The association of PD-L1 expression status and PD-1/PD-L1 inhibitors-related toxicities profile in non-small cell lung cancer

The association of PD-L1 expression status and PD-1/PD-L1 inhibitors-related toxicities profile in non-small cell lung cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The association of PD-L1 expression status and PD-1/PD-L1 inhibitors-related toxicities profile in non-small cell lung cancer Qian Zhu, Hao Hu, Li-Ying OuYang, Rong Yang, Wen-Xiao Wei, Pin Huang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5748321/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Apr, 2025 Read the published version in BMC Cancer → Version 1 posted 4 You are reading this latest preprint version Abstract Purpose PD-L1 expression has been explored to guide the treatment options for programmed cell death 1 and its ligand (PD-1/PD-L1) inhibitors-based therapy in non-small cell lung cancer (NSCLC), but the association of its treatments-related toxicities profile with PD-L1 expression status is unclear. To make the optimized and personalized use of such agents, we performed current study. Experimental Design : Multiple databases (Cochrane Library, EMBASE, and PubMed databases) from inception to June 30, 2024 were retrieved to search PD-1/PD-L1 inhibitors-related clinical trials of NSCLC that had described data regarding treatment-related adverse events (TRAEs) and PD-L1 expression. Results Twenty-six trials, involving 5,453 patients, were eligible for final analysis. PD-L1-positive patients suffered a higher frequency of AEs leading to discontinuation, and grade 3–4 treatment-related adverse events (TRAEs) compared with PD-L1-negative patients at most cut-off value. However, the frequency of all-grade TRAEs, SAEs, and FAEs showed numerically difference among PD-L1-positive and PD-L1-negative patients at most cut-off value. Different PD-1/PD-L1 inhibitors type did not detect a consistent dose-dependent pattern between PD-L1-positive and toxicities profile. Subgroup analyses noted that patients using 22C3 immunohistochemistry assay have a higher frequency of all-grade TRAEs. Moreover, patients receiving first-line therapy and those enrolled in open-label trials experienced a higher frequency of grade 3–4 TRAEs. Conclusions We suggested that clinicians, and patients should be informed of the association of PD-L1 expression status and toxicities profile prior to PD-1/PD-L1 inhibitors administration. non-small cell lung cancer programmed cell death ligand 1 serious adverse event toxicities profile Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Non-small cell lung cancer (NSCLC) poses a major public health threat worldwide because of with high incidence, and mortality[ 1 ]. Currently, immunotherapies targeting the programmed cell death 1 (PD-1) and its ligand (PD-L1) have changed into standard therapy in advanced NSCLC patients without actionable driver mutation ( EGFR or ALK genes). This situation has led to the widespread adoption of these approval agents in clinical practice worldwide. Besides efficacy, toxicity profile is one primary concern among patients, and usually as a deciding factor for clinicians when patients who are going to start any treatment in clinical. The PD-1/PD-L1 pathway is necessary to avoid hyperactivation of the immune system, and to keep it balanced, thus PD-1/PD-L1 inhibitors may correlate to various categories of toxicities including rash, diarrhea, pneumonitis, hypothyroidism, hepatotoxicity, and others[ 2 ]. These treatment-related toxicities are common, and maybe debilitating, permanent and even life-threatening[ 2 , 3 ], which could cause serious consequences for patients, their families, and society. Such condition will further increase social, and economic burdens attributable to the PD-1/PD-L1 inhibitors. Moreover, early detection, and early intervention are the crucial management strategy for treatment-related adverse events (TRAEs). Thus, there is a massive unmet healthcare requirement for choosing the appropriate biomarkers to detect toxicities profile correlated to PD-1/PD-L1 inhibitors, prevent costly social and economic burdens, and further enable the optimisation and personalisation of the use of such drugs. Treatment options for PD-1/PD-L1 inhibitors-based therapy have been guided by PD-L1 expression, in accordance with the National Comprehensive Cancer Network guideline, and multiple guidelines (e.g., European Society for Medical Oncology). Indeed, previous studies[ 4 – 6 ] have implied that PD-L1 expression status was a useful biomarker for predicting response to these agents, and that its efficacy increased with PD-L1 expression. Yet, the association of toxicity profile with PD-L1 expression among these agents remain unclear, largely owing to the absence of PD-L1 expression-based safety data. Furthermore, a recent study[ 7 ] revealed that PD-1/PD-L1 inhibitors were correlated to a greater likelihood of developing TRAEs. Nevertheless, the toxicities profile linked to PD-1/PD-L1 inhibitors was often understated during the decision-making for treatment processes[ 8 ]. Hence, PD-1/PD-L1 inhibitors-induced toxicity profile makes optimising and personalising the use of these drugs a major goal of global public health. To tackle these issues, we perform this research to explore the association of PD-1/PD-L1 inhibitors-related toxicities profile with PD-L1 expression status to make the optimized and personalized use of such agents for treating patients with NSCLC. Materials and Methods The current study of toxicities analyses was did in strict based on the preferred reporting items for systematic reviews and meta-analyses statement[ 9 ]. Trial search strategy On June 30, 2024, three independent researchers (Q. Z., H. H. and L-Y.OY.) carried out systematic searches of Cochrane Library, EMBASE, and PubMed databases without language restrictions and confirmed by the third investigator (X-Y. H.). Supplementary Table S1 showed details of the searched strategy. And, we also searched unpublished/ongoing trials in https://clinicaltrials.gov/ and meeting abstracts (World Conference on Lung Cancer, and American Association of Cancer Research, etc.) between January 1, 2012 and June 30, 2024. Furthermore, we scanned the references of included articles. Criteria for selection and exclusion Two independent researchers (Q. Z., and H. H.) screened the studies, and the third investigator (L-Y.OY.) verified it. To reduce the bias, we further excluded studies adopting PD-1/PD-L1 inhibitors-based combination therapy because different combination therapies may contribute substantially to the toxicities profile. Based on the PICO checklist, the eligibility criteria were thus provided as follows: (1) participant: clinical trials prospectively enrolling NSCLC patients; (2) intervention: PD-1/PD-L1 inhibitors monotherapy; (3) control: none; and (4) outcome: the occurrence of TRAEs (events/incidence and sample size). Hence, non-prospective clinical trials including retrospective studies, case reports, and reviews were excluded. When same trials were identified, researchers retain the trial with longest follow-up time and/or with the most recent. Data extraction and appraisement of risk of bias Two researchers (P.H. and R.Y.) independently retrieved the standardized data and the third researcher (W-X. W.) confirmed it as following: study name, study design, study type, tumor stage, line of therapy, median age, male (%), PD-1/PD-L1 inhibitors type, sample size (number of participants evaluable for toxicity), immunohistochemistry (IHC) assay, median treatment duration, PD-L1 staining cell type, and PD-L1 expression. Treatment-related toxicity profile (all-grade, grade 3–4, serious adverse events (SAEs), AEs leading to discontinuation, and fatal adverse events (FAEs)) was determined by the principal investigator of the originally trial. We then extracted the aforementioned treatment-related toxicity profile to conduct current study. When detailed information regarding TRAEs was not available, we sought to communicate with the correspondence author of the original trial for confirmation, and identified the ambiguous interpretation as “not available (NA)”. AEs meet the criteria of the National Cancer Institute Common Terminology Criteria guidelines. Two independent researchers (P.H. and R.Y.) employed the 9-point Newcastle-Ottawa Scale (NOS)[ 10 ] with eight items to assess the study quality in non-randomized clinical trials. Each trial was classified into three main groups (selection, comparability, and outcomes for cohort studies)[ 10 ]. High-quality studies were identified as a score of 7 or higher. For randomized clinical trials, the above-mentioned two researchers independently appraised each trial using the 7-item Cochrane collaboration’s tool[ 11 ]. Any discrepancies will be settled through discussing or consulting with the third researcher (X-Y. H.). Statistical analysis GraphPad Prism software (Version 10.1.0; GraphPad Software, San Diego, CA) was utilised to perform all statistical analyses, and statistical significance was P values less than 0.05, two-tailed. Among different PD-L1 expression, Chi-square test or Fisher’s exact (if appropriate) was conducted via calculating the frequencies of toxicity profile. When one (or more) value is zero, 0.5 was added to each value before exploring the odds ratio (OR) and confidence interval (CI). In trials enrolling same anti-PD-1/PD-L1 drug, we evaluated the toxicities profile for different PD-L1 expression to study whether the toxicities were PD-L1 expression dependent. Subgroup analysis was carried out to measure the relationship of line of therapy (2 or later line vs. first-line), study design (double-blind vs. open-label), clinical phase (phase 3 vs. phase 1/2), and IHC assay type (22C3 vs. other) with the frequency of toxicities profile in those trials enrolling same PD-L1 expression, and PD-1/PD-L1 inhibitor. Results Search results and major clinical characteristics As Fig. 1 shows, we screened a total of 16,442 publications via both electronic databases and manual searches. After initial screening, 133 trials were used for detailed eligibility assessment. Finally, the remaining 26 prospective studies[ 12 – 37 ] were identified for the final toxicities analyses. Except three trials[ 15 , 23 , 30 ], all trials were conducted in multi-center, and the major clinical features are listed in Table 1 . Three trials[ 22 , 29 , 37 ] were double-blind trials, and the majority of trials (23 trials, 88.5%)[ 12 – 21 , 23 – 28 , 30 – 36 ] were open-label. Seventeen trials (65.4%) involved PD-1 inhibitors (fourteen with pembrolizumab[ 15 , 18 , 22 – 24 , 26 – 28 , 30 , 32 – 35 , 37 ], and three with nivolumab[ 12 , 13 , 31 ]), and nine trials (34.6%) involved PD-L1 inhibitors (five with durvalumab[ 17 , 19 – 21 , 36 ], and four with atezolizumab[ 14 , 16 , 25 , 29 ]). All trials focused on non-resectable NSCLC patients (one trial[ 15 ] with EGFR -positive mutations), except one trial[ 23 ] including resectable NSCLC patients (stage II/IIIA). Fifteen trials (57.7%)[ 13 , 15 , 21 , 22 , 25 , 27 – 33 , 35 – 37 ] were performed in the 1st-line setting, seven trials (26.9%)[ 12 , 18 – 20 , 24 , 26 , 34 ] in 2 or later line setting, three trials (11.5%)[ 14 , 16 , 17 ] in mix-line setting (first-line, and 2 or later line setting), and the remaining one trial[ 23 ] in neoadjuvant setting. Table 1 The major clinical features of included clinical trials Study name Study design Study type Tumor stage Line of therapy Sample Size Age (years), median (range) Male (%) PD-1/PD-L1 inhibitors MTD PD-L1 SCT IHC assay PD-L1 (%) CheckMate 057, multi-centre 12 open 3 RCT Adv. 2 or later 121 61 (37–84) 151 (52) Nivo 3mg/kg q2w 6 doses TC 28 − 8 > 1 106 Nivo 3mg/kg q2w 5 BIRCH, multi-centre 14 open 2 single-arm Adv. mix-line 659 64 (28–88) 389 (59) Atezo 1200mg q3w 4.2 months TC and IC SP142 > 5 NCT02879994, single center 15 open 2 single-arm Adv. EGFR+ 1st 11 61 (35–71) 4 (36) Pembro 200mg q3w 3.0 months TC 22C3 > 1 FIR, multi-centre 16 open 2 single-arm Adv. mix-line 137 66 (42–85) 79 (58) Atezo 1200mg q3w 2.9 months TC and IC SP142 > 5 Study1108, multi-centre 17 open 1/2 single-arm Adv. mix-line 165 65 (26–85) 100 (61) Durva 10mg/kg q2w 16.3 weeks TC SP263 > 25 120 64 (35–87) 60 (50) Durva 10mg/kg q2w 12.0 weeks 1 ATLANTIC, multi-centre 19 open 2 single-arm Adv. 3 or later 68 61 (55–67) 39 (57) Durva 10mg/kg q2w 24.1 weeks TC SP263 > 90 ARCTIC, multicenter 20 open 3 RCT Adv. 3 or later 62 63.5 (35–79) 42 (68) Durva 10 mg/kg q2w 21.1 weeks TC SP263 > 25 117 63 (19–83) 73 (62) Durva 10 mg/kg q2w 16.0 weeks 25 KEYNOTE-598, multi-center 22 blind 3 RCT Adv. 1st 281 65 (35–85) 191 (67) Pembro 200 mg q3w 9.7 months TC 22C3 > 50 NEOMUN, single center 23 open 2 single-arm stage II/IIIA Neo. 10 59 (40–83) 7 (70) Pembro 200 mg q3w 9.7 months TC SP263 > 1 5 61 (49–67) 4 (80) Pembro 200 mg q3w 1 Impower110, multicenter 25 open 3 RCT Adv. 1st 286 64 (30–81) 196 (71) Atezo 1200mg q3w 5.3 months TC and IC SP142 > 1 REPLAY trial, multicenter 26 open 2 single-arm Adv. 2 or later 55 63.7 (NA) 40 (73) Pembro 200 mg q3w 5.3 cycles TC NA > 1 KEYNOTE-024, multi-centre 27 open 3 RCT Adv. 1st 154 64.5 (33–90) 92 (60) Pembro 200 mg q3w 7.9 months TC 22C3 > 50 CYPRESS 1, multicenter 28 open 2 RCT Adv. 1st 48 68 (49–83) 32 (64) Pembro 200 mg q3w 24.4 weeks TC 22C3 > 50 CITYSCAPE, multicenter 29 blind 2 RCT Adv. 1st 68 68 (58–73) 48 (71) Atezo 1200 mg q3w 2.81 months TC 22C3 > 1 PEOPLE, single center 30 open 2 single-arm Adv. 1st 65 70.9 (64–77) 44 (68) Pembro 200 mg q3w NA TC 22C3 1 INTR@PID LUNG 037, multicenter 32 open 3 RCT Adv. 1st 152 68 (61–75) 116 (76) Pembro 200mg q3w 37.6 months TC 73 − 10 > 80 KEYNOTE-042, multi-centre 33 open 3 RCT Adv. 1st 636 63 (57–69) 450 (71) Pembro 200mg q3w 6.75 months TC 22C3 > 1 KEYNOTE-033, multicenter 34 open 3 RCT Adv. 2 or later 213 61 (28–83) 157 (74) Pembro 2mg/kg q3w 4.2 months TC 22C3 > 1 CTONG1901, multicenter 35 open 2 RCT Adv. 1st 14 59 (51–73) 11 (79) Pembro 200mg q3w 13 cycles TC 22C3 > 50 SAKK 19/17, multicenter 36 open 2 single-arm Adv. 1st 48 76 (37–87) 29 (60) Durva 1500mg q4w 2.8 months TC NA > 25 LEAP-007, multicenter 37 blind 3 RCT Adv. 1st 312 66 (37–87) 224 (71) Pembro 200mg q3w 5.5 months TC 22C3 > 1 Data are listed as median (range), and n (%), unless otherwise stated. Abbreviations : Adv.: advanced; Atezo: Atezolizumab; Durva: Durvalumab; EGFR: epidermal growth factor receptor; IC: immune cells; IHC: immunohistochemistry; MTD: Median treatment durations; Nivo: Nivolumab; Neo.: neoadjuvant therapy; NA, not available; PD-1: programmed cell death 1; PD-L1: programmed death ligand 1; Pembro: Pembrolizumab; q4w: every 4 weeks; q3w: every 3 weeks; q2w: every 2 weeks; RCT: randomized clinical trial; SCT: staining cell type; TC: tumour cells. Overall, the total of safety population was 5,453 patients with a performance status between 0 and 2 and with the minimum one dose of treatment. The number of patients tested for PD-L1 expression ranged from 5 to 683 per trial, and median age of all patients enrolled ranged between 59 and 76. The percentage of male patients differed among trials, varying from 36–78.6% of all safety papulation. In the assessment of PD-L1 expression, all included trials used two different staining cell types; tumour and immune cells assessed for PD-L1 expression in three trials[ 14 , 16 , 25 ], and tumour cells assessed in remaining 23 trials (88.5%). Totally, five PD-L1 IHC assays that using 5 different PD-L1 antibodies (28 − 8, SP142, 73 − 10, SP263, and 22C3) were adopted for the estimation of PD-L1 expression, and two studies (7.7%)[ 26 , 36 ] did not show the detailed PD-L1 IHC assay, and PD-L1 antibody (Table 1 ). Study quality and risk bias assessment After excluding one trial[ 26 ] with the conference abstract only, the methodological quality of non-randomized clinical trials was listed in Supplementary Table S2. The NOS results suggested that all trials included were considered as high-quality, and the average overall score was 7.3 (range 7–8). As summarized in Supplementary Table S3 , we did not detect any major flaws in the assessment of risk of bias among randomized clinical trials. Yet, the performance and detection bias were generally at high risk because most trials were open-labelled, and the absence of blinded intervention. The association between PD-L1 expression status and the frequency of all-grade TRAEs The pooled frequency of all-grade TRAEs was 66.3% (3,581 of 5,405 evaluable patients), and we further evaluated the frequency of all-grade TRAEs based on PD-1/PD-L1 inhibitors type to minimize the bias. Compared with patients with PD-L1 expression ≥ 1%, the frequency of nivolumab-induced all-grade TRAEs did not significantly differ among patients with PD-L1 expression < 1% and those with PD-L1 expression ≥ 1% (61.3% vs. 67.8%, OR 0.75, 95% CI 0.49–1.16, P = 0.20, Fig. 2 A). A similar pattern was found at 1% cut-off value in the frequency of pembrolizumab-induced all-grade TRAEs (60.0% vs. 66.6%, OR 0.75, 95% CI 0.15–4.25, P = 0.75, Fig. 3 A). When using 25% cut-off value to define positive or negative PD-L1 expression, we also did not find any significant differences among them in the durvalumab cohorts (59.1% vs. 61.1%, OR 0.92, 95% CI 0.66–1.28, P = 0.62, Fig. 4 A). Yet, PD-L1-negative patients have a significant lower frequency of pembrolizumab-induced all-grade TRAEs than PD-L1-positive patients at 50% cut-off value (59.1% vs. 71.3%, OR 0.41, 95% CI 0.24–0.70, P < 0.001, Fig. 3 A). The association between PD-L1 expression status and the frequency of grade 3–4 TRAEs The overall frequency of grade 3–4 TRAEs was 15.9% (867 of the 5,453 evaluable patients). As mentioned above, we also assessed the frequency of grade 3–4 TRAEs based on PD-1/PD-L1 inhibitors type, respectively. With setting 1% cut-off value, patients with PD-L1-negative have a significantly lower frequency of grade 3–4 TRAEs than those with PD-L1-positive tumours in the nivolumab cohorts (7.5% vs. 18.2%, OR 0.37, 95% CI 0.18–0.77, P < 0.01, Fig. 2 B). Conversely, PD-L1-negative (< 1%) patients suffered a significantly greater frequency of grade 3–4 TRAEs compared with PD-L1-positive (≥ 1%) patients in the pembrolizumab cohorts (60% vs. 16.2%, OR 7.74, 95% CI 1.57–43.4, P < 0.01, Fig. 3 