# Risk of Rash in PD-1 or PD-L1-Related Cancer Clinical Trials: A Systematic Review and Meta-Analysis

Authors: Yuan Tian; Chi Zhang; Qi Dang; Kaiyong Wang; Qian Liu; Hongmei Liu; Heli Shang; Junyan Zhao; Yuedong Xu; Tong Wu; Wei Liu; Xiaowei Yang; Mohammed Safi
Journal: Journal of Oncology
 (2022)

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## Abstract

Background. Given that immune-related rash was the most frequently reported PD-1 or PD-L1-related skin toxicity, this systematic review and meta-analysis were conducted to elucidate its incidence risk. Methods. The meta-analysis was carried out according to the PRISMA guidelines. The random effect model was used in the process of all analyses. Skin rash of all grades and grades 3–5 were calculated and gathered in the final comprehensive analyses. Results. The study included 86 clinical trials classified into 15 groups. Compared with chemotherapy, PD-1 or PD-L1 inhibitors significantly strengthened the risk of developing rash across all grades (OR = 1.66, 95% CI: [1.31, 2.11]; p<0.0001). This trend was significantly stronger when the control group was placebo (OR = 2.62, 95% CI: [1.88, 3.65]; p<0.00001). Similar results were observed when PD-1 or PD-L1 inhibitors were given together with chemotherapy (OR = 1.87, 95% CI: [1.59, 2.20]; p<0.00001), even in patients with grades 3–5. As with other combination therapies, the risk of developing rash for all grades was enhanced when PD-1 or PD-L1 was given together with chemotherapy as the second-line option (OR = 2.98, 95% CI: [1.87, 4.75]; p=0.05). No statistically significant differences could be found in skin rash between the PD-1 and PD-L1-related subgroups. Conclusion. Whether PD-1 or PD-L1 inhibitors were given alone or together with others, the risk of developing rash would be enhanced. Furthermore, the risk of developing rash appeared to be higher when PD-1 or PD-L1 inhibitors together with other antitumor drugs were given as the second-line options. No statistically significant results of developing rash between PD-1 and PD-L1 subgroups were obtained owing to the participation of PD-1 or PD-L1 inhibitors.


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## Body

## 1. Introduction

Due to tobacco cessation, advancements in early diagnosis and treatment, the death rate of various cancers has been falling year after year in the United States, while the survival rate has been improving, particularly for non-small-cell lung cancer (NSCLC) [1]. Among the several therapeutic options available, cancer immunotherapy is extremely successful in increasing cancer patients’ survival rates, particularly when PD-1 or PD-L1 inhibitors are given [2]. On the basis of research into the mechanisms of immune escape, PD-1 or PD-L1 inhibitors have reshaped the therapy landscape for cancer by activating the immune system, while also gradually reporting plenty of treatment-related side effects [3]. Although the association between some adverse events and PD-1 or PD-L1 inhibitors has been extensively examined and documented [4–9], many toxicities remain unexplored, including skin toxicities [3].Skin toxicities, such as rash, pruritus, vitiligo, palmar-plantar erythrodysasthesia (PPE), erythema, eczema, urticaria, dermatitis, dry skin, and maculopapular rash, were frequently observed in cancer patients treated with PD-1 or PD-L1 [3, 10, 11]. Additionally, autoimmune skin toxicities associated with PD-1 or PD-L1 have been reported to be significantly more prevalent in patients with NSCLC who are in complete or partial remission [10]. This pattern may also be observed in other types of tumors [11, 12]. Correlations between adverse events and clinical benefit are not uncommon [13–15]. However, the correlations between the risk of developing skin toxicities and PD-1 or PD-L1 inhibitors, as well as their effect on patient prognosis, remain unknown. Therefore, the rash with the highest rate of occurrence among PD-1 or PD-L1-related skin toxicities was chosen for the comprehensive analysis. To begin, subgroup analysis would be used to assess the difference in rash risk between the PD-1 and PD-L1 subgroups; second, the effect of different administration timing on rash would be assessed; and then, detailed subgroup analysis would be used to elucidate the source of heterogeneity.


## 2. Methods

The design and specific procedures of the meta-analysis were carried out step-by-step as recommended by the PRISMA [16].


### 2.1. Eligibility Screening for All Clinical Trials

Phase III clinical trials involving PD-1 or PD-L1 inhibitors with control groups would be preferred. Other clinical trials with control groups would be placed in an alternate location. With the exception of hematological malignancies, the types of solid tumors would not be limited. All data involving rash would be extracted and recorded in preparation for the subsequent adequate subgroup analysis. Four authors were appointed for eligibility screening.


### 2.2. Formulation and Implementation of Literature Search Strategy

According to the principle of PICOS (participants, interventions, comparisons, outcomes, and study design), the specific strategy of literature search was specified and implemented by all authors [16]. First, neoplasm was firstly searched as the MeSH keyword, not limited to specific solid tumor types. Then, all kinds of PD-1 or PD-L1 inhibitors, including common names, trade names, and abbreviations, would be searched as keywords and the search results would be unioned.The publication time of relevant studies would be limited from July 09, 2013, to September 14, 2021. If one clinical trial was repeatedly reported several times, only the one with full detailed data could be selected for the analysis.


### 2.3. Quality Evaluation and Publication Bias Screening

The revised Cochrane Collaboration tool was adopted for bias risk screening in all selected trials [17], and the Funnel plot and Egger’s test were used for publication bias assessments [18]. A p value < 0.05 was considered as the evidence for the existence of publication bias.The quality screening of all the enrolled clinical trials were also carried out by the above four authors. The screening criteria were listed as the following 5 items: (a) selection bias, (b) performance bias, (c) detection bias, (d) attrition bias, and (e) reporting bias [17].


