Abstract

Background: Immune checkpoint inhibitors (ICIs) emerged as the preferred therapy in advanced lung cancer, understanding the treatment- and immune-related adverse events of these drugs is of great significance for clinical practice.

Materials and methods: PubMed, Embase, Cochrane library and major conference proceedings were systematically searched for all randomized controlled trials (RCTs) in lung cancer using PD-1/PD-L1/CTLA-4 inhibitors. The outcomes included treatment-related adverse events (TRAEs) and several organ specific immune-related adverse events (IRAEs).

Results: 24 RCTs involving 14,256 patients were included. There was a significant difference for ICI therapy in the incidence of any grade of TRAEs (RR: 0.90; 95%CI: 0.84–0.95; P=0.001) and a lower frequency of grade 3-5 of TRAEs (RR: 0.65; 95%CI: 0.51–0.82; P<0.001). Patients treated with ICI therapy in non–small-cell lung cancer (NSCLC) were less reported TRAEs than in small cell lung cancer (SCLC). A lower risk of TRAEs was favored by anti-PD-1 inhibitors over anti-PD-L1 antibodies and anti-CTLA-4 drugs. The most common organ specific IRAE was hypothyroidism that occurred 8.7%. The incidence of pneumonitis and hepatitis reached 4.5% and 4.0% respectively. Compared with patients treated in control arms, those treated with ICI drugs were at higher risk for each organ specific adverse event including colitis, hepatitis, pneumonitis, hypothyroidism and hypophysitis.

Conclusions: ICI therapy was safer than chemotherapy, especially ICI monotherapy such as anti-PD-1 antibodies in NSCLC. Compared with standard treatments, ICI drugs increased the risk of organ-specific IRAEs, although the overall incidence remained low.

Introduction

Lung cancer still remains the most commonly diagnosed carcinoma type and the leading cause of cancer death globally [1]. According to the GLOBCAN report, an estimated 2.09 million new cases were diagnosed in 2018 [2]. Non–small-cell lung cancer (NSCLC) represents 85% of all lung tumors, and the other 15% is small-cell lung cancer (SCLC) [3]. Approximately one-third of patients with NSCLC have locally advanced disease at diagnosis [4]. Conventional therapy standard of first-line care treatment for advanced NSCLC and extensive-stage small-cell lung cancer (ES-SCLC) is platinum-doublet chemotherapy [5]. Despite over 30 years of clinical research, little progress has been made, and outcome of lung cancer remains poor [6]. Even in the most recent large randomized clinical trials (RCTs), the median overall survival (OS) of metastatic SCLC patients receiving standardized chemotherapy was still between 9 and 11 months [7–9]. The discovery of anaplastic lymphoma kinase (ALK) gene rearrangement in NSCLC in 2007 led to an understanding of its significance of disease biology and natural history [10]. Subsequently, the targetable genetic alterations of lung cancer have been gradually identified such as epidermal growth factor receptor (EGFR) mutations, kirsten rat sarcoma (KRAS) mutations and rat osteosarcoma (ROS1), and the development of targeted drugs greatly affected the prognosis of patients [11,12]. However, only a small proportion of patients harbor these mutations, and targeted drug therapy did not significantly improve 5-year overall survival of lung cancer patients [13].

The rapid development of immune checkpoint inhibitor (ICI), a revolutionary form of immunotherapy, has transformed the way numerous cancer are managed [14]. Inhibitory checkpoint molecules produced during T-cell activation, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that regulates the immune synapses between T cells and lymph node dendritic cells to inhibit T-cell activation, or programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) suppressing the immune synapses between T cells and tumor cells, are currently the most relevant targets for immunotherapy [15]. In 2011, Food and Drug Administration (FDA) approved the first checkpoint inhibitor ipilimumab, which is a fully human anti-CTLA-4 monoclonal antibody. Later, several immune checkpoint inhibitors directed at PD-1 (nivolumab and pembrolizumab) and PD-L1 (atezolizumab, durvalumab and avelumab) were approved for the treatment of multiple cancers [16,17]. These drugs improved clinical survival outcomes of solid cancer such as lung cancer dramatically. In a review of the literature, pembrolizumab has showed a significant survival benefit over chemotherapy when given as monotherapy or as part of combination therapy for metastatic, squamous or non-squamous NSCLC [18–20].

Like chemotherapy, immunotherapy can have serious treatment-related adverse events (TRAEs) leading to low compliance, dose reduction, delayed treatment or treatment rejection, although some studies illustrated anti-PD-1 drugs were overall less toxic than standard chemotherapy [21–23]. At the same time, ICI drugs have immune-related adverse events (IRAEs) reported on clinical trials. The IRAEs including colitis, hepatitis, pneumonitis, hypothyroidism, hyperthyroidism and so on affect multiple organ systems including skin, colon, endocrine organs, liver and lungs [24]. Here, we performed a systematic and meta-analysis of immunotherapy safety. High quality studies focusing on adverse events are required to aid clinicians to improve early management and identify IRAEs.