B). PD-L1-negative patients noted a significantly lower frequency of durvalumab-induced grade 3–4 TRAEs than PD-L1-positive patients at 25% cut-off value (8.8% vs. 15.4%, OR 0.53, 95% CI 0.31–0.90, P = 0.02, Fig. 4 B). Among patients receiving pembrolizumab, PD-L1-negative patients (< 50%) also experienced lower frequency of grade 3–4 TRAEs (9.2% vs. 19.7%, OR 0.41, 95% CI 0.19–0.97, P = 0.04, Fig. 3 B). The relationship between PD-L1 expression status and the frequency of AEs leading to discontinuation Collectively, AEs leading to discontinuation was reported in 357 of the 5,054 evaluable patients, resulted in an overall incidence of 7.1%. Similarly, we investigated it according to different PD-1/PD-L1 inhibitors, respectively. The frequency of AEs leading to discontinuation was lower among patients with PD-L1-negative (< 1%) than those with PD-L1-positive (≥ 1%) in the nivolumab cohorts (2.8% vs. 10.6%, OR 0.25, 95% CI 0.08–0.76, P = 0.01, Fig. 2 C). For pembrolizumab cohorts at 1% cut-off value, we failed to study the correlation between the frequency of AEs leading to discontinuation and PD-L1 expression status because of the unavailable data in PD-L1-negative (< 1%) patients. Similar to the nivolumab cohorts, we observed the similar results in the durvalumab cohorts for patients who were PD-L1-negative (< 25%) versus PD-L1-positive (≥ 25%) (2.5% vs. 6.4%, OR 0.38, 95% CI 0.16–0.89, P = 0.03, Fig. 4 C). Although patients with PD-L1-negative (< 50%) have a lower trend of the frequency of AEs leading to discontinuation than those with PD-L1-positive (≥ 50%), the difference was not significant (3.1% vs. 10.1%, OR 0.28, 95% CI 0.07–1.12, P = 0.07, Fig. 3 C), and the relatively small number of PD-L1-negative patients (n = 65) may influenced the non-significance. The association between PD-L1 expression status and the frequency of treatment-related SAEs The frequency of treatment-related SAEs was 10.9% (332 of the 3,034 evaluable patients). In order to reduce the bias, we continue estimated it according to PD-1/PD-L1 inhibitors type. No difference was detected among PD-L1-negative patients (< 1%) vs. PD-L1-positive patients (≥ 1%) in the nivolumab cohorts (6.6% vs. 10.2%, OR 0.63, 95% CI 0.27–1.40, P = 0.26, Fig. 2 D). For cut-off value of 1%, the correlation between the frequency of pembrolizumab-related SAEs and PD-L1 expression status cannot be assessed due to the unavailable safety data in PD-L1-negative patients. Any statistical significances were not yet reached in the durvalumab cohorts using PD-L1 expression at cut-off value of 25% (4.2% vs. 8.0%, OR 0.51, 95% CI 0.25–1.05, P = 0.06, Fig. 4 D). With a 50% cut-off value, the frequency of pembrolizumab-related SAEs was lower among PD-L1-negative patients versus PD-L1-positive patients (3.1% vs. 16.7%, OR 0.16, 95% CI 0.04–0.60, P < 0.01, Fig. 3 D). The relationship between PD-L1 expression status and the frequency of treatment-related FAE s The frequency of treatment-related FAEs was 0.81% (44 of the 5453 evaluable patients). The major reason of such treatment-related FAEs was respiratory distress/failure including interstitial lung disease, and pneumonitis/pneumonia (50%, 22 of 44 patients). Thirty-four of 2677 patients (1.27%) experienced FAEs (due to respiratory distress/interstitial lung disease or pneumonitis/pneumonia in 17 patients, cardiac failure including myocardial infarction, and myocarditis/myositis in 4 patients, sudden death of unknown cause in 3 patients, haemoptysis, malignant neoplasm progression, sepsis, cerebrovascular accident, encephalopathy, ileus, hypovolaemic shock, pulmonary embolism, death, and klebsiella infection in one patient each) in the pembrolizumab cohorts, 4 of 885 patients (0.45%) experienced FAEs (due to pneumonitis in 2 patients, multiorgan failure, and critical neutropenia and sepsis in one patient each) in the nivolumab cohorts, 4 of 741 patients (0.54%) experienced FAEs (due to pneumonitis in 2 patients, colitis and colonic perforation in one patient each) in the durvalumab group, and 2 of 1150 patients (0.17%) experienced FAEs in the atezolizumab cohorts (pneumonia, and constrictive pericarditis in one patient each). As depicted in Fig. 2 E, PD-L1-negative and PD-L1-positive patients have a similar frequency of nivolumab-related FAEs at 1% cut-off value (0.0% vs. 3.9%, OR 0.96, 95% CI 0.05–20.1, P = 1.0). For patients treated with pembrolizumab, a consistent outcome was detected in PD-L1-negative (< 1%) patients vs. PD-L1-positive (≥ 1%) patients (0.0% vs. 1.5%, OR 5.95, 95% CI 0.32–110.0, P = 1.0, Fig. 3 E). Same result was noted among PD-L1-negative (< 25%) patients vs. PD-L1-positive (≥ 25%) patients in the durvalumab cohorts (0.42% vs. 0.69%, OR 0.61, 95% CI 0.05–4.12, P = 1.0, Fig. 4 E). For patients in the pembrolizumab cohorts, statistically difference was still not detected in PD-L1-negative (< 50%) and PD-L1-positive patients (≥ 50%) (0.0% vs. 0.78%, OR 0.88, 95% CI 0.05–16.18, P = 1.0, Fig. 3 E). The relationship between the dose-dependent results of PD-L1-positive and toxicities profile We further assessed the PD-L1-positive-related dose-dependent results by performing an assessment of included trials describing toxicities profile at cut-off value of 1%, 5%, 25%, 50%, and 90%. A consistent dose-dependent pattern between PD-L1-positive and toxicities profile was not noted among different PD-1/PD-L1 inhibitors type, (Fig. 2 – 5 ). As illustrated in Fig. 4 , significant difference was not reported among PD-L1 > 25% patients and PD-L1 > 90% patients for all included toxicities profile in the durvalumab cohorts. For the nivolumab cohorts, we did not detect any significantly differences among PD-L1 > 1% patients and PD-L1 > 5% patients for all included toxicities profile, except for treatment-related SAEs (Fig. 2 ). Though PD-L1 > 1% patients suffered a greater incidence of AEs leading to discontinuation compared with PD-L1 > 5% patients, it makes no difference between PD-L1 > 1% and PD-L1 > 5% patients for the other toxicities profile (all-grade, grade 3–4, and FAEs) in the atezolizumab cohorts (Fig. 5 ). Meanwhile, the significantly differences in the frequency of all-grade, grade 3–4, and SAEs among PD-L1 > 1% patients and PD-L1 > 50% patients were seen in the pembrolizumab cohorts; Yet, no difference was found in the pooled frequency of AEs leading to discontinuation, and FAEs (Fig. 3 ). Subgroup analyses We further conducted a subgroup analysis to evaluate the association of line therapy (first-line vs. 2 or later line), study design (open-label vs. double-blind), clinical phase (phase 3 vs. phase 1/2), and IHC assay type (22C3 vs. other) with the frequency of toxicities profile, which was done by including PD-L1 > 1% patients treated with pembrolizumab because of its relatively large number sample size available. As listed in Table 2 , we did not observe any significantly differences in most subgroup analysis. Notably, we detected patients using 22C3 IHC assay have a higher frequency of all-grade TRAEs. Compared with patients receiving 2 or later line therapy, patients receiving first-line therapy experienced a higher frequency of grade 3–4 TRAEs. Moreover, the frequency of grade 3–4 TRAEs was significant lower in open-label trials than double-blind trials. Table 2 Subgroup analyses of the frequency of pembrolizumab-related TRAEs All-grade TRAEs Frequency (%) OR and 95%CI P-value line of therapy (first-line vs. 2 or later line) 65.2% (632/969) vs. 67.9% (672/989) 0.88 (0.73–1.07) 0.21 study design (open-label vs. double-blind) 65.9% (1085/1646) vs. 70.2% (219/312) 0.82 (0.63–1.07) 0.15 clinical phase (phase 3 vs. phase 1/2) 67.0% (1236/1844) vs. 59.7% (68/114) 1.38 (0.94–2.03) 0.12 IHC assay type (22C3 vs. other) 67.3% (1274/1893) vs. 46.2% (30/65) 2.39 (1.46–3.92) < 0.001 Grade 3–4 TRAEs Frequency (%) OR and 95%CI P-value line of therapy (first-line vs. 2 or later line) 18.6% (180/969) vs. 13.9% (138/989) 1.41 (1.11–1.79) 0.006 study design (open-label vs. double-blind) 15.1% (248/1646) vs.22.4 (70/312) 0.61 (0.46–0.82) 0.002 clinical phase (phase 3 vs. phase 1/2) 16.4% (302/1844) vs. 14.0% (16/114) 1.20 (0.69–2.12) 0.6 IHC assay type (22C3 vs. other) 16.5% (313/1893) vs. 7.7% (5/65) 2.34 (1.01–5.55) 0.06 AEs leading to discontinuation Frequency (%) OR and 95%CI P-value line of therapy (first-line vs. 2 or later line) 8.8% (84/959) vs. 7.1% (66/934) 1.26 (0.90–1.76) 0.17 study design (open-label vs. double-blind) 7.9% (125/1581) vs. 8.0% (25/312) 0.99 (0.64–1.55) 0.91 clinical phase (phase 3 vs. phase 1/2) 7.8% (144/1844) vs. 12.2% (6/49) 0.61 (0.27–1.35) 0.28 IHC assay type (22C3 vs. other) 7.9% (150/1893) vs. NA (NA/65) NA NA Treatment-related SAEs Frequency (%) OR and 95%CI P-value line of therapy (first-line vs. 2 or later line) NA vs.11.3% (77/683) NA NA study design (open-label vs. double-blind) 11.3% (77/683) vs. NA/312 NA NA clinical phase (phase 3 vs. phase 1/2) 11.3% (77/683) vs. NA/114 NA NA IHC assay type (22C3 vs. other) 11.3% (77/683) vs. NA/65 NA NA Treatment-related FAEs Frequency (%) OR and 95%CI P-value line of therapy (first-line vs. 2 or later line) 1.9% (19/969) vs. 1.0 (10/989) 1.96 (0.94–4.03) 0.09 study design (open-label vs. double-blind) 1.4% (23/1646) vs. 1.9% (6/312) 0.72 (0.30–1.69) 0.45 clinical phase (phase 3 vs. phase 1/2) 1.5% (28/1844) vs. 0.9% (1/114) 1.74 (0.30–18.1) 1 IHC assay type (22C3 vs. other) 1.5% (29/1893) vs. 0% (0/65) 2.07 (0.13–34.29) 0.62 Abbreviations : CI: confidence interval; FAEs: fatal adverse events; OR: odds ratio; PD-1: programmed cell death 1; PD-L1: programmed cell death ligand 1; IHC: immunohistochemistry; SAEs: serious adverse events; TRAEs: treatment-related adverse events. Discussion Compared with historical data of convention chemotherapy, TRAEs were well-tolerated in early trials of PD-1/PD-L1 inhibitors[ 38 , 39 ]. As suggested in present study, the overall frequency of its all-grade TRAEs, grade 3–4 TRAEs, AEs leading to discontinuation in patients with NSCLC was 66.3%, 15.9%, and 7.1%, respectively. Moreover, the pooled incidence of treatment-related SAEs and FAEs was 10.9%, and 0.81%, respectively. The pooled toxicities analyses suggested that although the overall frequency of all-grade TRAEs is relatively high, the overall safety profile of PD-1/PD-L1 inhibitors was tolerable in NSCLC patients. With the increasingly adoption of PD-1/PD-L1 inhibitors in clinical, distinguishing the risk factors of toxicities profiles are need to optimize the clinical administration of these drugs in patients with NSCLC. Considering the impaired the quality of life, and high social and economic burdens related to TRAEs, we recommend that clinicians should make a discussion with patients before PD-1/PD-L1 inhibitors administration to apprise them of the correlation between PD-L1 expression status and the frequency of TRAEs, rather than making a therapeutic decision just on the basis of a clinical practice guideline. Previous studies[ 40 – 42 ] assessing PD-1/PD-L1 inhibitors have reported several biomarkers that can predict the frequency of organ-specific TRAEs in NSCLC. Maekura et al. (n = 64) conducted a study and found pre-treatment thyroid peroxidase antibody, and thyroglobulin antibody may indicate the development of nivolumab-related hypothyroidism[ 40 ]. Similarly, a study performed by Sarocchi et al. (n = 59) suggested that serum troponin levels are correlated with nivolumab-related cardiotoxicity[ 42 ]. However, low statistical power could result in false-positive results because of the relatively limited number of included patients. Although previous studies[ 4 – 6 ] have widely assessed the influence of PD-L1 expression in PD-1/PD-L1 inhibitors-based efficacy, the correlation of PD-L1 expression status and PD-1/PD-L1 inhibitors-related toxicities profile in patients with NSCLC was unclear. Present study clearly showed that these agents have its special correlation between PD-L1 expression status and toxicities profile in treating NSCLC patients. Because of the increasing use of PD-L1 expression to guide the PD-1/PD-L1 inhibitors-based therapeutic regimens, it is especially essential that clinicians and patients are well-informed and conscious of the relationship between treatment-related toxicities profile and PD-L1 expression status in NSCLC patients. It is well understood that PD-1 is a broadly distribution intracellular membrane surface receptor on immune cells (e.g. T-cells), which are able to recognize and bind to the intrinsic counterparts PD-L1 and PD-L2, thereby enabling the acquisition of immune tolerance, and preventing the development of autoimmunity[ 2 ]. Given its pharmacological mechanisms, it was thus plausible that the toxicities profile of these drugs could differ depending on PD-L1 expression status. Previously, autoimmunity pre-clinical models have assessed the frequency of adverse events linked to PD-1/PD-L1 inhibitors[ 43 – 45 ], and implied that these agents would accelerate the development of tissue-specific autoimmunity rather than systemic autoimmunity. For instance, more serious colitis was seen in mice treated with PD-1 inhibitors and dextran sulfate sodium compared with those treated dextran sulfate sodium alone[ 45 ]. Interestingly, a pre-clinical model[ 46 ] (the inversion-induced joined neoantigen mouse that a defined group of auto-antigens can be induced in selected organs) could be useful to evaluate the several PD-1/PD-L1 inhibitors-related TRAEs. Notably, the association between autoimmune susceptibility and TRAEs (especially the relatively rare antibody-mediated TRAEs) associated with PD-1/PD-L1 inhibitors in human patients was yet unknown, and it is an uncertainty about the widespread use of preclinical models[ 47 ]. Furthermore, it is particularly difficult to evaluate adverse events induced by PD-1/PD-L1 inhibitors in preclinical models based on different PD-L1 expression. In addition, it is challenging to investigate TRAEs induced by PD-1/PD-L1 inhibitors in human patient tissues due to the rarity of certain adverse events, the inaccessibility of the tissues, and the variability in their presentation. Overall, this background provided further evidence of the practical usefulness of our study. Current study can be useful to incorporate with pre-clinical models to improve the knowledge of these PD-L1 expression-associated unique toxicities profile. The frequency of all-grade TRAEs in PD-L1-negative patients was comparable to PD-L1-positive patients at both 1%, and 25% cut-off value. However, the results were not yet noted at 50% cut-off value, which may be subject to the small sample size analysed of PD-L1-negative (< 50%) patients (n = 65). Also, the frequency of treatment-related SAEs in PD-L1-negative patients was comparable with PD-L1-positive patients at both 1%, and 25% cut-off value. Nonetheless, statistically difference was found at 50% cut-off value, and the limited sample size of PD-L1-negative (< 50%) patients (n = 65) may also contribute to this situation. The frequency of overall treatment-related FAEs was low (0.81%, 44/5,453), and the main cause of such death was respiratory distress/failure including interstitial lung disease, and pneumonitis/pneumonia (50%). We did not obtain any significant differences in the frequency of treatment-related FAEs among PD-L1-negative and PD-L1-positive patients at 1%, 25%, and 50% cut-off value. Subsequent analyses did not explore a dose-dependent pattern between the frequency and PD-L1 positivity in the safety outcome of all-grade TRAEs, SAEs, and FAEs. Thus, PD-L1-negative patients may show similar frequency of all-grade TRAEs, SAEs, and FAEs in comparison with PD-L1-positive patients. Further large, prospective clinical trials are need to confirm it. In the term of AEs leading to discontinuation, we also detected a lower frequency among PD-L1-negative patients versus PD-L1-positive patients at cut-off value of 1%, and 25%. Moreover, there is a dose-dependent effect of PD-L1-positive between PD-L1 > 1% and PD-L1 > 5% patients in the atezolizumab cohorts. Though PD-L1-negative patients have a less frequency of AEs leading to discontinuation than PD-L1-positive patients at 50% cut-off value, the result was not numerically significant ( P = 0.07), which may also have been biased with the small sample size (n = 65) of PD-L1-negative patients. PD-L1-negative patients experienced a lower frequency of grade 3–4 TRAEs at 1%, 25%, and 50% cut-off value, compared to PD-L1-positive patients. The analyses of the dose-dependent results of toxicities profile and PD-L1-positive further suggested a similar trend between PD-L1 > 1% and PD-L1 > 50% patients in the pembrolizumab cohorts. Notably, the observed frequency of grade 3–4 TRAEs was higher in PD-L1-negative (< 1%) patients in the pembrolizumab cohorts in comparison with PD-L1-positive (≥ 1%) patients (60% vs. 16.2%, OR 7.74, 95% CI 1.57–43.4, P < 0.01, P < 0.01); the small number size (n = 5) of PD-L1-negative patients, and the wide variation in ORs may bias the results. Therefore, PD-L1-positive patients may have a higher frequency of AEs leading to discontinuation, and grade 3–4 TRAEs compared with PD-L1-negative patients. Current study implied that safety evaluation should consider PD-L1 expression status before the adoption of PD-1/PD-L1 inhibitors in future. Moreover, we should take more attention to the clinical signs, diagnostics, and management of these safety profile after initiating PD-1/PD-L1 inhibitors treatment in NSCLC patients, particularly in PD-L1-positive patients. Although non-significant differences were detected in most subgroup analysis, a higher frequency of all-grade TRAEs was found in patients using 22C3 IHC assay for PD-L1 expression assessment, which was caused by the differences in inherent sensitivity across different IHC assays. Moreover, a lower frequency of grade 3–4 TRAEs among patients enrolled in open-label trials than those in double-blind trials may be because the reporting bias in open-label trials. In addition, patients receiving first-line therapy have a higher frequency of grade 3–4 TRAEs. It is possible that these patients have a longer median treatment duration, and previous therapy (i.e. chemotherapy) may results in immune suppression[ 48 ]. For PD-1/PD-L1 inhibitors in the treatment of NSCLC patients with certain genetic mutation, there was no study to compare the difference of safety profile among PD-L1-negative and PD-L1-positive patients. Lisberg et al.