). Shen et al. saw an improvement, whereas Wang et al. found very little effect of an increased DCR. The conclusion of a superior DCR was likely to be the result of the combination of immunosuppressive agents and chemotherapy, as these agents may act synergistically. In this study, we compared immunosuppressive agents and chemotherapy separately, avoiding the effects of drug interactions. Conversely, the pathological types of solid tumors we studied were consistent with NSCLC. Our study summarized the clinical trials in recent years to compare the effectiveness and safety of PD-1/PD-L1 checkpoint immunotherapy and chemotherapy in patients with advanced NSCLC. These results are very important for doctors’ clinical decision-making and follow-up researches.
This article does not contain any studies with human participants or animals performed by any of the authors.
We thank the anonymous reviewers for their insights and great efforts to improve this manuscript.
Conflicts of interest
There are no conflicts of interest.
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