Materials and methods

Search strategy

A literature search of studies published up to March 2019 was performed from major citation databases, including PubMed, Embase and Cochrane Library. The following search terms were used: immune checkpoint inhibitor, PD-1 or programmed death 1, PD-L1 or programmed death ligand 1, CTLA-4 or cytotoxic T-lymphocyte-associated protein 4, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, ipilimumab, or tremelimumab, and lung cancer, randomized controlled trial. To identify additional studies, we also searched the major international congresses’ proceedings (American Society of Clinical Oncology, the European Society of Medical Oncology and the World Conference of Lung Cancer). When duplicate publications were identified, the most recent, relevant and comprehensive data were accepted. The present study was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement [25].

Study selection

Trails were eligible for inclusion if they met several criteria: (1) patients were pathologically diagnosed with lung cancer; (2) studies involving participants treated with ICI or ICI plus chemotherapy; (3) trails which the control was chemotherapy alone; (4) main outcome was treatment-related adverse events of any grade and grade 3-5; (5) phase II or III randomized controlled trials. Studies were exclusion: (1) retrospective or prospective cohort studies; (2) reviews, letters, commentaries, irrelevant abstract, quality of life studies, cost effectiveness analyses; (3) publications without detailed safety data.

Data extraction and quality assessment

Two investigators independently extracted data from each study with a piloted collection form: name of first author, year, trial phases, study ID, region, trial phase, types of tumor, treatment, the size of intervention and control group, TRAEs reporting rate, the frequency of specific adverse event and median follow-up time. The risk of bias was assessed by using Cochrane Risk of Bias Tool [26]. This scale evaluates six criteria: randomized sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; incomplete outcome data; selective reporting, and other bias. Each aspect was labeled as high, low or unclear risk. All disagreements in the study selection, data extraction and quality assessment were resolved by consensus.

Our primary outcome was the incidence of TRAEs, which indicated the toxicity of therapy. Our secondary outcome was the incidence of commonly described organ specific adverse events (colitis, hepatitis, pneumonitis, hypothyroidism and hypophysitis). We recorded data from full article and supplementary appendix. Common terms classified by clinical adverse events (CTCAE) were used to identify grade 3-5 as serious and grade 1-2 as other. Data from different dosing arms within the same study were extracted and reported separately.

Statistical analysis

For each of the included studies, we calculated the odds ratio and 95% confidence interval of event incidence between the intervention group and the control group based on the number of reported events and sample size. Risk ratio (RR) and 95% confidence interval (CI) were pooled to quantify the therapeutic effect. The heterogeneity of effect size estimates across studies was described with the I2 index and Q statistic’s P value. If significant heterogeneity was not present (P>0.1), the risk ratio was calculated with fixed effect meta-analysis; otherwise, a random effects model was applied to calculate pooled odds ratio and 95% confidence interval if significant heterogeneity was present (P≤0.1). We used funnel plots to assess publication bias. Two-sided P values less than 0.05 were considered statistically significant. All statistical analyses were conducted using Stata version 15.0 (StataCorp, College Station, TX).

Results

Eligible studies and characteristics

A total of 2993 records were initially in line based on the literature search, of which 1013 excluded because of duplications. After screening the titles, abstracts, full article, 24 randomized controlled trials (RCTs) were finally identified in strict inclusion and exclusion criteria. Data were obtained from published manuscripts and conference proceedings. The selection process was presented in Figure 1.

Flow chart of study selection and design/study flow diagram

Figure 1
Flow chart of study selection and design/study flow diagram
Figure 1
Flow chart of study selection and design/study flow diagram

All 24 studies included 14,256 patients representing advanced lung cancer were international multi center studies [8,18–20,27–46]. Twenty-one studies evaluated NSCLC, and the other three studies investigated ES-SCLC. About 7613 patients who received ICI monotherapy or combination therapy served as the investigational arm and 6643 patients who received chemotherapy as the control arms. KEYNOTE010 that analyzed two different doses (2 and 10 mg/kg) compared with standard control was divided into two trails. All grades, grade 3 and grade 4 adverse events indicate complete, severe and life threatening toxicity, respectively. The main characteristics of the included studies are summarized in Table 1.