### 2.4. Screening of Results

The main outcome measure was the risk of PD-1 or PD-L1 involving rash across all grades, while the second was the rash for grades 3–5. The main information of all trials would be extracted and summarized in the single table (Table1). The main content included in the table was listed as the following items: the first author’s name, publication years, trial title, registered trial number, therapies lines, treatment regimens, participants, phase, tumor type, RCT, and the number of rash events.Table 1
Basic information of all selected clinical trials.
Trial no.ReferenceNCT numberDrugTreatment RegimensInvolving PatientsRashPrevious therapyPhaseTumor Type1Borghaei H,et al. 2015 [22]NCT01673867 (CheckMate 057)Nivolumab (PD-1)Nivolumab versus Docetaxel55535YesIIIAdvanced non-squamous NSCLC2Weber JS,et al. 2015 [23]NCT01721746 (CheckMate 037)Nivolumab (PD-1)Nivolumab versus Dacarbazine/Paclitaxel plus Carboplatin37030NoIIIAdvanced melanoma3Brahmer J,et al. 2015 [24]NCT01642004 (CheckMate 017)Nivolumab (PD-1)Nivolumab versus Docetaxel26013YesIIIAdvanced squamous cell NSCLC4Motzer RJ,et al. 2015 [25]NCT01668784 (CheckMate 025)Nivolumab (PD-1)Nivolumab versus Everolimus803120YesIIIAdvanced RCC5Herbst RS,et al. 2016A [26]NCT01905657 (KEYNOTE-010)Pembrolizumab (PD-1)Pembrolizumab 2 mg/kg versus Pembrolizumab 10 mg/kg99173YesII/IIIAdvanced NSCLCHerbst RS,et al. 2016B [26]Pembrolizumab 2 mg/kg versus Docetaxel43Herbst RS,et al. 2016C [26]Pembrolizumab 10 mg/kg versus Docetaxel586Langer CJ,et al. 2016 [27]NCT02039674 (KEYNOTE-021)Pembrolizumab (PD-1)Pembrolizumab plus Carboplatin plus Pemetrexed versus Carboplatin plus Pemetrexed12125NoIIAdvanced nonsquamous NSCLCAwad MM,et al. 2021 [28]7Antonia SJ,et al. 2016 [29]NCT01928394 (CheckMate 032)Nivolumab (PD-1)Nivolumab versus Nivolumab plus Ipilimumab1526YesI/IIRecurrent SCLC8Ferris RL,et al. 2016 [30]NCT02105636 (CheckMate 141)Nivolumab (PD-1)Nivolumab versus (Methotrexate, Docetaxel, or Cetuximab)34723YesIIIRecurrent HNSCC9Hodi FS,et al. 2016 [31]NCT01927419 (CheckMate 069)Nivolumab (PD-1)Nivolumab plus Ipilimumab versus Ipilimumab14054NoIIAdvanced melanoma10Bellmunt J,et al. 2017 [32]NCT02256436 (KEYNOTE-045)Pembrolizumab (PD-1)Pembrolizumab versus Chemotherapy53145YesIIIAdvanced UC11Kang YK,et al. 2017 [33]NCT02267343 (ONO-4538-12, ATTRACTION-2)Nivolumab (PD-1)Nivolumab versus Placebo49124YesIIIAdvanced gastric or GJC12Schachter J,et al. 2017A [34]NCT01866319 (KEYNOTE-006)Pembrolizumab (PD-1)Pembrolizumab every 2 weeks versus Pembrolizumab every 3 weeks81192YesIIIAdvanced melanomaSchachter J,et al. 2017B [34]Pembrolizumab every 2 weeks versus Ipilimumab84Schachter J,et al. 2017C [34]Pembrolizumab every 3 weeks versus Ipilimumab8813Antonia SJ,et al. 2017 [35]NCT02125461 (PACIFIC)Durvalumab (PD-L1)Durvalumab versus Placebo70950YesIIIAdvanced, unresectable, stage III NSCLC14Socinski MA,et al. 2018 [36]NCT02366143 (IMpower150)Atezolizumab (PD-L1)Atezolizumab plus Bevacizumab plus Carboplatin plus Paclitaxel (ABCP) versus Bevacizumab plus Carboplatin plus Paclitaxel (BCP)78772NoIIIMetastatic nonsquamous NSCLC15Paz-Ares L,et al. 2018 [37]NCT02775435 (KEYNOTE-407)Pembrolizumab (PD-1)Pembrolizumab plus chemotherapy versus chemotherapy55879NoIIISquamous NSCLC16Horn L,et al. 2018 [38]NCT02763579 (IMpower133)Atezolizumab (PD-L1)Atezolizumab plus Carboplatin plus Etoposide versus Carboplatin plus Etoposide39457NoIIIExtensive-stage SCLC17Antonia SJ,et al. 2018 [39]NCT02125461 (PACIFIC)Durvalumab (PD-L1)Durvalumab versus Placebo70976YesIIIStage III NSCLC18Gandhi L,et al. 2018 [40]NCT02578680 (KEYNOTE-189)Pembrolizumab (PD-1)Pembrolizumab plus Pemetrexed plus A platinum-based drug versus Pemetrexed plus A platinum-based drug607105NoIIMetastatic nonsquamous NSCLCGadgeel S,et al. 2020 [41]Rodríguez-Abreu D,et al. 2021 [42]19Hida T,et al. 2018 [43]NCT02008227 (OAK)Atezolizumab (PD-L1)Atezolizumab versus Docetaxel10122YesIIIAdvanced/metastatic NSCLC20Eggermont AMM,et al. 2018 [44]NCT02362594Pembrolizumab (PD-1)Pembrolizumab versus Placebo1011136NoIIIResected stage III melanoma21Schmid P,et al. 2018 [45]NCT02425891 (IMpassion130)Atezolizumab (PD-L1)Atezolizumab plus Nab-paclitaxel versus Nab-paclitaxel890113NoIIIUnresectable locally advanced or metastatic TNBCEmens LA,et al. 2021 [46]22Hellmann MD,et al. 2018A [47]NCT02477826 (CheckMate 227)Nivolumab (PD-1)Nivolumab plus Ipilimumab versus Nivolumab1537139NoIIIStage IV or recurrent NSCLCHellmann MD,et al. 2018B [47]Nivolumab plus Ipilimumab versus Chemotherapy (platinum doublet)125Hellmann MD,et al. 2018C [47]Nivolumab versus Chemotherapy (platinum doublet)72Reck M,et al. 2021A [48]Nivolumab plus Ipilimumab versus Nivolumab139Reck M,et al. 2021B [48]Nivolumab plus Ipilimumab versus Chemotherapy (platinum doublet)125Reck M,et al. 2021C [48]Nivolumab versus Chemotherapy (platinum doublet)7223Powles T,et al. 2018A [49]NCT02302807 (IMvigor211)Atezolizumab (PD-L1)Atezolizumab versus Chemotherapy (vinflunine paclitaxel or docetaxel)112820YSEIIILocally advanced or metastatic UCPowles T,et al. 2018B [49]Atezolizumab versus Chemotherapy (vinflunine paclitaxel or docetaxel)6124Paz-Ares L,et al. 2019 [50]NCT03043872 (CASPIAN)Durvalumab (PD-L1)Durvalumab plus EP versus EP5316NoIIIExtensive-stage SCLC25Motzer RJ,et al. 2019 [51]NCT02684006 (JAVELIN Renal 101)Avelumab (PD-L1)Avelumab plus Axitinib versus Sunitinib87396YesIIIAdvanced RCCMotzer RJ,et al. 2020 [52]26West H,et al. 2019 [53]NCT02367781 (IMpower130)Atezolizumab (PD-L1)Atezolizumab plus Carboplatin plus Nab-paclitaxel versus Carboplatin plus Nab-paclitaxel70525NoIIIMetastatic nonsquamous NSCLC27Kato K,et al. 2019 [54]NCT02569242 (ATTRACTION-3)Nivolumab (PD-1)Nivolumab versus Paclitaxel/Docetaxel41754YesIIIAdvanced OSCC28Motzer R,et al. 2019 [55]NCT02231749 (CheckMate 214)Nivolumab (PD-1)Nivolumab plus Ipilimumab versus Sunitinib1082193NoIIIAdvanced RCC29Rini BI,et al. 2019 [56]NCT02420821 (IMmotion151)Atezolizumab (PD-L1)Atezolizumab plus Bevacizumab versus Sunitinib907128NoIIIMetastatic RCC30Sullivan RJ,et al. 2019 [57]NCT01656642Atezolizumab (PD-L1)Atezolizumab plus Vemurafenib versus Atezolizumab plus Cobimetinib plus Vemurafenib5620NoIbBRAF-mutated melanoma31Hellmann MD,et al. 2019A [58]NCT02477826 (CheckMate 227)Nivolumab (PD-1)Nivolumab plus Ipilimumab versus Nivolumab1537139NoIIIAdvanced NSCLCHellmann MD,et al. 2019B [58]Nivolumab plus Ipilimumab versus Chemotherapy (platinum doublet)125Hellmann MD,et al. 2019C [58]Nivolumab versus Chemotherapy (platinum doublet)7232Wu YL,et al. 2019 [59]NCT02613507 (CheckMate 078)Nivolumab (PD-1)Nivolumab versus Docetaxel49343YesIIIAdvanced NSCLC33Cohen EEW,et al. 2019 [60]NCT02252042 (KEYNOTE-040)Pembrolizumab (PD-1)Pembrolizumab versus (Methotrexate, Docetaxel, or Cetuximab)48053YesIIIRecurrent or metastatic HNSCC34Mok TSK,et al. 2019 [61]NCT02220894 (KEYNOTE-042)Pembrolizumab (PD-1)Pembrolizumab versus Chemotherapy125173NoIIILocally advanced or metastatic NSCLCWu YL,et al. 2021 [62]35Burtness B,et al. 2019A [63]NCT02358031 (KEYNOTE-048)Pembrolizumab (PD-1)Pembrolizumab versus Pembrolizumab plus Chemotherapy86359NoIIIRecurrent or Metastatic HNSCCBurtness B,et al. 2019B [63]Pembrolizumab versus Cetuximab plus Chemotherapy141Burtness B,et al. 2019C [63]Pembrolizumab plus Chemotherapy versus Cetuximab plus Chemotherapy14036Finn RS,et al. 2020 [64]NCT03434379Atezolizumab (PD-L1)Atezolizumab plus Bevacizumab versus Sorafenib48568NoIIIUnresectable hepatocellular carcinoma37Gutzmer R,et al. 2020 [65]NCT02908672 (IMspire150)Atezolizumab (PD-L1)Atezolizumab plus Vemurafenib plus Cobimetinib versus Vemurafenib plus Cobimetinib511209NoIIIUnresectable advanced BRAFV600 mutation-positive melanoma38Mittendorf EA,et al. 2020 [66]NCT03197935 (IMpassion031)Atezolizumab (PD-L1)Atezolizumab + Chemotherapy versus Chemotherapy33188NoIIIEarly stage TNBC39Ascierto PA,et al. 2020 [67]NCT02388906 (CheckMate 238)Nivolumab (PD-1)Nivolumab versus Ipilimumab905197NoIIIResected stage IIIB–C and stage IV Melanoma40Herbst RS,et al. 2020 [68]NCT02409342 (IMpower110)Atezolizumab (PD-L1)Atezolizumab versus Chemotherapy (platinum-based)54963NoIIIPD-L1-selected NSCLC41Emens LA,et al. 2020 [69]NCT02924883 (KATE2)Atezolizumab (PD-L1)Atezolizumab plus Trastuzumab emtansine versus Trastuzumab emtansine20034YesIIHER2-positive advanced breast cancer42Huang J,et al. 2020 [70]NCT03099382 (ESCORT)Camrelizumab (PD-1)Camrelizumab versus Chemotherapy (Docetaxel or Irinotecan)448189YesIIIAdvanced or metastatic OSCC43Powles,et al. 2020 [71]NCT02603432 (JAVELIN Bladder 100)Avelumab (PD-L1)Avelumab versus Best Supportive Care (BSC)68944YesIIIAdvanced or metastatic UC44André T,et al. 2020 [72]NCT02563002 (KEYNOTE-177)Pembrolizumab (PD-1)Pembrolizumab versus Chemotherapy (5-fluorouracil–based therapy with or without bevacizumab or cetuximab)29636NoIIIColorectal cancer45Schmid P,et al. 2020 [73]NCT03036488 (KEYNOTE-522)Pembrolizumab (PD-1)Pembrolizumab plus Chemotherapy (Paclitaxel plus Carboplatin) versus Placebo plus Chemotherapy (Paclitaxel plus Carboplatin)1170229NoIIIStage II or stage III TNBC46Jotte R,et al. 2020 [74]NCT02367794 (IMpower131)Atezolizumab (PD-L1)Atezolizumab plus Carboplatin plus Nab-paclitaxel versus Carboplatin plus Nab-paclitaxel66838YesIIIAdvanced squamous NSCLC47Zhou C,et al. 2020 [75]NCT03134872 (CameL)Camrelizumab (PD-1)Camrelizumab plus Carboplatin plus Pemetrexed versus Carboplatin plus Pemetrexed41236NoIIINonsquamous NSCLC48Zimmer L,et al. 2020A [76]NCT02523313 (IMMUNED)Nivolumab (PD-1)Nivolumab plus Ipilimumab versus Nivolumab1626YesIIResected stage IV melanomaZimmer L,et al. 2020B [76]Nivolumab plus Ipilimumab versus PlaceboN/AZimmer L,et al. 2020C [76]Nivolumab versus PlaceboN/A49Galsky MD,et al. 2020A [77]NCT02807636 (IMvigor130)Atezolizumab (PD-L1)Atezolizumab plus Chemotherapy (platinum-based) versus Atezolizumab120375NoIIILocally advanced or metastatic UCGalsky MD,et al. 2020B [77]Atezolizumab plus Chemotherapy versus Chemotherapy80Galsky MD,et al. 2020C [77]Atezolizumab versus Placebo plus Chemotherapy4150Powles T,et al. 2020A [78]NCT02516241 (DANUBE)Durvalumab (PD-L1)Durvalumab versus Durvalumab plus Tremelimumab99873NoIIIUnresectable advanced or metastatic UCPowles T,et al. 2020B [78]Durvalumab versus Chemotherapy (gemcitabine plus cisplatin/carboplatin)3451Rudin CM,et al. 2020 [79]NCT03066778 (KEYNOTE-604)Pembrolizumab (PD-1)Pembrolizumab plus EP versus Placebo plus EP44643NoIIIExtensive-stage SCLC52Shitara K,et al. 2020A [80]NCT02494583 (KEYNOTE-062)Pembrolizumab (PD-1)Pembrolizumab versus Pembrolizumab plus Chemotherapy (Cisplatin plus Fluorouracil/Capecitabine)74843NoIIIAdvanced GCShitara K,et al. 2020B [80]Pembrolizumab versus Chemotherapy26Shitara K,et al. 2020C [80]Pembrolizumab plus Chemotherapy versus Chemotherapy3753Ribas A,et al. 2020A [81]NCT02027961Durvalumab (PD-L1)Durvalumab plus Dabrafenib plus Trametinib versus Durvalumab plus Trametinib (concurrent)6816YesIAdvanced melanomaRibas A,et al. 2020B [81]Durvalumab plus Dabrafenib plus Trametinib versus Durvalumab plus Trametinib (sequential)20Ribas A,et al. 2020C [81]Durvalumab plus Trametinib (concurrent) versus Durvalumab plus Trametinib (sequential)1854Winer EP,et al. 2021 [82]NCT02555657 (KEYNOTE-119)Pembrolizumab (PD-1)Pembrolizumab versus Single-drug Chemotherapy6018YesIIIMetastatic TNBC55Lee NY,et al. 2021 [83]NCT02952586Avelumab (PD-L1)Avelumab plus Chemoradiotherapy versus placebo plus Chemoradiotherapy69256NoIIILocally advanced HNSCC56Miles D,et al. 2021 [84]NCT03125902 (IMpassion131)Atezolizumab (PD-L1)Atezolizumab plus Paclitaxel versus Placebo plus Paclitaxel649207NoIIILocally advanced/metastatic TNBC57Ren Z,et al. 2021 [85]NCT03794440 (ORIENT-32)Sintilimab (PD-1)Sintilimab plus Bevacizumab biosimilar (IBI305) versus sorafenib56549NoII-IIIUnresectable hepatocellular carcinoma58Powles T,et al. 2021A [86]NCT02853305 (KEYNOTE-361)Pembrolizumab (PD-1)Pembrolizumab versus Chemotherapy99364NoIIIAdvanced UCPowles T,et al. 2021B [86]Pembrolizumab plus Chemotherapy versus Chemotherapy107Powles T,et al. 2021C [86]Pembrolizumab versus Pembrolizumab plus Chemotherapy12359Bajorin DF,et al. 2021 [87]NCT02632409 (CheckMate 274)Nivolumab (PD-1)Nivolumab (Adjuvant) versus placebo69972YesIIIMuscle-invasive UC60Brufsky A,et al. 2021A [88]NCT02322814 (COLET)Atezolizumab (PD-L1)Cobimetinib plus atezolizumab plus paclitaxel versus Cobimetinib plus paclitaxel15232NoIIAdvanced or metastatic TNBCBrufsky A,et al. 2021B [88]Cobimetinib plus atezolizumab plus paclitaxel versus Cobimetinib plus atezolizumab plus Nab-paclitaxel28Brufsky A,et al. 2021C [88]Cobimetinib plus paclitaxel versus Placebo plus paclitaxel2561Motzer R,et al. 2021A [89]NCT02811861 (CLEAR)Pembrolizumab (PD-1)Lenvatinib plus Pembrolizumab versus Sunitinib1047143NoIIIAdvanced RCCMotzer R,et al. 2021B [89]Lenvatinib plus Pembrolizumab versus Lenvatinib plus Everolimus184Motzer R,et al. 2021C [89]Lenvatinib plus Everolimus versus Sunitinib13562Bellmunt J,et al. 2021 [90]NCT02450331 (IMvigor010)Atezolizumab (PD-L1)Atezolizumab versus Observation787101NoIIIMuscle-invasive UC63Choueiri TK,et al. 2021 [91]NCT03141177 (CheckMate 9ER)Nivolumab (PD-1)Nivolumab plus Cabozantinib versus Sunitinib64095NoIIIAdvanced RCC64Sezer A,et al. 2021 [92]NCT03088540 (EMPOWER-Lung 1)Cemiplimab (PD-1)Cemiplimab versus Chemotherapy (platinum-doublet)69726NoIIIAdvanced NSCLC65Paz-Ares L,et al. 2021 [93]NCT03215706 (CheckMate 9LA)Nivolumab (PD-1)Nivolumab plus Ipilimumab plus Chemotherapy versus Chemotherapy70778NoIIIStage IV or recurrent NSCLC66Baas P,et al. 2021 [94]NCT02899299 (CheckMate 743)Nivolumab (PD-1)Nivolumab plus Ipilimumab versus Chemotherapy58458NoIIIUnresectable malignant pleural mesothelioma67Goldman JW,et al. 2021A [95]NCT03043872 (CASPIAN)Durvalumab (PD-L1)Durvalumab plus EP versus EP79726NoIIIExtensive-stage SCLCGoldman JW,et al. 2021B [95]Durvalumab plus Tremelimumab (CTLA-4) plus EP versus EP46Goldman JW,et al. 2021C [95]Durvalumab plus Tremelimumab (CTLA-4) plus EP versus Durvalumab plus EP5268Pujade-Lauraine E,et al. 2021A [96]NCT02580058 (JAVELIN Ovarian 200)Avelumab (PD-L1)Avelumab plus PLD (Pegylated Liposomal Doxorubicin) versus PLD54661YesIIIPlatinum-resistant or platinum-refractory OCPujade-Lauraine E,et al. 2021B [96]Avelumab plus PLD versus Avelumab54Pujade-Lauraine E,et al. 2021C [96]Avelumab versus PLD2569Kelly RJ,et al. 2021 [97]NCT02743494 (CheckMate 577)Nivolumab (PD-1)Nivolumab versus Placebo79262YesIIIResected esophageal or GJC70Sugawara S,et al. 2021 [98]NCT03117049 (ONO-4538-52/TASUKI-5)Nivolumab (PD-1)Nivolumab versus Placebo548121NoIIIStage IIIB/IV or recurrent nonsquamous NSCLC71Yang Y,et al. 2021 [99]NCT03707509 (CAPTAIN-1st)Camrelizumab (PD-1)Camrelizumab plus Gemcitabine plus Cisplatin versus Gemcitabine plus Cisplatin26372NoIIINC72Liu SV,et al. 2021 [100]NCT02763579 (IMpower133)Atezolizumab (PD-L1)Atezolizumab plus CP/ET versus Placebo plus CP/ET39461NoI/IIIExtensive-stage SCLC73Monk BJ,et al. 2021A [101]NCT02718417 (JAVELIN Ovarian 100)Avelumab (PD-L1)Avelumab plus Chemotherapy + Avelumab (maintenance) versus Chemotherapy99191NoIIIStage III–IV epithelial OCMonk BJ,et al. 2021B [101]Avelumab plus Chemotherapy plus Avelumab (maintenance) versus Chemotherapy plus Avelumab (maintenance)125Monk BJ,et al. 2021C [101]Chemotherapy plus Avelumab (maintenance) versus Chemotherapy8474Choueiri TK,et al. 2021 [102]NCT03142334 (KEYNOTE-564)Pembrolizumab (PD-1)Pembrolizumab versus Placebo984151NoIIIClear-cell, advanced RCC75Moore KN,et al. 2021 [103](NCT03038100) (IMagyn050/GOG 3015/ENGOT-OV39)Atezolizumab (PD-L1)Atezolizumab plus CP plus Bevacizumab versus Placebo plus CP plus Bevacizumab1285252NoIIIStage III or IV OC76Gogas H,et al. 2021 [104]NCT03273153 (IMspire170)Atezolizumab (PD-L1)Cobimetinib plus Atezolizumab versus Pembrolizumab436118NoIIIBRAFV600 wild-type melanoma77Owonikoko TK,et al. 2021A [105]NCT02538666 (CheckMate 451)Nivolumab (PD-1)Nivolumab plus Ipilimumab versus Nivolumab83082YesIIIExtensive-disease SCLCOwonikoko TK,et al. 2021B [105]Nivolumab plus Ipilimumab versus Placebo76Owonikoko TK,et al. 2021C [105]Nivolumab versus Placebo2878Luo H,et al. 2021 [106]NCT03691090 ((ESCORT-1st)Camrelizumab (PD-1)Camrelizumab plus Chemotherapy versus Chemotherapy59522NoIIIAdvanced or metastatic ESCC79Colombo N,et al. 2021A [107]NCT03635567 (KEYNOTE-826)Pembrolizumab (PD-1)Pembrolizumab plus Chemotherapy plus Bevacizumab versus Chemotherapy plus Bevacizumab38965NoIIIPersistent, recurrent, or metastatic cervical cancerColombo N,et al. 2021B [107]Pembrolizumab plus Chemotherapy versus Chemotherapy2271780Fennell DA,et al. 2021 [108]NCT03063450 (CONFIRM)Nivolumab (PD-1)Nivolumab versus Placebo3321YesIIIMalignant mesothelioma81Pusztai L,et al. 2021 [109](NCT01042379) (I-SPY2)Durvalumab (PD-L1)Durvalumab plus Olaparib plus Paclitaxel (DOP) versus Paclitaxel37263NoIIHER2-negative stage II/III breast cancer82Zhu X,et al. 2021 [110]NCT02704156Pembrolizumab (PD-1)SBRT plus Pembrolizumab plus Trametinib versus SBRT plus Gemcitabine17022YesIILocally recurrent pancreatic cancer after surgical resection83Sun JM,et al. 2021 [111]NCT03189719 (KEYNOTE-590)Pembrolizumab (PD-1)Pembrolizumab plus Chemotherapy versus Placebo plus Chemotherapy74047NoIIIAdvanced esophageal cancer84Mai HQ,et al. 2021 [112]NCT03581786Toripalimab (PD-1)Toripalimab plus GP versus Placebo plus GP28971NoIIIAdvanced NC85Felip E,et al. 2021 [113]NCT02486718 (IMpower010)Atezolizumab (PD-L1)Atezolizumab versus BSC990102YesIIIResected stage IB–IIIA NSCLC86Larkin J,et al. 2019A [114]NCT01844505 (CheckMate 067)Nivolumab (PD-1)Nivolumab plus Ipilimumab versus Nivolumab937167NoIIIAdvanced melanomaLarkin J,et al. 2019B [114]Nivolumab plus Ipilimumab versus Ipilimumab162Larkin J,et al. 2019C [114]Nivolumab versus Ipilimumab143Wolchok JD,et al. 2017A [115]Nivolumab plus Ipilimumab versus Nivolumab165Wolchok JD,et al. 2017B [115]Nivolumab plus Ipilimumab versus Ipilimumab161Wolchok JD,et al. 2017C [115]Nivolumab versus Ipilimumab140Hodi FS,et al. 2018A [116]Nivolumab plus Ipilimumab versus Nivolumab167Hodi FS,et al. 2018B [116]Nivolumab plus Ipilimumab versus Ipilimumab162Hodi FS,et al. 2018C [116]Nivolumab versus Ipilimumab143Larkin J,et al. 2015A [117]Nivolumab versus Nivolumab plus Ipilimumab207Larkin J,et al. 2015B [117]Nivolumab versus Ipilimumab183Larkin J,et al. 2015C [117]Nivolumab plus Ipilimumab versus Ipilimumab228RCT = randomized controlled trial, N/A = not available, NSCLC=non-small-cell lung cancer, SCLC = small-cell lung cancer, UC = urothelial carcinoma, HNSCC = head and neck squamous-cell carcinoma, TNBC = triple-negative breast cancer, NC = nasopharyngeal carcinoma, GJC = gastroesophageal junction cancer, GC = gastric cancer, ESCC = esophageal squamous cell carcinoma, OC= ovarian cancer, and RCC = renal cell carcinoma.


