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Lung cancer is the worldwide leading cause of cancer-related deaths in both genders. Pembrolizumab is a IgG4 monoclonal antibody, which is highly selective, humanized, and binds to the programmed cell death protein 1 (PD-1) receptor and blocks its interaction with the PD-L1and PD-L2 ligands. We conducted a systematic review of the literature, without time restrictions, in the Medline database, using the following PICO: Adult patients with advanced NSCLC; Treatment with pembrolizumab alone or associated with chemotherapy, compared with chemotherapy, except for monochemotherapy with docetaxel and death outcomes (due to any cause) and adverse events. We selected 244 papers to answer the clinical question. The details of the methodology and the results of this guideline are set out in ^{Annex 1} ANNEX I The purpose of this assessment is to identify the benefits of immunotherapy with pembrolizumab, associated or not with chemotherapy, in the treatment of patients with locally advanced or metastatic NSCLC, without mutations of the EGFR gene or gene rearrangement of the ALK, with PD-L1 gene expression, in comparison to chemotherapy alone (current standard treatment). Clinical question What is the impact of pembrolizumab, associated or not to chemotherapy, on the outcomes of overall mortality (death from any cause) and adverse events in the treatment of patients with advanced NSCLC when compared to chemotherapy alone? Structured question Patient – Adult patients with advanced NSCLC; Intervention – Treatment with Pembrolizumab alone or combined with chemotherapy; Comparison – Chemotherapy, except monochemotherapy with docetaxel; Outcomes – Death (due to any cause) and adverse events. Eligibility criteria Excluded the outcomes − quality of life, objective response, survival free of progression − analyses of tumor proportion score (TPS) of the PD-L1 biomarker on the tumor tissue were not evaluated. Randomized clinical trial. Without time or language restrictions. Full text available for access. Search strategies used The search for evidence will be conducted on Medline virtual scientific information database, using the following search strategy: (((((Pulmonary Neoplasms OR Lung Neoplasm OR Pulmonary Neoplasm OR Lung Neoplasms OR Lung Cancers OR Lung Cancer OR Lung Neoplasm OR Lung Neoplasms OR PD-L1))) AND ((pembrolizumab) AND Random*))) OR ((((Pulmonary Neoplasms OR Lung Neoplasm OR Pulmonary Neoplasm OR Lung Neoplasms OR Lung Cancers OR Lung Cancer OR Lung Neoplasm OR Lung Neoplasms))) AND ((pembrolizumab OR PD-L1) AND Random*)). In the Central/Cochrane databases, the search strategy will be: (Lung Neoplasm OR Pulmonary Neoplasm OR Lung Cancer) AND pembrolizumab. Extraction of results We will extract the following data from the studies: name of the author and year of publication, study population, intervention and comparison methods, the absolute number of deaths and adverse events, time of follow-up. Randomized clinical trials will have their risk of biases analyzed according to the following criteria: randomization, blinded allocation, double-blinding, losses, prognostic characteristics, presence of relevant outcome, time for the outcome, method for outcome measurement, sample size calculation, early interruption, presence of other biases. The results will be presented as the difference in the risk of death or adverse events between pembrolizumab therapy alone or in combination with chemotherapy, and the treatment with chemotherapy alone. The confidence level adopted was 95%. The results of the studies included will be combined and meta-analyzed by RevMan 5.3 8 , and the difference in overall risk will be the final measure used to support the synthesis of evidence that will answer the clinical question of this review. Furthermore, the quality of evidence will be graded as high, moderate, low, or very low using the Grade instrument 6 and taking into account the risk of bias, the presence of inconsistency, vagueness or indirect evidence in the meta-analysis of the outcomes of death and adverse events, and the presence of publication bias. Table 5 . Quality of evidence (GRADE). TABLE 5 QUALITY OF EVIDENCE (GRADE). Evaluation of certainty № of patients Effect Certainty Importance № of studies Design of the study Risk of bias Inconsistency Indirect evidence Imprecision Other considerations Levosimendan Dobutamine Relative (95% CI) Absolute (95% CI) Mortality at 24 hours (assessed with: Number of deaths in 24 hours) 4 randomized clinical trials severe a not severe not severe not severe b none 1/208 (0.5%) 4/204 (2.0%) RR 3.05 (0.49 to 18.90) 40 more per 1,000 (from minus 10 to 351 more) ⊕⊕⊕◯MODERATE IMPORTANT Mortality at 30 days (assessed with: Number of deaths up to 30 days) 3 randomized clinical trials not severe severe c not severe severe d none 93/836 (11.1%) 125/831 (15.0%) RR 1.74 (0.94 to 3.19) 111 more per 1,000 (from minus 9 to 329 more) ⊕⊕◯ LOW IMPORTANT Mortality between 120 and 180 days (follow-up: variation 120 days to 180 days; assessed with: Number of deaths in this period) 4 randomized clinical trials severe e not severe not severe severe f none 206/811 (25.4%) 236/807 (29.2%) RR 1.15 (0.98 to 1.35) 44 more per 1,000 (from minus 6 to 102 more) ⊕⊕◯◯ LOW IMPORTANT CI: Confidence interval; RR: Relative Risk Explanation: a. 50% with randomization inadequate or not described; only one with blinded allocation, three studies without blinding; only with sample size calculation; b. The overall result does not exclude the benefit or harm; c. Test for inconsistency I2 equal to 70%; small overlap of confidence intervals; d. The result does not exclude great harm or benefit; e. 2 studies with Jadad = 1 and 2 studies with Jadad >= 3; f. The result does not exclude great harm or benefit Critical evaluation and level of evidence All evidence retrieved was evaluated according to their risk of bias (level of error estimated and inherent in the delineation of research or study design used). For the evaluation of the risk of bias of the RCTs, the following items were considered: if the issue was focal, appropriate randomization, blinded allocation, double-blind, losses (>20%), prognostic characteristics, outcomes (time, adequacy, measurement), analysis by intention to treat (ITT), sample size calculation, Jadad scale 7 . Reflecting the level of uncertainty of the results (effects of benefit or harm), the strength of the evidence can be very low, low, moderate, or strong, depending on: The risks of bias of each individual and meta-analyzed study. The magnitude and accuracy of the results for each outcome analyzed. The relevance, applicability, and generalization of these results. Presentation of the results In the search for evidence, we retrieved 244 papers, selecting by title and abstract nine studies of immunotherapy with pembrolizumab, associated or not to chemotherapy, in the treatment of patients with NSCLC, compared with chemotherapy alone, of which six studies were accessed since they met the eligibility criteria for analysis of the full text. Of the six studies, five were selected to support this assessment 1 - 5 ; the grounds for exclusion