Table 1
Characteristics of patients comparing ICI therapy with Chemotherapy in included randomized controlled trials
First authorStudy IDTrial PhaseCancer TypeTreatmentICI drugNO OF PatientsTRAEs all gradeTRAEs grade 3-5
Borghaei, 2018 KEYNOTE021 II NSCLC Pembrolizumab+Chemotherapy PD-1 55 24 59 
    Chemotherapy  57 17 62 
Gandhi, 2018 KEYNOTE189 III NSCLC Pembrolizumab+Chemotherapy PD-1 404 272 405 
    Chemotherapy  200 133 202 
Paz-Ares, 2018 KEYNOTE407 III NSCLC Pembrolizumab+Chemotherapy PD-1 273 194 278 
    Chemotherapy  274 191 280 
Herbst, 2016 KEYNOTE010 II/III NSCLC Pembrolizumab, 2 mg/kg PD-1 215 43 339 
    Pembrolizumab, 10 mg/kg PD-1 226 55 343 
    Chemotherapy  251 109 309 
Reck, 2016 KEYNOTE024 III NSCLC Pembrolizumab PD-1 113 41 154 
    Chemotherapy  135 80 150 
Lopes, 2018 KEYNOTE042 III NSCLC Pembrolizumab PD-1 399 113 636 
    Chemotherapy  553 252 615 
Borghaei, 2018 CheckMate227(a) III NSCLC Nivolumab+Chemotherapy PD-1 158 89 172 
    Chemotherapy  141 64 183 
Hellmann, 2018 CheckMate227(b) III NSCLC Nivolumab PD-1 42 30 391 
    Chemotherapy  79 61 570 
Brahmer, 2015 CheckMate017 III NSCLC Nivolumab PD-1 76 131 
    Chemotherapy  111 71 129 
Carbone, 2017 CheckMate026 III NSCLC Nivolumab PD-1 190 47 267 
    Chemotherapy  243 133 263 
Borghaei, 2015 CheckMate057 III NSCLC Nivolumab PD-1 199 30 287 
    Chemotherapy  236 144 268 
Wu, 2019 CheckMate078 III NSCLC Nivolumab PD-1 216 35 337 
    Chemotherapy  130 74 156 
Jotte, 2018 IMpower131 III NSCLC Atezolizumab+Chemotherapy PD-L1 316 231 334 
    Chemotherapy  303 193 334 
Papadimitrakopoulou, 2018 IMpower132 III NSCLC Atezolizumab+Chemotherapy PD-L1 267 167 291 
    Chemotherapy  239 114 274 
Horn, 2018 IMpower133 III ES-SCLC Atezolizumab+Chemotherapy PD-L1 188 115 198 
    Chemotherapy  181 113 196 
Socinski, 2018 IMpower150 III NSCLC Atezolizumab+Chemotherapy PD-L1 371 230 393 
    Chemotherapy  376 197 394 
Rittmeyer, 2017 OAK III NSCLC Atezolizumab PD-L1 390 90 609 
    Chemotherapy  496 247 578 
Fehrenbacher, 2016 POPLAR II NSCLC Atezolizumab PD-L1 95 17 142 
    Chemotherapy  119 55 135 
Barlesi, 2018 JAVELIN Lung 200 III NSCLC Avelumab PD-L1 251 39 393 
    Chemotherapy  313 180 365 
Antonia, 2018 PACIFIC III NSCLC Durvalumab+Chemoradiotherapy PD-L1 460 142 475 
    Chemotherapy  222 61 234 
Lynch, 2012 CA184-041(a) II NSCLC Ipilimumab+Chemotherapy CTLA-4 54 29 71 
    Chemotherapy  52 24 65 
Reck, 2013 CA184-041(b) II ES-SCLC Ipilimumab+Chemotherapy CTLA-4 35 18 42 
    Chemotherapy  40 13 44 
Govindan, 2017 CA184-104 III NSCLC Ipilimumab+Chemotherapy CTLA-4 344 205 388 
    Chemotherapy  292 129 361 
Reck, 2016 CA184-156 III ES-SCLC Ipilimumab+Chemotherapy CTLA-4 391 231 478 
    Chemotherapy  361 214 476 
First authorStudy IDTrial PhaseCancer TypeTreatmentICI drugNO OF PatientsTRAEs all gradeTRAEs grade 3-5
Borghaei, 2018 KEYNOTE021 II NSCLC Pembrolizumab+Chemotherapy PD-1 55 24 59 
    Chemotherapy  57 17 62 
Gandhi, 2018 KEYNOTE189 III NSCLC Pembrolizumab+Chemotherapy PD-1 404 272 405 
    Chemotherapy  200 133 202 
Paz-Ares, 2018 KEYNOTE407 III NSCLC Pembrolizumab+Chemotherapy PD-1 273 194 278 
    Chemotherapy  274 191 280 
Herbst, 2016 KEYNOTE010 II/III NSCLC Pembrolizumab, 2 mg/kg PD-1 215 43 339 
    Pembrolizumab, 10 mg/kg PD-1 226 55 343 
    Chemotherapy  251 109 309 
Reck, 2016 KEYNOTE024 III NSCLC Pembrolizumab PD-1 113 41 154 
    Chemotherapy  135 80 150 
Lopes, 2018 KEYNOTE042 III NSCLC Pembrolizumab PD-1 399 113 636 
    Chemotherapy  553 252 615 
Borghaei, 2018 CheckMate227(a) III NSCLC Nivolumab+Chemotherapy PD-1 158 89 172 
    Chemotherapy  141 64 183 
Hellmann, 2018 CheckMate227(b) III NSCLC Nivolumab PD-1 42 30 391 
    Chemotherapy  79 61 570 
Brahmer, 2015 CheckMate017 III NSCLC Nivolumab PD-1 76 131 
    Chemotherapy  111 71 129 
Carbone, 2017 CheckMate026 III NSCLC Nivolumab PD-1 190 47 267 
    Chemotherapy  243 133 263 
Borghaei, 2015 CheckMate057 III NSCLC Nivolumab PD-1 199 30 287 
    Chemotherapy  236 144 268 
Wu, 2019 CheckMate078 III NSCLC Nivolumab PD-1 216 35 337 
    Chemotherapy  130 74 156 
Jotte, 2018 IMpower131 III NSCLC Atezolizumab+Chemotherapy PD-L1 316 231 334 
    Chemotherapy  303 193 334 
Papadimitrakopoulou, 2018 IMpower132 III NSCLC Atezolizumab+Chemotherapy PD-L1 267 167 291 
    Chemotherapy  239 114 274 
Horn, 2018 IMpower133 III ES-SCLC Atezolizumab+Chemotherapy PD-L1 188 115 198 
    Chemotherapy  181 113 196 
Socinski, 2018 IMpower150 III NSCLC Atezolizumab+Chemotherapy PD-L1 371 230 393 
    Chemotherapy  376 197 394 
Rittmeyer, 2017 OAK III NSCLC Atezolizumab PD-L1 390 90 609 
    Chemotherapy  496 247 578 
Fehrenbacher, 2016 POPLAR II NSCLC Atezolizumab PD-L1 95 17 142 
    Chemotherapy  119 55 135 
Barlesi, 2018 JAVELIN Lung 200 III NSCLC Avelumab PD-L1 251 39 393 
    Chemotherapy  313 180 365 
Antonia, 2018 PACIFIC III NSCLC Durvalumab+Chemoradiotherapy PD-L1 460 142 475 
    Chemotherapy  222 61 234 
Lynch, 2012 CA184-041(a) II NSCLC Ipilimumab+Chemotherapy CTLA-4 54 29 71 
    Chemotherapy  52 24 65 
Reck, 2013 CA184-041(b) II ES-SCLC Ipilimumab+Chemotherapy CTLA-4 35 18 42 
    Chemotherapy  40 13 44 
Govindan, 2017 CA184-104 III NSCLC Ipilimumab+Chemotherapy CTLA-4 344 205 388 
    Chemotherapy  292 129 361 
Reck, 2016 CA184-156 III ES-SCLC Ipilimumab+Chemotherapy CTLA-4 391 231 478 
    Chemotherapy  361 214 476 