### 2.5. Heterogeneity Screening and Statistical Analyses

Cochrane’s Q and I2 statistics were used for heterogeneity screening, as described by Higgins and colleagues [16, 19], while the Harbord test was used for publication bias evaluation [19]. Three grades of heterogeneity were defined according to the I2 value: The two separation thresholds were 25% and 50%, respectively [20]. Using Review Manager 5.3, odds ratios (OR) and 95% confidence intervals (CI) across all enrolled clinical trials using the random effect (RE) method were calculated [21], whereas funnel plots were constructed using the fixed effect (FE) model. All statistical tests were two-sided, and p<0.05 was taken as a statistically significant result. In the process of analyses, adequate subgroup evaluations would be carried out according to the actual situation.


## 2.1. Eligibility Screening for All Clinical Trials

Phase III clinical trials involving PD-1 or PD-L1 inhibitors with control groups would be preferred. Other clinical trials with control groups would be placed in an alternate location. With the exception of hematological malignancies, the types of solid tumors would not be limited. All data involving rash would be extracted and recorded in preparation for the subsequent adequate subgroup analysis. Four authors were appointed for eligibility screening.


## 2.2. Formulation and Implementation of Literature Search Strategy

According to the principle of PICOS (participants, interventions, comparisons, outcomes, and study design), the specific strategy of literature search was specified and implemented by all authors [16]. First, neoplasm was firstly searched as the MeSH keyword, not limited to specific solid tumor types. Then, all kinds of PD-1 or PD-L1 inhibitors, including common names, trade names, and abbreviations, would be searched as keywords and the search results would be unioned.The publication time of relevant studies would be limited from July 09, 2013, to September 14, 2021. If one clinical trial was repeatedly reported several times, only the one with full detailed data could be selected for the analysis.


## 2.3. Quality Evaluation and Publication Bias Screening

The revised Cochrane Collaboration tool was adopted for bias risk screening in all selected trials [17], and the Funnel plot and Egger’s test were used for publication bias assessments [18]. A p value < 0.05 was considered as the evidence for the existence of publication bias.The quality screening of all the enrolled clinical trials were also carried out by the above four authors. The screening criteria were listed as the following 5 items: (a) selection bias, (b) performance bias, (c) detection bias, (d) attrition bias, and (e) reporting bias [17].