and the list of studies excluded are available in the references, Figure 6 and Table 9 in the Annexes. FIGURE 6 FLOWCHART TABLE 9 STUDIES EXCLUDED AND REASON FOR EXCLUSION Study Reason for exclusion Barlesi F, et al. 2019 Docetaxel intervention and quality of life outcome Reck M, et al. 2019 Follow-up time of 2 years Brahmer JR, et al. 2017 Outcome of quality of life Herbst RS, et al. 2016 Docetaxel intervention NSCLC = Non-small-cell lung carcinoma; CNS = Central nervous system; AUC = Area under the concentration-time curve; OS = overall survival; SFP = Survival free of progression; PD-L1 = Programmed death ligand 1; TPS = Tumor proportion score of biomarker PD-L1 in tumor tissue; EGFR = Epidermal growth factor receptor; ALK = Anaplastic Lymphoma Kinase; Ecog = Eastern Cooperative Oncology Group; Recist = Response Evaluation Criteria in solid tumors. TABLE 2 DESCRIPTION OF THE BIASES IN THE STUDIES INCLUDED Study and year Random Blinded allocation Double-blind Losses Characteristics Prognosis Outcomes Analysis per ITT Sample size calculation Jadad 7 Mok TSK 2019 4 Reck M 2016 4 Gandhi L 2018 5 Paz-Ares L 2018 5 Langer CJ 2016 4 ITT = intention-to-treat analysis Unclear risk of bias Presence of bias Low risk of bias the TABLE 1 DESCRIPTION OF THE STUDIES INCLUDED STUDY Population Intervention Comparison Outcomes Time (median, months) Mok TSK, et al. 2019 Keynote-042 ≥18 years) with locally advanced or metastatic NSCLC, not previously treated, without EGFR mutation or ALK translocation, and with a score of 0 or 1 in the Ecog performance scale, life expectancy of three months or more, and a PD-L1 TPS of 1% or greater. Excluded if: unstable or untreated CNS metastases, a history of noninfectious pneumonitis requiring systemic glucocorticoids, active autoimmune disease, systemic immunosuppressive treatment, or active infection by the virus of hepatitis B or C. Pembrolizumab 200 mg every three weeks, in up to 35 cycles Carboplatin to achieve an AUC of 5-6 mg/mL per minute plus paclitaxel 200 mg/m 2 or pemetrexed 500 mg/m 2 OS SFP Adverse events 12.8 Reck M, et al. 2016 Keynote-024 ≥18 years, NSCLC histologically or cytologically confirmed in stage IV, without EGFR mutations or ALKtranslocation, without prior systemic therapy for metastatic disease, with a 0 or 1 score in the ECOG performance status, at least one measurable lesion according to Recist version 1.1, life expectancy of at least three months, and a 50% or more score of PD-L1 tumor proportion. Excluded if: receiving systemic glucocorticoids (excluding daily replacement therapy with glucocorticoids for conditions such as pituitary or adrenal insufficiency) or other immunosuppressive treatment, with untreated brain metastases, active autoimmune disease for which they received systemic treatment over the past two years, active interstitial lung disease or pneumonitis history for which they received glucocorticoids. Pembrolizumab in a fixed dose of 200 mg every three weeks. Platinum-based chemotherapy to the choice of the researcher during 4 to 6 cycles: carboplatin plus pemetrexed, cisplatin plus pemetrexed, carboplatin plus gemcitabine, cisplatin plus gemcitabine, cisplatin plus gemcitabine or carboplatin plus paclitaxel. The chemotherapy regimens that included pemetrexed were allowed only for patients who had non-squamous tumors. Crossover allowed. OS SFP Adverse events 25.2 Gandhi L et al. 2018 Keynote-189 ≥18 years, metastatic NSCLC, non-squamous, without mutations in the EGFR gene and ALK rearrangement, without prior therapy for the disease. Other conditions: an ECOG performance status of 0 or 1; at least one measurable lesion according to Recist version 1.1, and provide a sample of the tumor for determining the PD-L1state. Excluded if: symptomatic CNS metastases, history of non-infectious pneumonitis requiring the use of glucocorticoids, autoimmune disease with systemic therapy in the past two years, medical condition requiring immunosuppression, received more than 30 Gy of radiotherapy to the chest over the past six months. Pemetrexed (500 mg/m 2 IV) and a platinum-based drug at the choice of the investigator (cisplatin 75 mg/m 2 of body surface or carboplatin AUC 5mg/mL/min intravenously) plus 200 mg of pembrolizumab every three weeks, for four cycles, followed by pembrolizumab until a total of 35 cycles, plus maintenance therapy with pemetrexed. Pemetrexed (500 mg/m 2 IV) and a platinum-based drug at the choice of the investigator (cisplatin 75 mg/m 2 of body surface or carboplatin AUC 5mg/mL/min intravenous) plus a placebo every three weeks, for four cycles, followed by a placebo until a total of 35 cycles, plus maintenance therapy with pemetrexed. OS SFP. Adverse events 10.5 Paz-Ares L et al. 2018 Keynote-407 ≥18 years; squamous NSCLC stage IV, without prior systemic therapy for metastatic disease, ECOG performance status score of 0 or 1, with at least one measurable lesion according to Recist version 1.1, provided a tumor sample for determining the PD-L1 state. Excluded if: symptomatic metastases of the CNS, history of non-infectious pneumonitis that required the use of glucocorticoids; autoimmune disease that required systemic therapy in the past two years; medical condition requiring immunosuppression. Pembrolizumab 200 mg for up to 35 cycles + carboplatin and paclitaxel or nanoparticle albumin-bound [NAB] - paclitaxel for the first four cycles. Saline (placebo) for up to 35 cycles + carboplatin and paclitaxel or nanopartícula albumin-bound [NAB] - paclitaxel during the first four cycles. SFP OS Adverse events 7.8 Langer CJ et al. 2016 Keynote-021 No previous systemic treatment for non-squamous NSCLC, cytologically or histologically confirmed, Stage IIIB or IV, and absence of EGFR target mutations or ALK translocations; ECOG performance status of 0 or 1, at least one measurable lesion evaluated by Recist version 1.1, life expectancy of three months or more, and supply of a sample of the tumor for evaluation of the PD-L1expression. Excluded if: received more than 30 Gy of radiation to the lungs in the previous six months; continuous use of systemic corticosteroids or other immunosuppressive treatment, active autoimmune disease that required systemic treatment in the past two years (excluding replacement therapy), untreated brain metastases (allowed treated, stable metastasis), or active interstitial lung disease, history of pneumonitis requiring intravenous glucocorticoids. Pembrolizumab 200 mg + carboplatin AUC 5 mg/mL/min and pemetrexed intravenous 500 mg/m 2 every three weeks followed by pembrolizumab for 24 months and maintenance therapy with undefined pemetrexed. Four cycles of carboplatin and pemetrexed, followed by maintenance therapy with undefined pemetrexed. Objective Response SFP OS Adverse events 23.9 Application of evidence - Recommendation The available evidence will follow some principles of exposure– it will be by outcome and will have as components: number of patients, type of comparison, magnitude, and precision (standard deviation and 95% CI). Its strength will be estimated (Oxford 16 /Grade 8 ) as 1b and 1c (grade A) or strong, and as 2a, 2b and 2c (grade B) or moderate weak, or very weak. .