[ 15 ] performed a clinical trial (NCT02879994, phase II) in 11 NSCLC patients with EGFR mutation-positive, and found the frequency of pembrolizumab-induced any-grade TRAEs, grade 3–4 TRAEs, and treatment-related mortality was 65%, 9.1%, and 0%, respectively; the frequency of any-grade TRAEs and treatment-related mortality in those EGFR mutation-positive patients were similar to the overall frequency in our study, while the frequency of grade 3–4 TRAEs seem be low compare to our study (9.1% vs 15.9%). However, the association between the frequency of treatment-related toxicities profile and PD-L1 expression status during PD-1/PD-L1 inhibitors in the treatment of NSCLC patients with EGFR mutation-positive remain unclear, and further study are needed. The present study, including 26 prospective trials and 5,453 patients, is the first and largest to study the relationship of PD-L1 expression status and treatment-related toxicities profile in patients with NSCLC during receiving PD-1/PD-L1 inhibitors. Also, current study may have some weaknesses. Firstly, we investigated the summary frequency of TRAEs rely on trial-level data, rather than individual patient-level data, and thus the results may limit the generalizability. Secondly, patients in real-world clinical practice may experience a higher frequency of TRAEs, as the included clinical trials only enrolled patients with better performance status. Thirdly, caution should be exercised in elucidating the results because subgroups analyses included small number of patients. With additional evidence available, it needs to be explored further in more trials to support our results. Conclusions In conclusion, our study indicated that the relationship of treatment-related toxicities profile and PD-L1 expression status maybe different across different PD-1/PD-L1 inhibitors type. Clinicians should make a discussion with patients prior to the administration of PD-1/PD-L1 inhibitors to inform them the correlation between PD-L1 expression status and the frequency of TRAEs, especially AEs leading to discontinuation and grade 3–4 TRAEs, rather than making a therapeutic decision according to the clinical practice guideline alone. Abbreviations CI confidence interval EGFR epidermal growth factor receptor FAEs fatal adverse events NSCLC non-small cell lung cancer OR odds ratio PD-1 programmed cell death 1 PD-L1 programmed cell death ligand 1 IHC immunohistochemistry SAEs serious adverse events TRAEs treatment-related adverse events. Declarations Acknowledgements We are grateful to the reviewers and editors whose comments and suggestions dramatically enhanced this manuscript. Authors’ contributions Conceptualization: X-R. H.; Investigation: Q. Z., H. H., L-Y. OY., R. Y., W-X. W., and P. H.; Formal Analysis and Visualization: Q. Z., H. H., L-Y. OY. and X-R H; Methodology: H. H., and Q. Z.; Writing Original Draft: Q. Z., H. H., L-Y. OY., R. Y., W-X. W., P. H. and X-R H; All authors read and approved the final manuscript. Conflict of interest None declared. Funding This work was supported by National Natural Science Foundation of China (No.82002872) and the Science and Technology Planning Project of General Hospital of Southern Theater Command (No. 2022NZC002). Inclusion and Ethics Statement All data used in this study was previously published References Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians. 2021;71: 209–249. Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, Shabafrouz K, Ribi C, Cairoli A, Guex-Crosier Y, Kuntzer T, Michielin O, Peters S, Coukos G, Spertini F, Thompson JA, Obeid M. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019;16:563–80. Yang F, Shay C, Abousaud M, Tang C, Li Y, Qin Z, Saba NF, Teng Y. Patterns of toxicity burden for FDA-approved immune checkpoint inhibitors in the United States. J Exp Clin Cancer Res. 2023;42:4. Liu X, Guo CY, Tou FF, Wen XM, Kuang YK, Zhu Q, Hu H. Association of PD-L1 expression status with the efficacy of PD-1/PD-L1 inhibitors and overall survival in solid tumours: A systematic review and meta-analysis. Int J Cancer. 2020;147:116–27. Shen X, Zhao B. Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis. BMJ. 2018;362:k3529. Kuang X, Xu R, Li J. Association of PD-L1 expression with survival benefit from PD-1/PD-L1 inhibitors in advanced cancer: Systematic review and meta-analysis of phase III randomized clinical trials. Crit Rev Oncol Hematol. 2024;198:104357. Hu H, Zhu Q, Tang H, Zhang SC, Huang YZ, Wang YF, Xu ZY, Yang XW, Zheng JH, Guo CY. The risk of treatment-related toxicities with PD-1/PD-L1 inhibitors in patients with lung cancer. Int J Cancer 2024. Simons EA, Smith DE, Gao D, Camidge DR. Variation in Toxicity Reporting Methods for Early Phase Lung Cancer Treatment Trials at Oncology Conferences. J Thorac Oncol. 2020;15: 1425–1433. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Int J Surg. 2010;8:336–41. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25:603–5. Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savović J, Schulz KF, Weeks L, Sterne JAC. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr., Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373:1627–39. Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, Felip E, van den Heuvel MM, Ciuleanu TE, Badin F, Ready N, Hiltermann TJN, Nair S, Juergens R, Peters S, Minenza E, Wrangle JM, Rodriguez-Abreu D, Borghaei H, Blumenschein GR Jr., Villaruz LC, Havel L, Krejci J, Corral Jaime J, Chang H, Geese WJ, Bhagavatheeswaran P, Chen AC, Socinski MA. First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. N Engl J Med. 2017;376:2415–26. Peters S, Gettinger S, Johnson ML, Jänne PA, Garassino MC, Christoph D, Toh CK, Rizvi NA, Chaft JE, Carcereny Costa E, Patel JD, Chow LQM, Koczywas M, Ho C, Früh M, van den Heuvel M, Rothenstein J, Reck M, Paz-Ares L, Shepherd FA, Kurata T, Li Z, Qiu J, Kowanetz M, Mocci S, Shankar G, Sandler A, Felip E. Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients With Programmed Death-Ligand 1-Selected Advanced Non-Small-Cell Lung Cancer (BIRCH). J Clin Oncol. 2017;35:2781–9. Lisberg A, Cummings A, Goldman JW, Bornazyan K, Reese N, Wang T, Coluzzi P, Ledezma B, Mendenhall M, Hunt J, Wolf B, Jones B, Madrigal J, Horton J, Spiegel M, Carroll J, Gukasyan J, Williams T, Sauer L, Wells C, Hardy A, Linares P, Lim C, Ma L, Adame C, Garon EB. A Phase II Study of Pembrolizumab in EGFR-Mutant, PD-L1+, Tyrosine Kinase Inhibitor Naïve Patients With Advanced NSCLC. J Thorac Oncol. 2018;13:1138–45. Spigel DR, Chaft JE, Gettinger S, Chao BH, Dirix L, Schmid P, Chow LQM, Hicks RJ, Leon L, Fredrickson J, Kowanetz M, Sandler A, Funke R, Rizvi NA. FIR: Efficacy, Safety, and Biomarker Analysis of a Phase II Open-Label Study of Atezolizumab in PD-L1-Selected Patients With NSCLC. J Thorac Oncol. 2018;13:1733–42. Antonia SJ, Balmanoukian A, Brahmer J, Ou SI, Hellmann MD, Kim SW, Ahn MJ, Kim DW, Gutierrez M, Liu SV, Schöffski P, Jäger D, Jamal R, Jerusalem G, Lutzky J, Nemunaitis J, Calabrò L, Weiss J, Gadgeel S, Bhosle J, Ascierto PA, Rebelatto MC, Narwal R, Liang M, Xiao F, Antal J, Abdullah S, Angra N, Gupta AK, Khleif SN, Segal NH. Clinical Activity, Tolerability, and Long-Term Follow-Up of Durvalumab in Patients With Advanced NSCLC. J Thorac Oncol. 2019;14:1794–806. Nishio M, Takahashi T, Yoshioka H, Nakagawa K, Fukuhara T, Yamada K, Ichiki M, Tanaka H, Seto T, Sakai H, Kasahara K, Satouchi M, Han SR, Noguchi K, Shimamoto T, Kato T. KEYNOTE-025: Phase 1b study of pembrolizumab in Japanese patients with previously treated programmed death ligand 1-positive advanced non-small-cell lung cancer. Cancer Sci. 2019;110:1012–20. Garassino MC, Cho BC, Kim JH, Mazières J, Vansteenkiste J, Lena H, Jaime JC, Gray JE, Powderly J, Chouaid C, Bidoli P, Wheatley-Price P, Park K, Soo RA, Poole L, Wadsworth C, Dennis PA, Rizvi NA. Final overall survival and safety update for durvalumab in third- or later-line advanced NSCLC: The phase II ATLANTIC study. Lung Cancer. 2020;147:137–42. Planchard D, Reinmuth N, Orlov S, Fischer JR, Sugawara S, Mandziuk S, Marquez-Medina D, Novello S, Takeda Y, Soo R, Park K, McCleod M, Geater SL, Powell M, May R, Scheuring U, Stockman P, Kowalski D. ARCTIC: durvalumab with or without tremelimumab as third-line or later treatment of metastatic non-small-cell lung cancer. Ann Oncol. 2020;31:609–18. Rizvi NA, Cho BC, Reinmuth N, Lee KH, Luft A, Ahn MJ, van den Heuvel MM, Cobo M, Vicente D, Smolin A, Moiseyenko V, Antonia SJ, Le Moulec S, Robinet G, Natale R, Schneider J, Shepherd FA, Geater SL, Garon EB, Kim ES, Goldberg SB, Nakagawa K, Raja R, Higgs BW, Boothman AM, Zhao L, Scheuring U, Stockman PK, Chand VK, Peters S. Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020;6:661–74. Boyer M, Şendur MAN, Rodríguez-Abreu D, Park K, Lee DH, Çiçin I, Yumuk PF, Orlandi FJ, Leal TA, Molinier O, Soparattanapaisarn N, Langleben A, Califano R, Medgyasszay B, Hsia TC, Otterson GA, Xu L, Piperdi B, Samkari A, Reck M. Pembrolizumab Plus Ipilimumab or Placebo for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50%: Randomized, Double-Blind Phase III KEYNOTE-598 Study. J Clin Oncol. 2021;39:2327–38. Eichhorn F, Klotz LV, Kriegsmann M, Bischoff H, Schneider MA, Muley T, Kriegsmann K, Haberkorn U, Heussel CP, Savai R, Zoernig I, Jaeger D, Thomas M, Hoffmann H, Winter H, Eichhorn ME. Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Lung Cancer. 2021;153:150–7. Herbst RS, Garon EB, Kim DW, Cho BC, Gervais R, Perez-Gracia JL, Han JY, Majem M, Forster MD, Monnet I, Novello S, Gubens MA, Boyer M, Su WC, Samkari A, Jensen EH, Kobie J, Piperdi B, Baas P. Five Year Survival Update From KEYNOTE-010: Pembrolizumab Versus Docetaxel for Previously Treated, Programmed Death-Ligand 1-Positive Advanced NSCLC. J Thorac Oncol. 2021;16:1718–32. Jassem J, de Marinis F, Giaccone G, Vergnenegre A, Barrios CH, Morise M, Felip E, Oprean C, Kim YC, Andric Z, et al. Updated Overall Survival Analysis From IMpower110: atezolizumab Versus Platinum-Based Chemotherapy in Treatment-Naive Programmed Death-Ligand 1-Selected NSCLC. J Thorac Oncol. 2021;16:1872–82. Ponce Aix S, Carcereny Costa E, Bosch-Barrera J, Felip Font E, Guirado M, Coves Sarto J, Majem Tarruella M, Juan Vidal OJ, Dalmau Portulas E, Diz P, Ortega Granados ALO, Domine Gomez M, Blasco Cordellat A, Mosquera Martinez J, Sala Gonzalez MA, Dorta M, de Calvo V, Zugazagoitia J, Enguita AB, Paz-Ares L. Pembrolizumab re-challenge in patients with relapsed non-small cell lung cancer (NSCLC): A preliminary report of the REPLAY phase II trial - cohort I. Ann Oncol. 2021;32:S1450. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leal TA, Riess JW, Jensen E, Zhao B, Pietanza MC, Brahmer JR. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50. J Clin Oncol. 2021;39:2339–49. Spigel D, Jotte R, Nemunaitis J, Shum M, Schneider J, Goldschmidt J, Eisenstein J, Berz D, Seneviratne L, Socoteanu M, Bhanderi V, Konduri K, Xia M, Wang H, Hozak RR, Gueorguieva I, Ferry D, Gandhi L, Chao BH, Rybkin I. Randomized Phase 2 Studies of Checkpoint Inhibitors Alone or in Combination With Pegilodecakin in Patients With Metastatic NSCLC (CYPRESS 1 and CYPRESS 2). J Thorac Oncol. 2021;16:327–33. Cho BC, Abreu DR, Hussein M, Cobo M, Patel AJ, Secen N, Lee KH, Massuti B, Hiret S, Yang JCH, Barlesi F, Lee DH, Ares LP, Hsieh RW, Patil NS, Twomey P, Yang X, Meng R, Johnson ML. Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and follow-up analyses of a randomised, double-blind, phase 2 study. Lancet Oncol. 2022;23:781–92. Lo Russo G, Sgambelluri F, Prelaj A, Galli F, Manglaviti S, Bottiglieri A, Di Mauro RM, Ferrara R, Galli G, Signorelli D, De Toma A, Occhipinti M, Brambilla M, Rulli E, Triulzi T, Torelli T, Agnelli L, Brich S, Martinetti A, Dumitrascu AD, Torri V, Pruneri G, Fabbri A, de Braud F, Anichini A, Proto C, Ganzinelli M, Mortarini R, Garassino MC. PEOPLE (NCT03447678), a first-line phase II pembrolizumab trial, in negative and low PD-L1 advanced NSCLC: clinical outcomes and association with circulating immune biomarkers. ESMO Open. 2022;7:100645. Brahmer JR, Lee JS, Ciuleanu TE, Bernabe Caro R, Nishio M, Urban L, Audigier-Valette C, Lupinacci L, Sangha R, Pluzanski A, Burgers J, Mahave M, Ahmed S, Schoenfeld AJ, Paz-Ares LG, Reck M, Borghaei H, O'Byrne KJ, Gupta RG, Bushong J, Li L, Blum SI, Eccles LJ, Ramalingam SS. Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small-Cell Lung Cancer in CheckMate 227. J Clin Oncol. 2023;41:1200–12. Cho BC, Lee JS, Wu YL, Cicin I, Dols MC, Ahn MJ, Cuppens K, Veillon R, Nadal E, Dias JM, Martin C, Reck M, Garon EB, Felip E, Paz-Ares L, Mornex F, Vokes EE, Adjei AA, Robinson C, Sato M, Vugmeyster Y, Machl A, Audhuy F, Chaudhary S, Barlesi F. Bintrafusp Alfa Versus Pembrolizumab in Patients With Treatment-Naive, Programmed Death-Ligand 1-High Advanced NSCLC: A Randomized, Open-Label, Phase 3 Trial. J Thorac Oncol. 2023;18:1731–42. de Castro G Jr., Kudaba I, Wu YL, Lopes G, Kowalski DM, Turna HZ, Caglevic C, Zhang L, Karaszewska B, Laktionov KK, Srimuninnimit V, Bondarenko I, Kubota K, Mukherjee R, Lin J, Souza F, Mok TSK, Cho BC. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy as First-Line Therapy in Patients With Non-Small-Cell Lung Cancer and Programmed Death Ligand-1 Tumor Proportion Score ≥ 1% in the KEYNOTE-042 Study. J Clin Oncol. 2023;41:1986–91. Ren S, Feng J, Ma S, Chen H, Ma Z, Huang C, Zhang L, He J, Wang C, Zhou J, Danchaivijtr P, Wang CC, Vynnychenko I, Wang K, Orlandi F, Sriuranpong V, Li B, Ge J, Dang T, Zhou C. KEYNOTE-033: Randomized phase 3 study of pembrolizumab vs docetaxel in previously treated, PD-L1-positive, advanced NSCLC. Int J Cancer. 2023;153:623–34. Maggie Liu S-Y, Huang J, Deng J-Y, Xu C-R, Yan H-H, Yang M-Y, Li Y-S, Ke EE, Zheng M-Y, Wang Z, Lin J-X, Gan B, Zhang X-C, Chen H-J, Wang B-C, Tu H-Y, Yang J-J, Zhong W-Z, Li Y, Zhou Q, Wu Y-L. PD-L1 expression guidance on sintilimab versus pembrolizumab with or without platinum-doublet chemotherapy in untreated patients with advanced non-small cell lung cancer (CTONG1901): A phase 2, randomized, controlled trial. Sci Bull. 2024;69:535–43. Mark M, Froesch P, Gysel K, Rothschild SI, Addeo A, Ackermann CJ, Chiquet S, Schneider M, Ribi K, Maranta AF, Bastian S, von Moos R, Joerger M, Früh M. First-line durvalumab in patients with PD-L1 positive, advanced non-small cell lung cancer (NSCLC) with a performance status of 2 (PS2). Primary analysis of the multicenter, single-arm phase II trial SAKK 19/17. Eur J Cancer. 2024;200:113600. Yang JC, Han B, De La Mora Jiménez E, Lee JS, Koralewski P, Karadurmus N, Sugawara S, Livi L, Basappa NS, Quantin X, Dudnik J, Ortiz DM, Mekhail T, Okpara CE, Dutcus C, Zimmer Z, Samkari A, Bhagwati N, Csőszi T. Pembrolizumab With or Without Lenvatinib for First-Line Metastatic NSCLC With Programmed Cell Death-Ligand 1 Tumor Proportion Score of at least 1% (LEAP-007): A Randomized, Double-Blind, Phase 3 Trial. J Thorac Oncol. 2024;19:941–53. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54. Maekura T, Naito M, Tahara M, Ikegami N, Kimura Y, Sonobe S, Kobayashi T, Tsuji T, Minomo S, Tamiya A, Atagi S. Predictive Factors of Nivolumab-induced Hypothyroidism in Patients with Non-small Cell Lung Cancer. Vivo. 2017;31:1035–9. Oyanagi J, Koh Y, Sato K, Mori K, Teraoka S, Akamatsu H, Kanai K, Hayata A, Tokudome N, Akamatsu K, Nakanishi M, Ueda H, Yamamoto N. Predictive value of serum protein levels in patients with advanced non-small cell lung cancer treated with nivolumab. Lung Cancer. 2019;132:107–13. Sarocchi M, Grossi F, Arboscello E, Bellodi A, Genova C, Dal Bello MG, Rijavec E, Barletta G, Rossi G, Biello F, Ghigliotti G, Canepa M, Mussap M, Brunelli C, Spallarossa P. Serial Troponin for Early Detection of Nivolumab Cardiotoxicity in Advanced Non-Small Cell Lung Cancer Patients. Oncologist. 2018;23:936–42. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107:4275–80. Liu J, Blake SJ, Smyth MJ, Teng MW. Improved mouse models to assess tumour immunity and irAEs after combination cancer immunotherapies. Clin Transl Immunol. 2014;3:e22. Perez-Ruiz E, Minute L, Otano I, Alvarez M, Ochoa MC, Belsue V, de Andrea C, Rodriguez-Ruiz ME, Perez-Gracia JL, Marquez-Rodas I, Llacer C, Alvarez M, de Luque V, Molina C, Teijeira A, Berraondo P, Melero I. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy. Nature. 2019;569:428–32. Damo M, Fitzgerald B, Lu Y, Nader M, William I, Cheung JF, Connolly KA, Foster GG, Akama-Garren E, Lee DY, Chang GP, Gocheva V, Schmidt LM, Boileve A, Wilson JH, Cui C, Monroy I, Gokare P, Cabeceiras P, Jacks T, Joshi NS. Inducible de novo expression of neoantigens in tumor cells and mice. Nat Biotechnol. 2021;39:64–73. Connolly KA, Fitzgerald B, Damo M, Joshi NS. Novel Mouse Models for Cancer Immunology. Annu Rev Cancer Biol. 2022;6:269–91. Monteran L, Ershaid N, Doron H, Zait Y, Scharff Ye, Ben-Yosef S, Avivi C, Barshack I, Sonnenblick A, Erez N. Chemotherapy-induced complement signaling modulates immunosuppression and metastatic relapse in breast cancer. Nat Commun. 