## 2.4. Screening of Results

The main outcome measure was the risk of PD-1 or PD-L1 involving rash across all grades, while the second was the rash for grades 3–5. The main information of all trials would be extracted and summarized in the single table (Table1). The main content included in the table was listed as the following items: the first author’s name, publication years, trial title, registered trial number, therapies lines, treatment regimens, participants, phase, tumor type, RCT, and the number of rash events.Table 1
Basic information of all selected clinical trials.
Trial no.ReferenceNCT numberDrugTreatment RegimensInvolving PatientsRashPrevious therapyPhaseTumor Type1Borghaei H,et al. 2015 [22]NCT01673867 (CheckMate 057)Nivolumab (PD-1)Nivolumab versus Docetaxel55535YesIIIAdvanced non-squamous NSCLC2Weber JS,et al. 2015 [23]NCT01721746 (CheckMate 037)Nivolumab (PD-1)Nivolumab versus Dacarbazine/Paclitaxel plus Carboplatin37030NoIIIAdvanced melanoma3Brahmer J,et al. 2015 [24]NCT01642004 (CheckMate 017)Nivolumab (PD-1)Nivolumab versus Docetaxel26013YesIIIAdvanced squamous cell NSCLC4Motzer RJ,et al. 2015 [25]NCT01668784 (CheckMate 025)Nivolumab (PD-1)Nivolumab versus Everolimus803120YesIIIAdvanced RCC5Herbst RS,et al. 2016A [26]NCT01905657 (KEYNOTE-010)Pembrolizumab (PD-1)Pembrolizumab 2 mg/kg versus Pembrolizumab 10 mg/kg99173YesII/IIIAdvanced NSCLCHerbst RS,et al. 2016B [26]Pembrolizumab 2 mg/kg versus Docetaxel43Herbst RS,et al. 2016C [26]Pembrolizumab 10 mg/kg versus Docetaxel586Langer CJ,et al. 2016 [27]NCT02039674 (KEYNOTE-021)Pembrolizumab (PD-1)Pembrolizumab plus Carboplatin plus Pemetrexed versus Carboplatin plus Pemetrexed12125NoIIAdvanced nonsquamous NSCLCAwad MM,et al. 2021 [28]7Antonia SJ,et al. 2016 [29]NCT01928394 (CheckMate 032)Nivolumab (PD-1)Nivolumab versus Nivolumab plus Ipilimumab1526YesI/IIRecurrent SCLC8Ferris RL,et al. 2016 [30]NCT02105636 (CheckMate 141)Nivolumab (PD-1)Nivolumab versus (Methotrexate, Docetaxel, or Cetuximab)34723YesIIIRecurrent HNSCC9Hodi FS,et al. 2016 [31]NCT01927419 (CheckMate 069)Nivolumab (PD-1)Nivolumab plus Ipilimumab versus Ipilimumab14054NoIIAdvanced melanoma10Bellmunt J,et al. 2017 [32]NCT02256436 (KEYNOTE-045)Pembrolizumab (PD-1)Pembrolizumab versus Chemotherapy53145YesIIIAdvanced UC11Kang YK,et al. 2017 [33]NCT02267343 (ONO-4538-12, ATTRACTION-2)Nivolumab (PD-1)Nivolumab versus Placebo49124YesIIIAdvanced gastric or GJC12Schachter J,et al. 2017A [34]NCT01866319 (KEYNOTE-006)Pembrolizumab (PD-1)Pembrolizumab every 2 weeks versus Pembrolizumab every 3 weeks81192YesIIIAdvanced melanomaSchachter J,et al. 2017B [34]Pembrolizumab every 2 weeks versus Ipilimumab84Schachter J,et al. 2017C [34]Pembrolizumab every 3 weeks versus Ipilimumab8813Antonia SJ,et al. 2017 [35]NCT02125461 (PACIFIC)Durvalumab (PD-L1)Durvalumab versus Placebo70950YesIIIAdvanced, unresectable, stage III NSCLC14Socinski MA,et al. 2018 [36]NCT02366143 (IMpower150)Atezolizumab (PD-L1)Atezolizumab plus Bevacizumab plus Carboplatin plus Paclitaxel (ABCP) versus Bevacizumab plus Carboplatin plus Paclitaxel (BCP)78772NoIIIMetastatic nonsquamous NSCLC15Paz-Ares L,et al. 2018 [37]NCT02775435 (KEYNOTE-407)Pembrolizumab (PD-1)Pembrolizumab plus chemotherapy versus chemotherapy55879NoIIISquamous NSCLC16Horn L,et al. 2018 [38]NCT02763579 (IMpower133)Atezolizumab (PD-L1)Atezolizumab plus Carboplatin plus Etoposide versus Carboplatin plus Etoposide39457NoIIIExtensive-stage SCLC17Antonia SJ,et al. 2018 [39]NCT02125461 (PACIFIC)Durvalumab (PD-L1)Durvalumab versus Placebo70976YesIIIStage III NSCLC18Gandhi L,et al. 2018 [40]NCT02578680 (KEYNOTE-189)Pembrolizumab (PD-1)Pembrolizumab plus Pemetrexed plus A platinum-based drug versus Pemetrexed plus A platinum-based drug607105NoIIMetastatic nonsquamous NSCLCGadgeel S,et al. 2020 [41]Rodríguez-Abreu D,et al. 2021 [42]19Hida T,et al. 2018 [43]NCT02008227 (OAK)Atezolizumab (PD-L1)Atezolizumab versus Docetaxel10122YesIIIAdvanced/metastatic NSCLC20Eggermont AMM,et al. 2018 [44]NCT02362594Pembrolizumab (PD-1)Pembrolizumab versus Placebo1011136NoIIIResected stage III melanoma21Schmid P,et al. 2018 [45]NCT02425891 (IMpassion130)Atezolizumab (PD-L1)Atezolizumab plus Nab-paclitaxel versus Nab-paclitaxel890113NoIIIUnresectable locally advanced or metastatic TNBCEmens LA,et al. 2021 [46]22Hellmann MD,et al. 2018A [47]NCT02477826 (CheckMate 227)Nivolumab (PD-1)Nivolumab plus Ipilimumab versus Nivolumab1537139NoIIIStage IV or recurrent NSCLCHellmann MD,et al. 2018B [47]Nivolumab plus Ipilimumab versus Chemotherapy (platinum doublet)125Hellmann MD,et al. 2018C [47]Nivolumab versus Chemotherapy (platinum doublet)72Reck M,et al. 2021A [48]Nivolumab plus Ipilimumab versus Nivolumab139Reck M,et al. 2021B [48]Nivolumab plus Ipilimumab versus Chemotherapy (platinum doublet)125Reck M,et al. 2021C [48]Nivolumab versus Chemotherapy (platinum doublet)7223Powles T,et al. 2018A [49]NCT02302807 (IMvigor211)Atezolizumab (PD-L1)Atezolizumab versus Chemotherapy (vinflunine paclitaxel or docetaxel)112820YSEIIILocally advanced or metastatic UCPowles T,et al. 2018B [49]Atezolizumab versus Chemotherapy (vinflunine paclitaxel or docetaxel)6124Paz-Ares L,et al. 2019 [50]NCT03043872 (CASPIAN)Durvalumab (PD-L1)Durvalumab plus EP versus EP5316NoIIIExtensive-stage SCLC25Motzer RJ,et al. 2019 [51]NCT02684006 (JAVELIN Renal 101)Avelumab (PD-L1)Avelumab plus Axitinib versus Sunitinib87396YesIIIAdvanced RCCMotzer RJ,et al. 2020 [52]26West H,et al. 2019 [53]NCT02367781 (IMpower130)Atezolizumab (PD-L1)Atezolizumab plus Carboplatin plus Nab-paclitaxel versus Carboplatin plus Nab-paclitaxel70525NoIIIMetastatic nonsquamous NSCLC27Kato K,et al. 2019 [54]NCT02569242 (ATTRACTION-3)Nivolumab (PD-1)Nivolumab versus Paclitaxel/Docetaxel41754YesIIIAdvanced OSCC28Motzer R,et al. 2019 [55]NCT02231749 (CheckMate 214)Nivolumab (PD-1)Nivolumab plus Ipilimumab versus Sunitinib1082193NoIIIAdvanced RCC29Rini BI,et al. 2019 [56]NCT02420821 (IMmotion151)Atezolizumab (PD-L1)Atezolizumab plus Bevacizumab versus Sunitinib907128NoIIIMetastatic RCC30Sullivan RJ,et al. 2019 [57]NCT01656642Atezolizumab (PD-L1)Atezolizumab plus Vemurafenib versus Atezolizumab plus Cobimetinib plus Vemurafenib5620NoIbBRAF-mutated melanoma31Hellmann MD,et al. 2019A [58]NCT02477826 (CheckMate 227)Nivolumab (PD-1)Nivolumab plus Ipilimumab versus Nivolumab1537139NoIIIAdvanced NSCLCHellmann MD,et al. 2019B [58]Nivolumab plus Ipilimumab versus Chemotherapy (platinum doublet)125Hellmann MD,et al. 2019C [58]Nivolumab versus Chemotherapy (platinum doublet)7232Wu YL,et al. 2019 [59]NCT02613507 (CheckMate 078)Nivolumab (PD-1)Nivolumab versus Docetaxel49343YesIIIAdvanced NSCLC33Cohen EEW,et al. 2019 [60]NCT02252042 (KEYNOTE-040)Pembrolizumab (PD-1)Pembrolizumab versus (Methotrexate, Docetaxel, or Cetuximab)48053YesIIIRecurrent or metastatic HNSCC34Mok TSK,et al. 2019 [61]NCT02220894 (KEYNOTE-042)Pembrolizumab (PD-1)Pembrolizumab versus Chemotherapy125173NoIIILocally advanced or metastatic NSCLCWu YL,et al. 2021 [62]35Burtness B,et al. 2019A [63]NCT02358031 (KEYNOTE-048)Pembrolizumab (PD-1)Pembrolizumab versus Pembrolizumab plus Chemotherapy86359NoIIIRecurrent or Metastatic HNSCCBurtness B,et al. 2019B [63]Pembrolizumab versus Cetuximab plus Chemotherapy141Burtness B,et al. 2019C [63]Pembrolizumab plus Chemotherapy versus Cetuximab plus Chemotherapy14036Finn RS,et al. 2020 [64]NCT03434379Atezolizumab (PD-L1)Atezolizumab plus Bevacizumab versus Sorafenib48568NoIIIUnresectable hepatocellular carcinoma37Gutzmer R,et al. 2020 [65]NCT02908672 (IMspire150)Atezolizumab (PD-L1)Atezolizumab plus Vemurafenib plus Cobimetinib versus Vemurafenib plus Cobimetinib511209NoIIIUnresectable advanced BRAFV600 mutation-positive melanoma38Mittendorf EA,et al. 2020 [66]NCT03197935 (IMpassion031)Atezolizumab (PD-L1)Atezolizumab + Chemotherapy versus Chemotherapy33188NoIIIEarly stage TNBC39Ascierto PA,et al. 2020 [67]NCT02388906 (CheckMate 238)Nivolumab (PD-1)Nivolumab versus Ipilimumab905197NoIIIResected stage IIIB–C and stage IV Melanoma40Herbst RS,et al. 2020 [68]NCT02409342 (IMpower110)Atezolizumab (PD-L1)Atezolizumab versus Chemotherapy (platinum-based)54963NoIIIPD-L1-selected NSCLC41Emens LA,et al. 2020 [69]NCT02924883 (KATE2)Atezolizumab (PD-L1)Atezolizumab plus Trastuzumab emtansine versus Trastuzumab emtansine20034YesIIHER2-positive advanced breast cancer42Huang J,et al. 2020 [70]NCT03099382 (ESCORT)Camrelizumab (PD-1)Camrelizumab versus Chemotherapy (Docetaxel or Irinotecan)448189YesIIIAdvanced or metastatic OSCC43Powles,et al. 2020 [71]NCT02603432 (JAVELIN Bladder 100)Avelumab (PD-L1)Avelumab versus Best Supportive Care (BSC)68944YesIIIAdvanced or metastatic UC44André T,et al. 2020 [72]NCT02563002 (KEYNOTE-177)Pembrolizumab (PD-1)Pembrolizumab versus Chemotherapy (5-fluorouracil–based therapy with or without bevacizumab or cetuximab)29636NoIIIColorectal cancer45Schmid P,et al. 2020 [73]NCT03036488 (KEYNOTE-522)Pembrolizumab (PD-1)Pembrolizumab plus Chemotherapy (Paclitaxel plus Carboplatin) versus Placebo plus Chemotherapy (Paclitaxel plus Carboplatin)1170229NoIIIStage II or stage III TNBC46Jotte R,et al. 2020 [74]NCT02367794 (IMpower131)Atezolizumab (PD-L1)Atezolizumab plus Carboplatin plus Nab-paclitaxel versus Carboplatin plus Nab-paclitaxel66838YesIIIAdvanced squamous NSCLC47Zhou C,et al. 2020 [75]NCT03134872 (CameL)Camrelizumab (PD-1)Camrelizumab plus Carboplatin plus Pemetrexed versus Carboplatin plus Pemetrexed41236NoIIINonsquamous NSCLC48Zimmer L,et al. 2020A [76]NCT02523313 (IMMUNED)Nivolumab (PD-1)Nivolumab plus Ipilimumab versus Nivolumab1626YesIIResected stage IV melanomaZimmer L,et al. 2020B [76]Nivolumab plus Ipilimumab versus PlaceboN/AZimmer L,et al. 2020C [76]Nivolumab versus PlaceboN/A49Galsky MD,et al. 2020A [77]NCT02807636 (IMvigor130)Atezolizumab (PD-L1)Atezolizumab plus Chemotherapy (platinum-based) versus Atezolizumab120375NoIIILocally advanced or metastatic UCGalsky MD,et al. 2020B [77]Atezolizumab plus Chemotherapy versus Chemotherapy80Galsky MD,et al. 2020C [77]Atezolizumab versus Placebo plus Chemotherapy4150Powles T,et al. 2020A [78]NCT02516241 (DANUBE)Durvalumab (PD-L1)Durvalumab versus Durvalumab plus Tremelimumab99873NoIIIUnresectable advanced or metastatic UCPowles T,et al. 2020B [78]Durvalumab versus Chemotherapy (gemcitabine plus cisplatin/carboplatin)3451Rudin CM,et al. 2020 [79]NCT03066778 (KEYNOTE-604)Pembrolizumab (PD-1)Pembrolizumab plus EP versus Placebo plus EP44643NoIIIExtensive-stage SCLC52Shitara K,et al. 2020A [80]NCT02494583 (KEYNOTE-062)Pembrolizumab (PD-1)Pembrolizumab versus Pembrolizumab plus Chemotherapy (Cisplatin plus Fluorouracil/Capecitabine)74843NoIIIAdvanced GCShitara K,et al. 2020B [80]Pembrolizumab versus Chemotherapy26Shitara K,et al. 2020C [80]Pembrolizumab plus Chemotherapy versus Chemotherapy3753Ribas A,et al. 2020A [81]NCT02027961Durvalumab (PD-L1)Durvalumab plus Dabrafenib plus Trametinib versus Durvalumab plus Trametinib (concurrent)6816YesIAdvanced melanomaRibas A,et al. 2020B [81]Durvalumab plus Dabrafenib plus Trametinib versus Durvalumab plus Trametinib (sequential)20Ribas A,et al. 2020C [81]Durvalumab plus Trametinib (concurrent) versus Durvalumab plus Trametinib (sequential)1854Winer EP,et al. 2021 [82]NCT02555657 (KEYNOTE-119)Pembrolizumab (PD-1)Pembrolizumab versus Single-drug Chemotherapy6018YesIIIMetastatic TNBC55Lee NY,et al. 2021 [83]NCT02952586Avelumab (PD-L1)Avelumab plus Chemoradiotherapy versus placebo plus Chemoradiotherapy69256NoIIILocally advanced HNSCC56Miles D,et al. 2021 [84]NCT03125902 (IMpassion131)Atezolizumab (PD-L1)Atezolizumab plus Paclitaxel versus Placebo plus Paclitaxel649207NoIIILocally advanced/metastatic TNBC57Ren Z,et al. 2021 [85]NCT03794440 (ORIENT-32)Sintilimab (PD-1)Sintilimab plus Bevacizumab biosimilar (IBI305) versus sorafenib56549NoII-IIIUnresectable hepatocellular carcinoma58Powles T,et al. 2021A [86]NCT02853305 (KEYNOTE-361)Pembrolizumab (PD-1)Pembrolizumab versus Chemotherapy99364NoIIIAdvanced UCPowles T,et al. 2021B [86]Pembrolizumab plus Chemotherapy versus Chemotherapy107Powles T,et al. 2021C [86]Pembrolizumab versus Pembrolizumab plus Chemotherapy12359Bajorin DF,et al. 2021 [87]NCT02632409 (CheckMate 274)Nivolumab (PD-1)Nivolumab (Adjuvant) versus placebo69972YesIIIMuscle-invasive UC60Brufsky A,et al. 2021A [88]NCT02322814 (COLET)Atezolizumab (PD-L1)Cobimetinib plus atezolizumab plus paclitaxel versus Cobimetinib plus paclitaxel15232NoIIAdvanced or metastatic TNBCBrufsky A,et al. 2021B [88]Cobimetinib plus atezolizumab plus paclitaxel versus Cobimetinib plus atezolizumab plus Nab-paclitaxel28Brufsky A,et al. 2021C [88]Cobimetinib plus paclitaxel versus Placebo plus paclitaxel2561Motzer R,et al. 2021A [89]NCT02811861 (CLEAR)Pembrolizumab (PD-1)Lenvatinib plus Pembrolizumab versus Sunitinib1047143NoIIIAdvanced RCCMotzer R,et al. 2021B [89]Lenvatinib plus Pembrolizumab versus Lenvatinib plus Everolimus184Motzer R,et al. 2021C [89]Lenvatinib plus Everolimus versus Sunitinib13562Bellmunt J,et al. 2021 [90]NCT02450331 (IMvigor010)Atezolizumab (PD-L1)Atezolizumab versus Observation787101NoIIIMuscle-invasive UC63Choueiri TK,et al. 2021 [91]NCT03141177 (CheckMate 9ER)Nivolumab (PD-1)Nivolumab plus Cabozantinib versus Sunitinib64095NoIIIAdvanced RCC64Sezer A,et al. 2021 [92]NCT03088540 (EMPOWER-Lung 1)Cemiplimab (PD-1)Cemiplimab versus Chemotherapy (platinum-doublet)69726NoIIIAdvanced NSCLC65Paz-Ares L,et al. 2021 [93]NCT03215706 (CheckMate 9LA)Nivolumab (PD-1)Nivolumab plus Ipilimumab plus Chemotherapy versus Chemotherapy70778NoIIIStage IV or recurrent NSCLC66Baas P,et al. 2021 [94]NCT02899299 (CheckMate 743)Nivolumab (PD-1)Nivolumab plus Ipilimumab versus Chemotherapy58458NoIIIUnresectable malignant pleural mesothelioma67Goldman JW,et al. 2021A [95]NCT03043872 (CASPIAN)Durvalumab (PD-L1)Durvalumab plus EP versus EP79726NoIIIExtensive-stage SCLCGoldman JW,et al. 2021B [95]Durvalumab plus Tremelimumab (CTLA-4) plus EP versus EP46Goldman JW,et al. 2021C [95]Durvalumab plus Tremelimumab (CTLA-4) plus EP versus Durvalumab plus EP5268Pujade-Lauraine E,et al. 2021A [96]NCT02580058 (JAVELIN Ovarian 200)Avelumab (PD-L1)Avelumab plus PLD (Pegylated Liposomal Doxorubicin) versus PLD54661YesIIIPlatinum-resistant or platinum-refractory OCPujade-Lauraine E,et al. 2021B [96]Avelumab plus PLD versus Avelumab54Pujade-Lauraine E,et al. 2021C [96]Avelumab versus PLD2569Kelly RJ,et al. 2021 [97]NCT02743494 (CheckMate 577)Nivolumab (PD-1)Nivolumab versus Placebo79262YesIIIResected esophageal or GJC70Sugawara S,et al. 2021 [98]NCT03117049 (ONO-4538-52/TASUKI-5)Nivolumab (PD-1)Nivolumab versus Placebo548121NoIIIStage IIIB/IV or recurrent nonsquamous NSCLC71Yang Y,et al. 2021 [99]NCT03707509 (CAPTAIN-1st)Camrelizumab (PD-1)Camrelizumab plus Gemcitabine plus Cisplatin versus Gemcitabine plus Cisplatin26372NoIIINC72Liu SV,et al. 2021 [100]NCT02763579 (IMpower133)Atezolizumab (PD-L1)Atezolizumab plus CP/ET versus Placebo plus CP/ET39461NoI/IIIExtensive-stage SCLC73Monk BJ,et al. 2021A [101]NCT02718417 (JAVELIN Ovarian 100)Avelumab (PD-L1)Avelumab plus Chemotherapy + Avelumab (maintenance) versus Chemotherapy99191NoIIIStage III–IV epithelial OCMonk BJ,et al. 2021B [101]Avelumab plus Chemotherapy plus Avelumab (maintenance) versus Chemotherapy plus Avelumab (maintenance)125Monk BJ,et al. 2021C [101]Chemotherapy plus Avelumab (maintenance) versus Chemotherapy8474Choueiri TK,et al. 2021 [102]NCT03142334 (KEYNOTE-564)Pembrolizumab (PD-1)Pembrolizumab versus Placebo984151NoIIIClear-cell, advanced RCC75Moore KN,et al. 2021 [103](NCT03038100) (IMagyn050/GOG 3015/ENGOT-OV39)Atezolizumab (PD-L1)Atezolizumab plus CP plus Bevacizumab versus Placebo plus CP plus Bevacizumab1285252NoIIIStage III or IV OC76Gogas H,et al. 2021 [104]NCT03273153 (IMspire170)Atezolizumab (PD-L1)Cobimetinib plus Atezolizumab versus Pembrolizumab436118NoIIIBRAFV600 wild-type melanoma77Owonikoko TK,et al. 2021A [105]NCT02538666 (CheckMate 451)Nivolumab (PD-1)Nivolumab plus Ipilimumab versus Nivolumab83082YesIIIExtensive-disease SCLCOwonikoko TK,et al. 2021B [105]Nivolumab plus Ipilimumab versus Placebo76Owonikoko TK,et al. 2021C [105]Nivolumab versus Placebo2878Luo H,et al. 2021 [106]NCT03691090 ((ESCORT-1st)Camrelizumab (PD-1)Camrelizumab plus Chemotherapy versus Chemotherapy59522NoIIIAdvanced or metastatic ESCC79Colombo N,et al. 2021A [107]NCT03635567 (KEYNOTE-826)Pembrolizumab (PD-1)Pembrolizumab plus Chemotherapy plus Bevacizumab versus Chemotherapy plus Bevacizumab38965NoIIIPersistent, recurrent, or metastatic cervical cancerColombo N,et al. 2021B [107]Pembrolizumab plus Chemotherapy versus Chemotherapy2271780Fennell DA,et al. 2021 [108]NCT03063450 (CONFIRM)Nivolumab (PD-1)Nivolumab versus Placebo3321YesIIIMalignant mesothelioma81Pusztai L,et al. 2021 [109](NCT01042379) (I-SPY2)Durvalumab (PD-L1)Durvalumab plus Olaparib plus Paclitaxel (DOP) versus Paclitaxel37263NoIIHER2-negative stage II/III breast cancer82Zhu X,et al. 2021 [110]NCT02704156Pembrolizumab (PD-1)SBRT plus Pembrolizumab plus Trametinib versus SBRT plus Gemcitabine17022YesIILocally recurrent pancreatic cancer after surgical resection83Sun JM,et al. 2021 [111]NCT03189719 (KEYNOTE-590)Pembrolizumab (PD-1)Pembrolizumab plus Chemotherapy versus Placebo plus Chemotherapy74047NoIIIAdvanced esophageal cancer84Mai HQ,et al. 2021 [112]NCT03581786Toripalimab (PD-1)Toripalimab plus GP versus Placebo plus GP28971NoIIIAdvanced NC85Felip E,et al. 2021 [113]NCT02486718 (IMpower010)Atezolizumab (PD-L1)Atezolizumab versus BSC990102YesIIIResected stage IB–IIIA NSCLC86Larkin J,et al. 2019A [114]NCT01844505 (CheckMate 067)Nivolumab (PD-1)Nivolumab plus Ipilimumab versus Nivolumab937167NoIIIAdvanced melanomaLarkin J,et al. 2019B [114]Nivolumab plus Ipilimumab versus Ipilimumab162Larkin J,et al. 2019C [114]Nivolumab versus Ipilimumab143Wolchok JD,et al. 2017A [115]Nivolumab plus Ipilimumab versus Nivolumab165Wolchok JD,et al. 2017B [115]Nivolumab plus Ipilimumab versus Ipilimumab161Wolchok JD,et al. 2017C [115]Nivolumab versus Ipilimumab140Hodi FS,et al. 2018A [116]Nivolumab plus Ipilimumab versus Nivolumab167Hodi FS,et al. 2018B [116]Nivolumab plus Ipilimumab versus Ipilimumab162Hodi FS,et al. 2018C [116]Nivolumab versus Ipilimumab143Larkin J,et al. 2015A [117]Nivolumab versus Nivolumab plus Ipilimumab207Larkin J,et al. 2015B [117]Nivolumab versus Ipilimumab183Larkin J,et al. 2015C [117]Nivolumab plus Ipilimumab versus Ipilimumab228RCT = randomized controlled trial, N/A = not available, NSCLC=non-small-cell lung cancer, SCLC = small-cell lung cancer, UC = urothelial carcinoma, HNSCC = head and neck squamous-cell carcinoma, TNBC = triple-negative breast cancer, NC = nasopharyngeal carcinoma, GJC = gastroesophageal junction cancer, GC = gastric cancer, ESCC = esophageal squamous cell carcinoma, OC= ovarian cancer, and RCC = renal cell carcinoma.


## 2.5. Heterogeneity Screening and Statistical Analyses

Cochrane’s Q and I2 statistics were used for heterogeneity screening, as described by Higgins and colleagues [16, 19], while the Harbord test was used for publication bias evaluation [19]. Three grades of heterogeneity were defined according to the I2 value: The two separation thresholds were 25% and 50%, respectively [20]. Using Review Manager 5.3, odds ratios (OR) and 95% confidence intervals (CI) across all enrolled clinical trials using the random effect (RE) method were calculated [21], whereas funnel plots were constructed using the fixed effect (FE) model. All statistical tests were two-sided, and p<0.05 was taken as a statistically significant result. In the process of analyses, adequate subgroup evaluations would be carried out according to the actual situation.


## 3. Results

### 3.1. Literature Search Results

After a preliminary PubMed search, 522 studies were retrieved (Figure1). After criteria screened, 95 studies involving 86 clinical trials, including 55207 participants, were used for the final comprehensive analyses [22–25], [26–30], [31–35], [36–40], [41–45], [46–50], [51–55], [56–60], [61–65], [66–70], [71–75], [76–80], [81–85], [86–90], [91–95], [96–110], [111–115], [116, 117]. According to the PICOS guidelines, the detailed process of literature screening was provided in the form of PRISMA flow diagram (Figure 1). All types of literature included in the quality checking were finished by the four authors independently and finally summarized by the corresponding author and then plotted as the (S Figure 1) [22–25], [26–30], [31–35], [36–40], [41–45], [46–50], [51–55], [56–60], [61–65], [66–70], [71–75], [76–80], [81–85], [86–90], [91–95], [96–110], [111–115], [116, 117].Figure 1
The flow diagram of all enrolled clinical trials.