INTRODUCTION

Lung cancer is the worldwide leading cause of cancer-related deaths in both genders, and smoking is its main etiological factor. The discovery of immunological checkpoints corroborates the hypothesis that ligands present in the tumor modulate the carcinogenesis mechanisms and immune activity of the tumor microenvironment. Among the most studied coregulatory molecules, the PD-1 (programmed cell death 1) and its ligand PD-L1 (programmed cell death ligand 1) stand out.

The PD-1 is a immunologic checkpoint that limits the activity of T cells (lymphocytes) in peripheral tissues. The PD-1 pathway is a immunological control checkpoint that can be coupled by tumor cells to inhibit immune surveillance of the active T cell.

Pembrolizumab is a IgG4 monoclonal antibody that is highly selective, humanized, and binds to the programmed cell death protein 1 (PD-1) receptor and blocks its interaction with the PD-L1 and PD-L2 ligands, which are expressed in antigen-presenting cells and may be expressed by tumors or other cells in the tumor microenvironment, assisting them in preventing of their detection and elimination by the immune system of the host.

Non-small cell lung neoplasms, without mutations in the epidermal growth factor receptor (EGFR) gene or rearrangement of the anaplastic lymphoma kinase (ALK) gene, with gene expression for PD-L1, are the target of pembrolizumab.

RESULTS

Our study population included a total of 2,877 patients with NSCLC, submitted to pembrolizumab therapy (N=791) and compared to chemotherapy (N=788), or pembrolizumab plus chemotherapy (N=748) compared with chemotherapy (N=550), and followed-up to measure the death and adverse events outcomes for 12 months ( Table 1 - ^{Annex I} ANNEX I The purpose of this assessment is to identify the benefits of immunotherapy with pembrolizumab, associated or not with chemotherapy, in the treatment of patients with locally advanced or metastatic NSCLC, without mutations of the EGFR gene or gene rearrangement of the ALK, with PD-L1 gene expression, in comparison to chemotherapy alone (current standard treatment). Clinical question What is the impact of pembrolizumab, associated or not to chemotherapy, on the outcomes of overall mortality (death from any cause) and adverse events in the treatment of patients with advanced NSCLC when compared to chemotherapy alone? Structured question Patient – Adult patients with advanced NSCLC; Intervention – Treatment with Pembrolizumab alone or combined with chemotherapy; Comparison – Chemotherapy, except monochemotherapy with docetaxel; Outcomes – Death (due to any cause) and adverse events. Eligibility criteria Excluded the outcomes − quality of life, objective response, survival free of progression − analyses of tumor proportion score (TPS) of the PD-L1 biomarker on the tumor tissue were not evaluated. Randomized clinical trial. Without time or language restrictions. Full text available for access. Search strategies used The search for evidence will be conducted on Medline virtual scientific information database, using the following search strategy: (((((Pulmonary Neoplasms OR Lung Neoplasm OR Pulmonary Neoplasm OR Lung Neoplasms OR Lung Cancers OR Lung Cancer OR Lung Neoplasm OR Lung Neoplasms OR PD-L1))) AND ((pembrolizumab) AND Random*))) OR ((((Pulmonary Neoplasms OR Lung Neoplasm OR Pulmonary Neoplasm OR Lung Neoplasms OR Lung Cancers OR Lung Cancer OR Lung Neoplasm OR Lung Neoplasms))) AND ((pembrolizumab OR PD-L1) AND Random*)). In the Central/Cochrane databases, the search strategy will be: (Lung Neoplasm OR Pulmonary Neoplasm OR Lung Cancer) AND pembrolizumab. Extraction of results We will extract the following data from the studies: name of the author and year of publication, study population, intervention and comparison methods, the absolute number of deaths and adverse events, time of follow-up. Randomized clinical trials will have their risk of biases analyzed according to the following criteria: randomization, blinded allocation, double-blinding, losses, prognostic characteristics, presence of relevant outcome, time for the outcome, method for outcome measurement, sample size calculation, early interruption, presence of other biases. The results will be presented as the difference in the risk of death or adverse events between pembrolizumab therapy alone or in combination with chemotherapy, and the treatment with chemotherapy alone. The confidence level adopted was 95%. The results of the studies included will be combined and meta-analyzed by RevMan 5.3 8 , and the difference in overall risk will be the final measure used to support the synthesis of evidence that will answer the clinical question of this review. Furthermore, the quality of evidence will be graded as high, moderate, low, or very low using the Grade instrument 6 and taking into account the risk of bias, the presence of inconsistency, vagueness or indirect evidence in the meta-analysis of the outcomes of death and adverse events, and the presence of publication bias. Table 5 . Quality of evidence (GRADE). TABLE 5 QUALITY OF EVIDENCE (GRADE). Evaluation of certainty № of patients Effect Certainty Importance № of studies Design of the study Risk of bias Inconsistency Indirect evidence Imprecision Other considerations Levosimendan Dobutamine Relative (95% CI) Absolute (95% CI) Mortality at 24 hours (assessed with: Number of deaths in 24 hours) 4 randomized clinical trials severe a not severe not severe not severe b none 1/208 (0.5%) 4/204 (2.0%) RR 3.05 (0.49 to 18.90) 40 more per 1,000 (from minus 10 to 351 more) ⊕⊕⊕◯MODERATE IMPORTANT Mortality at 30 days (assessed with: Number of deaths up to 30 days) 3 randomized clinical trials not severe severe c not severe severe d none 93/836 (11.1%) 125/831 (15.0%) RR 1.74 (0.94 to 3.19) 111 more per 1,000 (from minus 9 to 329 more) ⊕⊕◯ LOW IMPORTANT Mortality between 120 and 180 days (follow-up: variation 120 days to 180 days; assessed with: Number of deaths in this period) 4 randomized clinical trials severe e not severe not severe severe f none 206/811 (25.4%) 236/807 (29.2%) RR 1.15 (0.98 to 1.35) 44 more per 1,000 (from minus 6 to 102 more) ⊕⊕◯◯ LOW IMPORTANT CI: Confidence interval; RR: Relative Risk Explanation: a. 50% with randomization inadequate or not described; only one with blinded allocation, three studies without blinding; only with sample size calculation; b. The overall result does not exclude the benefit or harm; c. Test for inconsistency I2 equal to 70%; small overlap of confidence intervals; d. The result does not exclude great harm or benefit; e. 2 studies with Jadad = 1 and 2 studies with Jadad >= 3; f. The result does not exclude great harm or benefit Critical evaluation and level of evidence All evidence retrieved was evaluated according to their risk of bias (level of error estimated and inherent in the delineation of research or study design used). For the evaluation of the risk of bias of the RCTs, the following items were considered: if the issue was focal, appropriate randomization, blinded allocation, double-blind, losses (>20%), prognostic characteristics, outcomes (time, adequacy, measurement), analysis by intention to treat (ITT), sample size calculation, Jadad scale 7 . Reflecting the level of uncertainty of the results (effects of benefit or harm), the strength of the evidence can be very low, low, moderate, or strong, depending on: The risks of bias of each individual and meta-analyzed study. The magnitude and accuracy of the results for each outcome analyzed. The relevance, applicability, and generalization of these results. Presentation of the results In the