2022;13:5797. Additional Declarations No competing interests reported. Supplementary Files suppmentalmaterials.doc Cite Share Download PDF Status: Published Journal Publication published 28 Apr, 2025 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Revision requested 08 Jan, 2025 Editor assigned by journal 06 Jan, 2025 Submission checks completed at journal 06 Jan, 2025 First submitted to journal 01 Jan, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5748321","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":398336423,"identity":"a06cfca0-01c5-4c9f-9642-4f48c77db97c","order_by":0,"name":"Qian Zhu","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Qian","middleName":"","lastName":"Zhu","suffix":""},{"id":398336424,"identity":"e5cb619d-a42c-48fd-8db7-fac7d7b21e00","order_by":1,"name":"Hao Hu","email":"","orcid":"","institution":"General Hospital of Southern Theater Command","correspondingAuthor":false,"prefix":"","firstName":"Hao","middleName":"","lastName":"Hu","suffix":""},{"id":398336425,"identity":"dfe9f606-c9f4-48df-8ce2-5e44fd7492aa","order_by":2,"name":"Li-Ying OuYang","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Li-Ying","middleName":"","lastName":"OuYang","suffix":""},{"id":398336426,"identity":"fa007551-611c-4255-af63-0311d5b2ed72","order_by":3,"name":"Rong Yang","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Rong","middleName":"","lastName":"Yang","suffix":""},{"id":398336427,"identity":"9433bcae-daf2-4a43-a65f-942601eda2ef","order_by":4,"name":"Wen-Xiao Wei","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Wen-Xiao","middleName":"","lastName":"Wei","suffix":""},{"id":398336428,"identity":"0d7cd30c-486c-454e-ba3a-b52dee802306","order_by":5,"name":"Pin Huang","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Pin","middleName":"","lastName":"Huang","suffix":""},{"id":398336429,"identity":"18f596c7-eddd-4a16-a808-dcc02525e459","order_by":6,"name":"Xin-Rong He","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvElEQVRIiWNgGAWjYBACAwYGxgcJFf/k2NjbDxCthdngw5kDxnw8ZxKI1sImObPtQOI8CQcD4rSYS+Q+kOZhu5PeJsGQwPCjYhthLZY9xw2MeXie5bZJNx5g7DlzmwiHHW9jSOaRYM5tkzmQwMzYRoyWw2wMh3kMmNPZJBIMiNRyvI2xcUbC4QQStJw5xszw4UCaYRswkA8S55cbaew/Ev/ZyMu3tx988KOCCC0o4ACJ6kfBKBgFo2AU4AIAzYA9Al8dOwQAAAAASUVORK5CYII=","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":true,"prefix":"","firstName":"Xin-Rong","middleName":"","lastName":"He","suffix":""}],"badges":[],"createdAt":"2025-01-02 02:53:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5748321/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5748321/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12885-025-14218-5","type":"published","date":"2025-04-28T15:57:14+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":73316086,"identity":"1567b46a-3800-4c82-b7a3-f0ec73f092ce","added_by":"auto","created_at":"2025-01-08 20:02:36","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":631908,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow diagram of the study.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e programmed cell death protein ligand-1, PD-L1\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5748321/v1/ef8651b90387a21b78191087.jpg"},{"id":73315119,"identity":"9666a089-72b7-477b-99b2-931510c88d50","added_by":"auto","created_at":"2025-01-08 19:54:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":782636,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe overall frequency of nivolumab-related TRAEs, including all-grade (A), grade 3-4 (B), AEs leading to discontinuation (C), SAEs (D), and FAEs (E), according to PD-L1 expression.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e AEs, adverse events; FAEs, fatal adverse events; PD-L1, programmed cell death protein ligand-1; SAEs, serious adverse events; TRAEs, treatment-related adverse events. The ns indicate non-significant differences (P\u0026gt;0.05), * indicate P\u0026lt;0.05, and ** indicate P\u0026lt;0.01.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5748321/v1/4c6b018fd420c6ec7ecf1991.png"},{"id":73315123,"identity":"088e9d3b-b04c-4c56-b708-03fddb7f8849","added_by":"auto","created_at":"2025-01-08 19:54:36","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":694790,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe overall frequency of pembrolizumab-related TRAEs, including all-grade (A), grade 3-4 (B), AEs leading to discontinuation (C), SAEs (D), and FAEs (E), according to PD-L1 expression.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e AEs, adverse events; FAEs, fatal adverse events; PD-L1, programmed cell death protein ligand-1; SAEs, serious adverse events; TRAEs, treatment-related adverse events. The ns indicate non-significant differences (P\u0026gt;0.05), * indicate P\u0026lt;0.05, ** indicate P\u0026lt;0.01, and *** indicate P\u0026lt;0.001.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-5748321/v1/864f5ff908f7452da2be176c.png"},{"id":73315128,"identity":"0bd9ccf1-fd42-44bc-b316-cae24ae6a319","added_by":"auto","created_at":"2025-01-08 19:54:36","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":816333,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe overall frequency of durvalumab-related TRAEs, including all-grade (A), grade 3-4 (B), AEs leading to discontinuation (C), SAEs (D), and FAEs (E), according to PD-L1 expression.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e AEs, adverse events; FAEs, fatal adverse events; PD-L1, programmed cell death protein ligand-1; SAEs, serious adverse events; TRAEs, treatment-related adverse events. The ns indicate non-significant differences (P\u0026gt;0.05), and * indicate P\u0026lt;0.05.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-5748321/v1/982631186219c148c0f1de26.png"},{"id":73315130,"identity":"386da7b4-e9c7-43a4-806e-b87d56337307","added_by":"auto","created_at":"2025-01-08 19:54:37","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":575728,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe overall frequency of atezolizumab-related TRAEs, including all-grade (A), grade 3-4 (B), AEs leading to discontinuation (C), and FAEs (D), according to PD-L1 expression.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e AEs, adverse events; FAEs, fatal adverse events; PD-L1, programmed cell death protein ligand-1; TRAEs, treatment-related adverse events. The ns indicate non-significant differences (P\u0026gt;0.05), and **** indicate P\u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-5748321/v1/0fd24582346a79dd110fce72.png"},{"id":81987696,"identity":"56fb7529-6f2e-47ae-805b-70cd99195aa4","added_by":"auto","created_at":"2025-05-05 16:04:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5594682,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5748321/v1/92b90c43-dad7-4d54-81fe-b93128dc8eef.pdf"},{"id":73315120,"identity":"cae74b32-499b-4614-931c-cd3c8a10f03c","added_by":"auto","created_at":"2025-01-08 19:54:36","extension":"doc","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":107508,"visible":true,"origin":"","legend":"","description":"","filename":"suppmentalmaterials.doc","url":"https://assets-eu.researchsquare.com/files/rs-5748321/v1/29c3115e1273f8e4f5e633f0.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"The association of PD-L1 expression status and PD-1/PD-L1 inhibitors-related toxicities profile in non-small cell lung cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNon-small cell lung cancer (NSCLC) poses a major public health threat worldwide because of with high incidence, and mortality[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Currently, immunotherapies targeting the programmed cell death 1 (PD-1) and its ligand (PD-L1) have changed into standard therapy in advanced NSCLC patients without actionable driver mutation (\u003cem\u003eEGFR\u003c/em\u003e or \u003cem\u003eALK\u003c/em\u003e genes). This situation has led to the widespread adoption of these approval agents in clinical practice worldwide.\u003c/p\u003e \u003cp\u003eBesides efficacy, toxicity profile is one primary concern among patients, and usually as a deciding factor for clinicians when patients who are going to start any treatment in clinical. The PD-1/PD-L1 pathway is necessary to avoid hyperactivation of the immune system, and to keep it balanced, thus PD-1/PD-L1 inhibitors may correlate to various categories of toxicities including rash, diarrhea, pneumonitis, hypothyroidism, hepatotoxicity, and others[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. These treatment-related toxicities are common, and maybe debilitating, permanent and even life-threatening[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], which could cause serious consequences for patients, their families, and society. Such condition will further increase social, and economic burdens attributable to the PD-1/PD-L1 inhibitors. Moreover, early detection, and early intervention are the crucial management strategy for treatment-related adverse events (TRAEs). Thus, there is a massive unmet healthcare requirement for choosing the appropriate biomarkers to detect toxicities profile correlated to PD-1/PD-L1 inhibitors, prevent costly social and economic burdens, and further enable the optimisation and personalisation of the use of such drugs.\u003c/p\u003e \u003cp\u003e Treatment options for PD-1/PD-L1 inhibitors-based therapy have been guided by PD-L1 expression, in accordance with the National Comprehensive Cancer Network guideline, and multiple guidelines (e.g., European Society for Medical Oncology). Indeed, previous studies[\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] have implied that PD-L1 expression status was a useful biomarker for predicting response to these agents, and that its efficacy increased with PD-L1 expression. Yet, the association of toxicity profile with PD-L1 expression among these agents remain unclear, largely owing to the absence of PD-L1 expression-based safety data. Furthermore, a recent study[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] revealed that PD-1/PD-L1 inhibitors were correlated to a greater likelihood of developing TRAEs. Nevertheless, the toxicities profile linked to PD-1/PD-L1 inhibitors was often understated during the decision-making for treatment processes[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Hence, PD-1/PD-L1 inhibitors-induced toxicity profile makes optimising and personalising the use of these drugs a major goal of global public health.\u003c/p\u003e \u003cp\u003eTo tackle these issues, we perform this research to explore the association of PD-1/PD-L1 inhibitors-related toxicities profile with PD-L1 expression status to make the optimized and personalized use of such agents for treating patients with NSCLC.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eThe current study of toxicities analyses was did in strict based on the preferred reporting items for systematic reviews and meta-analyses statement[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eTrial search strategy\u003c/h2\u003e \u003cp\u003eOn June 30, 2024, three independent researchers (Q. Z., H. H. and L-Y.OY.) carried out systematic searches of Cochrane Library, EMBASE, and PubMed databases without language restrictions and confirmed by the third investigator (X-Y. H.). \u003cb\u003eSupplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e showed details of the searched strategy. And, we also searched unpublished/ongoing trials in \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://clinicaltrials.gov/\u003c/span\u003e\u003cspan address=\"https://clinicaltrials.gov/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e and meeting abstracts (World Conference on Lung Cancer, and American Association of Cancer Research, etc.) between January 1, 2012 and June 30, 2024. Furthermore, we scanned the references of included articles.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCriteria for selection and exclusion\u003c/h3\u003e\n\u003cp\u003eTwo independent researchers (Q. Z., and H. H.) screened the studies, and the third investigator (L-Y.OY.) verified it. To reduce the bias, we further excluded studies adopting PD-1/PD-L1 inhibitors-based combination therapy because different combination therapies may contribute substantially to the toxicities profile. Based on the PICO checklist, the eligibility criteria were thus provided as follows: (1) participant: clinical trials prospectively enrolling NSCLC patients; (2) intervention: PD-1/PD-L1 inhibitors monotherapy; (3) control: none; and (4) outcome: the occurrence of TRAEs (events/incidence and sample size). Hence, non-prospective clinical trials including retrospective studies, case reports, and reviews were excluded. When same trials were identified, researchers retain the trial with longest follow-up time and/or with the most recent.\u003c/p\u003e\n\u003ch3\u003eData extraction and appraisement of risk of bias\u003c/h3\u003e\n\u003cp\u003eTwo researchers (P.H. and R.Y.) independently retrieved the standardized data and the third researcher (W-X. W.) confirmed it as following: study name, study design, study type, tumor stage, line of therapy, median age, male (%), PD-1/PD-L1 inhibitors type, sample size (number of participants evaluable for toxicity), immunohistochemistry (IHC) assay, median treatment duration, PD-L1 staining cell type, and PD-L1 expression. Treatment-related toxicity profile (all-grade, grade 3\u0026ndash;4, serious adverse events (SAEs), AEs leading to discontinuation, and fatal adverse events (FAEs)) was determined by the principal investigator of the originally trial. We then extracted the aforementioned treatment-related toxicity profile to conduct current study. When detailed information regarding TRAEs was not available, we sought to communicate with the correspondence author of the original trial for confirmation, and identified the ambiguous interpretation as \u0026ldquo;not available (NA)\u0026rdquo;. AEs meet the criteria of the National Cancer Institute Common Terminology Criteria guidelines.\u003c/p\u003e \u003cp\u003eTwo independent researchers (P.H. and R.Y.) employed the 9-point Newcastle-Ottawa Scale (NOS)[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] with eight items to assess the study quality in non-randomized clinical trials. Each trial was classified into three main groups (selection, comparability, and outcomes for cohort studies)[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. High-quality studies were identified as a score of 7 or higher. For randomized clinical trials, the above-mentioned two researchers independently appraised each trial using the 7-item Cochrane collaboration\u0026rsquo;s tool[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Any discrepancies will be settled through discussing or consulting with the third researcher (X-Y. H.).\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eGraphPad Prism software (Version 10.1.0; GraphPad Software, San Diego, CA) was utilised to perform all statistical analyses, and statistical significance was P values less than 0.05, two-tailed. Among different PD-L1 expression, Chi-square test or Fisher\u0026rsquo;s exact (if appropriate) was conducted via calculating the frequencies of toxicity profile. When one (or more) value is zero, 0.5 was added to each value before exploring the odds ratio (OR) and confidence interval (CI). In trials enrolling same anti-PD-1/PD-L1 drug, we evaluated the toxicities profile for different PD-L1 expression to study whether the toxicities were PD-L1 expression dependent. Subgroup analysis was carried out to measure the relationship of line of therapy (2 or later line vs. first-line), study design (double-blind vs. open-label), clinical phase (phase 3 vs. phase 1/2), and IHC assay type (22C3 vs. other) with the frequency of toxicities profile in those trials enrolling same PD-L1 expression, and PD-1/PD-L1 inhibitor.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSearch results and major clinical characteristics\u003c/h2\u003e \u003cp\u003eAs Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows, we screened a total of 16,442 publications via both electronic databases and manual searches. After initial screening, 133 trials were used for detailed eligibility assessment. Finally, the remaining 26 prospective studies[\u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34 CR35 CR36\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] were identified for the final toxicities analyses.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eExcept three trials[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], all trials were conducted in multi-center, and the major clinical features are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Three trials[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] were double-blind trials, and the majority of trials (23 trials, 88.5%)[\u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan additionalcitationids=\"CR24 CR25 CR26 CR27\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan additionalcitationids=\"CR31 CR32 CR33 CR34 CR35\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] were open-label. Seventeen trials (65.4%) involved PD-1 inhibitors (fourteen with pembrolizumab[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan additionalcitationids=\"CR33 CR34\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], and three with nivolumab[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]), and nine trials (34.6%) involved PD-L1 inhibitors (five with durvalumab[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], and four with atezolizumab[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]). All trials focused on non-resectable NSCLC patients (one trial[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] with \u003cem\u003eEGFR\u003c/em\u003e-positive mutations), except one trial[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] including resectable NSCLC patients (stage II/IIIA). Fifteen trials (57.7%)[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan additionalcitationids=\"CR28 CR29 CR30 CR31 CR32\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan additionalcitationids=\"CR36\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] were performed in the 1st-line setting, seven trials (26.9%)[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] in 2 or later line setting, three trials (11.5%)[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] in mix-line setting (first-line, and 2 or later line setting), and the remaining one trial[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] in neoadjuvant setting.