### 3.2. Basic Information for All Included Clinical Trials

Basic characteristics of 86 clinical trials included in the study were extracted and shown in Table1 [5], [22–25], [26–30], [31–35], [36–40], [41–45], [46–50], [51–55], [56–60], [61–65], [66–70], [71–75], [76–80], [81–85], [86–90], [91–95], [96–110], [111–115], [116, 117]. 6 clinical trials, including KEYNOTE-021 [27, 28], KEYNOTE-189 [40–42], CheckMate 227 [47, 48], JAVELIN Renal 101 [51, 52], KEYNOTE-042 [61, 62], and CheckMate 067 [114–117], were repeatedly reported multiple times by different reporters, and only one with the detailed data could be selected for the final analyses. Among them, there were 72 Phase III, 8 Phase II, 2 Phase II/III, 1 Phase I/II, 1 Phase I/III, 1 Phase Ib, and 1 Phase I clinical trials. In 55 clinical trials, PD-1 or PD-L1 inhibitors were given alone or together with other antitumor drugs as the first-line regimens [23, 27, 28, 31], [36–38, 40–42], [44–48, 50, 53], [55–58], [61–68], [72, 73, 75], [77–80, 83–86], [88–95], [98–104], [106, 107, 109, 111, 112], [114–117], while previous therapies were found in the other 31 clinical trials [22, 24–26, 29, 30, 32–35, 39, 43, 49, 51, 52, 54, 59, 60, 69–71, 74, 76, 81, 82, 87, 96, 97, 105, 108, 110, 113]. Among the tumor types involved in all enrolled clinical trials, NSCLC accounted for the highest proportion (n = 22) [22, 24, 26–28, 35–37, 39–43, 47, 48, 53, 58, 59, 61, 62, 68, 74, 75, 92, 93, 98, 113], followed by melanoma (n = 11) [23, 31, 34, 44, 57, 65, 67, 76, 81, 104, 114–117], urothelial carcinoma (n = 8) [32, 49, 71, 77, 78, 86, 87, 90], renal cell carcinoma (n = 7) [25, 51, 52, 55, 56, 89, 91, 102], SCLC (n = 7) [29, 38, 50, 79, 95, 100, 105], triple-negative breast cancer (n = 6) [46, 66, 73, 82, 84, 88], and head and neck squamous cell carcinoma (n = 4) [30, 60, 63, 84].All enrolled clinical trials were classified into 15 groups in view of the treatment regimens of all the control groups, which were listed as follows: Group A (PD-1 or PD-L1 versus Chemotherapy) [22–24, 26, 32, 43, 47, 49, 54, 59, 61, 68, 77, 78, 80, 82, 86, 92, 96], Group B (PD-1 or PD-L1 plus Chemotherapy versus Chemotherapy) [27, 37, 41, 45, 53, 66, 73, 74, 77, 79, 80, 84, 86, 95, 96, 100, 101, 103, 107, 111, 112], Group C (Camrelizumab plus Chemotherapy versus Chemotherapy) [75, 99, 106], Group D (PD-1 or PD-L1 plus Chemotherapy plus Bevacizumab versus Chemotherapy plus Bevacizumab) [36, 107], Group E (PD-1 or PD-L1 versus Placebo) [33, 39, 44, 71, 87, 90, 91, 97, 98, 105, 108], Group F (PD-1 or PD-L1 plus Chemotherapy versus PD-1 or PD-L1) [63, 77, 80, 96], Group G (PD-1 or PD-L1 plus CTLA-4 versus PD-1 or PD-L1) [29, 47, 76, 78, 105, 118], Group H (PD-1 or PD-L1 versus CTLA-4) [34, 67, 117], Group I (PD-1 or PD-L1 plus CTLA-4 versus Chemotherapy) [47, 94], Group J (PD-1 or PD-L1 plus CTLA-4 plus Chemotherapy versus Chemotherapy) [93, 95], Group K (PD-1 or PD-L1 plus Bevacizumab versus Sorafenib) [64, 85], Group L (PD-1 or PD-L1 plus CTLA-4 versus CTLA-4) [31, 117], Group M (PD-1 or PD-L1 versus Methotrexate/docetaxel/cetuximab) [30, 60], and Group N (PD-1 or PD-L1 plus Antineoplastic Drug versus Sunitinib) [51, 55, 56, 89, 91]. The others would just be used for the systematic review [25, 26, 34, 57, 63, 65, 69, 72, 81, 83, 88, 89, 95, 101, 104, 105, 109, 110]. Within each group, the differences between the PD-1 and PD-L1 subgroups would be assessed firstly, followed by the treatment lines.


### 3.3. Risk of Bias

86 clinical trials, involving 95 literatures, were all screened for 5 relevant bias risks, and the results were shown in the (S Figure1) [22–25], [26–30], [31–35], [36–40], [41–45], [46–50], [51–55], [56–60], [61–65], [66–70], [71–75], [76–80], [81–85], [86–90], [91–95], [96–110], [111–115], [116, 117]. Data with high bias would not be adopted for the final meta-analysis (S Figure 1) [57, 114–116]. The funnel plots for publication bias assessments were constructed and shown in the corresponding figures (S Figures 2–6).


### 3.4. Risk Assessments of Rash for All Grades in Group A (PD-1 or PD-L1 versus Chemotherapy)

Reactive cutaneous capillary endothelial proliferation (RCCEP) was the characteristic rash of camrelizumab, so the clinical trials including camrelizumab were evaluated separately [70]. 19 clinical trials in Group A were summarized and prepared for the final analyses [22–24, 26, 32, 43, 47, 49, 54, 59, 61, 68, 77, 78, 80, 82, 86, 92, 96]. Among all tumor types, NSCLC was the most common one (n = 10) [22, 24, 26, 43, 47, 59, 61, 68, 92], followed by UC (n = 5) [32, 49, 77, 78, 86].Through analyses, we found that PD-1 or PD-L1 inhibitors significantly increased the risk of developing rash for all grades (OR = 1.66, 95% CI: [1.31, 2.11]; I2 = 57%, Z = 4.19, p<0.0001; Figures 2(a)–2(d)). Compared with the PD-L1 subgroup, the risk of developing rash appeared to be higher in PD-1 subgroup (OR = 1.92, 95% CI: [1.48, 2.50]; I2 = 46%, Z = 4.86, p=0.03; Figure 2(a)). Similar trend was also found when subgroup was divided based on the treatment lines (OR = 1.82, 95% CI: [1.48, 2.24]; I2 = 0%, Z = 5.67, p<0.00001; Figure 2(b)). However, no statistically significant subgroup differences were found in the above two subgroups (Chi2 = 2.62, p=0.11, I2 = 61.8%, Figure 2(a); Chi2 = 0.46, p=0.50, I2 = 0%, Figure 2(b)).Figure 2
Forest plots of comparison in Group A (PD-1 or PD-L1 versus Chemotherapy). (a) The OR of rash for all grades calculated by the random effect (RE) model: subgroup analyses were performed according to the types of immune checkpoint inhibitors (PD-1 or PD-L1). (b) The OR of rash for all grades calculated by the random effect (RE) model: subgroup analyses were performed according to the treatment lines (first or second line). (c) The OR of rash for all grades calculated by the random effect (RE) model: subgroup analyses were performed based on drug name, tumor type, and immune checkpoint type. (d) The OR of rash for all grades calculated by the random effect (RE) model: subgroup analyses were performed based on drug name, tumor type, immune checkpoint type, and I2 value.
(a)(b)(c)(d)High heterogeneity (I2 = 57%) could be found in the analysis results (Figures 2(a)–2(d)). After adequate subgroup analyses, it was found that this high degree of heterogeneity stemmed mainly from the two clinical trials of NSCLC (I2 = 76%, Figure 2(c); I2 = 83%, Figure 2(d)) [22, 24]. The funnel plots of them are shown in S Figures 2(a)–2(d).


### 3.5. Risk Assessments of Rash for All Grades in Group B, Group C, and Group D

21 clinical trials in Group B were enrolled for the final analysis [27, 37, 41, 45, 53, 66, 73, 74, 77, 79, 80, 84, 86, 95, 96, 100, 101, 103, 107, 111, 112]. Among all enrolled clinical trials, clinical trials involving NSCLC (n = 5) still accounted for the highest proportion [27, 37, 41, 53, 74], followed by triple-negative breast cancer (TNBC) (n = 4) [45, 66, 73, 84], small cell lung cancer (SCLC) (n = 3) [79, 95, 100], ovarian cancer (OC) (n = 3) [96, 101, 103], and urothelial carcinoma (UC) (n = 2) [77, 86].Compared with chemotherapy in Group B, it was found that PD-1 or PD-L1 together with chemotherapy significantly increased the risk of rash for all grades (OR = 1.87, 95% CI: [1.59, 2.20]; I2 = 53%, Z = 7.50, p<0.00001; Figures 3(a)–3(d)), even in each evaluable subgroups (Figures 3(c) and 3(d)). Similar to the former analysis result of Group A, the PD-1 subgroup appeared to have a higher risk of rash (OR = 2.01, 95% CI: [1.63, 2.47]; Figure 3(a)) with no statistical significant differences [27, 37, 41, 73, 79, 80, 86, 107, 111, 112], when it was compared to the PD-L1 subgroup (Chi2 = 0.66, p=0.42; Figure 3(a)) [45, 53, 66, 74, 77, 84, 95, 96, 100, 101, 103]. Different from the previous analyses (Figure 2(b)), the incidence risk of rash was higher when PD-1 or PD-L1 together with chemotherapy was given as the second-line option (OR = 2.98, 95% CI: [1.87, 4.75]; Chi2 = 3.95, p=0.05; Figure 3(b)) [74, 96]. Subgroup analyses indicated that the incidence risk of rash was different among different tumor types, especially in UC subgroup (OR = 2.66, 95% CI: [1.73, 4.09]; I2 = 61%, Z = 4.48, p<0.00001; Figure 3(c)) [77, 86]. Through subgroup analyses (Figures 3(c) and 3(d)), it was found that the high heterogeneity (I2 = 53%) might be mainly derived from the clinical trial KEYNOTE-361 (Figure 3(d)) [86].Figure 3
Forest plots of comparison in combination regimens. (a) The OR of rash for all grades checked using the random effect (RE) model in Group B (PD-1 or PD-L1 plus Chemotherapy versus Chemotherapy): subgroup analyses were carried out according to the types of immune checkpoint inhibitors (PD-1 or PD-L1). (b) The OR of rash for all grades checked using the random effect (RE) model in Group B (PD-1 or PD-L1 plus Chemotherapy versus Chemotherapy): subgroup analyses were carried out according to the treatment lines (first or second line). (c) The OR of rash for all grades checked using the random effect (RE) model in Group B (PD-1 or PD-L1 plus Chemotherapy versus Chemotherapy): subgroup analyses were carried out based on tumor type. (d) The OR of rash for all grades checked using the random effect (RE) model in Group B (PD-1 or PD-L1 plus Chemotherapy versus Chemotherapy): subgroup analyses were carried out based on tumor type and immune checkpoint type. (e) The OR of rash for all-grade checked using the random effect (RE) model in Group C (Camrelizumab plus Chemotherapy versus Chemotherapy). (f) The OR of rash for all-grade checked using the random effect (RE) model in Group D (PD-1 or PD-L1 plus Chemotherapy plus Bevacizumab versus Chemotherapy plus Bevacizumab).
(a)(b)(c)(d)(e)(f)Similar to the analysis result in Group B, the incidence risk of rash was also significantly increased when camrelizumab was given together with chemotherapy (OR = 2.30, 95% CI: [1.54, 3.44]; I2 = 0%, Z = 4.04, p<0.0001; Figure 3(e)) [75, 99, 106]. However, when PD-1 or PD-L1 was given with bevacizumab and chemotherapy, no statistically significant analysis result was found (OR = 1.90, 95% CI: [0.86, 4.20]; I2 = 77%, Z = 1.60, p=0.11; Figure 3(e)). All the corresponding funnel lots are shown in S Figures 3(a)–3(f).


### 3.6. Risk Assessments of Rash for All Grades in Groups E and F

11 clinical trials in Group E were enrolled for the final analyses [33, 39, 44, 71, 87, 90, 91, 97, 98, 105, 108]. Among all clinical trials, clinical trials involving UC (n = 3) accounted for the highest proportion [71, 87, 90], followed by NSCLC (n = 2) [39, 98]. In 5 clinical studies [44, 90, 91, 98, 108], PD-1 or PD-L1 inhibitors were given as the first-line choice, whereas they were utilized as second-line or alternative therapeutic choices in the other 6 trials [33, 39, 71, 87, 97, 105].Compared with placebo, it was found that PD-1 or PD-L1 inhibitors significantly increased the risk of developing rash for all grades (OR = 2.62, 95% CI: [1.88, 3.65]; I2 = 69%, Z = 5.71, p<0.00001; Figures 4(a)–4(d)), especially for UC (OR = 5.81, 95% CI: [2.78, 12.15]; I2 = 71%, Z = 4.68, p<0.00001; Figure 4(d)) [71, 87, 90]. Subgroup comparison indicated that the risk of developing rash was higher in the PD-L1 subgroup and first-line subgroup (Figures 4(a)–4(d)), which no statistical subgroup difference could be found. Overall heterogeneity in high degree (I2 = 69%) could be found, which was mainly caused by the clinical trial CheckMate 274 (I2 = 0%, Figure 4(c); I2 = 71%, Figure 4(d)) [87]. The corresponding funnel plots are shown in S Figures 4(a)–4(d).Figure 4
Forest plots of different comparison groups. (a) The OR of rash for all grades checked using the random effect (RE) model in Group E (PD-1 or PD-L1 versus Placebo): subgroup analyses were carried out according to the types of immune checkpoint inhibitors (PD-1 or PD-L1). (b) The OR of rash for all grades checked using the random effect (RE) model in Group E (PD-1 or PD-L1 versus Placebo): subgroup analyses were carried out according to the treatment lines (first or second line). (c) The OR of rash for all grades checked using the random effect (RE) model in Group E (PD-1 or PD-L1 versus Placebo): subgroup analyses were carried out based on tumor type. (d) The OR of rash for all grades checked using the random effect (RE) model in Group E (PD-1 or PD-L1 versus Placebo): subgroup analyses were carried out based on tumor type and I2 value. (e) The OR of rash for all grades checked using the random effect (RE) model in Group F (PD-1 or PD-L1 plus Chemotherapy VS PD-1 or PD-L1): subgroup analyses were carried out according to the types of immune checkpoint inhibitors (PD-1 or PD-L1). (f) The OR of rash for all grades checked using the random effect (RE) model in Group F (PD-1 or PD-L1 plus Chemotherapy versus PD-1 or PD-L1): subgroup analyses were carried out according to the treatment lines (first or second line).
(a)(b)(c)(d)(e)(f)4 clinical trials in Group F were enrolled for the final analyses [63, 77, 80, 96]. For PD-1/PD-L1 alone, the risk of rash was significantly increased when they were given with chemotherapy (OR = 2.33, 95% CI: [1.15, 4.75]; I2 = 81%, Z = 2.34, p=0.02; Figures 4(e) and 4(f)). Furthermore, this trend was much more pronounced when PD-L1 was combined with chemotherapy (OR = 4.02, 95% CI: [1.70, 9.53]; I2 = 71%, Z = 3.16, p=0.002; Figure 4(e)) or prescribed as the second line (OR = 6.50, 95% CI: [3.07, 13.75]; Figure 4(f)). Through subgroup analysis, it could be indicated that the high degree heterogeneity might be caused by the clinical trial JAVELIN Ovarian 200 (Figures 4(e) and 4(f)) [96]. The corresponding funnel plots were constructed and are shown in S Figures 4(e) and 4(f).