search for evidence, we retrieved 244 papers, selecting by title and abstract nine studies of immunotherapy with pembrolizumab, associated or not to chemotherapy, in the treatment of patients with NSCLC, compared with chemotherapy alone, of which six studies were accessed since they met the eligibility criteria for analysis of the full text. Of the six studies, five were selected to support this assessment 1 - 5 ; the grounds for exclusion and the list of studies excluded are available in the references, Figure 6 and Table 9 in the Annexes. FIGURE 6 FLOWCHART TABLE 9 STUDIES EXCLUDED AND REASON FOR EXCLUSION Study Reason for exclusion Barlesi F, et al. 2019 Docetaxel intervention and quality of life outcome Reck M, et al. 2019 Follow-up time of 2 years Brahmer JR, et al. 2017 Outcome of quality of life Herbst RS, et al. 2016 Docetaxel intervention NSCLC = Non-small-cell lung carcinoma; CNS = Central nervous system; AUC = Area under the concentration-time curve; OS = overall survival; SFP = Survival free of progression; PD-L1 = Programmed death ligand 1; TPS = Tumor proportion score of biomarker PD-L1 in tumor tissue; EGFR = Epidermal growth factor receptor; ALK = Anaplastic Lymphoma Kinase; Ecog = Eastern Cooperative Oncology Group; Recist = Response Evaluation Criteria in solid tumors. TABLE 2 DESCRIPTION OF THE BIASES IN THE STUDIES INCLUDED Study and year Random Blinded allocation Double-blind Losses Characteristics Prognosis Outcomes Analysis per ITT Sample size calculation Jadad 7 Mok TSK 2019 4 Reck M 2016 4 Gandhi L 2018 5 Paz-Ares L 2018 5 Langer CJ 2016 4 ITT = intention-to-treat analysis Unclear risk of bias Presence of bias Low risk of bias the TABLE 1 DESCRIPTION OF THE STUDIES INCLUDED STUDY Population Intervention Comparison Outcomes Time (median, months) Mok TSK, et al. 2019 Keynote-042 ≥18 years) with locally advanced or metastatic NSCLC, not previously treated, without EGFR mutation or ALK translocation, and with a score of 0 or 1 in the Ecog performance scale, life expectancy of three months or more, and a PD-L1 TPS of 1% or greater. Excluded if: unstable or untreated CNS metastases, a history of noninfectious pneumonitis requiring systemic glucocorticoids, active autoimmune disease, systemic immunosuppressive treatment, or active infection by the virus of hepatitis B or C. Pembrolizumab 200 mg every three weeks, in up to 35 cycles Carboplatin to achieve an AUC of 5-6 mg/mL per minute plus paclitaxel 200 mg/m 2 or pemetrexed 500 mg/m 2 OS SFP Adverse events 12.8 Reck M, et al. 2016 Keynote-024 ≥18 years, NSCLC histologically or cytologically confirmed in stage IV, without EGFR mutations or ALKtranslocation, without prior systemic therapy for metastatic disease, with a 0 or 1 score in the ECOG performance status, at least one measurable lesion according to Recist version 1.1, life expectancy of at least three months, and a 50% or more score of PD-L1 tumor proportion. Excluded if: receiving systemic glucocorticoids (excluding daily replacement therapy with glucocorticoids for conditions such as pituitary or adrenal insufficiency) or other immunosuppressive treatment, with untreated brain metastases, active autoimmune disease for which they received systemic treatment over the past two years, active interstitial lung disease or pneumonitis history for which they received glucocorticoids. Pembrolizumab in a fixed dose of 200 mg every three weeks. Platinum-based chemotherapy to the choice of the researcher during 4 to 6 cycles: carboplatin plus pemetrexed, cisplatin plus pemetrexed, carboplatin plus gemcitabine, cisplatin plus gemcitabine, cisplatin plus gemcitabine or carboplatin plus paclitaxel. The chemotherapy regimens that included pemetrexed were allowed only for patients who had non-squamous tumors. Crossover allowed. OS SFP Adverse events 25.2 Gandhi L et al. 2018 Keynote-189 ≥18 years, metastatic NSCLC, non-squamous, without mutations in the EGFR gene and ALK rearrangement, without prior therapy for the disease. Other conditions: an ECOG performance status of 0 or 1; at least one measurable lesion according to Recist version 1.1, and provide a sample of the tumor for determining the PD-L1state. Excluded if: symptomatic CNS metastases, history of non-infectious pneumonitis requiring the use of glucocorticoids, autoimmune disease with systemic therapy in the past two years, medical condition requiring immunosuppression, received more than 30 Gy of radiotherapy to the chest over the past six months. Pemetrexed (500 mg/m 2 IV) and a platinum-based drug at the choice of the investigator (cisplatin 75 mg/m 2 of body surface or carboplatin AUC 5mg/mL/min intravenously) plus 200 mg of pembrolizumab every three weeks, for four cycles, followed by pembrolizumab until a total of 35 cycles, plus maintenance therapy with pemetrexed. Pemetrexed (500 mg/m 2 IV) and a platinum-based drug at the choice of the investigator (cisplatin 75 mg/m 2 of body surface or carboplatin AUC 5mg/mL/min intravenous) plus a placebo every three weeks, for four cycles, followed by a placebo until a total of 35 cycles, plus maintenance therapy with pemetrexed. OS SFP. Adverse events 10.5 Paz-Ares L et al. 2018 Keynote-407 ≥18 years; squamous NSCLC stage IV, without prior systemic therapy for metastatic disease, ECOG performance status score of 0 or 1, with at least one measurable lesion according to Recist version 1.1, provided a tumor sample for determining the PD-L1 state. Excluded if: symptomatic metastases of the CNS, history of non-infectious pneumonitis that required the use of glucocorticoids; autoimmune disease that required systemic therapy in the past two years; medical condition requiring immunosuppression. Pembrolizumab 200 mg for up to 35 cycles + carboplatin and paclitaxel or nanoparticle albumin-bound [NAB] - paclitaxel for the first four cycles. Saline (placebo) for up to 35 cycles + carboplatin and paclitaxel or nanopartícula albumin-bound [NAB] - paclitaxel during the first four cycles. SFP OS Adverse events 7.8 Langer CJ et al. 2016 Keynote-021 No previous systemic treatment for non-squamous NSCLC, cytologically or histologically confirmed, Stage IIIB or IV, and absence of EGFR target mutations or ALK translocations; ECOG performance status of 0 or 1, at least one measurable lesion evaluated by Recist version 1.1, life expectancy of three months or more, and supply of a sample of the tumor for evaluation of the PD-L1expression. Excluded if: received more than 30 Gy of radiation to the lungs in the previous six months; continuous use of systemic corticosteroids or other immunosuppressive treatment, active autoimmune disease that required systemic treatment in the past two years (excluding replacement therapy), untreated brain metastases (allowed treated, stable metastasis), or active interstitial lung disease, history of pneumonitis requiring intravenous glucocorticoids. Pembrolizumab 200 mg + carboplatin AUC 5 mg/mL/min and pemetrexed intravenous 500 mg/m 2 every three weeks followed by pembrolizumab for 24 months and maintenance therapy with undefined pemetrexed. Four cycles of carboplatin and pemetrexed, followed by maintenance therapy with undefined pemetrexed. Objective Response SFP OS Adverse events 23.9 Application of evidence - Recommendation The available evidence will follow some principles of exposure– it will be by outcome and will have as components: number of patients, type of comparison, magnitude, and precision (standard deviation and 95% CI). Its strength will be estimated (Oxford 16 /Grade 8 ) as 1b and 1c (grade A) or strong, and as 2a, 2b and 2c (grade B) or moderate weak, or very weak. ).