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe major clinical features of included clinical trials\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"13\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy name\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudy design\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStudy type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTumor stage\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLine of therapy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSample Size\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAge (years), median\u003c/p\u003e \u003cp\u003e(range)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMale (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePD-1/PD-L1\u003c/p\u003e \u003cp\u003einhibitors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eMTD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003ePD-L1 SCT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003eIHC assay\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c13\"\u003e \u003cp\u003ePD-L1 (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCheckMate 057, multi-centre\u003csup\u003e12\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 or later\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e121\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e61\u003c/p\u003e \u003cp\u003e(37\u0026ndash;84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e151\u003c/p\u003e \u003cp\u003e(52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNivo\u003c/p\u003e \u003cp\u003e3mg/kg q2w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e6 doses\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e28\u0026thinsp;\u0026minus;\u0026thinsp;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNivo\u003c/p\u003e \u003cp\u003e3mg/kg q2w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCheckMate 026, multi-centre\u003csup\u003e13\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1st\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e267\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e63\u003c/p\u003e \u003cp\u003e(32\u0026ndash;89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e87\u003c/p\u003e \u003cp\u003e(32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNivo\u003c/p\u003e \u003cp\u003e3mg/kg q2w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3.7 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e28\u0026thinsp;\u0026minus;\u0026thinsp;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e 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\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4.2 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC and IC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eSP142\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNCT02879994,\u003c/p\u003e \u003cp\u003esingle center\u003csup\u003e15\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003esingle-arm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv. EGFR+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1st\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e61\u003c/p\u003e \u003cp\u003e(35\u0026ndash;71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e(36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePembro\u003c/p\u003e \u003cp\u003e200mg q3w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3.0 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e22C3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFIR,\u003c/p\u003e \u003cp\u003emulti-centre\u003csup\u003e16\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003esingle-arm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003emix-line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e137\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e66\u003c/p\u003e \u003cp\u003e(42\u0026ndash;85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e79\u003c/p\u003e \u003cp\u003e(58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAtezo\u003c/p\u003e \u003cp\u003e1200mg q3w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2.9 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC and IC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eSP142\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy1108, multi-centre\u003csup\u003e17\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 1/2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003esingle-arm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003emix-line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e165\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e65\u003c/p\u003e \u003cp\u003e(26\u0026ndash;85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e100\u003c/p\u003e \u003cp\u003e(61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDurva\u003c/p\u003e \u003cp\u003e10mg/kg q2w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e16.3 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSP263\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e64\u003c/p\u003e \u003cp\u003e(35\u0026ndash;87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e60\u003c/p\u003e \u003cp\u003e(50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDurva\u003c/p\u003e \u003cp\u003e10mg/kg q2w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e12.0 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKEYNOTE-025,\u003c/p\u003e \u003cp\u003emulticenter\u003csup\u003e18\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003esingle-arm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 or later\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e66\u003c/p\u003e \u003cp\u003e(41\u0026ndash;78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e26\u003c/p\u003e \u003cp\u003e(68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePembro 10mg/kg q3w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e22C3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eATLANTIC,\u003c/p\u003e \u003cp\u003emulti-centre\u003csup\u003e19\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003esingle-arm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 or later\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e61\u003c/p\u003e \u003cp\u003e(55\u0026ndash;67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e39\u003c/p\u003e \u003cp\u003e(57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDurva\u003c/p\u003e \u003cp\u003e10mg/kg q2w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e24.1 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eSP263\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eARCTIC,\u003c/p\u003e \u003cp\u003emulticenter\u003csup\u003e20\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 or later\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e63.5\u003c/p\u003e \u003cp\u003e(35\u0026ndash;79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e42\u003c/p\u003e \u003cp\u003e(68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDurva\u003c/p\u003e \u003cp\u003e10\u0026nbsp;mg/kg q2w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e21.1 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSP263\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e117\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e63\u003c/p\u003e \u003cp\u003e(19\u0026ndash;83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e73\u003c/p\u003e \u003cp\u003e(62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDurva\u003c/p\u003e \u003cp\u003e10\u0026nbsp;mg/kg q2w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e16.0 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMYSTIC,\u003c/p\u003e \u003cp\u003emulti-center\u003csup\u003e21\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1st\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e161\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e64\u003c/p\u003e \u003cp\u003e(32\u0026ndash;84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e113 (69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDurva\u003c/p\u003e \u003cp\u003e20\u0026nbsp;mg/kg q4w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e16.0 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eSP263\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKEYNOTE-598, multi-center\u003csup\u003e22\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eblind 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1st\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e281\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e65\u003c/p\u003e \u003cp\u003e(35\u0026ndash;85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e191\u003c/p\u003e \u003cp\u003e(67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePembro\u003c/p\u003e \u003cp\u003e200 mg q3w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e9.7 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e22C3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNEOMUN,\u003c/p\u003e \u003cp\u003esingle center\u003csup\u003e23\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003esingle-arm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003estage II/IIIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNeo.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e59\u003c/p\u003e \u003cp\u003e(40\u0026ndash;83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7\u003c/p\u003e \u003cp\u003e(70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePembro\u003c/p\u003e \u003cp\u003e200 mg q3w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e9.7 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSP263\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e61\u003c/p\u003e \u003cp\u003e(49\u0026ndash;67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e(80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePembro\u003c/p\u003e \u003cp\u003e200 mg q3w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKEYNOTE-010, multi-centre\u003csup\u003e24\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 2/3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 or later\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e683\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e63\u003c/p\u003e \u003cp\u003e(56\u0026ndash;69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e425\u003c/p\u003e \u003cp\u003e(62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePembro\u003c/p\u003e \u003cp\u003e2/10mg/kg q3w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3.5 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e22C3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImpower110,\u003c/p\u003e \u003cp\u003emulticenter\u003csup\u003e25\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1st\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e286\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e64\u003c/p\u003e \u003cp\u003e(30\u0026ndash;81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e196\u003c/p\u003e \u003cp\u003e(71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAtezo\u003c/p\u003e \u003cp\u003e1200mg q3w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5.3 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC and IC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eSP142\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eREPLAY trial,\u003c/p\u003e \u003cp\u003emulticenter\u003csup\u003e26\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003esingle-arm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 or later\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e63.7\u003c/p\u003e \u003cp\u003e(NA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e40\u003c/p\u003e \u003cp\u003e(73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePembro\u003c/p\u003e \u003cp\u003e200 mg q3w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5.3 cycles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKEYNOTE-024,\u003c/p\u003e \u003cp\u003emulti-centre\u003csup\u003e27\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1st\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e154\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e64.5\u003c/p\u003e \u003cp\u003e(33\u0026ndash;90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e92\u003c/p\u003e \u003cp\u003e(60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePembro\u003c/p\u003e \u003cp\u003e200 mg q3w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e7.9 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e22C3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCYPRESS 1,\u003c/p\u003e \u003cp\u003emulticenter\u003csup\u003e28\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1st\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e68\u003c/p\u003e \u003cp\u003e(49\u0026ndash;83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e32\u003c/p\u003e \u003cp\u003e(64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePembro\u003c/p\u003e \u003cp\u003e200 mg q3w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e24.4 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e22C3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCITYSCAPE,\u003c/p\u003e \u003cp\u003emulticenter\u003csup\u003e29\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eblind 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1st\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e68\u003c/p\u003e \u003cp\u003e(58\u0026ndash;73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e48\u003c/p\u003e \u003cp\u003e(71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAtezo\u003c/p\u003e \u003cp\u003e1200 mg q3w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2.81 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e22C3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePEOPLE,\u003c/p\u003e \u003cp\u003esingle center\u003csup\u003e30\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003esingle-arm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1st\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e70.9\u003c/p\u003e \u003cp\u003e(64\u0026ndash;77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e44\u003c/p\u003e \u003cp\u003e(68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePembro\u003c/p\u003e \u003cp\u003e200 mg q3w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e22C3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCheckMate 227,\u003c/p\u003e \u003cp\u003emulti-centre\u003csup\u003e31\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1st\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e391\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e64\u003c/p\u003e \u003cp\u003e(41\u0026ndash;87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e272\u003c/p\u003e \u003cp\u003e(69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNivo\u003c/p\u003e \u003cp\u003e240mg q2w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4.6 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e28\u0026thinsp;\u0026minus;\u0026thinsp;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eINTR@PID LUNG 037, multicenter\u003csup\u003e32\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1st\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e152\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e68\u003c/p\u003e \u003cp\u003e(61\u0026ndash;75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e116 (76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePembro\u003c/p\u003e \u003cp\u003e200mg q3w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e37.6 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e73\u0026thinsp;\u0026minus;\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;80\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKEYNOTE-042,\u003c/p\u003e \u003cp\u003emulti-centre\u003csup\u003e33\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1st\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e636\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e63\u003c/p\u003e \u003cp\u003e(57\u0026ndash;69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e450\u003c/p\u003e \u003cp\u003e(71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePembro\u003c/p\u003e \u003cp\u003e200mg q3w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6.75 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e22C3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKEYNOTE-033,\u003c/p\u003e \u003cp\u003emulticenter\u003csup\u003e34\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 or later\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e213\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e61\u003c/p\u003e \u003cp\u003e(28\u0026ndash;83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e157\u003c/p\u003e \u003cp\u003e(74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePembro\u003c/p\u003e \u003cp\u003e2mg/kg q3w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4.2 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e22C3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCTONG1901,\u003c/p\u003e \u003cp\u003emulticenter\u003csup\u003e35\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1st\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e59\u003c/p\u003e \u003cp\u003e(51\u0026ndash;73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11\u003c/p\u003e \u003cp\u003e(79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePembro\u003c/p\u003e \u003cp\u003e200mg q3w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e13 cycles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e22C3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSAKK 19/17,\u003c/p\u003e \u003cp\u003emulticenter\u003csup\u003e36\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eopen 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003esingle-arm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1st\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e76\u003c/p\u003e \u003cp\u003e(37\u0026ndash;87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e29\u003c/p\u003e \u003cp\u003e(60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDurva\u003c/p\u003e \u003cp\u003e1500mg q4w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2.8 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLEAP-007,\u003c/p\u003e \u003cp\u003emulticenter\u003csup\u003e37\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eblind 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdv.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1st\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e312\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e66\u003c/p\u003e \u003cp\u003e(37\u0026ndash;87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e224\u003c/p\u003e \u003cp\u003e(71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePembro\u003c/p\u003e \u003cp\u003e200mg q3w\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5.5 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e22C3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"13\"\u003eData are listed as median (range), and n (%), unless otherwise stated.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"13\"\u003e\u003cb\u003eAbbreviations\u003c/b\u003e: Adv.: advanced; Atezo: Atezolizumab; Durva: Durvalumab; EGFR: epidermal growth factor receptor; IC: immune cells; IHC: immunohistochemistry; MTD: Median treatment durations; Nivo: Nivolumab; Neo.: neoadjuvant therapy; NA, not available; PD-1: programmed cell death 1; PD-L1: programmed death ligand 1; Pembro: Pembrolizumab; q4w: every 4 weeks; q3w: every 3 weeks; q2w: every 2 weeks; RCT: randomized clinical trial; SCT: staining cell type; TC: tumour cells.