### 3.7. The Incidence Risk of Rash for All Grades in Groups G–N

6 clinical trials in Group G were used for the final analysis [29, 47, 76, 78, 105, 118]. In 3 clinical trials [47, 78, 118], PD-1 or PD-L1 inhibitors were given as the first-line choice, while they were used as second-line or other treatment options in the other 3 trials [29, 76, 105]. Compared with the adoption of PD-1 or PD-L1 inhibitor alone, the combination regimen (PD-1 or PD-L1 plus CTLA-4) significantly increased the risk of developing rash (OR = 2.39, 95% CI: [1.67, 3.42]; I2 = 54%, Z = 4.79, p<0.00001; Figures 5(a)–5(c)). Subgroup analysis suggested that the risk of rash in SCLC was higher than that in other tumor types (OR = 4.61, 95% CI: [2.70, 7.88]; I2 = 0%, Z = 5.59, p<0.00001; Figure 5(b)). Furthermore, the incidence risk of rash was higher when PD-1 or PD-L1 together with CTLA-4 was given as the second-line choice (OR = 4.31, 95% CI: [2.58, 7.20]; I2 = 0%, Z = 5.59, p<0.00001; Figure 5(c)). By comprehensively evaluating the results of various subgroup analyses (Figures 5(a)–5(c)), we inferred that the high degree of heterogeneity might be mainly caused by the clinical trial CheckMate 227 [47]. The corresponding funnel plots are shown in S Figures 5(a)–5(c).Figure 5
Forest plots of comparison groups (Groups G-M). (a) The OR of rash for all grades checked using the random effect (RE) model in Group G (PD-1 or PD-L1 plus CTLA-4 versus PD-1 or PD-L1): subgroup analyses were carried out according to the types of immune checkpoint inhibitors (PD-1 or PD-L1). (b) The OR of rash for all grades checked using the random effect (RE) model in Group G (PD-1 or PD-L1 plus CTLA-4 versus PD-1 or PD-L1): subgroup analyses were carried out based on tumor type. (c) The OR of rash for all grades checked using the random effect (RE) model in Group G (PD-1 or PD-L1 plus CTLA-4 versus PD-1 or PD-L1): subgroup analyses were carried out according to the treatment lines (first or second line). (d) The OR of rash for all grades checked using the random effect (RE) model in Group H (PD-1 or PD-L1 versus CTLA-4). (e) The odds ratio of rash for all grades calculated by the random effect (RE) model in Group H (PD-1 or PD-L1 versus CTLA-4): subgroup analyses were carried out according to the treatment lines (first or second line). (f) The OR of rash for all-grade checked using the random effect (RE) model in Group I (PD-1 or PD-L1 plus CTLA-4 versus Chemotherapy): subgroup analyses were carried out based on tumor type. (g) The OR of rash for all grades checked using the random effect (RE) model in Group J (PD-1 or PD-L1 plus CTLA-4 plus Chemotherapy versus Chemotherapy): subgroup analyses were carried out based on treatment regimens. (h) The OR of rash for all grades checked using the random effect (RE) model in Group K (PD-1 or PD-L1 plus Bevacizumab versus Sorafenib): subgroup analyses were carried out according to the types of immune checkpoint inhibitors (PD-1 or PD-L1). (i) The odds ratio of rash for all-grade checked using the random effect (RE) model in Group L (PD-1 or PD-L1 plus CTLA-4 versus CTLA-4). (j) The odds ratio of rash for all grades checked using the random effect (RE) model in Group M (PD-1 or PD-L1 versus Methotrexate/docetaxel/cetuximab).
(a)(b)(c)(d)(e)(f)(g)(h)(i)(j)3 clinical trials in Group H (PD-1 or PD-L1 versus CTLA-4) were selected for the final meta-analysis [34, 67, 117]. The risk of developing rash caused by PD-1 was found to be significantly lower than that of CTLA-4 only in the first-line therapy subgroup (OR = 0.51, 95% CI: [0.26, 0.99]; I2 = 87%, Z = 1.99, p=0.05; Figure 5(e)), whereas the overall effect was not statistically significant (OR = 0.73, 95% CI: [0.43, 1.22]; I2 = 86%, Z = 1.20, p=0.23; Figure 5(d)). The subgroup analysis suggested that the high heterogeneity might be mainly caused by CheckMate 238 and CheckMate 067 [67, 117]. The corresponding funnel plots are shown in S Figures 5(d) and 5(e).For chemotherapy alone, PD-1 or PD-L1 together with CTLA-4 (Group I) [47, 94], or together with chemotherapy on this basis (Group J) [93, 95], would significantly increase the risk of developing rash (Figures 5(f) and 5(g)). However, the conclusion was still controversial due to few studies included in those analyses (Figures 5(f) and 5(g)). The corresponding funnel plots are shown in (S Figures 5(f) and 5(g)).For sorafenib (Group K), the risk of developing rash was lower (OR = 0.60, 95% CI: [0.41, 0.89]; I2 = 0%, Z = 2.52, p=0.01; Figure 5(h)). When PD-1 or PD-L1 was given with CTLA-4 (Group L), the risk of developing rash was higher than that of CTLA-4 subgroup (OR = 1.43, 95% CI: [1.06, 1.93]; I2 = 0%, Z = 2.32, p=0.02; Figure 5(i)). When PD-1 was compared with chemotherapy (Group M), no statistical significant result was found (OR = 0.87, 95% CI: [0.25, 2.98]; I2 = 78%, Z = 0.23, p=0.82; Figure 5(j)). The corresponding funnel plots are shown in S Figures 5(k)–5(m).In 5 of the 6 clinical trials of renal cell carcinoma, the control group was sunitinib [51, 55, 56, 89, 91]. In these 5 clinical trials, we found that PD-1 or PD-L1 increased the incidence risk of rash regardless of which antitumor drug was used in combination [51, 55, 56, 89, 91]. However, the meta-analysis could not be performed due to the lack of consistency in the experimental groups in these 5 clinical trials [51, 55, 56, 89, 91]. The types of combination therapy regimens involving PD-1 or PD-L1 have been increasingly used in different tumors [26, 34, 57, 63, 65, 69, 72, 81, 83, 88, 95, 101, 104, 105, 109, 110]. In those combined treatment regimens, rash has been reported, which further verified the correlation between PD-1 or PD-L1 and the incidence of rash [26, 34, 57, 63, 65, 69, 72, 81, 83, 88, 95, 101, 104, 105, 109, 110].


### 3.8. Risk Assessments of Rash for Grades 3–5

The risk of developing rash for grades 3–5 was reported in 18 clinical trials (Group A) [22–24, 26, 32, 47, 54, 59, 61, 68, 70, 72, 77, 78, 82, 86, 92, 96]. Through analyses, statistically significant result was found only in NSCLC (OR = 2.51, 95% CI: [1.03, 6.11]; I2 = 0%, Z = 2.02, p=0.04; Figure 6(a)) [22, 24, 47, 59, 61, 64, 68, 92], while the overall effect across all tumor types was not statistically different (OR = 1.73, 95% CI: [0.91, 3.31]; I2 = 0%, Z = 1.66, p=0.10; Figure 6(a)).Figure 6
Forest plots of comparison groups for grades 3–5. (a) The OR of rash for grades 3–5 checked using the random effect (RE) model in Group A (PD-1 or PD-L1 versus Chemotherapy): subgroup analyses were carried out based on tumor types. (b) The OR of rash for grades 3–5 checked using the random effect (RE) model in Group B (PD-1 or PD-L1 plus Chemotherapy versus Chemotherapy): subgroup analyses were carried out based on tumor types. (c) The OR of rash for grades 3–5 checked using the random effect (RE) model in Group E (PD-1 or PD-L1 versus Placebo): subgroup analyses were carried out based on tumor types. (d) The OR of rash for grades 3–5 checked using the random effect (RE) model in Group G (PD-1 or PD-L1 plus CTLA-4 versus PD-1 or PD-L1): subgroup analyses were carried out based on tumor types. (e) The OR of rash for grades 3–5 checked using the random effect (RE) model in Group F (PD-1 or PD-L1 plus Chemotherapy versus PD-1 or PD-L1): subgroup analyses were carried out based on the types of immune checkpoint inhibitors (PD-1 or PD-L1). (f) The OR of rash for grades 3–5 checked using the random effect (RE) model in Group H (PD-1 or PD-L1 versus CTLA-4). (g) The odds ratio of rash for grades 3–5 checked using the random effect (RE) model in Group M (PD-1 or PD-L1 versus Methotrexate/docetaxel/cetuximab). (h) The OR of rash for grades 3–5 checked using the random effect (RE) model in Group K (PD-1 or PD-L1 plus Bevacizumab versus Sorafenib): subgroup analyses were carried out based on the name of immune checkpoint inhibitors. (i) The OR of rash for grades 3–5 checked using the random effect (RE) model in Group J (PD-1 or PD-L1 plus CTLA-4 plus Chemotherapy versus Chemotherapy): subgroup analyses were carried out based on treatment regimens.
(a)(b)(c)(d)(e)(f)(g)(h)(i)Similar to the risk of rash for all grades in Group B, the risk of developing rash was significantly higher than that of the control chemotherapy group [27, 36, 38, 41, 45, 53, 66, 73–75, 79, 80, 84, 86, 96, 101, 103, 107, 111, 112], when PD-1 or PD-L1 was given together with chemotherapy (OR = 2.61, 95% CI: [1.67, 4.08]; I2 = 0%, Z = 4.20, p<0.0001; Figure 6(b)), especially for ovarian cancer (OR = 4.34, 95% CI: [1.89, 9.96]; I2 = 0%, Z = 3.46, p=0.0005; Figure 6(b)) [96, 101, 103]. The positive result could also be found in Group C (OR = 3.42, 95% CI: [1.49, 7.85]; I2 = 0%, Z = 2.89, p=0.004; Figure 6(c)), Group G (OR = 3.39, 95% CI: [1.54, 7.49]; I2 = 0%, Z = 3.02, p=0.002; Figure 6(d)), and Group J (OR = 9.64, 95% CI: [1.22, 76.16]; I2 = 0%, Z = 2.15, p=0.03; Figure 6(i)) [39, 44, 47, 77, 78, 81, 90, 91, 93, 95, 98, 105, 117]. However, when PD-1 or PD-L1 plus bevacizumab were compared with sorafenib, the risk of developing rash was lower than that of the control group (OR = 0.13, 95% CI: [0.02, 0.83]; I2 = 0%, Z = 2.16, p=0.03; Figure 6(h)). In the other groups, no statistical significant results could be found (Figures 6(e)–6(g)). All the corresponding funnel plots were constructed and are shown in S Figures 6(a)–6(i).


## 3.1. Literature Search Results

After a preliminary PubMed search, 522 studies were retrieved (Figure1). After criteria screened, 95 studies involving 86 clinical trials, including 55207 participants, were used for the final comprehensive analyses [22–25], [26–30], [31–35], [36–40], [41–45], [46–50], [51–55], [56–60], [61–65], [66–70], [71–75], [76–80], [81–85], [86–90], [91–95], [96–110], [111–115], [116, 117]. According to the PICOS guidelines, the detailed process of literature screening was provided in the form of PRISMA flow diagram (Figure 1). All types of literature included in the quality checking were finished by the four authors independently and finally summarized by the corresponding author and then plotted as the (S Figure 1) [22–25], [26–30], [31–35], [36–40], [41–45], [46–50], [51–55], [56–60], [61–65], [66–70], [71–75], [76–80], [81–85], [86–90], [91–95], [96–110], [111–115], [116, 117].Figure 1
The flow diagram of all enrolled clinical trials.


## 3.2. Basic Information for All Included Clinical Trials

Basic characteristics of 86 clinical trials included in the study were extracted and shown in Table1 [5], [22–25], [26–30], [31–35], [36–40], [41–45], [46–50], [51–55], [56–60], [61–65], [66–70], [71–75], [76–80], [81–85], [86–90], [91–95], [96–110], [111–115], [116, 117]. 6 clinical trials, including KEYNOTE-021 [27, 28], KEYNOTE-189 [40–42], CheckMate 227 [47, 48], JAVELIN Renal 101 [51, 52], KEYNOTE-042 [61, 62], and CheckMate 067 [114–117], were repeatedly reported multiple times by different reporters, and only one with the detailed data could be selected for the final analyses. Among them, there were 72 Phase III, 8 Phase II, 2 Phase II/III, 1 Phase I/II, 1 Phase I/III, 1 Phase Ib, and 1 Phase I clinical trials. In 55 clinical trials, PD-1 or PD-L1 inhibitors were given alone or together with other antitumor drugs as the first-line regimens [23, 27, 28, 31], [36–38, 40–42], [44–48, 50, 53], [55–58], [61–68], [72, 73, 75], [77–80, 83–86], [88–95], [98–104], [106, 107, 109, 111, 112], [114–117], while previous therapies were found in the other 31 clinical trials [22, 24–26, 29, 30, 32–35, 39, 43, 49, 51, 52, 54, 59, 60, 69–71, 74, 76, 81, 82, 87, 96, 97, 105, 108, 110, 113]. Among the tumor types involved in all enrolled clinical trials, NSCLC accounted for the highest proportion (n = 22) [22, 24, 26–28, 35–37, 39–43, 47, 48, 53, 58, 59, 61, 62, 68, 74, 75, 92, 93, 98, 113], followed by melanoma (n = 11) [23, 31, 34, 44, 57, 65, 67, 76, 81, 104, 114–117], urothelial carcinoma (n = 8) [32, 49, 71, 77, 78, 86, 87, 90], renal cell carcinoma (n = 7) [25, 51, 52, 55, 56, 89, 91, 102], SCLC (n = 7) [29, 38, 50, 79, 95, 100, 105], triple-negative breast cancer (n = 6) [46, 66, 73, 82, 84, 88], and head and neck squamous cell carcinoma (n = 4) [30, 60, 63, 84].All enrolled clinical trials were classified into 15 groups in view of the treatment regimens of all the control groups, which were listed as follows: Group A (PD-1 or PD-L1 versus Chemotherapy) [22–24, 26, 32, 43, 47, 49, 54, 59, 61, 68, 77, 78, 80, 82, 86, 92, 96], Group B (PD-1 or PD-L1 plus Chemotherapy versus Chemotherapy) [27, 37, 41, 45, 53, 66, 73, 74, 77, 79, 80, 84, 86, 95, 96, 100, 101, 103, 107, 111, 112], Group C (Camrelizumab plus Chemotherapy versus Chemotherapy) [75, 99, 106], Group D (PD-1 or PD-L1 plus Chemotherapy plus Bevacizumab versus Chemotherapy plus Bevacizumab) [36, 107], Group E (PD-1 or PD-L1 versus Placebo) [33, 39, 44, 71, 87, 90, 91, 97, 98, 105, 108], Group F (PD-1 or PD-L1 plus Chemotherapy versus PD-1 or PD-L1) [63, 77, 80, 96], Group G (PD-1 or PD-L1 plus CTLA-4 versus PD-1 or PD-L1) [29, 47, 76, 78, 105, 118], Group H (PD-1 or PD-L1 versus CTLA-4) [34, 67, 117], Group I (PD-1 or PD-L1 plus CTLA-4 versus Chemotherapy) [47, 94], Group J (PD-1 or PD-L1 plus CTLA-4 plus Chemotherapy versus Chemotherapy) [93, 95], Group K (PD-1 or PD-L1 plus Bevacizumab versus Sorafenib) [64, 85], Group L (PD-1 or PD-L1 plus CTLA-4 versus CTLA-4) [31, 117], Group M (PD-1 or PD-L1 versus Methotrexate/docetaxel/cetuximab) [30, 60], and Group N (PD-1 or PD-L1 plus Antineoplastic Drug versus Sunitinib) [51, 55, 56, 89, 91]. The others would just be used for the systematic review [25, 26, 34, 57, 63, 65, 69, 72, 81, 83, 88, 89, 95, 101, 104, 105, 109, 110]. Within each group, the differences between the PD-1 and PD-L1 subgroups would be assessed firstly, followed by the treatment lines.