Regarding the bias risk of the five studies included, three of them were not double-blind ¹1. Barlesi F , Garon EB , Kim DW , Felip E , Han JY , Kim JH , et al . Health-Related Quality of Life in KEYNOTE-010: a Phase II/III Study of Pembrolizumab Versus Docetaxel in Patients With Previously Treated Advanced, Programmed Death Ligand 1-Expressing NSCLC . J Thorac Oncol 2019 ; 14 : 793 - 801 . PMID: 30711649

2. Reck M , Rodríguez-Abreu D , Robinson AG , Hui R , Csőszi T , Fülöp A , Gottfried M , et al . Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater . J Clin Oncol 2019 1 ; 37 : 537 - 546 . PMID: 30620668 - ³3. Brahmer JR , Rodríguez-Abreu D , Robinson AG , Hui R , Csőszi T , Fülöp A , Gottfried M , et al . Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial . Lancet Oncol 2017 ; 18 : 1600 - 1609 . PMID: 29129441 , so the overall risk of the studies can be considered low ( Table 2 - ^{Annex I} ANNEX I The purpose of this assessment is to identify the benefits of immunotherapy with pembrolizumab, associated or not with chemotherapy, in the treatment of patients with locally advanced or metastatic NSCLC, without mutations of the EGFR gene or gene rearrangement of the ALK, with PD-L1 gene expression, in comparison to chemotherapy alone (current standard treatment). Clinical question What is the impact of pembrolizumab, associated or not to chemotherapy, on the outcomes of overall mortality (death from any cause) and adverse events in the treatment of patients with advanced NSCLC when compared to chemotherapy alone? Structured question Patient – Adult patients with advanced NSCLC; Intervention – Treatment with Pembrolizumab alone or combined with chemotherapy; Comparison – Chemotherapy, except monochemotherapy with docetaxel; Outcomes – Death (due to any cause) and adverse events. Eligibility criteria Excluded the outcomes − quality of life, objective response, survival free of progression − analyses of tumor proportion score (TPS) of the PD-L1 biomarker on the tumor tissue were not evaluated. Randomized clinical trial. Without time or language restrictions. Full text available for access. Search strategies used The search for evidence will be conducted on Medline virtual scientific information database, using the following search strategy: (((((Pulmonary Neoplasms OR Lung Neoplasm OR Pulmonary Neoplasm OR Lung Neoplasms OR Lung Cancers OR Lung Cancer OR Lung Neoplasm OR Lung Neoplasms OR PD-L1))) AND ((pembrolizumab) AND Random*))) OR ((((Pulmonary Neoplasms OR Lung Neoplasm OR Pulmonary Neoplasm OR Lung Neoplasms OR Lung Cancers OR Lung Cancer OR Lung Neoplasm OR Lung Neoplasms))) AND ((pembrolizumab OR PD-L1) AND Random*)). In the Central/Cochrane databases, the search strategy will be: (Lung Neoplasm OR Pulmonary Neoplasm OR Lung Cancer) AND pembrolizumab. Extraction of results We will extract the following data from the studies: name of the author and year of publication, study population, intervention and comparison methods, the absolute number of deaths and adverse events, time of follow-up. Randomized clinical trials will have their risk of biases analyzed according to the following criteria: randomization, blinded allocation, double-blinding, losses, prognostic characteristics, presence of relevant outcome, time for the outcome, method for outcome measurement, sample size calculation, early interruption, presence of other biases. The results will be presented as the difference in the risk of death or adverse events between pembrolizumab therapy alone or in combination with chemotherapy, and the treatment with chemotherapy alone. The confidence level adopted was 95%. The results of the studies included will be combined and meta-analyzed by RevMan 5.3 8 , and the difference in overall risk will be the final measure used to support the synthesis of evidence that will answer the clinical question of this review. Furthermore, the quality of evidence will be graded as high, moderate, low, or very low using the Grade instrument 6 and taking into account the risk of bias, the presence of inconsistency, vagueness or indirect evidence in the meta-analysis of the outcomes of death and adverse events, and the presence of publication bias. Table 5 . Quality of evidence (GRADE). TABLE 5 QUALITY OF EVIDENCE (GRADE). Evaluation of certainty № of patients Effect Certainty Importance № of studies Design of the study Risk of bias Inconsistency Indirect evidence Imprecision Other considerations Levosimendan Dobutamine Relative (95% CI) Absolute (95% CI) Mortality at 24 hours (assessed with: Number of deaths in 24 hours) 4 randomized clinical trials severe a not severe not severe not severe b none 1/208 (0.5%) 4/204 (2.0%) RR 3.05 (0.49 to 18.90) 40 more per 1,000 (from minus 10 to 351 more) ⊕⊕⊕◯MODERATE IMPORTANT Mortality at 30 days (assessed with: Number of deaths up to 30 days) 3 randomized clinical trials not severe severe c not severe severe d none 93/836 (11.1%) 125/831 (15.0%) RR 1.74 (0.94 to 3.19) 111 more per 1,000 (from minus 9 to 329 more) ⊕⊕◯ LOW IMPORTANT Mortality between 120 and 180 days (follow-up: variation 120 days to 180 days; assessed with: Number of deaths in this period) 4 randomized clinical trials severe e not severe not severe severe f none 206/811 (25.4%) 236/807 (29.2%) RR 1.15 (0.98 to 1.35) 44 more per 1,000 (from minus 6 to 102 more) ⊕⊕◯◯ LOW IMPORTANT CI: Confidence interval; RR: Relative Risk Explanation: a. 50% with randomization inadequate or not described; only one with blinded allocation, three studies without blinding; only with sample size calculation; b. The overall result does not exclude the benefit or harm; c. Test for inconsistency I2 equal to 70%; small overlap of confidence intervals; d. The result does not exclude great harm or benefit; e. 2 studies with Jadad = 1 and 2 studies with Jadad >= 3; f. The result does not exclude great harm or benefit Critical evaluation and level of evidence All evidence retrieved was evaluated according to their risk of bias (level of error estimated and inherent in the delineation of research or study design used). For the evaluation of the risk of bias of the RCTs, the following items were considered: if the issue was focal, appropriate randomization, blinded allocation, double-blind, losses (>20%), prognostic characteristics, outcomes (time, adequacy, measurement), analysis by intention to treat (ITT), sample size calculation, Jadad scale 7 . Reflecting the level of uncertainty of the results (effects of benefit or harm), the strength of the evidence can be very low, low, moderate, or strong, depending on: The risks of bias of each individual and meta-analyzed study. The magnitude and accuracy of the results for each outcome analyzed. The relevance, applicability, and generalization of these results. Presentation of the results In the search for evidence, we retrieved 244 papers, selecting by title and abstract nine studies of immunotherapy with pembrolizumab, associated or not to chemotherapy, in the treatment of patients with NSCLC, compared with chemotherapy alone, of which six studies were accessed since they met the eligibility criteria for analysis of the full text. Of the six studies, five were selected to support this assessment 