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOverall, the total of safety population was 5,453 patients with a performance status between 0 and 2 and with the minimum one dose of treatment. The number of patients tested for PD-L1 expression ranged from 5 to 683 per trial, and median age of all patients enrolled ranged between 59 and 76. The percentage of male patients differed among trials, varying from 36\u0026ndash;78.6% of all safety papulation. In the assessment of PD-L1 expression, all included trials used two different staining cell types; tumour and immune cells assessed for PD-L1 expression in three trials[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], and tumour cells assessed in remaining 23 trials (88.5%). Totally, five PD-L1 IHC assays that using 5 different PD-L1 antibodies (28\u0026thinsp;\u0026minus;\u0026thinsp;8, SP142, 73\u0026thinsp;\u0026minus;\u0026thinsp;10, SP263, and 22C3) were adopted for the estimation of PD-L1 expression, and two studies (7.7%)[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] did not show the detailed PD-L1 IHC assay, and PD-L1 antibody (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy quality and risk bias assessment\u003c/h3\u003e\n\u003cp\u003eAfter excluding one trial[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] with the conference abstract only, the methodological quality of non-randomized clinical trials was listed in \u003cb\u003eSupplementary Table S2.\u003c/b\u003e The NOS results suggested that all trials included were considered as high-quality, and the average overall score was 7.3 (range 7\u0026ndash;8). As summarized in \u003cb\u003eSupplementary Table S3\u003c/b\u003e, we did not detect any major flaws in the assessment of risk of bias among randomized clinical trials. Yet, the performance and detection bias were generally at high risk because most trials were open-labelled, and the absence of blinded intervention.\u003c/p\u003e\n\u003ch3\u003eThe association between PD-L1 expression status and the frequency of all-grade TRAEs\u003c/h3\u003e\n\u003cp\u003eThe pooled frequency of all-grade TRAEs was 66.3% (3,581 of 5,405 evaluable patients), and we further evaluated the frequency of all-grade TRAEs based on PD-1/PD-L1 inhibitors type to minimize the bias. Compared with patients with PD-L1 expression\u0026thinsp;\u0026ge;\u0026thinsp;1%, the frequency of nivolumab-induced all-grade TRAEs did not significantly differ among patients with PD-L1 expression\u0026thinsp;\u0026lt;\u0026thinsp;1% and those with PD-L1 expression\u0026thinsp;\u0026ge;\u0026thinsp;1% (61.3% vs. 67.8%, OR 0.75, 95% CI 0.49\u0026ndash;1.16, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.20, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). A similar pattern was found at 1% cut-off value in the frequency of pembrolizumab-induced all-grade TRAEs (60.0% vs. 66.6%, OR 0.75, 95% CI 0.15\u0026ndash;4.25, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.75, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). When using 25% cut-off value to define positive or negative PD-L1 expression, we also did not find any significant differences among them in the durvalumab cohorts (59.1% vs. 61.1%, OR 0.92, 95% CI 0.66\u0026ndash;1.28, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.62, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA). Yet, PD-L1-negative patients have a significant lower frequency of pembrolizumab-induced all-grade TRAEs than PD-L1-positive patients at 50% cut-off value (59.1% vs. 71.3%, OR 0.41, 95% CI 0.24\u0026ndash;0.70, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eThe association between PD-L1 expression status and the frequency of grade 3\u0026ndash;4 TRAEs\u003c/h2\u003e \u003cp\u003eThe overall frequency of grade 3\u0026ndash;4 TRAEs was 15.9% (867 of the 5,453 evaluable patients). As mentioned above, we also assessed the frequency of grade 3\u0026ndash;4 TRAEs based on PD-1/PD-L1 inhibitors type, respectively. With setting 1% cut-off value, patients with PD-L1-negative have a significantly lower frequency of grade 3\u0026ndash;4 TRAEs than those with PD-L1-positive tumours in the nivolumab cohorts (7.5% vs. 18.2%, OR 0.37, 95% CI 0.18\u0026ndash;0.77, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Conversely, PD-L1-negative (\u0026lt;\u0026thinsp;1%) patients suffered a significantly greater frequency of grade 3\u0026ndash;4 TRAEs compared with PD-L1-positive (\u0026ge;\u0026thinsp;1%) patients in the pembrolizumab cohorts (60% vs. 16.2%, OR 7.74, 95% CI 1.57\u0026ndash;43.4, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). PD-L1-negative patients noted a significantly lower frequency of durvalumab-induced grade 3\u0026ndash;4 TRAEs than PD-L1-positive patients at 25% cut-off value (8.8% vs. 15.4%, OR 0.53, 95% CI 0.31\u0026ndash;0.90, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB). Among patients receiving pembrolizumab, PD-L1-negative patients (\u0026lt;\u0026thinsp;50%) also experienced lower frequency of grade 3\u0026ndash;4 TRAEs (9.2% vs. 19.7%, OR 0.41, 95% CI 0.19\u0026ndash;0.97, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eThe relationship between PD-L1 expression status and the frequency of AEs leading to discontinuation\u003c/h2\u003e \u003cp\u003eCollectively, AEs leading to discontinuation was reported in 357 of the 5,054 evaluable patients, resulted in an overall incidence of 7.1%. Similarly, we investigated it according to different PD-1/PD-L1 inhibitors, respectively. The frequency of AEs leading to discontinuation was lower among patients with PD-L1-negative (\u0026lt;\u0026thinsp;1%) than those with PD-L1-positive (\u0026ge;\u0026thinsp;1%) in the nivolumab cohorts (2.8% vs. 10.6%, OR 0.25, 95% CI 0.08\u0026ndash;0.76, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). For pembrolizumab cohorts at 1% cut-off value, we failed to study the correlation between the frequency of AEs leading to discontinuation and PD-L1 expression status because of the unavailable data in PD-L1-negative (\u0026lt;\u0026thinsp;1%) patients. Similar to the nivolumab cohorts, we observed the similar results in the durvalumab cohorts for patients who were PD-L1-negative (\u0026lt;\u0026thinsp;25%) versus PD-L1-positive (\u0026ge;\u0026thinsp;25%) (2.5% vs. 6.4%, OR 0.38, 95% CI 0.16\u0026ndash;0.89, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC). Although patients with PD-L1-negative (\u0026lt;\u0026thinsp;50%) have a lower trend of the frequency of AEs leading to discontinuation than those with PD-L1-positive (\u0026ge;\u0026thinsp;50%), the difference was not significant (3.1% vs. 10.1%, OR 0.28, 95% CI 0.07\u0026ndash;1.12, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.07, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC), and the relatively small number of PD-L1-negative patients (n\u0026thinsp;=\u0026thinsp;65) may influenced the non-significance.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eThe association between PD-L1 expression status and the frequency of treatment-related SAEs\u003c/h2\u003e \u003cp\u003eThe frequency of treatment-related SAEs was 10.9% (332 of the 3,034 evaluable patients). In order to reduce the bias, we continue estimated it according to PD-1/PD-L1 inhibitors type. No difference was detected among PD-L1-negative patients (\u0026lt;\u0026thinsp;1%) vs. PD-L1-positive patients (\u0026ge;\u0026thinsp;1%) in the nivolumab cohorts (6.6% vs. 10.2%, OR 0.63, 95% CI 0.27\u0026ndash;1.40, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.26, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD). For cut-off value of 1%, the correlation between the frequency of pembrolizumab-related SAEs and PD-L1 expression status cannot be assessed due to the unavailable safety data in PD-L1-negative patients. Any statistical significances were not yet reached in the durvalumab cohorts using PD-L1 expression at cut-off value of 25% (4.2% vs. 8.0%, OR 0.51, 95% CI 0.25\u0026ndash;1.05, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.06, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eD). With a 50% cut-off value, the frequency of pembrolizumab-related SAEs was lower among PD-L1-negative patients versus PD-L1-positive patients (3.1% vs. 16.7%, OR 0.16, 95% CI 0.04\u0026ndash;0.60, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eThe relationship between PD-L1 expression status and the frequency of treatment-related FAE s\u003c/h2\u003e \u003cp\u003eThe frequency of treatment-related FAEs was 0.81% (44 of the 5453 evaluable patients). The major reason of such treatment-related FAEs was respiratory distress/failure including interstitial lung disease, and pneumonitis/pneumonia (50%, 22 of 44 patients). Thirty-four of 2677 patients (1.27%) experienced FAEs (due to respiratory distress/interstitial lung disease or pneumonitis/pneumonia in 17 patients, cardiac failure including myocardial infarction, and myocarditis/myositis in 4 patients, sudden death of unknown cause in 3 patients, haemoptysis, malignant neoplasm progression, sepsis, cerebrovascular accident, encephalopathy, ileus, hypovolaemic shock, pulmonary embolism, death, and klebsiella infection in one patient each) in the pembrolizumab cohorts, 4 of 885 patients (0.45%) experienced FAEs (due to pneumonitis in 2 patients, multiorgan failure, and critical neutropenia and sepsis in one patient each) in the nivolumab cohorts, 4 of 741 patients (0.54%) experienced FAEs (due to pneumonitis in 2 patients, colitis and colonic perforation in one patient each) in the durvalumab group, and 2 of 1150 patients (0.17%) experienced FAEs in the atezolizumab cohorts (pneumonia, and constrictive pericarditis in one patient each).\u003c/p\u003e \u003cp\u003eAs depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE, PD-L1-negative and PD-L1-positive patients have a similar frequency of nivolumab-related FAEs at 1% cut-off value (0.0% vs. 3.9%, OR 0.96, 95% CI 0.05\u0026ndash;20.1, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.0). For patients treated with pembrolizumab, a consistent outcome was detected in PD-L1-negative (\u0026lt;\u0026thinsp;1%) patients vs. PD-L1-positive (\u0026ge;\u0026thinsp;1%) patients (0.0% vs. 1.5%, OR 5.95, 95% CI 0.32\u0026ndash;110.0, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.0, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eE). Same result was noted among PD-L1-negative (\u0026lt;\u0026thinsp;25%) patients vs. PD-L1-positive (\u0026ge;\u0026thinsp;25%) patients in the durvalumab cohorts (0.42% vs. 0.69%, OR 0.61, 95% CI 0.05\u0026ndash;4.12, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.0, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eE). For patients in the pembrolizumab cohorts, statistically difference was still not detected in PD-L1-negative (\u0026lt;\u0026thinsp;50%) and PD-L1-positive patients (\u0026ge;\u0026thinsp;50%) (0.0% vs. 0.78%, OR 0.88, 95% CI 0.05\u0026ndash;16.18, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.0, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eE).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eThe relationship between the dose-dependent results of PD-L1-positive and toxicities profile\u003c/h2\u003e \u003cp\u003eWe further assessed the PD-L1-positive-related dose-dependent results by performing an assessment of included trials describing toxicities profile at cut-off value of 1%, 5%, 25%, 50%, and 90%. A consistent dose-dependent pattern between PD-L1-positive and toxicities profile was not noted among different PD-1/PD-L1 inhibitors type, (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). As illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, significant difference was not reported among PD-L1\u0026thinsp;\u0026gt;\u0026thinsp;25% patients and PD-L1\u0026thinsp;\u0026gt;\u0026thinsp;90% patients for all included toxicities profile in the durvalumab cohorts. For the nivolumab cohorts, we did not detect any significantly differences among PD-L1\u0026thinsp;\u0026gt;\u0026thinsp;1% patients and PD-L1\u0026thinsp;\u0026gt;\u0026thinsp;5% patients for all included toxicities profile, except for treatment-related SAEs (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Though PD-L1\u0026thinsp;\u0026gt;\u0026thinsp;1% patients suffered a greater incidence of AEs leading to discontinuation compared with PD-L1\u0026thinsp;\u0026gt;\u0026thinsp;5% patients, it makes no difference between PD-L1\u0026thinsp;\u0026gt;\u0026thinsp;1% and PD-L1\u0026thinsp;\u0026gt;\u0026thinsp;5% patients for the other toxicities profile (all-grade, grade 3\u0026ndash;4, and FAEs) in the atezolizumab cohorts (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Meanwhile, the significantly differences in the frequency of all-grade, grade 3\u0026ndash;4, and SAEs among PD-L1\u0026thinsp;\u0026gt;\u0026thinsp;1% patients and PD-L1\u0026thinsp;\u0026gt;\u0026thinsp;50% patients were seen in the pembrolizumab cohorts; Yet, no difference was found in the pooled frequency of AEs leading to discontinuation, and FAEs (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eSubgroup analyses\u003c/h2\u003e \u003cp\u003eWe further conducted a subgroup analysis to evaluate the association of line therapy (first-line vs. 2 or later line), study design (open-label vs. double-blind), clinical phase (phase 3 vs. phase 1/2), and IHC assay type (22C3 vs. other) with the frequency of toxicities profile, which was done by including PD-L1\u0026thinsp;\u0026gt;\u0026thinsp;1% patients treated with pembrolizumab because of its relatively large number sample size available. As listed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, we did not observe any significantly differences in most subgroup analysis. Notably, we detected patients using 22C3 IHC assay have a higher frequency of all-grade TRAEs. Compared with patients receiving 2 or later line therapy, patients receiving first-line therapy experienced a higher frequency of grade 3\u0026ndash;4 TRAEs. Moreover, the frequency of grade 3\u0026ndash;4 TRAEs was significant lower in open-label trials than double-blind trials.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSubgroup analyses of the frequency of pembrolizumab-related TRAEs\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll-grade TRAEs\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFrequency (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOR and 95%CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eline of therapy (first-line vs. 2 or later line)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65.2% (632/969) vs. 67.9% (672/989)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.88 (0.73\u0026ndash;1.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003estudy design (open-label vs. double-blind)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65.9% (1085/1646) vs. 70.2% (219/312)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.82 (0.63\u0026ndash;1.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eclinical phase (phase 3 vs. phase 1/2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67.0% (1236/1844) vs. 59.7% (68/114)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.38 (0.94\u0026ndash;2.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIHC assay type (22C3 vs. other)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67.3% (1274/1893) vs. 46.2% (30/65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.39 (1.46\u0026ndash;3.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGrade 3\u0026ndash;4 TRAEs\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eFrequency (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOR and 95%CI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eP-value\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eline of therapy (first-line vs. 2 or later line)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.6% (180/969) vs. 13.9% (138/989)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.41 (1.11\u0026ndash;1.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003estudy design (open-label vs. double-blind)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.1% (248/1646) vs.22.4 (70/312)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.61 (0.46\u0026ndash;0.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eclinical phase (phase 3 vs. phase 1/2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.4% (302/1844) vs. 14.0% (16/114)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.20 (0.69\u0026ndash;2.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIHC assay type (22C3 vs. other)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.5% (313/1893) vs. 7.7% (5/65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.34 (1.01\u0026ndash;5.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAEs leading to discontinuation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eFrequency (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOR and 95%CI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eP-value\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eline of therapy (first-line vs. 2 or later line)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.8% (84/959) vs. 7.1% (66/934)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.26 (0.90\u0026ndash;1.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003estudy design (open-label vs. double-blind)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.9% (125/1581) vs. 8.0% (25/312)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.99 (0.64\u0026ndash;1.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.91\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eclinical phase (phase 3 vs. phase 1/2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.8% (144/1844) vs. 12.2% (6/49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.61 (0.27\u0026ndash;1.