## 3.3. Risk of Bias

86 clinical trials, involving 95 literatures, were all screened for 5 relevant bias risks, and the results were shown in the (S Figure1) [22–25], [26–30], [31–35], [36–40], [41–45], [46–50], [51–55], [56–60], [61–65], [66–70], [71–75], [76–80], [81–85], [86–90], [91–95], [96–110], [111–115], [116, 117]. Data with high bias would not be adopted for the final meta-analysis (S Figure 1) [57, 114–116]. The funnel plots for publication bias assessments were constructed and shown in the corresponding figures (S Figures 2–6).


## 3.4. Risk Assessments of Rash for All Grades in Group A (PD-1 or PD-L1 versus Chemotherapy)

Reactive cutaneous capillary endothelial proliferation (RCCEP) was the characteristic rash of camrelizumab, so the clinical trials including camrelizumab were evaluated separately [70]. 19 clinical trials in Group A were summarized and prepared for the final analyses [22–24, 26, 32, 43, 47, 49, 54, 59, 61, 68, 77, 78, 80, 82, 86, 92, 96]. Among all tumor types, NSCLC was the most common one (n = 10) [22, 24, 26, 43, 47, 59, 61, 68, 92], followed by UC (n = 5) [32, 49, 77, 78, 86].Through analyses, we found that PD-1 or PD-L1 inhibitors significantly increased the risk of developing rash for all grades (OR = 1.66, 95% CI: [1.31, 2.11]; I2 = 57%, Z = 4.19, p<0.0001; Figures 2(a)–2(d)). Compared with the PD-L1 subgroup, the risk of developing rash appeared to be higher in PD-1 subgroup (OR = 1.92, 95% CI: [1.48, 2.50]; I2 = 46%, Z = 4.86, p=0.03; Figure 2(a)). Similar trend was also found when subgroup was divided based on the treatment lines (OR = 1.82, 95% CI: [1.48, 2.24]; I2 = 0%, Z = 5.67, p<0.00001; Figure 2(b)). However, no statistically significant subgroup differences were found in the above two subgroups (Chi2 = 2.62, p=0.11, I2 = 61.8%, Figure 2(a); Chi2 = 0.46, p=0.50, I2 = 0%, Figure 2(b)).Figure 2
Forest plots of comparison in Group A (PD-1 or PD-L1 versus Chemotherapy). (a) The OR of rash for all grades calculated by the random effect (RE) model: subgroup analyses were performed according to the types of immune checkpoint inhibitors (PD-1 or PD-L1). (b) The OR of rash for all grades calculated by the random effect (RE) model: subgroup analyses were performed according to the treatment lines (first or second line). (c) The OR of rash for all grades calculated by the random effect (RE) model: subgroup analyses were performed based on drug name, tumor type, and immune checkpoint type. (d) The OR of rash for all grades calculated by the random effect (RE) model: subgroup analyses were performed based on drug name, tumor type, immune checkpoint type, and I2 value.
(a)(b)(c)(d)High heterogeneity (I2 = 57%) could be found in the analysis results (Figures 2(a)–2(d)). After adequate subgroup analyses, it was found that this high degree of heterogeneity stemmed mainly from the two clinical trials of NSCLC (I2 = 76%, Figure 2(c); I2 = 83%, Figure 2(d)) [22, 24]. The funnel plots of them are shown in S Figures 2(a)–2(d).


## 3.5. Risk Assessments of Rash for All Grades in Group B, Group C, and Group D

21 clinical trials in Group B were enrolled for the final analysis [27, 37, 41, 45, 53, 66, 73, 74, 77, 79, 80, 84, 86, 95, 96, 100, 101, 103, 107, 111, 112]. Among all enrolled clinical trials, clinical trials involving NSCLC (n = 5) still accounted for the highest proportion [27, 37, 41, 53, 74], followed by triple-negative breast cancer (TNBC) (n = 4) [45, 66, 73, 84], small cell lung cancer (SCLC) (n = 3) [79, 95, 100], ovarian cancer (OC) (n = 3) [96, 101, 103], and urothelial carcinoma (UC) (n = 2) [77, 86].Compared with chemotherapy in Group B, it was found that PD-1 or PD-L1 together with chemotherapy significantly increased the risk of rash for all grades (OR = 1.87, 95% CI: [1.59, 2.20]; I2 = 53%, Z = 7.50, p<0.00001; Figures 3(a)–3(d)), even in each evaluable subgroups (Figures 3(c) and 3(d)). Similar to the former analysis result of Group A, the PD-1 subgroup appeared to have a higher risk of rash (OR = 2.01, 95% CI: [1.63, 2.47]; Figure 3(a)) with no statistical significant differences [27, 37, 41, 73, 79, 80, 86, 107, 111, 112], when it was compared to the PD-L1 subgroup (Chi2 = 0.66, p=0.42; Figure 3(a)) [45, 53, 66, 74, 77, 84, 95, 96, 100, 101, 103]. Different from the previous analyses (Figure 2(b)), the incidence risk of rash was higher when PD-1 or PD-L1 together with chemotherapy was given as the second-line option (OR = 2.98, 95% CI: [1.87, 4.75]; Chi2 = 3.95, p=0.05; Figure 3(b)) [74, 96]. Subgroup analyses indicated that the incidence risk of rash was different among different tumor types, especially in UC subgroup (OR = 2.66, 95% CI: [1.73, 4.09]; I2 = 61%, Z = 4.48, p<0.00001; Figure 3(c)) [77, 86]. Through subgroup analyses (Figures 3(c) and 3(d)), it was found that the high heterogeneity (I2 = 53%) might be mainly derived from the clinical trial KEYNOTE-361 (Figure 3(d)) [86].Figure 3
Forest plots of comparison in combination regimens. (a) The OR of rash for all grades checked using the random effect (RE) model in Group B (PD-1 or PD-L1 plus Chemotherapy versus Chemotherapy): subgroup analyses were carried out according to the types of immune checkpoint inhibitors (PD-1 or PD-L1). (b) The OR of rash for all grades checked using the random effect (RE) model in Group B (PD-1 or PD-L1 plus Chemotherapy versus Chemotherapy): subgroup analyses were carried out according to the treatment lines (first or second line). (c) The OR of rash for all grades checked using the random effect (RE) model in Group B (PD-1 or PD-L1 plus Chemotherapy versus Chemotherapy): subgroup analyses were carried out based on tumor type. (d) The OR of rash for all grades checked using the random effect (RE) model in Group B (PD-1 or PD-L1 plus Chemotherapy versus Chemotherapy): subgroup analyses were carried out based on tumor type and immune checkpoint type. (e) The OR of rash for all-grade checked using the random effect (RE) model in Group C (Camrelizumab plus Chemotherapy versus Chemotherapy). (f) The OR of rash for all-grade checked using the random effect (RE) model in Group D (PD-1 or PD-L1 plus Chemotherapy plus Bevacizumab versus Chemotherapy plus Bevacizumab).
(a)(b)(c)(d)(e)(f)Similar to the analysis result in Group B, the incidence risk of rash was also significantly increased when camrelizumab was given together with chemotherapy (OR = 2.30, 95% CI: [1.54, 3.44]; I2 = 0%, Z = 4.04, p<0.0001; Figure 3(e)) [75, 99, 106]. However, when PD-1 or PD-L1 was given with bevacizumab and chemotherapy, no statistically significant analysis result was found (OR = 1.90, 95% CI: [0.86, 4.20]; I2 = 77%, Z = 1.60, p=0.11; Figure 3(e)). All the corresponding funnel lots are shown in S Figures 3(a)–3(f).


## 3.6. Risk Assessments of Rash for All Grades in Groups E and F

11 clinical trials in Group E were enrolled for the final analyses [33, 39, 44, 71, 87, 90, 91, 97, 98, 105, 108]. Among all clinical trials, clinical trials involving UC (n = 3) accounted for the highest proportion [71, 87, 90], followed by NSCLC (n = 2) [39, 98]. In 5 clinical studies [44, 90, 91, 98, 108], PD-1 or PD-L1 inhibitors were given as the first-line choice, whereas they were utilized as second-line or alternative therapeutic choices in the other 6 trials [33, 39, 71, 87, 97, 105].Compared with placebo, it was found that PD-1 or PD-L1 inhibitors significantly increased the risk of developing rash for all grades (OR = 2.62, 95% CI: [1.88, 3.65]; I2 = 69%, Z = 5.71, p<0.00001; Figures 4(a)–4(d)), especially for UC (OR = 5.81, 95% CI: [2.78, 12.15]; I2 = 71%, Z = 4.68, p<0.00001; Figure 4(d)) [71, 87, 90]. Subgroup comparison indicated that the risk of developing rash was higher in the PD-L1 subgroup and first-line subgroup (Figures 4(a)–4(d)), which no statistical subgroup difference could be found. Overall heterogeneity in high degree (I2 = 69%) could be found, which was mainly caused by the clinical trial CheckMate 274 (I2 = 0%, Figure 4(c); I2 = 71%, Figure 4(d)) [87]. The corresponding funnel plots are shown in S Figures 4(a)–4(d).Figure 4
Forest plots of different comparison groups. (a) The OR of rash for all grades checked using the random effect (RE) model in Group E (PD-1 or PD-L1 versus Placebo): subgroup analyses were carried out according to the types of immune checkpoint inhibitors (PD-1 or PD-L1). (b) The OR of rash for all grades checked using the random effect (RE) model in Group E (PD-1 or PD-L1 versus Placebo): subgroup analyses were carried out according to the treatment lines (first or second line). (c) The OR of rash for all grades checked using the random effect (RE) model in Group E (PD-1 or PD-L1 versus Placebo): subgroup analyses were carried out based on tumor type. (d) The OR of rash for all grades checked using the random effect (RE) model in Group E (PD-1 or PD-L1 versus Placebo): subgroup analyses were carried out based on tumor type and I2 value. (e) The OR of rash for all grades checked using the random effect (RE) model in Group F (PD-1 or PD-L1 plus Chemotherapy VS PD-1 or PD-L1): subgroup analyses were carried out according to the types of immune checkpoint inhibitors (PD-1 or PD-L1). (f) The OR of rash for all grades checked using the random effect (RE) model in Group F (PD-1 or PD-L1 plus Chemotherapy versus PD-1 or PD-L1): subgroup analyses were carried out according to the treatment lines (first or second line).
(a)(b)(c)(d)(e)(f)4 clinical trials in Group F were enrolled for the final analyses [63, 77, 80, 96]. For PD-1/PD-L1 alone, the risk of rash was significantly increased when they were given with chemotherapy (OR = 2.33, 95% CI: [1.15, 4.75]; I2 = 81%, Z = 2.34, p=0.02; Figures 4(e) and 4(f)). Furthermore, this trend was much more pronounced when PD-L1 was combined with chemotherapy (OR = 4.02, 95% CI: [1.70, 9.53]; I2 = 71%, Z = 3.16, p=0.002; Figure 4(e)) or prescribed as the second line (OR = 6.50, 95% CI: [3.07, 13.75]; Figure 4(f)). Through subgroup analysis, it could be indicated that the high degree heterogeneity might be caused by the clinical trial JAVELIN Ovarian 200 (Figures 4(e) and 4(f)) [96]. The corresponding funnel plots were constructed and are shown in S Figures 4(e) and 4(f).