1 - 5 ; the grounds for exclusion and the list of studies excluded are available in the references, Figure 6 and Table 9 in the Annexes. FIGURE 6 FLOWCHART TABLE 9 STUDIES EXCLUDED AND REASON FOR EXCLUSION Study Reason for exclusion Barlesi F, et al. 2019 Docetaxel intervention and quality of life outcome Reck M, et al. 2019 Follow-up time of 2 years Brahmer JR, et al. 2017 Outcome of quality of life Herbst RS, et al. 2016 Docetaxel intervention NSCLC = Non-small-cell lung carcinoma; CNS = Central nervous system; AUC = Area under the concentration-time curve; OS = overall survival; SFP = Survival free of progression; PD-L1 = Programmed death ligand 1; TPS = Tumor proportion score of biomarker PD-L1 in tumor tissue; EGFR = Epidermal growth factor receptor; ALK = Anaplastic Lymphoma Kinase; Ecog = Eastern Cooperative Oncology Group; Recist = Response Evaluation Criteria in solid tumors. TABLE 2 DESCRIPTION OF THE BIASES IN THE STUDIES INCLUDED Study and year Random Blinded allocation Double-blind Losses Characteristics Prognosis Outcomes Analysis per ITT Sample size calculation Jadad 7 Mok TSK 2019 4 Reck M 2016 4 Gandhi L 2018 5 Paz-Ares L 2018 5 Langer CJ 2016 4 ITT = intention-to-treat analysis Unclear risk of bias Presence of bias Low risk of bias the TABLE 1 DESCRIPTION OF THE STUDIES INCLUDED STUDY Population Intervention Comparison Outcomes Time (median, months) Mok TSK, et al. 2019 Keynote-042 ≥18 years) with locally advanced or metastatic NSCLC, not previously treated, without EGFR mutation or ALK translocation, and with a score of 0 or 1 in the Ecog performance scale, life expectancy of three months or more, and a PD-L1 TPS of 1% or greater. Excluded if: unstable or untreated CNS metastases, a history of noninfectious pneumonitis requiring systemic glucocorticoids, active autoimmune disease, systemic immunosuppressive treatment, or active infection by the virus of hepatitis B or C. Pembrolizumab 200 mg every three weeks, in up to 35 cycles Carboplatin to achieve an AUC of 5-6 mg/mL per minute plus paclitaxel 200 mg/m 2 or pemetrexed 500 mg/m 2 OS SFP Adverse events 12.8 Reck M, et al. 2016 Keynote-024 ≥18 years, NSCLC histologically or cytologically confirmed in stage IV, without EGFR mutations or ALKtranslocation, without prior systemic therapy for metastatic disease, with a 0 or 1 score in the ECOG performance status, at least one measurable lesion according to Recist version 1.1, life expectancy of at least three months, and a 50% or more score of PD-L1 tumor proportion. Excluded if: receiving systemic glucocorticoids (excluding daily replacement therapy with glucocorticoids for conditions such as pituitary or adrenal insufficiency) or other immunosuppressive treatment, with untreated brain metastases, active autoimmune disease for which they received systemic treatment over the past two years, active interstitial lung disease or pneumonitis history for which they received glucocorticoids. Pembrolizumab in a fixed dose of 200 mg every three weeks. Platinum-based chemotherapy to the choice of the researcher during 4 to 6 cycles: carboplatin plus pemetrexed, cisplatin plus pemetrexed, carboplatin plus gemcitabine, cisplatin plus gemcitabine, cisplatin plus gemcitabine or carboplatin plus paclitaxel. The chemotherapy regimens that included pemetrexed were allowed only for patients who had non-squamous tumors. Crossover allowed. OS SFP Adverse events 25.2 Gandhi L et al. 2018 Keynote-189 ≥18 years, metastatic NSCLC, non-squamous, without mutations in the EGFR gene and ALK rearrangement, without prior therapy for the disease. Other conditions: an ECOG performance status of 0 or 1; at least one measurable lesion according to Recist version 1.1, and provide a sample of the tumor for determining the PD-L1state. Excluded if: symptomatic CNS metastases, history of non-infectious pneumonitis requiring the use of glucocorticoids, autoimmune disease with systemic therapy in the past two years, medical condition requiring immunosuppression, received more than 30 Gy of radiotherapy to the chest over the past six months. Pemetrexed (500 mg/m 2 IV) and a platinum-based drug at the choice of the investigator (cisplatin 75 mg/m 2 of body surface or carboplatin AUC 5mg/mL/min intravenously) plus 200 mg of pembrolizumab every three weeks, for four cycles, followed by pembrolizumab until a total of 35 cycles, plus maintenance therapy with pemetrexed. Pemetrexed (500 mg/m 2 IV) and a platinum-based drug at the choice of the investigator (cisplatin 75 mg/m 2 of body surface or carboplatin AUC 5mg/mL/min intravenous) plus a placebo every three weeks, for four cycles, followed by a placebo until a total of 35 cycles, plus maintenance therapy with pemetrexed. OS SFP. Adverse events 10.5 Paz-Ares L et al. 2018 Keynote-407 ≥18 years; squamous NSCLC stage IV, without prior systemic therapy for metastatic disease, ECOG performance status score of 0 or 1, with at least one measurable lesion according to Recist version 1.1, provided a tumor sample for determining the PD-L1 state. Excluded if: symptomatic metastases of the CNS, history of non-infectious pneumonitis that required the use of glucocorticoids; autoimmune disease that required systemic therapy in the past two years; medical condition requiring immunosuppression. Pembrolizumab 200 mg for up to 35 cycles + carboplatin and paclitaxel or nanoparticle albumin-bound [NAB] - paclitaxel for the first four cycles. Saline (placebo) for up to 35 cycles + carboplatin and paclitaxel or nanopartícula albumin-bound [NAB] - paclitaxel during the first four cycles. SFP OS Adverse events 7.8 Langer CJ et al. 2016 Keynote-021 No previous systemic treatment for non-squamous NSCLC, cytologically or histologically confirmed, Stage IIIB or IV, and absence of EGFR target mutations or ALK translocations; ECOG performance status of 0 or 1, at least one measurable lesion evaluated by Recist version 1.1, life expectancy of three months or more, and supply of a sample of the tumor for evaluation of the PD-L1expression. Excluded if: received more than 30 Gy of radiation to the lungs in the previous six months; continuous use of systemic corticosteroids or other immunosuppressive treatment, active autoimmune disease that required systemic treatment in the past two years (excluding replacement therapy), untreated brain metastases (allowed treated, stable metastasis), or active interstitial lung disease, history of pneumonitis requiring intravenous glucocorticoids. Pembrolizumab 200 mg + carboplatin AUC 5 mg/mL/min and pemetrexed intravenous 500 mg/m 2 every three weeks followed by pembrolizumab for 24 months and maintenance therapy with undefined pemetrexed. Four cycles of carboplatin and pemetrexed, followed by maintenance therapy with undefined pemetrexed. Objective Response SFP OS Adverse events 23.9 Application of evidence - Recommendation The available evidence will follow some principles of exposure– it will be by outcome and will have as components: number of patients, type of comparison, magnitude, and precision (standard deviation and 95% CI). Its strength will be estimated (Oxford 16 /Grade 8 ) as 1b and 1c (grade A) or strong, and as 2a, 2b and 2c (grade B) or moderate weak, or very weak. ).