Abbreviations: CTLA-4, cytotoxic T-lymphocyte-associated protein 4; ES-SCLC, extensive-stage small cell lung cancer; ICI, immune checkpoint inhibitors; NSCLC: non–small cell lung cancer; PD-1, programmed death 1; PD-L1, programmed death ligand 1; TRAE, treatment-related adverse event.

Treatment-related adverse event

In terms of ICI therapy in advanced lung cancer, there was a significant difference in the probability of any grade of TRAEs (RR: 0.90; 95%CI: 0.84–0.95; P=0.001) and a lower frequency of grade 3-5 of TRAEs (RR: 0.65; 95%CI: 0.51–0.82; P<0.001) (Figure 2). However, subgroup analysis demonstrated ICI-chemotherapy associated with the risk of TRAEs (any grade: RR: 1.03; 95%CI: 1.01–1.06; P=0.017; grade 3-5: RR: 1.18; 95%CI: 1.09–1.28; P<0.001). ICI monotherapy was safer in the risk of grade 1-5 (RR: 0.76; 95%CI: 0.73–0.78; P<0.001)and grade 3-5 (RR: 0.33; 95%CI: 0.26–0.41; P<0.001) adverse events than standard control. The finding indicated that ICI therapy led to a significant difference in NSCLC for TRAEs (any grade: RR: 0.88; 95%CI: 0.82–0.95; P=0.001; grade 3-5: RR: 0.60; 95%CI: 0.46–0.78; P<0.001), but no statistical significance in SCLC (any grade: RR: 1.03; 95%CI: 0.97–1.10; P=0.318; grade 3-5: RR: 1.06; 95%CI: 0.95–1.18; P=0.280). A lower risk of any grade (RR: 0.85; 95%CI: 0.74–0.97; P=0.018) or grade 3-5 (RR: 0.50; 95%CI: 0.35–0.73; P<0.001) adverse events was favored by anti-PD-1 antibodies over anti-PD-L1 antibodies (any grade: RR: 0.92; 95%CI: 0.83–1.01; P=0.090; grade 3-5: RR: 0.70; 95%CI: 0.46–1.05; P=0.086). Anti-CTLA-4 antibodies was not different from conventional therapy in any grade TRAEs (RR: 1.05; 95%CI: 0.98–1.12; P=0.179), but less safe in grade 3-5 (RR: 1.25; 95%CI: 1.00–1.55; P=0.047; Table 2).