## 3.7. The Incidence Risk of Rash for All Grades in Groups G–N

6 clinical trials in Group G were used for the final analysis [29, 47, 76, 78, 105, 118]. In 3 clinical trials [47, 78, 118], PD-1 or PD-L1 inhibitors were given as the first-line choice, while they were used as second-line or other treatment options in the other 3 trials [29, 76, 105]. Compared with the adoption of PD-1 or PD-L1 inhibitor alone, the combination regimen (PD-1 or PD-L1 plus CTLA-4) significantly increased the risk of developing rash (OR = 2.39, 95% CI: [1.67, 3.42]; I2 = 54%, Z = 4.79, p<0.00001; Figures 5(a)–5(c)). Subgroup analysis suggested that the risk of rash in SCLC was higher than that in other tumor types (OR = 4.61, 95% CI: [2.70, 7.88]; I2 = 0%, Z = 5.59, p<0.00001; Figure 5(b)). Furthermore, the incidence risk of rash was higher when PD-1 or PD-L1 together with CTLA-4 was given as the second-line choice (OR = 4.31, 95% CI: [2.58, 7.20]; I2 = 0%, Z = 5.59, p<0.00001; Figure 5(c)). By comprehensively evaluating the results of various subgroup analyses (Figures 5(a)–5(c)), we inferred that the high degree of heterogeneity might be mainly caused by the clinical trial CheckMate 227 [47]. The corresponding funnel plots are shown in S Figures 5(a)–5(c).Figure 5
Forest plots of comparison groups (Groups G-M). (a) The OR of rash for all grades checked using the random effect (RE) model in Group G (PD-1 or PD-L1 plus CTLA-4 versus PD-1 or PD-L1): subgroup analyses were carried out according to the types of immune checkpoint inhibitors (PD-1 or PD-L1). (b) The OR of rash for all grades checked using the random effect (RE) model in Group G (PD-1 or PD-L1 plus CTLA-4 versus PD-1 or PD-L1): subgroup analyses were carried out based on tumor type. (c) The OR of rash for all grades checked using the random effect (RE) model in Group G (PD-1 or PD-L1 plus CTLA-4 versus PD-1 or PD-L1): subgroup analyses were carried out according to the treatment lines (first or second line). (d) The OR of rash for all grades checked using the random effect (RE) model in Group H (PD-1 or PD-L1 versus CTLA-4). (e) The odds ratio of rash for all grades calculated by the random effect (RE) model in Group H (PD-1 or PD-L1 versus CTLA-4): subgroup analyses were carried out according to the treatment lines (first or second line). (f) The OR of rash for all-grade checked using the random effect (RE) model in Group I (PD-1 or PD-L1 plus CTLA-4 versus Chemotherapy): subgroup analyses were carried out based on tumor type. (g) The OR of rash for all grades checked using the random effect (RE) model in Group J (PD-1 or PD-L1 plus CTLA-4 plus Chemotherapy versus Chemotherapy): subgroup analyses were carried out based on treatment regimens. (h) The OR of rash for all grades checked using the random effect (RE) model in Group K (PD-1 or PD-L1 plus Bevacizumab versus Sorafenib): subgroup analyses were carried out according to the types of immune checkpoint inhibitors (PD-1 or PD-L1). (i) The odds ratio of rash for all-grade checked using the random effect (RE) model in Group L (PD-1 or PD-L1 plus CTLA-4 versus CTLA-4). (j) The odds ratio of rash for all grades checked using the random effect (RE) model in Group M (PD-1 or PD-L1 versus Methotrexate/docetaxel/cetuximab).
(a)(b)(c)(d)(e)(f)(g)(h)(i)(j)3 clinical trials in Group H (PD-1 or PD-L1 versus CTLA-4) were selected for the final meta-analysis [34, 67, 117]. The risk of developing rash caused by PD-1 was found to be significantly lower than that of CTLA-4 only in the first-line therapy subgroup (OR = 0.51, 95% CI: [0.26, 0.99]; I2 = 87%, Z = 1.99, p=0.05; Figure 5(e)), whereas the overall effect was not statistically significant (OR = 0.73, 95% CI: [0.43, 1.22]; I2 = 86%, Z = 1.20, p=0.23; Figure 5(d)). The subgroup analysis suggested that the high heterogeneity might be mainly caused by CheckMate 238 and CheckMate 067 [67, 117]. The corresponding funnel plots are shown in S Figures 5(d) and 5(e).For chemotherapy alone, PD-1 or PD-L1 together with CTLA-4 (Group I) [47, 94], or together with chemotherapy on this basis (Group J) [93, 95], would significantly increase the risk of developing rash (Figures 5(f) and 5(g)). However, the conclusion was still controversial due to few studies included in those analyses (Figures 5(f) and 5(g)). The corresponding funnel plots are shown in (S Figures 5(f) and 5(g)).For sorafenib (Group K), the risk of developing rash was lower (OR = 0.60, 95% CI: [0.41, 0.89]; I2 = 0%, Z = 2.52, p=0.01; Figure 5(h)). When PD-1 or PD-L1 was given with CTLA-4 (Group L), the risk of developing rash was higher than that of CTLA-4 subgroup (OR = 1.43, 95% CI: [1.06, 1.93]; I2 = 0%, Z = 2.32, p=0.02; Figure 5(i)). When PD-1 was compared with chemotherapy (Group M), no statistical significant result was found (OR = 0.87, 95% CI: [0.25, 2.98]; I2 = 78%, Z = 0.23, p=0.82; Figure 5(j)). The corresponding funnel plots are shown in S Figures 5(k)–5(m).In 5 of the 6 clinical trials of renal cell carcinoma, the control group was sunitinib [51, 55, 56, 89, 91]. In these 5 clinical trials, we found that PD-1 or PD-L1 increased the incidence risk of rash regardless of which antitumor drug was used in combination [51, 55, 56, 89, 91]. However, the meta-analysis could not be performed due to the lack of consistency in the experimental groups in these 5 clinical trials [51, 55, 56, 89, 91]. The types of combination therapy regimens involving PD-1 or PD-L1 have been increasingly used in different tumors [26, 34, 57, 63, 65, 69, 72, 81, 83, 88, 95, 101, 104, 105, 109, 110]. In those combined treatment regimens, rash has been reported, which further verified the correlation between PD-1 or PD-L1 and the incidence of rash [26, 34, 57, 63, 65, 69, 72, 81, 83, 88, 95, 101, 104, 105, 109, 110].


## 3.8. Risk Assessments of Rash for Grades 3–5

The risk of developing rash for grades 3–5 was reported in 18 clinical trials (Group A) [22–24, 26, 32, 47, 54, 59, 61, 68, 70, 72, 77, 78, 82, 86, 92, 96]. Through analyses, statistically significant result was found only in NSCLC (OR = 2.51, 95% CI: [1.03, 6.11]; I2 = 0%, Z = 2.02, p=0.04; Figure 6(a)) [22, 24, 47, 59, 61, 64, 68, 92], while the overall effect across all tumor types was not statistically different (OR = 1.73, 95% CI: [0.91, 3.31]; I2 = 0%, Z = 1.66, p=0.10; Figure 6(a)).Figure 6
Forest plots of comparison groups for grades 3–5. (a) The OR of rash for grades 3–5 checked using the random effect (RE) model in Group A (PD-1 or PD-L1 versus Chemotherapy): subgroup analyses were carried out based on tumor types. (b) The OR of rash for grades 3–5 checked using the random effect (RE) model in Group B (PD-1 or PD-L1 plus Chemotherapy versus Chemotherapy): subgroup analyses were carried out based on tumor types. (c) The OR of rash for grades 3–5 checked using the random effect (RE) model in Group E (PD-1 or PD-L1 versus Placebo): subgroup analyses were carried out based on tumor types. (d) The OR of rash for grades 3–5 checked using the random effect (RE) model in Group G (PD-1 or PD-L1 plus CTLA-4 versus PD-1 or PD-L1): subgroup analyses were carried out based on tumor types. (e) The OR of rash for grades 3–5 checked using the random effect (RE) model in Group F (PD-1 or PD-L1 plus Chemotherapy versus PD-1 or PD-L1): subgroup analyses were carried out based on the types of immune checkpoint inhibitors (PD-1 or PD-L1). (f) The OR of rash for grades 3–5 checked using the random effect (RE) model in Group H (PD-1 or PD-L1 versus CTLA-4). (g) The odds ratio of rash for grades 3–5 checked using the random effect (RE) model in Group M (PD-1 or PD-L1 versus Methotrexate/docetaxel/cetuximab). (h) The OR of rash for grades 3–5 checked using the random effect (RE) model in Group K (PD-1 or PD-L1 plus Bevacizumab versus Sorafenib): subgroup analyses were carried out based on the name of immune checkpoint inhibitors. (i) The OR of rash for grades 3–5 checked using the random effect (RE) model in Group J (PD-1 or PD-L1 plus CTLA-4 plus Chemotherapy versus Chemotherapy): subgroup analyses were carried out based on treatment regimens.
(a)(b)(c)(d)(e)(f)(g)(h)(i)Similar to the risk of rash for all grades in Group B, the risk of developing rash was significantly higher than that of the control chemotherapy group [27, 36, 38, 41, 45, 53, 66, 73–75, 79, 80, 84, 86, 96, 101, 103, 107, 111, 112], when PD-1 or PD-L1 was given together with chemotherapy (OR = 2.61, 95% CI: [1.67, 4.08]; I2 = 0%, Z = 4.20, p<0.0001; Figure 6(b)), especially for ovarian cancer (OR = 4.34, 95% CI: [1.89, 9.96]; I2 = 0%, Z = 3.46, p=0.0005; Figure 6(b)) [96, 101, 103]. The positive result could also be found in Group C (OR = 3.42, 95% CI: [1.49, 7.85]; I2 = 0%, Z = 2.89, p=0.004; Figure 6(c)), Group G (OR = 3.39, 95% CI: [1.54, 7.49]; I2 = 0%, Z = 3.02, p=0.002; Figure 6(d)), and Group J (OR = 9.64, 95% CI: [1.22, 76.16]; I2 = 0%, Z = 2.15, p=0.03; Figure 6(i)) [39, 44, 47, 77, 78, 81, 90, 91, 93, 95, 98, 105, 117]. However, when PD-1 or PD-L1 plus bevacizumab were compared with sorafenib, the risk of developing rash was lower than that of the control group (OR = 0.13, 95% CI: [0.02, 0.83]; I2 = 0%, Z = 2.16, p=0.03; Figure 6(h)). In the other groups, no statistical significant results could be found (Figures 6(e)–6(g)). All the corresponding funnel plots were constructed and are shown in S Figures 6(a)–6(i).


## 4. Discussion

Among several therapeutic options available, cancer immunotherapy is extremely successful in increasing tumor patients’ survival rates, particularly with PD-1/PD-L1 inhibitors [2]. Currently, PD-1 or PD-L1 inhibitors are extensively employed in the treatment of many types of malignancies, and the combination regimens using PD-1 or PD-L1 inhibitors are diversified [22–25], [26–30], [31–35], [36–40], [41–45], [46–50], [51–55], [56–60], [61–65], [66–70], [71–75], [76–80], [81–85], [86–90], [91–95], [96–110], [111–115], [116, 117], [118]. As with cetuximab [119, 120], rash associated with therapeutic benefit was one of the most frequently reported skin toxicities associated with PD-1 or PD-L1 inhibitors [13–15]. The correlation between rash and PD-1 or PD-L1 inhibitors, on the other hand, has to be further clarified in detail, particularly in diverse combination treatment regimens. Therefore, a systematic review and meta-analysis were conducted with the guidelines of the PRISMA criteria (Figure 1) [16].After quality screening (S Figure1), 86 clinical trials with complete data were adopted for the final comprehensive analyses [22–25], [26–30], [31–35], [36–40], [41–45], [46–50], [51–55], [56–60], [61–65], [66–70], [71–75], [76–80], [81–85], [86–90], [91–95], [96–110], [111–115], [116, 117], which avoided the high risk of attrition bias. With the development of clinical research, PD-1 or PD-L1 inhibitors have been increasingly prescribed as the first-line antitumor options (n = 51) [23, 27, 28], [31, 36–38], [40–42], [44–48], [50, 53], [55–58], [61–68], [72, 73], [75, 77–80], [83–86], [88–95], [98–104], [106, 107, 109], [111, 112], [114–117], especially for PD-1 or PD-L1 combined regimens [27, 36, 38, 41, 45, 53, 66, 73, 75, 79, 80, 84, 86, 99, 101, 103, 107, 111, 112], which also increase the difficulty of elucidating the relationship between PD-1 or PD-L1 and the risk of rash. Therefore, it is necessary for us to conduct this meta-analysis.According to the compositions of all the control groups, all the enrolled clinical trials were firstly classified into different groups (Groups A-N), and then, analyses were carried out for each group (Figures2–6 and S Figures 2–6). Through the analyses, it was found that PD-1 or PD-L1 inhibitors raised the risk of developing rash (Figure 2, Figures 4(a)–4(d), and Figure 6(a)), whether compared with chemotherapy or placebo alone (Group A and Group E) [22–24, 26, 32, 33, 39, 43, 44, 47, 49, 54, 59, 61, 68, 71, 77, 78, 80, 82, 86, 87, 90–92, 96–98, 105, 108]. However, this effect was weaker than CTLA-4 with no statistical significance (Group H) (Figures 5(d)–5(e) and 6(f)) [34, 67, 117]. In the combined antitumor treatment regimens containing PD-1 or PD-L1 inhibitors (Group B, Group C, Group D, and Group L) [27, 31, 36, 37, 41, 45, 53, 66, 73–75, 77, 79, 80, 84, 86, 95, 96, 99–101, 103, 106, 107, 111, 112, 117], it was also found that the risk of rash was increased due to the involvement of PD-1 or PD-L1 inhibitors (Figure 3, Figures 5(a)–5(c), Figure 6(b), S Figure 3, S Figure 5(a)–5(c), and S Figure 6(b)). Similar trend was also found in other PD-1 or PD-L1 inhibitor-based combination regimens (Group F, Group G, Group I, and Group G) (Figures 4(e) and 4(f); Figures 5(a)–5(c), 5(f), 5(g), 6(d), 6(e), and 6(i); S Figures 4(e)–4(f); S Figures 5(a)–5(c), 5(f), 5(g), 6(d), 6(e), and 6(i)) [29, 47, 63, 76–78, 80, 93–96, 105, 117]. In the other clinical trials for which meta-analysis could not be performed, the experimental group of PD-1 or PD-L1 inhibitors involved also indicated an increased risk of rash [25, 26, 34, 51, 55–57, 63, 65, 69, 72, 81, 83, 88, 89, 91, 95, 101, 104, 105, 109, 110]. From the above, it could be concluded that the risk of rash would be increased when PD-1 or PD-L-1 inhibitors were given alone or together with other antitumor regimens.For the lack of head-to-head contrast between PD-1 and PD-L1 [22–25], [26–30], [31–35], [36–40], [41–45], [46–50], [51–55], [56–60], [61–65], [66–70], [71–75], [76–80], [81–85], [86–90], [91–95], [96–110], [111–115], [116, 117], we tried to investigate the differences between PD-1 and PD-L1 subgroups and indirectly observe the differences of rash risk. Although the analyses indicated that the risk of rash differed between PD-1 and PD-L1-related subgroups (Figures 2(a), 3(a) and 4(a)), no statistically significant results were found due to the involvement of PD-1 or PD-L1 inhibitors [22–24], [26, 27, 32], [33, 37, 39], [41, 43–45], [47, 49, 53], [54, 59, 61, 66], [68, 71–74], [77–80], [82, 84, 86], [87, 90–92], [95–98], [100, 101, 103], [105, 107, 108], [111, 112]. However, compared with the PD-1 involved subgroup (Figure 4(e)), the participation of chemotherapy significantly increased the risk of rash in the PD-L1 subgroup (p=0.03) [63, 77, 80, 96].The similar strategy was used to elucidate the influence of PD-1 or PD-L1 involved treatment lines on the risk of developing rash (Figures2(b), 3(b), 4(b), 4(f), 5(c), and 5(e)). Subgroup studies revealed an increased risk of rash when PD-1 or PD-L1 inhibitors were given together with other antitumor agents as the second-line choice (Figure 3(b), 4(f), and 5(c)) [27, 29, 37, 41, 45, 47, 53, 63, 66, 73, 74, 76–80, 84, 86, 95, 96, 100, 101, 103, 105, 107, 111, 112, 117]. When PD-1 or PD-L1 inhibitors were given alone, this incidence trend was only seen in Group H (Figure 5(e)) [34, 67, 117]. The reasons leading to the above results might be related to the combined treatment drugs, and the specific reasons were still need to be further studied.The formation of heterogeneity is inevitable in the course of detailed examination (Figures2–6). By conducting adequate subgroup analyses and comparing the results of rash between all grades and grades 3–5, the clinical trials responsible for the heterogeneity were identified, and further analyses revealed that the heterogeneity might be primarily due to the data themselves (Figure 6), implying that it would have little effect on the overall analysis results. Additionally, no noticeable publication bias was detected using funnel plots (S Figures 2–6). This further increased the reliability and rigor of this meta-analysis.Although the correlation between skin toxicities and tumor regression had been reported frequently in some studies [10–12], no such data were found in all the enrolled clinical trials [22–25], [26–30], [31–35], [36–40], [41–45], [46–50], [51–55], [56–60], [61–65], [66–70], [71–75], [76–80], [81–85], [86–90], [91–95], [96–110], [111–115], [116, 117]. Therefore, to elucidate the correlation between the rash risk and tumor prognosis, more and more relevant clinical trials should be put into practice [13–15]. Furthermore, researchers needed to pay more attention to this kind of data and report it in a timely manner. In clinical work, we need to use treatment-related rashes cautiously to judge the treatment response and prognosis of patients.


## 5. Conclusions

The risk of developing rash would be enhanced whether PD-1 or PD-L1 inhibitors were given alone or together with others. Furthermore, the incidence risk of rash appeared to be higher when PD-1 or PD-L1 inhibitors together with other antitumor drugs were given as the second-line choice. No statistically significant differences in the results of the rash between the PD-1 and PD-L1 subgroups were found due to the involvement of PD-1 or PD-L1 inhibitors.



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