META-ANALYSIS

Two RCTs ¹1. Barlesi F , Garon EB , Kim DW , Felip E , Han JY , Kim JH , et al . Health-Related Quality of Life in KEYNOTE-010: a Phase II/III Study of Pembrolizumab Versus Docetaxel in Patients With Previously Treated Advanced, Programmed Death Ligand 1-Expressing NSCLC . J Thorac Oncol 2019 ; 14 : 793 - 801 . PMID: 30711649 present sufficient data to allow for a meta-analysis, considering results (number of deaths) up to 12 months, comparing pembrolizumab with chemotherapy in advanced NSCLC ( Table 3 ).

The incidence of death was 48.92% (387 in 791 patients) in the Pembrolizumab group and 55.58% in the Chemotherapy group (438 in 788 patients). Pembrolizumab reduced the risk of death by 7% at 12 months [ARR 7%; 95% CI -12% to -2%; p=0.006; I ² =0%, NNT=15 (95% CI 9 to 56)], Figure 2 .

For this comparison, we also evaluated the adverse events due to any cause, degree ≥3, in the population treated ( Table 4 ).

The incidence of adverse events ≥3 was 19.5% (154 in 790 patients) in the Pembrolizumab group and 43.4% in the Chemotherapy group (332 in 765 patients). Pembrolizumab reduced the risk of adverse events by 24% at 12 months [ARR = 24%; 95% CI -28% to -19%; p< 0.00001; I ² =0%, NNT=4 (95% CI 9 to 5)], Figure 2 .

Three primary assays ³3. Brahmer JR , Rodríguez-Abreu D , Robinson AG , Hui R , Csőszi T , Fülöp A , Gottfried M , et al . Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial . Lancet Oncol 2017 ; 18 : 1600 - 1609 . PMID: 29129441

4. Herbst RS , Baas P , Kim DW , Felip E , Pérez-Gracia JL , Han JY , et al . Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial . Lancet 2016 9 ; 387 : 1540 - 50 . PMID: 26712084 - ⁵5. Paz-Ares L , Luft A , Vicente D , Tafreshi A , Gümüş M , Mazières J , et al . Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer . N Engl J Med 2018 22 ; 379 : 2040 - 2051 . PMID: 30280635 comparing pembrolizumab plus chemotherapy versus chemotherapy allow to combine the results and assess the risk of death in 12 months, as the outcome ( Table 5 ).

In all three studies, patients were randomized (1: 1) in blocks of four, stratified by tumor proportion score of PD-L1 (<1% vs. ≥1%).

In the meta-analysis of the results of these three studies, there is a significant difference in the reduction of death, in a 12-month follow-up, of 8% (95% CI -13% to -4%); favorable to the treatment with pembrolizumab plus chemotherapy; [I ² =0%; NNT=12 (95% CI 7 to 25)] - ( Figure 4 ).

These three RCTs analyzed adverse events of any cause, degree ≥3 in the population treated, for comparison between pembrolizumab plus chemotherapy versus chemotherapy ( Table 6 ).

PEMBROLIZUMAB VS CHEMOTHERAPY

In the meta-analysis of three combined studies, there was no significative difference in adverse events with a degree ≥3, in a 12-month follow-up, between both groups (ARR =3%, 95% CI −0.03 to 0.08; NNT=NS; I ² =0%) ( Figure 5 ).

SUMMARY OF THE META-ANALYSIS RESULTS

PEMBROLIZUMAB VERSUS CHEMOTHERAPY

PEMBROLIZUMAB + CHEMOTHERAPY VERSUS CHEMOTHERAPY

QUALITY OF EVIDENCE FOR THE DEATH OUTCOME

Pembrolizumab versus Chemotherapy

Question: Mortality with the use of pembrolizumab compared to chemotherapy for locally advanced or metastatic NSCLC.

Pembrolizumab + Chemotherapy versus Chemotherapy

Question: Pembrolizumab + Chemotherapy compared to chemotherapy for locally advanced or metastatic NSCLC.

SYNTHESIS OF EVIDENCE

In adult patients with squamous or non-squamous NSCLC, locally advanced or metastatic, without previous systemic therapy, without mutations in the EGFR gene and gene rearrangement of the ALK, with a score of 0 or 1 in the Ecog performance scale, with at least one measurable lesion evaluated by Recist version 1.1, the treatment with pembrolizumab, associated or not to chemotherapy, compared with standard chemotherapy reduces the risk of death in 12 months by 7% and 8%, respectively. The quality of the evidence that supports this result is high.

For these patients, pembrolizumab reduced adverse events of degree ≥3 by 24% in comparison with chemotherapy, and when associated with it, it showed no difference in adverse events of degree ≥3 in comparison with chemotherapy alone, in up to 12 months. The quality of the evidence that supports this result is high.

RECOMMENDATION

The treatment with Pembrolizumab, associated or not with chemotherapy, in adult patients with squamous or non-squamous NSCLC, locally advanced or metastatic, without previous systemic therapy, without mutations in the EGFR gene and gene rearrangement of the ALK, with a score of 0 or 1 in the Ecog performance scale, with at least one measurable lesion evaluated by Recist version 1.1, and PD-L1 expression [Tumor Proportion Score (TPS)] ≥1% (positive PDL-1). High quality of evidence.

DISCUSSION

Among human neoplasms for which the investigation of PD-L1 immunohistochemical expression is validated by clinical studies, with an undeniable predictive value of the response to anti-PD-1 therapies available, the non-small cell lung carcinomas stand out. The PD-L1 expression on the tumor-cell membrane is indicated as an aid in the identification of patients for treatment with pembrolizumab. The result of the PD-L1 expression is determined by the percentage of tumor cells with membrane immunostaining (full or basolateral) of any intensity and/or by the percentage of immune cells associated with the tumor with immunostaining of any intensity, according to the type of neoplasia under analysis. Patients with a tumor proportion score (TPS) <1% of the PD-L1 biomarker in the tumor tissue are considered PD-L1 negative and with TPS ≥1% positive.

In the comparison pembrolizumab versus chemotherapy, we included two studies ¹1. Barlesi F , Garon EB , Kim DW , Felip E , Han JY , Kim JH , et al . Health-Related Quality of Life in KEYNOTE-010: a Phase II/III Study of Pembrolizumab Versus Docetaxel in Patients With Previously Treated Advanced, Programmed Death Ligand 1-Expressing NSCLC . J Thorac Oncol 2019 ; 14 : 793 - 801 . PMID: 30711649 that included only patients with TPS ≥1% (PDL-1 positive). However, in the comparison of pembrolizumab plus chemotherapy versus chemotherapy alone, the three studies assessed ³3. Brahmer JR , Rodríguez-Abreu D , Robinson AG , Hui R , Csőszi T , Fülöp A , Gottfried M , et al . Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial . Lancet Oncol 2017 ; 18 : 1600 - 1609 . PMID: 29129441

4. Herbst RS , Baas P , Kim DW , Felip E , Pérez-Gracia JL , Han JY , et al . Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial . Lancet 2016 9 ; 387 : 1540 - 50 . PMID: 26712084 - ⁵5. Paz-Ares L , Luft A , Vicente D , Tafreshi A , Gümüş M , Mazières J , et al . Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer . N Engl J Med 2018 22 ; 379 : 2040 - 2051 . PMID: 30280635 included patients with TPS <1% (PDL-1 negative) and TPS ≥1% (1−49% and ≥50%), uniformly distributed between the groups, with an analysis of these subgroups.

It should be emphasized, however, that the greater the number of subgroups analyzed in one sample, the higher the probability of false-positive results; it is also added to that limitation the frequent tendency of reporting, after various analyses, only the significant results, which can potentially distort the interpretation of the results. In the event of a positive result, is there effectively a significant difference in the treatment effect, or it is mere occurrence at random (considering the absence of a prior determination of sampling and subsequent statistical power for such difference) ³3. Brahmer JR , Rodríguez-Abreu D , Robinson AG , Hui R , Csőszi T , Fülöp A , Gottfried M , et al . Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial . Lancet Oncol 2017 ; 18 : 1600 - 1609 . PMID: 29129441 ?

Considering that: there is a lack of RCTs with a prior determination of sampling comparing positive and negative PDL-1 patients, and the mechanism of action of pembrolizumab in patients with NSCLC.

ANNEX I

The purpose of this assessment is to identify the benefits of immunotherapy with pembrolizumab, associated or not with chemotherapy, in the treatment of patients with locally advanced or metastatic NSCLC, without mutations of the EGFR gene or gene rearrangement of the ALK, with PD-L1 gene expression, in comparison to chemotherapy alone (current standard treatment).