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIHC assay type (22C3 vs. other)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.9% (150/1893) vs. NA (NA/65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTreatment-related SAEs\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eFrequency (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOR and 95%CI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eP-value\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eline of therapy (first-line vs. 2 or later line)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA vs.11.3% (77/683)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003estudy design (open-label vs. double-blind)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.3% (77/683) vs. NA/312\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eclinical phase (phase 3 vs. phase 1/2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.3% (77/683) vs. NA/114\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIHC assay type (22C3 vs. other)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.3% (77/683) vs. NA/65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTreatment-related FAEs\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eFrequency (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOR and 95%CI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eP-value\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eline of therapy (first-line vs. 2 or later line)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.9% (19/969) vs. 1.0 (10/989)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.96 (0.94\u0026ndash;4.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003estudy design (open-label vs. double-blind)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.4% (23/1646) vs. 1.9% (6/312)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.72 (0.30\u0026ndash;1.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eclinical phase (phase 3 vs. phase 1/2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.5% (28/1844) vs. 0.9% (1/114)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.74 (0.30\u0026ndash;18.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIHC assay type (22C3 vs. other)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.5% (29/1893) vs. 0% (0/65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.07 (0.13\u0026ndash;34.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cb\u003eAbbreviations\u003c/b\u003e: CI: confidence interval; FAEs: fatal adverse events; OR: odds ratio; PD-1: programmed cell death 1; PD-L1: programmed cell death ligand 1; IHC: immunohistochemistry; SAEs: serious adverse events; TRAEs: treatment-related adverse events.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eCompared with historical data of convention chemotherapy, TRAEs were well-tolerated in early trials of PD-1/PD-L1 inhibitors[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. As suggested in present study, the overall frequency of its all-grade TRAEs, grade 3\u0026ndash;4 TRAEs, AEs leading to discontinuation in patients with NSCLC was 66.3%, 15.9%, and 7.1%, respectively. Moreover, the pooled incidence of treatment-related SAEs and FAEs was 10.9%, and 0.81%, respectively. The pooled toxicities analyses suggested that although the overall frequency of all-grade TRAEs is relatively high, the overall safety profile of PD-1/PD-L1 inhibitors was tolerable in NSCLC patients. With the increasingly adoption of PD-1/PD-L1 inhibitors in clinical, distinguishing the risk factors of toxicities profiles are need to optimize the clinical administration of these drugs in patients with NSCLC. Considering the impaired the quality of life, and high social and economic burdens related to TRAEs, we recommend that clinicians should make a discussion with patients before PD-1/PD-L1 inhibitors administration to apprise them of the correlation between PD-L1 expression status and the frequency of TRAEs, rather than making a therapeutic decision just on the basis of a clinical practice guideline.\u003c/p\u003e \u003cp\u003ePrevious studies[\u003cspan additionalcitationids=\"CR41\" citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e] assessing PD-1/PD-L1 inhibitors have reported several biomarkers that can predict the frequency of organ-specific TRAEs in NSCLC. Maekura et al. (n\u0026thinsp;=\u0026thinsp;64) conducted a study and found pre-treatment thyroid peroxidase antibody, and thyroglobulin antibody may indicate the development of nivolumab-related hypothyroidism[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Similarly, a study performed by Sarocchi et al. (n\u0026thinsp;=\u0026thinsp;59) suggested that serum troponin levels are correlated with nivolumab-related cardiotoxicity[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. However, low statistical power could result in false-positive results because of the relatively limited number of included patients. Although previous studies[\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] have widely assessed the influence of PD-L1 expression in PD-1/PD-L1 inhibitors-based efficacy, the correlation of PD-L1 expression status and PD-1/PD-L1 inhibitors-related toxicities profile in patients with NSCLC was unclear. Present study clearly showed that these agents have its special correlation between PD-L1 expression status and toxicities profile in treating NSCLC patients. Because of the increasing use of PD-L1 expression to guide the PD-1/PD-L1 inhibitors-based therapeutic regimens, it is especially essential that clinicians and patients are well-informed and conscious of the relationship between treatment-related toxicities profile and PD-L1 expression status in NSCLC patients.\u003c/p\u003e \u003cp\u003eIt is well understood that PD-1 is a broadly distribution intracellular membrane surface receptor on immune cells (e.g. T-cells), which are able to recognize and bind to the intrinsic counterparts PD-L1 and PD-L2, thereby enabling the acquisition of immune tolerance, and preventing the development of autoimmunity[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Given its pharmacological mechanisms, it was thus plausible that the toxicities profile of these drugs could differ depending on PD-L1 expression status. Previously, autoimmunity pre-clinical models have assessed the frequency of adverse events linked to PD-1/PD-L1 inhibitors[\u003cspan additionalcitationids=\"CR44\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e], and implied that these agents would accelerate the development of tissue-specific autoimmunity rather than systemic autoimmunity. For instance, more serious colitis was seen in mice treated with PD-1 inhibitors and dextran sulfate sodium compared with those treated dextran sulfate sodium alone[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Interestingly, a pre-clinical model[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e] (the inversion-induced joined neoantigen mouse that a defined group of auto-antigens can be induced in selected organs) could be useful to evaluate the several PD-1/PD-L1 inhibitors-related TRAEs. Notably, the association between autoimmune susceptibility and TRAEs (especially the relatively rare antibody-mediated TRAEs) associated with PD-1/PD-L1 inhibitors in human patients was yet unknown, and it is an uncertainty about the widespread use of preclinical models[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. Furthermore, it is particularly difficult to evaluate adverse events induced by PD-1/PD-L1 inhibitors in preclinical models based on different PD-L1 expression. In addition, it is challenging to investigate TRAEs induced by PD-1/PD-L1 inhibitors in human patient tissues due to the rarity of certain adverse events, the inaccessibility of the tissues, and the variability in their presentation. Overall, this background provided further evidence of the practical usefulness of our study. Current study can be useful to incorporate with pre-clinical models to improve the knowledge of these PD-L1 expression-associated unique toxicities profile.\u003c/p\u003e \u003cp\u003eThe frequency of all-grade TRAEs in PD-L1-negative patients was comparable to PD-L1-positive patients at both 1%, and 25% cut-off value. However, the results were not yet noted at 50% cut-off value, which may be subject to the small sample size analysed of PD-L1-negative (\u0026lt;\u0026thinsp;50%) patients (n\u0026thinsp;=\u0026thinsp;65). Also, the frequency of treatment-related SAEs in PD-L1-negative patients was comparable with PD-L1-positive patients at both 1%, and 25% cut-off value. Nonetheless, statistically difference was found at 50% cut-off value, and the limited sample size of PD-L1-negative (\u0026lt;\u0026thinsp;50%) patients (n\u0026thinsp;=\u0026thinsp;65) may also contribute to this situation. The frequency of overall treatment-related FAEs was low (0.81%, 44/5,453), and the main cause of such death was respiratory distress/failure including interstitial lung disease, and pneumonitis/pneumonia (50%). We did not obtain any significant differences in the frequency of treatment-related FAEs among PD-L1-negative and PD-L1-positive patients at 1%, 25%, and 50% cut-off value. Subsequent analyses did not explore a dose-dependent pattern between the frequency and PD-L1 positivity in the safety outcome of all-grade TRAEs, SAEs, and FAEs. Thus, PD-L1-negative patients may show similar frequency of all-grade TRAEs, SAEs, and FAEs in comparison with PD-L1-positive patients. Further large, prospective clinical trials are need to confirm it.\u003c/p\u003e \u003cp\u003eIn the term of AEs leading to discontinuation, we also detected a lower frequency among PD-L1-negative patients versus PD-L1-positive patients at cut-off value of 1%, and 25%. Moreover, there is a dose-dependent effect of PD-L1-positive between PD-L1\u0026thinsp;\u0026gt;\u0026thinsp;1% and PD-L1\u0026thinsp;\u0026gt;\u0026thinsp;5% patients in the atezolizumab cohorts. Though PD-L1-negative patients have a less frequency of AEs leading to discontinuation than PD-L1-positive patients at 50% cut-off value, the result was not numerically significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.07), which may also have been biased with the small sample size (n\u0026thinsp;=\u0026thinsp;65) of PD-L1-negative patients. PD-L1-negative patients experienced a lower frequency of grade 3\u0026ndash;4 TRAEs at 1%, 25%, and 50% cut-off value, compared to PD-L1-positive patients. The analyses of the dose-dependent results of toxicities profile and PD-L1-positive further suggested a similar trend between PD-L1\u0026thinsp;\u0026gt;\u0026thinsp;1% and PD-L1\u0026thinsp;\u0026gt;\u0026thinsp;50% patients in the pembrolizumab cohorts. Notably, the observed frequency of grade 3\u0026ndash;4 TRAEs was higher in PD-L1-negative (\u0026lt;\u0026thinsp;1%) patients in the pembrolizumab cohorts in comparison with PD-L1-positive (\u0026ge;\u0026thinsp;1%) patients (60% vs. 16.2%, OR 7.74, 95% CI 1.57\u0026ndash;43.4, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01); the small number size (n\u0026thinsp;=\u0026thinsp;5) of PD-L1-negative patients, and the wide variation in ORs may bias the results. Therefore, PD-L1-positive patients may have a higher frequency of AEs leading to discontinuation, and grade 3\u0026ndash;4 TRAEs compared with PD-L1-negative patients. Current study implied that safety evaluation should consider PD-L1 expression status before the adoption of PD-1/PD-L1 inhibitors in future. Moreover, we should take more attention to the clinical signs, diagnostics, and management of these safety profile after initiating PD-1/PD-L1 inhibitors treatment in NSCLC patients, particularly in PD-L1-positive patients.\u003c/p\u003e \u003cp\u003eAlthough non-significant differences were detected in most subgroup analysis, a higher frequency of all-grade TRAEs was found in patients using 22C3 IHC assay for PD-L1 expression assessment, which was caused by the differences in inherent sensitivity across different IHC assays. Moreover, a lower frequency of grade 3\u0026ndash;4 TRAEs among patients enrolled in open-label trials than those in double-blind trials may be because the reporting bias in open-label trials. In addition, patients receiving first-line therapy have a higher frequency of grade 3\u0026ndash;4 TRAEs. It is possible that these patients have a longer median treatment duration, and previous therapy (i.e. chemotherapy) may results in immune suppression[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFor PD-1/PD-L1 inhibitors in the treatment of NSCLC patients with certain genetic mutation, there was no study to compare the difference of safety profile among PD-L1-negative and PD-L1-positive patients. Lisberg et al.[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] performed a clinical trial (NCT02879994, phase II) in 11 NSCLC patients with \u003cem\u003eEGFR\u003c/em\u003e mutation-positive, and found the frequency of pembrolizumab-induced any-grade TRAEs, grade 3\u0026ndash;4 TRAEs, and treatment-related mortality was 65%, 9.1%, and 0%, respectively; the frequency of any-grade TRAEs and treatment-related mortality in those \u003cem\u003eEGFR\u003c/em\u003e mutation-positive patients were similar to the overall frequency in our study, while the frequency of grade 3\u0026ndash;4 TRAEs seem be low compare to our study (9.1% vs 15.9%). However, the association between the frequency of treatment-related toxicities profile and PD-L1 expression status during PD-1/PD-L1 inhibitors in the treatment of NSCLC patients with \u003cem\u003eEGFR\u003c/em\u003e mutation-positive remain unclear, and further study are needed.\u003c/p\u003e \u003cp\u003eThe present study, including 26 prospective trials and 5,453 patients, is the first and largest to study the relationship of PD-L1 expression status and treatment-related toxicities profile in patients with NSCLC during receiving PD-1/PD-L1 inhibitors. Also, current study may have some weaknesses. Firstly, we investigated the summary frequency of TRAEs rely on trial-level data, rather than individual patient-level data, and thus the results may limit the generalizability. Secondly, patients in real-world clinical practice may experience a higher frequency of TRAEs, as the included clinical trials only enrolled patients with better performance status. Thirdly, caution should be exercised in elucidating the results because subgroups analyses included small number of patients. With additional evidence available, it needs to be explored further in more trials to support our results.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, our study indicated that the relationship of treatment-related toxicities profile and PD-L1 expression status maybe different across different PD-1/PD-L1 inhibitors type. Clinicians should make a discussion with patients prior to the administration of PD-1/PD-L1 inhibitors to inform them the correlation between PD-L1 expression status and the frequency of TRAEs, especially AEs leading to discontinuation and grade 3\u0026ndash;4 TRAEs, rather than making a therapeutic decision according to the clinical practice guideline alone.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEGFR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eepidermal growth factor receptor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFAEs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efatal adverse events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNSCLC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enon-small cell lung cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eodds ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePD-1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogrammed cell death 1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePD-L1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogrammed cell death ligand 1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIHC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eimmunohistochemistry\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSAEs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eserious adverse events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTRAEs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etreatment-related adverse events.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful to the reviewers and editors whose comments and suggestions dramatically enhanced this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization:\u0026nbsp;X-R. H.; Investigation: Q. Z., H. H., L-Y. OY., R. Y., W-X. W., and P. H.; Formal Analysis and Visualization: Q. Z., H. H., L-Y. OY. and X-R H;\u0026nbsp;Methodology: H. H., and Q. Z.; Writing Original Draft: Q. Z., H. H., L-Y. OY., R. Y., W-X. W., P. H. and X-R H; All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone declared.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by National Natural Science Foundation of China (No.82002872) and the Science and Technology Planning Project of General Hospital of Southern Theater Command (No. 2022NZC002).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion and Ethics Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data used in this study was previously published\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians. 2021;71: 209\u0026ndash;249.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMartins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, Shabafrouz K, Ribi C, Cairoli A, Guex-Crosier Y, Kuntzer T, Michielin O, Peters S, Coukos G, Spertini F, Thompson JA, Obeid M. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019;16:563\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang F, Shay C, Abousaud M, Tang C, Li Y, Qin Z, Saba NF, Teng Y. Patterns of toxicity burden for FDA-approved immune checkpoint inhibitors in the United States. J Exp Clin Cancer Res. 2023;42:4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu X, Guo CY, Tou FF, Wen XM, Kuang YK, Zhu Q, Hu H. Association of PD-L1 expression status with the efficacy of PD-1/PD-L1 inhibitors and overall survival in solid tumours: A systematic review and meta-analysis. Int J Cancer. 2020;147:116\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShen X, Zhao B. Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis. BMJ. 2018;362:k3529.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuang X, Xu R, Li J. Association of PD-L1 expression with survival benefit from PD-1/PD-L1 inhibitors in advanced cancer: Systematic review and meta-analysis of phase III randomized clinical trials. Crit Rev Oncol Hematol. 2024;198:104357.