Forest plot of all grade (A) and grade 3-5 (B) TRAEs in lung cancer patients treated with ICI versus chemotherapy

Figure 2
Forest plot of all grade (A) and grade 3-5 (B) TRAEs in lung cancer patients treated with ICI versus chemotherapy
Figure 2
Forest plot of all grade (A) and grade 3-5 (B) TRAEs in lung cancer patients treated with ICI versus chemotherapy
Table 2
Risk ratios for treatment-related adverse events (TRAEs) comparing ICI therapy with Chemotherapy
All gradeGrade 3-5
No. of trialsNo. of patientsI2 (P)RR (95%CI)PNo. of trialsNo. of patientsI2 (P)RR (95%CI)P
Overall* 25 14256 97.1% (<0.001) 0.90 (0.84,0.95) 0.001 Overall 25 14256 96.7% (<0.001) 0.65 (0.52,0.82) <0.001 
Subgroup      Subgroup      
Method      Method      
ICI-Chem 13 6689 77.4% (<0.001) 1.03 (1.01,1.06) 0.017 ICI-Chem 13 6689 61.8% (0.002) 1.18 (1.09,1.28) <0.001 
ICI 12 7567 19.0% (0.257) 0.76 (0.73,0.78) <0.001 ICI 12 7567 82.9% (<0.001) 0.33 (0.26,0.41) <0.001 
Cancer Type      Cancer Type      
NSCLC 22 12822 97.8% (<0.001) 0.88 (0.82,0.95) 0.001 NSCLC 22 12822 97.1% (<0.001) 0.60 (0.46,0.78) <0.001 
SCLC 1434 50.0% (0.135) 1.03 (0.97,1.10) 0.318 SCLC 1434 0.0% (0.460) 1.06 (0.95,1.18) 0.280 
ICI drug      ICI drug      
Anti-PD-1 13 6986 98.8% (<0.001) 0.85 (0.74,0.97) 0.018 Anti-PD-1 13 6986 96.8% (<0.001) 0.50 (0.35,0.73) <0.001 
Anti-PD-L1 5345 96.7% (<0.001) 0.92 (0.83,1.01) 0.090 Anti-PD-L1 5345 97.5% (<0.001) 0.70 (0.46,1.05) 0.086 
Anti-CTLA-4 1925 47.6% (0.126) 1.05 (0.98,1.12) 0.179 Anti-CTLA-4 1925 66.6% (0.030) 1.25 (1.00,1.55) 0.047 
All gradeGrade 3-5
No. of trialsNo. of patientsI2 (P)RR (95%CI)PNo. of trialsNo. of patientsI2 (P)RR (95%CI)P
Overall* 25 14256 97.1% (<0.001) 0.90 (0.84,0.95) 0.001 Overall 25 14256 96.7% (<0.001) 0.65 (0.52,0.82) <0.001 
Subgroup      Subgroup      
Method      Method      
ICI-Chem 13 6689 77.4% (<0.001) 1.03 (1.01,1.06) 0.017 ICI-Chem 13 6689 61.8% (0.002) 1.18 (1.09,1.28) <0.001 
ICI 12 7567 19.0% (0.257) 0.76 (0.73,0.78) <0.001 ICI 12 7567 82.9% (<0.001) 0.33 (0.26,0.41) <0.001 
Cancer Type      Cancer Type      
NSCLC 22 12822 97.8% (<0.001) 0.88 (0.82,0.95) 0.001 NSCLC 22 12822 97.1% (<0.001) 0.60 (0.46,0.78) <0.001 
SCLC 1434 50.0% (0.135) 1.03 (0.97,1.10) 0.318 SCLC 1434 0.0% (0.460) 1.06 (0.95,1.18) 0.280 
ICI drug      ICI drug      
Anti-PD-1 13 6986 98.8% (<0.001) 0.85 (0.74,0.97) 0.018 Anti-PD-1 13 6986 96.8% (<0.001) 0.50 (0.35,0.73) <0.001 
Anti-PD-L1 5345 96.7% (<0.001) 0.92 (0.83,1.01) 0.090 Anti-PD-L1 5345 97.5% (<0.001) 0.70 (0.46,1.05) 0.086 
Anti-CTLA-4 1925 47.6% (0.126) 1.05 (0.98,1.12) 0.179 Anti-CTLA-4 1925 66.6% (0.030) 1.25 (1.00,1.55) 0.047 

Abbreviations: CI, confidence interval; RR, risk ratio.

Immune-related adverse event

Among intervention group, the most common IRAE was hypothyroidism that occurred 8.7%, while colitis, hepatitis, pneumonitis and hypophysitis occurred 1.6%, 4.0%, 4.5% and 0.6% respectively. Looking at serious organ specific IRAEs, 1.8% patients had hepatitis, 1.5% patients with pneumonitis, 0.8% patients with colitis, 0.3% patients with hypothyroidism and 0.3% patients had hypophysitis. Table 3 shows the rates of organ specific serious immune-related adverse events.