Clinical question

What is the impact of pembrolizumab, associated or not to chemotherapy, on the outcomes of overall mortality (death from any cause) and adverse events in the treatment of patients with advanced NSCLC when compared to chemotherapy alone?

Structured question

Patient – Adult patients with advanced NSCLC;

Intervention – Treatment with Pembrolizumab alone or combined with chemotherapy;

Comparison – Chemotherapy, except monochemotherapy with docetaxel;

Outcomes – Death (due to any cause) and adverse events.

Eligibility criteria

Excluded the outcomes − quality of life, objective response, survival free of progression − analyses of tumor proportion score (TPS) of the PD-L1 biomarker on the tumor tissue were not evaluated.

Randomized clinical trial.

Without time or language restrictions.

Full text available for access.

Search strategies used

The search for evidence will be conducted on Medline virtual scientific information database, using the following search strategy:

(((((Pulmonary Neoplasms OR Lung Neoplasm OR Pulmonary Neoplasm OR Lung Neoplasms OR Lung Cancers OR Lung Cancer OR Lung Neoplasm OR Lung Neoplasms OR PD-L1))) AND ((pembrolizumab) AND Random*))) OR ((((Pulmonary Neoplasms OR Lung Neoplasm OR Pulmonary Neoplasm OR Lung Neoplasms OR Lung Cancers OR Lung Cancer OR Lung Neoplasm OR Lung Neoplasms))) AND ((pembrolizumab OR PD-L1) AND Random*)).

In the Central/Cochrane databases, the search strategy will be: (Lung Neoplasm OR Pulmonary Neoplasm OR Lung Cancer) AND pembrolizumab.

Extraction of results

We will extract the following data from the studies: name of the author and year of publication, study population, intervention and comparison methods, the absolute number of deaths and adverse events, time of follow-up.

Randomized clinical trials will have their risk of biases analyzed according to the following criteria: randomization, blinded allocation, double-blinding, losses, prognostic characteristics, presence of relevant outcome, time for the outcome, method for outcome measurement, sample size calculation, early interruption, presence of other biases.

The results will be presented as the difference in the risk of death or adverse events between pembrolizumab therapy alone or in combination with chemotherapy, and the treatment with chemotherapy alone. The confidence level adopted was 95%.

The results of the studies included will be combined and meta-analyzed by RevMan 5.3 ⁸8. Review Manager (RevMan) [ Computer program ]. Version 5.3 . Copenhagen : The Nordic Cochrane Centre, The Cochrane Collaboration , 2014 . , and the difference in overall risk will be the final measure used to support the synthesis of evidence that will answer the clinical question of this review.

Furthermore, the quality of evidence will be graded as high, moderate, low, or very low using the Grade instrument ⁶6. GRADEpro GDT: GRADEpro Guideline Development Tool [ Software ]. McMaster University , 2015 ( developed by Evidence Prime, Inc. ). Available from gradepro.org .
gradepro.org... and taking into account the risk of bias, the presence of inconsistency, vagueness or indirect evidence in the meta-analysis of the outcomes of death and adverse events, and the presence of publication bias. Table 5 . Quality of evidence (GRADE).

Explanation: a. 50% with randomization inadequate or not described; only one with blinded allocation, three studies without blinding; only with sample size calculation; b. The overall result does not exclude the benefit or harm; c. Test for inconsistency I2 equal to 70%; small overlap of confidence intervals; d. The result does not exclude great harm or benefit; e. 2 studies with Jadad = 1 and 2 studies with Jadad >= 3; f. The result does not exclude great harm or benefit

Critical evaluation and level of evidence

All evidence retrieved was evaluated according to their risk of bias (level of error estimated and inherent in the delineation of research or study design used).

For the evaluation of the risk of bias of the RCTs, the following items were considered: if the issue was focal, appropriate randomization, blinded allocation, double-blind, losses (>20%), prognostic characteristics, outcomes (time, adequacy, measurement), analysis by intention to treat (ITT), sample size calculation, Jadad scale ⁷7. Jadad AR , Moore RA , Carroll D , Jenkinson C , Reynolds DJ , Gavaghan DJ , et al . Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996 ; 17 : 1 - 12 . .

Reflecting the level of uncertainty of the results (effects of benefit or harm), the strength of the evidence can be very low, low, moderate, or strong, depending on:

1. The risks of bias of each individual and meta-analyzed study.

2. The magnitude and accuracy of the results for each outcome analyzed.

3. The relevance, applicability, and generalization of these results.

Presentation of the results

In the search for evidence, we retrieved 244 papers, selecting by title and abstract nine studies of immunotherapy with pembrolizumab, associated or not to chemotherapy, in the treatment of patients with NSCLC, compared with chemotherapy alone, of which six studies were accessed since they met the eligibility criteria for analysis of the full text. Of the six studies, five were selected to support this assessment ¹1. Barlesi F , Garon EB , Kim DW , Felip E , Han JY , Kim JH , et al . Health-Related Quality of Life in KEYNOTE-010: a Phase II/III Study of Pembrolizumab Versus Docetaxel in Patients With Previously Treated Advanced, Programmed Death Ligand 1-Expressing NSCLC . J Thorac Oncol 2019 ; 14 : 793 - 801 . PMID: 30711649

2. Reck M , Rodríguez-Abreu D , Robinson AG , Hui R , Csőszi T , Fülöp A , Gottfried M , et al . Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater . J Clin Oncol 2019 1 ; 37 : 537 - 546 . PMID: 30620668

3. Brahmer JR , Rodríguez-Abreu D , Robinson AG , Hui R , Csőszi T , Fülöp A , Gottfried M , et al . Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial . Lancet Oncol 2017 ; 18 : 1600 - 1609 . PMID: 29129441

4. Herbst RS , Baas P , Kim DW , Felip E , Pérez-Gracia JL , Han JY , et al . Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial . Lancet 2016 9 ; 387 : 1540 - 50 . PMID: 26712084 - ⁵5. Paz-Ares L , Luft A , Vicente D , Tafreshi A , Gümüş M , Mazières J , et al . Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer . N Engl J Med 2018 22 ; 379 : 2040 - 2051 . PMID: 30280635 ; the grounds for exclusion and the list of studies excluded are available in the references, Figure 6 and Table 9 in the Annexes.

NSCLC = Non-small-cell lung carcinoma; CNS = Central nervous system; AUC = Area under the concentration-time curve; OS = overall survival; SFP = Survival free of progression; PD-L1 = Programmed death ligand 1; TPS = Tumor proportion score of biomarker PD-L1 in tumor tissue; EGFR = Epidermal growth factor receptor; ALK = Anaplastic Lymphoma Kinase; Ecog = Eastern Cooperative Oncology Group; Recist = Response Evaluation Criteria in solid tumors.

Application of evidence - Recommendation

The available evidence will follow some principles of exposure– it will be by outcome and will have as components: number of patients, type of comparison, magnitude, and precision (standard deviation and 95% CI).

Its strength will be estimated (Oxford ¹⁶ /Grade ⁸8. Review Manager (RevMan) [ Computer program ]. Version 5.3 . Copenhagen : The Nordic Cochrane Centre, The Cochrane Collaboration , 2014 . ) as 1b and 1c (grade A) or strong, and as 2a, 2b and 2c (grade B) or moderate weak, or very weak.

Publication Dates

History