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

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.


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][5][6][7][8][9], many toxicities remain unexplored, including skin toxicities [3].
Skin toxicities, such as rash, pruritus, vitiligo, palmarplantar 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]. is pattern may also be observed in other types of tumors [11,12]. Correlations between adverse events and clinical benefit are not uncommon [13][14][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. erefore, 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.

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

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.

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. en, 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. e 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.

Quality Evaluation and Publication Bias Screening.
e 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.
e quality screening of all the enrolled clinical trials were also carried out by the above four authors. e 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].

Screening of Results.
e 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. e main information of all trials would be extracted and summarized in the single table (Table 1). e 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.

Heterogeneity Screening and Statistical Analyses.
Cochrane's Q and I 2 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]. ree grades of heterogeneity were defined according to the I 2 value: e 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.  Journal of Oncology  Journal of Oncology Journal of Oncology 7  Journal of Oncology

Risk Assessments of Rash for All Grades in Groups
Compared with placebo, it was found that PD-1 or PD-L1 inhibitors significantly increased the risk of developing rash for all grades (

e 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]; I 2 � 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]; I 2 � 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 e subgroup analysis suggested that the high heterogeneity might be mainly caused by CheckMate 238 and CheckMate 067 [67,117]. e 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)). e corresponding funnel plots are shown in (S Figures 5(f ) and 5(g)).
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 (Figures 2-6 and S Figures 2-6).

Conclusions
e 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.