Table 3
Incidence of organ specific immune-related adverse events (IRAEs); value are percentage (95% confidence intervals)
AuthorStudy IDInterventionColitisHepatitisPneumonitisHypothyroidismHypophysitis
AllSeriousAllSeriousAllSeriousAllSeriousAllSerious
Borghaei, 2018 KEYNOTE021 59 1.7 0.0 NA NA 6.8 1.7 15.3 0.0 NA NA 
Gandhi, 2018 KEYNOTE189 405 2.2 0.7 1.2 1.0 4.4 2.7 6.7 0.5 0.7 0.0 
Paz-Ares, 2018 KEYNOTE407 278 2.5 2.2 1.8 1.8 6.5 2.5 7.9 0.4 1.1 0.7 
Herbst, 2016 KEYNOTE010(a) 339 1.2 0.9 NA NA 4.7 2.1 8.3 0.0 0.3 0.3 
Herbst, 2016 KEYNOTE010(b) 343 0.6 0.3 NA NA 4.4 2.0 8.2 0.0 0.3 0.3 
Reck, 2016 KEYNOTE024 154 1.9 1.3 NA NA 5.8 2.6 9.1 0.0 0.6 0.6 
Wu, 2019 CheckMate078 337 NA NA NA NA 3.0 1.2 NA NA NA NA 
Jotte, 2018 IMpower131 334 1.8 1.2 17.4 5.4 6.9 1.2 10.2 0.6 NA NA 
Papadimitrakopoulou, 2018 IMpower132 291 1.7 0.7 4.5 2.4 5.5 2.1 7.9 0.7 NA NA 
Horn, 2018 IMpower133 198 1.5 1.0 7.1 3.5 2.0 0.5 12.6 0.0 0.5 0.0 
Socinski, 2018 IMpower150 393 2.3 1.3 2.0 1.0 2.8 1.3 12.7 0.3 0.8 0.3 
Rittmeyer, 2017 OAK 609 0.3 0.0 0.3 0.3 1.0 0.7 NA NA NA NA 
Fehrenbacher, 2016 POPLAR 142 1.4 0.7 0.7 0.0 2.8 0.7 5.6 0.7 NA NA 
Barlesi, 2018 JAVELIN Lung 200 393 0.3 NA NA NA 2.3 NA 4.8 NA NA NA 
Antonia, 2018 PACIFIC 475 NA NA NA NA 10.7 1.7 9.3 0.2 NA NA 
Lynch, 2012 CA184-041(a) 71 NA NA NA NA NA NA NA NA 1.4 1.4 
Reck, 2013 CA184-041(b) 42 2.4 2.4 2.4 2.4 NA NA NA NA 0.0 0.0 
Govindan, 2017 CA184-104 388 4.4 2.3 NA NA NA NA NA NA NA NA 
TOTAL   1.6 (1.3–2.0) 0.8 (0.6–1.1) 4.0 (3.3–4.8) 1.8 (1.3–2.4) 4.5 (3.9–5.1) 1.5 (1.2–1.9) 8.7 (7.8–9.6) 0.3 (0.2–0.5) 0.6 (0.3–1.0) 0.3 (0.1–0.6) 
AuthorStudy IDInterventionColitisHepatitisPneumonitisHypothyroidismHypophysitis
AllSeriousAllSeriousAllSeriousAllSeriousAllSerious
Borghaei, 2018 KEYNOTE021 59 1.7 0.0 NA NA 6.8 1.7 15.3 0.0 NA NA 
Gandhi, 2018 KEYNOTE189 405 2.2 0.7 1.2 1.0 4.4 2.7 6.7 0.5 0.7 0.0 
Paz-Ares, 2018 KEYNOTE407 278 2.5 2.2 1.8 1.8 6.5 2.5 7.9 0.4 1.1 0.7 
Herbst, 2016 KEYNOTE010(a) 339 1.2 0.9 NA NA 4.7 2.1 8.3 0.0 0.3 0.3 
Herbst, 2016 KEYNOTE010(b) 343 0.6 0.3 NA NA 4.4 2.0 8.2 0.0 0.3 0.3 
Reck, 2016 KEYNOTE024 154 1.9 1.3 NA NA 5.8 2.6 9.1 0.0 0.6 0.6 
Wu, 2019 CheckMate078 337 NA NA NA NA 3.0 1.2 NA NA NA NA 
Jotte, 2018 IMpower131 334 1.8 1.2 17.4 5.4 6.9 1.2 10.2 0.6 NA NA 
Papadimitrakopoulou, 2018 IMpower132 291 1.7 0.7 4.5 2.4 5.5 2.1 7.9 0.7 NA NA 
Horn, 2018 IMpower133 198 1.5 1.0 7.1 3.5 2.0 0.5 12.6 0.0 0.5 0.0 
Socinski, 2018 IMpower150 393 2.3 1.3 2.0 1.0 2.8 1.3 12.7 0.3 0.8 0.3 
Rittmeyer, 2017 OAK 609 0.3 0.0 0.3 0.3 1.0 0.7 NA NA NA NA 
Fehrenbacher, 2016 POPLAR 142 1.4 0.7 0.7 0.0 2.8 0.7 5.6 0.7 NA NA 
Barlesi, 2018 JAVELIN Lung 200 393 0.3 NA NA NA 2.3 NA 4.8 NA NA NA 
Antonia, 2018 PACIFIC 475 NA NA NA NA 10.7 1.7 9.3 0.2 NA NA 
Lynch, 2012 CA184-041(a) 71 NA NA NA NA NA NA NA NA 1.4 1.4 
Reck, 2013 CA184-041(b) 42 2.4 2.4 2.4 2.4 NA NA NA NA 0.0 0.0 
Govindan, 2017 CA184-104 388 4.4 2.3 NA NA NA NA NA NA NA NA 
TOTAL   1.6 (1.3–2.0) 0.8 (0.6–1.1) 4.0 (3.3–4.8) 1.8 (1.3–2.4) 4.5 (3.9–5.1) 1.5 (1.2–1.9) 8.7 (7.8–9.6) 0.3 (0.2–0.5) 0.6 (0.3–1.0) 0.3 (0.1–0.6) 