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHu H, Zhu Q, Tang H, Zhang SC, Huang YZ, Wang YF, Xu ZY, Yang XW, Zheng JH, Guo CY. The risk of treatment-related toxicities with PD-1/PD-L1 inhibitors in patients with lung cancer. Int J Cancer 2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSimons EA, Smith DE, Gao D, Camidge DR. Variation in Toxicity Reporting Methods for Early Phase Lung Cancer Treatment Trials at Oncology Conferences. J Thorac Oncol. 2020;15: 1425\u0026ndash;1433.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Int J Surg. 2010;8:336\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25:603\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHiggins JPT, Altman DG, G\u0026oslash;tzsche PC, J\u0026uuml;ni P, Moher D, Oxman AD, Savović J, Schulz KF, Weeks L, Sterne JAC. The Cochrane Collaboration\u0026rsquo;s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBorghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlh\u0026auml;ufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crin\u0026ograve; L, Blumenschein GR Jr., Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373:1627\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, Felip E, van den Heuvel MM, Ciuleanu TE, Badin F, Ready N, Hiltermann TJN, Nair S, Juergens R, Peters S, Minenza E, Wrangle JM, Rodriguez-Abreu D, Borghaei H, Blumenschein GR Jr., Villaruz LC, Havel L, Krejci J, Corral Jaime J, Chang H, Geese WJ, Bhagavatheeswaran P, Chen AC, Socinski MA. First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. N Engl J Med. 2017;376:2415\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeters S, Gettinger S, Johnson ML, J\u0026auml;nne PA, Garassino MC, Christoph D, Toh CK, Rizvi NA, Chaft JE, Carcereny Costa E, Patel JD, Chow LQM, Koczywas M, Ho C, Fr\u0026uuml;h M, van den Heuvel M, Rothenstein J, Reck M, Paz-Ares L, Shepherd FA, Kurata T, Li Z, Qiu J, Kowanetz M, Mocci S, Shankar G, Sandler A, Felip E. Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients With Programmed Death-Ligand 1-Selected Advanced Non-Small-Cell Lung Cancer (BIRCH). J Clin Oncol. 2017;35:2781\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLisberg A, Cummings A, Goldman JW, Bornazyan K, Reese N, Wang T, Coluzzi P, Ledezma B, Mendenhall M, Hunt J, Wolf B, Jones B, Madrigal J, Horton J, Spiegel M, Carroll J, Gukasyan J, Williams T, Sauer L, Wells C, Hardy A, Linares P, Lim C, Ma L, Adame C, Garon EB. A Phase II Study of Pembrolizumab in EGFR-Mutant, PD-L1+, Tyrosine Kinase Inhibitor Na\u0026iuml;ve Patients With Advanced NSCLC. J Thorac Oncol. 2018;13:1138\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpigel DR, Chaft JE, Gettinger S, Chao BH, Dirix L, Schmid P, Chow LQM, Hicks RJ, Leon L, Fredrickson J, Kowanetz M, Sandler A, Funke R, Rizvi NA. FIR: Efficacy, Safety, and Biomarker Analysis of a Phase II Open-Label Study of Atezolizumab in PD-L1-Selected Patients With NSCLC. J Thorac Oncol. 2018;13:1733\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAntonia SJ, Balmanoukian A, Brahmer J, Ou SI, Hellmann MD, Kim SW, Ahn MJ, Kim DW, Gutierrez M, Liu SV, Sch\u0026ouml;ffski P, J\u0026auml;ger D, Jamal R, Jerusalem G, Lutzky J, Nemunaitis J, Calabr\u0026ograve; L, Weiss J, Gadgeel S, Bhosle J, Ascierto PA, Rebelatto MC, Narwal R, Liang M, Xiao F, Antal J, Abdullah S, Angra N, Gupta AK, Khleif SN, Segal NH. Clinical Activity, Tolerability, and Long-Term Follow-Up of Durvalumab in Patients With Advanced NSCLC. J Thorac Oncol. 2019;14:1794\u0026ndash;806.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNishio M, Takahashi T, Yoshioka H, Nakagawa K, Fukuhara T, Yamada K, Ichiki M, Tanaka H, Seto T, Sakai H, Kasahara K, Satouchi M, Han SR, Noguchi K, Shimamoto T, Kato T. KEYNOTE-025: Phase 1b study of pembrolizumab in Japanese patients with previously treated programmed death ligand 1-positive advanced non-small-cell lung cancer. Cancer Sci. 2019;110:1012\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarassino MC, Cho BC, Kim JH, Mazi\u0026egrave;res J, Vansteenkiste J, Lena H, Jaime JC, Gray JE, Powderly J, Chouaid C, Bidoli P, Wheatley-Price P, Park K, Soo RA, Poole L, Wadsworth C, Dennis PA, Rizvi NA. Final overall survival and safety update for durvalumab in third- or later-line advanced NSCLC: The phase II ATLANTIC study. Lung Cancer. 2020;147:137\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePlanchard D, Reinmuth N, Orlov S, Fischer JR, Sugawara S, Mandziuk S, Marquez-Medina D, Novello S, Takeda Y, Soo R, Park K, McCleod M, Geater SL, Powell M, May R, Scheuring U, Stockman P, Kowalski D. ARCTIC: durvalumab with or without tremelimumab as third-line or later treatment of metastatic non-small-cell lung cancer. Ann Oncol. 2020;31:609\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRizvi NA, Cho BC, Reinmuth N, Lee KH, Luft A, Ahn MJ, van den Heuvel MM, Cobo M, Vicente D, Smolin A, Moiseyenko V, Antonia SJ, Le Moulec S, Robinet G, Natale R, Schneider J, Shepherd FA, Geater SL, Garon EB, Kim ES, Goldberg SB, Nakagawa K, Raja R, Higgs BW, Boothman AM, Zhao L, Scheuring U, Stockman PK, Chand VK, Peters S. Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020;6:661\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoyer M, Şendur MAN, Rodr\u0026iacute;guez-Abreu D, Park K, Lee DH, \u0026Ccedil;i\u0026ccedil;in I, Yumuk PF, Orlandi FJ, Leal TA, Molinier O, Soparattanapaisarn N, Langleben A, Califano R, Medgyasszay B, Hsia TC, Otterson GA, Xu L, Piperdi B, Samkari A, Reck M. Pembrolizumab Plus Ipilimumab or Placebo for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score\u0026thinsp;\u0026ge;\u0026thinsp;50%: Randomized, Double-Blind Phase III KEYNOTE-598 Study. J Clin Oncol. 2021;39:2327\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEichhorn F, Klotz LV, Kriegsmann M, Bischoff H, Schneider MA, Muley T, Kriegsmann K, Haberkorn U, Heussel CP, Savai R, Zoernig I, Jaeger D, Thomas M, Hoffmann H, Winter H, Eichhorn ME. Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Lung Cancer. 2021;153:150\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHerbst RS, Garon EB, Kim DW, Cho BC, Gervais R, Perez-Gracia JL, Han JY, Majem M, Forster MD, Monnet I, Novello S, Gubens MA, Boyer M, Su WC, Samkari A, Jensen EH, Kobie J, Piperdi B, Baas P. Five Year Survival Update From KEYNOTE-010: Pembrolizumab Versus Docetaxel for Previously Treated, Programmed Death-Ligand 1-Positive Advanced NSCLC. J Thorac Oncol. 2021;16:1718\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJassem J, de Marinis F, Giaccone G, Vergnenegre A, Barrios CH, Morise M, Felip E, Oprean C, Kim YC, Andric Z, et al. Updated Overall Survival Analysis From IMpower110: atezolizumab Versus Platinum-Based Chemotherapy in Treatment-Naive Programmed Death-Ligand 1-Selected NSCLC. J Thorac Oncol. 2021;16:1872\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePonce Aix S, Carcereny Costa E, Bosch-Barrera J, Felip Font E, Guirado M, Coves Sarto J, Majem Tarruella M, Juan Vidal OJ, Dalmau Portulas E, Diz P, Ortega Granados ALO, Domine Gomez M, Blasco Cordellat A, Mosquera Martinez J, Sala Gonzalez MA, Dorta M, de Calvo V, Zugazagoitia J, Enguita AB, Paz-Ares L. Pembrolizumab re-challenge in patients with relapsed non-small cell lung cancer (NSCLC): A preliminary report of the REPLAY phase II trial - cohort I. Ann Oncol. 2021;32:S1450.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReck M, Rodr\u0026iacute;guez-Abreu D, Robinson AG, Hui R, Csőszi T, F\u0026uuml;l\u0026ouml;p A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leal TA, Riess JW, Jensen E, Zhao B, Pietanza MC, Brahmer JR. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score\u0026thinsp;\u0026ge;\u0026thinsp;50. J Clin Oncol. 2021;39:2339\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpigel D, Jotte R, Nemunaitis J, Shum M, Schneider J, Goldschmidt J, Eisenstein J, Berz D, Seneviratne L, Socoteanu M, Bhanderi V, Konduri K, Xia M, Wang H, Hozak RR, Gueorguieva I, Ferry D, Gandhi L, Chao BH, Rybkin I. Randomized Phase 2 Studies of Checkpoint Inhibitors Alone or in Combination With Pegilodecakin in Patients With Metastatic NSCLC (CYPRESS 1 and CYPRESS 2). J Thorac Oncol. 2021;16:327\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCho BC, Abreu DR, Hussein M, Cobo M, Patel AJ, Secen N, Lee KH, Massuti B, Hiret S, Yang JCH, Barlesi F, Lee DH, Ares LP, Hsieh RW, Patil NS, Twomey P, Yang X, Meng R, Johnson ML. Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and follow-up analyses of a randomised, double-blind, phase 2 study. Lancet Oncol. 2022;23:781\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLo Russo G, Sgambelluri F, Prelaj A, Galli F, Manglaviti S, Bottiglieri A, Di Mauro RM, Ferrara R, Galli G, Signorelli D, De Toma A, Occhipinti M, Brambilla M, Rulli E, Triulzi T, Torelli T, Agnelli L, Brich S, Martinetti A, Dumitrascu AD, Torri V, Pruneri G, Fabbri A, de Braud F, Anichini A, Proto C, Ganzinelli M, Mortarini R, Garassino MC. PEOPLE (NCT03447678), a first-line phase II pembrolizumab trial, in negative and low PD-L1 advanced NSCLC: clinical outcomes and association with circulating immune biomarkers. ESMO Open. 2022;7:100645.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrahmer JR, Lee JS, Ciuleanu TE, Bernabe Caro R, Nishio M, Urban L, Audigier-Valette C, Lupinacci L, Sangha R, Pluzanski A, Burgers J, Mahave M, Ahmed S, Schoenfeld AJ, Paz-Ares LG, Reck M, Borghaei H, O'Byrne KJ, Gupta RG, Bushong J, Li L, Blum SI, Eccles LJ, Ramalingam SS. Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small-Cell Lung Cancer in CheckMate 227. J Clin Oncol. 2023;41:1200\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCho BC, Lee JS, Wu YL, Cicin I, Dols MC, Ahn MJ, Cuppens K, Veillon R, Nadal E, Dias JM, Martin C, Reck M, Garon EB, Felip E, Paz-Ares L, Mornex F, Vokes EE, Adjei AA, Robinson C, Sato M, Vugmeyster Y, Machl A, Audhuy F, Chaudhary S, Barlesi F. Bintrafusp Alfa Versus Pembrolizumab in Patients With Treatment-Naive, Programmed Death-Ligand 1-High Advanced NSCLC: A Randomized, Open-Label, Phase 3 Trial. J Thorac Oncol. 2023;18:1731\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede Castro G Jr., Kudaba I, Wu YL, Lopes G, Kowalski DM, Turna HZ, Caglevic C, Zhang L, Karaszewska B, Laktionov KK, Srimuninnimit V, Bondarenko I, Kubota K, Mukherjee R, Lin J, Souza F, Mok TSK, Cho BC. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy as First-Line Therapy in Patients With Non-Small-Cell Lung Cancer and Programmed Death Ligand-1 Tumor Proportion Score\u0026thinsp;\u0026ge;\u0026thinsp;1% in the KEYNOTE-042 Study. J Clin Oncol. 2023;41:1986\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRen S, Feng J, Ma S, Chen H, Ma Z, Huang C, Zhang L, He J, Wang C, Zhou J, Danchaivijtr P, Wang CC, Vynnychenko I, Wang K, Orlandi F, Sriuranpong V, Li B, Ge J, Dang T, Zhou C. KEYNOTE-033: Randomized phase 3 study of pembrolizumab vs docetaxel in previously treated, PD-L1-positive, advanced NSCLC. Int J Cancer. 2023;153:623\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaggie Liu S-Y, Huang J, Deng J-Y, Xu C-R, Yan H-H, Yang M-Y, Li Y-S, Ke EE, Zheng M-Y, Wang Z, Lin J-X, Gan B, Zhang X-C, Chen H-J, Wang B-C, Tu H-Y, Yang J-J, Zhong W-Z, Li Y, Zhou Q, Wu Y-L. PD-L1 expression guidance on sintilimab versus pembrolizumab with or without platinum-doublet chemotherapy in untreated patients with advanced non-small cell lung cancer (CTONG1901): A phase 2, randomized, controlled trial. Sci Bull. 2024;69:535\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMark M, Froesch P, Gysel K, Rothschild SI, Addeo A, Ackermann CJ, Chiquet S, Schneider M, Ribi K, Maranta AF, Bastian S, von Moos R, Joerger M, Fr\u0026uuml;h M. First-line durvalumab in patients with PD-L1 positive, advanced non-small cell lung cancer (NSCLC) with a performance status of 2 (PS2). Primary analysis of the multicenter, single-arm phase II trial SAKK 19/17. Eur J Cancer. 2024;200:113600.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang JC, Han B, De La Mora Jim\u0026eacute;nez E, Lee JS, Koralewski P, Karadurmus N, Sugawara S, Livi L, Basappa NS, Quantin X, Dudnik J, Ortiz DM, Mekhail T, Okpara CE, Dutcus C, Zimmer Z, Samkari A, Bhagwati N, Csőszi T. Pembrolizumab With or Without Lenvatinib for First-Line Metastatic NSCLC With Programmed Cell Death-Ligand 1 Tumor Proportion Score of at least 1% (LEAP-007): A Randomized, Double-Blind, Phase 3 Trial. J Thorac Oncol. 2024;19:941\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTopalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaekura T, Naito M, Tahara M, Ikegami N, Kimura Y, Sonobe S, Kobayashi T, Tsuji T, Minomo S, Tamiya A, Atagi S. Predictive Factors of Nivolumab-induced Hypothyroidism in Patients with Non-small Cell Lung Cancer. Vivo. 2017;31:1035\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOyanagi J, Koh Y, Sato K, Mori K, Teraoka S, Akamatsu H, Kanai K, Hayata A, Tokudome N, Akamatsu K, Nakanishi M, Ueda H, Yamamoto N. Predictive value of serum protein levels in patients with advanced non-small cell lung cancer treated with nivolumab. Lung Cancer. 2019;132:107\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSarocchi M, Grossi F, Arboscello E, Bellodi A, Genova C, Dal Bello MG, Rijavec E, Barletta G, Rossi G, Biello F, Ghigliotti G, Canepa M, Mussap M, Brunelli C, Spallarossa P. Serial Troponin for Early Detection of Nivolumab Cardiotoxicity in Advanced Non-Small Cell Lung Cancer Patients. Oncologist. 2018;23:936\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCurran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107:4275\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu J, Blake SJ, Smyth MJ, Teng MW. Improved mouse models to assess tumour immunity and irAEs after combination cancer immunotherapies. Clin Transl Immunol. 2014;3:e22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerez-Ruiz E, Minute L, Otano I, Alvarez M, Ochoa MC, Belsue V, de Andrea C, Rodriguez-Ruiz ME, Perez-Gracia JL, Marquez-Rodas I, Llacer C, Alvarez M, de Luque V, Molina C, Teijeira A, Berraondo P, Melero I. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy. Nature. 2019;569:428\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDamo M, Fitzgerald B, Lu Y, Nader M, William I, Cheung JF, Connolly KA, Foster GG, Akama-Garren E, Lee DY, Chang GP, Gocheva V, Schmidt LM, Boileve A, Wilson JH, Cui C, Monroy I, Gokare P, Cabeceiras P, Jacks T, Joshi NS. Inducible de novo expression of neoantigens in tumor cells and mice. Nat Biotechnol. 2021;39:64\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eConnolly KA, Fitzgerald B, Damo M, Joshi NS. Novel Mouse Models for Cancer Immunology. Annu Rev Cancer Biol. 2022;6:269\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMonteran L, Ershaid N, Doron H, Zait Y, Scharff Ye, Ben-Yosef S, Avivi C, Barshack I, Sonnenblick A, Erez N. Chemotherapy-induced complement signaling modulates immunosuppression and metastatic relapse in breast cancer. Nat Commun. 2022;13:5797.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"non-small cell lung cancer, programmed cell death ligand 1, serious adverse event, toxicities profile","lastPublishedDoi":"10.21203/rs.3.rs-5748321/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5748321/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003e PD-L1 expression has been explored to guide the treatment options for programmed cell death 1 and its ligand (PD-1/PD-L1) inhibitors-based therapy in non-small cell lung cancer (NSCLC), but the association of its treatments-related toxicities profile with PD-L1 expression status is unclear. To make the optimized and personalized use of such agents, we performed current study.\u003c/p\u003e\u003ch2\u003eExperimental Design\u003c/h2\u003e \u003cp\u003e: Multiple databases (Cochrane Library, EMBASE, and PubMed databases) from inception to June 30, 2024 were retrieved to search PD-1/PD-L1 inhibitors-related clinical trials of NSCLC that had described data regarding treatment-related adverse events (TRAEs) and PD-L1 expression.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eTwenty-six trials, involving 5,453 patients, were eligible for final analysis. PD-L1-positive patients suffered a higher frequency of AEs leading to discontinuation, and grade 3\u0026ndash;4 treatment-related adverse events (TRAEs) compared with PD-L1-negative patients at most cut-off value. However, the frequency of all-grade TRAEs, SAEs, and FAEs showed numerically difference among PD-L1-positive and PD-L1-negative patients at most cut-off value. Different PD-1/PD-L1 inhibitors type did not detect a consistent dose-dependent pattern between PD-L1-positive and toxicities profile. Subgroup analyses noted that patients using 22C3 immunohistochemistry assay have a higher frequency of all-grade TRAEs. Moreover, patients receiving first-line therapy and those enrolled in open-label trials experienced a higher frequency of grade 3\u0026ndash;4 TRAEs.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eWe suggested that clinicians, and patients should be informed of the association of PD-L1 expression status and toxicities profile prior to PD-1/PD-L1 inhibitors administration.\u003c/p\u003e","manuscriptTitle":"The association of PD-L1 expression status and PD-1/PD-L1 inhibitors-related toxicities profile in non-small cell lung cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-08 19:54:31","doi":"10.21203/rs.3.rs-5748321/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-01-08T11:10:20+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-01-06T14:05:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-01-06T14:03:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2025-01-02T02:45:50+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"85ded938-5eb3-4c46-81fa-a3df41d4a2e5","owner":[],"postedDate":"January 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-05T15:59:41+00:00","versionOfRecord":{"articleIdentity":"rs-5748321","link":"https://doi.org/10.1186/s12885-025-14218-5","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2025-04-28 15:57:14","publishedOnDateReadable":"April 28th, 2025"},"versionCreatedAt":"2025-01-08 19:54:31","video":"","vorDoi":"10.1186/s12885-025-14218-5","vorDoiUrl":"https://doi.org/10.1186/s12885-025-14218-5","workflowStages":[]},"version":"v1","identity":"rs-5748321","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5748321","identity":"rs-5748321","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}