All 1: includes all Common Terms classified by Clinical Adverse Events (CTCAE) grades.

Serious2: includes CTCAE grades 3,4, or 5. NA: not available

In the present study, compared with patients treated in control arms, those treated with ICI were at higher risk for IRAEs. Figure 3 showed that ICI therapy increased the frequency of immune-related colitis (RR: 5.54; 95%CI: 3.06–10.02; P<0.001), though events were rare. Patients treated with ICI drugs were at a higher risk for any grade hepatitis (RR: 2.49; 95%CI: 1.77–3.50; P<0.001) and pneumonitis (RR: 2.57; 95%CI: 1.96–3.37; P<0.001). Patients were more likely to experience hypothyroidism (RR: 6.33; 95%CI: 4.66–8.61; P<0.001) and hypophysitis (RR: 3.91; 95%CI: 1.33–11.54; P=0.013) compared with patients in the chemotherapy.

Forest plot of colitis (A), hepatitis (B), pneumonitis (C), hypothyroidism (D) and hypophysitis (E) in lung cancer patients treated with ICI versus chemotherapy

Figure 3
Forest plot of colitis (A), hepatitis (B), pneumonitis (C), hypothyroidism (D) and hypophysitis (E) in lung cancer patients treated with ICI versus chemotherapy
Figure 3
Forest plot of colitis (A), hepatitis (B), pneumonitis (C), hypothyroidism (D) and hypophysitis (E) in lung cancer patients treated with ICI versus chemotherapy

Quality of included studies and sensitivity analysis

Risk of bias of the included RCTs was showed in Supplementary Table S1. Most studies have experienced low risk, especially the generation of random sequences. Unclear risk of bias was mainly focused on performance bias (blinding of participants and personnel). To examine the stability of the combined results, we conducted a sensitivity analysis after removing conference proceedings (Supplementary Figure S1). After these analyses, the results indicated that the outcome remained consistent.

Discussion

Included more than 14,000 patients in advanced lung cancer, the present study was performed to analyze adverse events of ICI therapy versus the standard treatment to further our understanding of the safety of this emerging class of drugs. The pooled study indicated that ICI therapy was safer than chemotherapy, especially ICI monotherapy or anti-PD-1 drug in NSCLC. But ICI-chemotherapy increased the incidence of TRAEs, and anti-CTLA-4 antibodies was less safe in grade 3-5 TRAEs. Organ special IRAEs including colitis, hepatitis, pneumonitis, hypothyroidism and hypophysitis were uncommon but the risk was increased compared with control treatment.

Chemotherapy has always been the most commonly used class of antineoplastic drugs for advanced cancers. Traditional chemotherapeutic drugs work by killing rapidly dividing cells, whether they are tumor or healthy. Due to the long-term clinical application, the toxicities of chemotherapy drugs that reduce the quality of life of patients have been clearly demonstrated [47]. In the era of precision medicine, it is proposed that the treatment should not only cure diseases, but also restore patients’ health with the maximum quality of life [48]. Fortunately, the development of immunotherapy challenged the management of treatment-related toxic effects. Like the prior study, ICI drugs were overall less toxic than chemotherapy especially in monotherapy, and combining an ICI with chemotherapy increased the rate of grade 3 or worse severity TRAEs [49,50]. Although combined therapy resulted in significantly longer overall survival and progression-free survival than chemotherapy, its cytotoxicity also improved, which should not be underestimated [51]. Moreover, it is worth mentioning that ICI therapy was safer in risk of TRAEs for NSCLC patients, but less safe for SCLC. This may be due to the different pathogenesis of these two cancer types. In terms of drugs, anti-PD-1 antibodies had the best safety profile in lung cancer, which was consistent with previous conclusions [52]. Theoretically, PD-1 antibody can bind to PD-1 protein on T cells, thus blocking the binding of PD-1 to PD-L1 and PD-L2, while PD-L1 antibody can only interact with PD-L1, so it can only block the binding of PD-1 to PD-L1. All that meant PD-1 antibody emerged as the best option for treatment in advance lung cancer patients with greater survival condition and low incidence of TRAEs.

IRAEs represent the immune effect of incorrect stimulation of the immune system on normal tissues. Compared with the toxicities caused by conventional treatment, the IRAEs of ICI drugs have unique characteristics in organs involved, pathogenesis patterns and severity [53]. A number of randomized controlled trials were summarized the general situation of IRAEs, including skin, gastrointestinal, pulmonary, hepatic and endocrine toxicities [29,32,33,42]. The present study focused on five organs special IRAEs, including colitis, hepatitis, pneumonitis, hypothyroidism, and hypophysitis. For lung cancer, the most common organ specific IRAE was hypothyroidism which occurred 8.7%. The incidence of pneumonitis and hepatitis reached 4.5% and 4.0%, respectively. In addition, a recent study evaluated the risk of IRAEs in patients treated with anti-PD-1 and anti-PD-L1 drugs [14]. Our findings regarding risk of IRAEs were similar that those treated with ICI drugs were at higher risk for each organ specific adverse event compared with patients treated in control arms. Precise explanations for these observed differences were unknown, but this high-risk situation suggests that routine thyroid function tests and chest CT examinations should be added to patients with ICI therapy [54,55].

All the results emphasized a need for increased awareness and careful monitoring of patients with lung cancer during immunotherapy for the possibility of adverse events, particularly in IRAEs. Although most IRAEs are typically manageable with supportive treatment and glucocorticoids, uncommon fatal events have been reported increasingly [56–58]. The mechanism of IRAEs was still unclear. Health care providers need to maintain a high index of suspicion when patients develop worsening of symptoms and take appropriate measures to diagnose, initiate corticosteroids at the right time. Moreover, careful multidisciplinary consultation should be conducted in each case of suspected IRAEs to avoid improper disease management. In addition to advances in treatment strategies, identifying and improving the use of predictive biomarkers will also be critical for identifying patients most likely to benefit from treatment [59].

There were several limitations in the current study. First, the follow-up time was different from included studies (range 8–24 months), and the patients might have been discharged from hospital at the time of measurement. For example, it was reported that pneumonitis occur between 7.4 and 24.3 months after taking ICI drugs. [60] Thus the frequency of adverse events might be influenced by the confounding effect of time. Second, the methods for identifying adverse events had not standardized. Even in CTCAE, overlapping definitions confuse the recognizing of specific adverse events which leaded to potential uncertainty about data quality. As such, recognizing adverse events that usually depended on investigators’ evaluation might cause errors. A classic example was that immune-related colitis could be classified as colitis or diarrhea. Third, we combined all ICI drugs into experience group, including several therapeutic agents. However, because such a subdivision would result in more subgroups with smaller sample sizes, the cohorts were not subdivided according to these agents. Looking ahead, longer follow-up and special attention to various adverse events are needed to enhance our understanding.

Conclusions

The present study indicated that immunotherapy was superior to chemotherapy in terms of safety profiles, especially ICI monotherapy. Patients treated with ICI therapy in NSCLC were less reported TRAEs than in SCLC. A lower risk of TRAEs was favored by anti-PD-1 antibodies over anti-PD-L1 antibodies and anti-CTLA-4 antibodies. Compared with standard treatments, ICI drugs increased the risk of organ-specific IRAEs, although the overall incidence remained low. For clinicians, it was important to monitor all IRAEs in lung cancer patients treated with ICI drugs.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

This work was supported by National Natural Science Foundation of China [grant numbers 91859203 and 81871890] and Chengdu Science and Technology Program Projects [grant number 2017-CY02-00030-GX].

Author Contribution

C.W., P.T. and W.L. designed the research study. J.S. and C.W. performed the search, extracted the data, drew the draft and revised the manuscript. P.R. and Y.J. analyzed the data. C.W., J.S., P.T. and W.L. contributed to discussion and reviewed the manuscript. All authors have participated sufficiently in the study and approved the final version.

Abbreviations

     
  • ALK

    anaplastic lymphoma kinase

  •  
  • CI

    confidence interval

  •  
  • CTCAE

    common terms classified by clinical adverse events

  •  
  • CTLA-4

    cytotoxic T-lymphocyte-associated protein 4

  •  
  • EGFR

    epidermal growth factor receptor

  •  
  • ES-SCLC

    extensive-stage small-cell lung cancer

  •  
  • FDA

    Food and Drug Administration

  •  
  • ICI

    immune checkpoint inhibitor

  •  
  • IRAE

    immune-related adverse event

  •  
  • KRAS

    kirsten rat sarcoma

  •  
  • NSCLC

    non–small-cell lung cancer

  •  
  • PD-1

    programmed death 1

  •  
  • PD-L1

    programmed death ligand 1

  •  
  • PD-L2

    programmed death ligand 2

  •  
  • RCT

    randomized controlled trial

  •  
  • ROS1

    rat osteosarcoma

  •  
  • RR

    risk ratio

  •  
  • SCLC

    small-cell lung cancer

  •  
  • TRAE

    treatment-related adverse event

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Author notes

*

These authors contributed equally to this work.

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