Pruritus and xerodermia in patients treated with checkpoint inhibitors for melanoma, lung and renal cancer: a meta-analysis

Pruritus and xerodermia in patients treated with checkpoint inhibitors for melanoma, lung and renal cancer: a meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Pruritus and xerodermia in patients treated with checkpoint inhibitors for melanoma, lung and renal cancer: a meta-analysis Igor Kiss, Michal Svoboda, Cecilie Horska, Samuel Buchler, Tomas Buchler This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4480556/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Dermatologic adverse events (DAEs) are common in patients treated with immune checkpoint inhibitors (ICI) for cancer. Objective: To evaluate the incidence of two selected dermatologic adverse events (DAEs), pruritus and xerodermia, reported as adverse events in phase 3 randomised clinical trials using ICI in patients with lung cancer, renal cancer, and melanoma. Methods: Phase 3 studies where treatment included an ICI in the experimental arm were analysed. For pruritus, 42 studies were analysed with a total of 29,502 evaluable patients. For xerodermia, the number of studies was 23 with 17,341 patients. Results: . Pruritus was associated with ICI therapy with OR of 3.02 (95% CI 2.57–3.55). Compared to renal cell carcinoma (RCC) treated with anti-programmed death (PD-1) agents, patients with melanoma had higher odds of reporting pruritus, reaching statistical significance for the anti-PD-1 and anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) treatment. Patient with lung cancer had significantly lower odds of pruritus across all ICI types compared to other analysed tumour types. Xerodermia was also associated with ICI treatment. Using RCC/PD-1 as a reference, there was a trend to higher incidence of xerodermia in patients with melanoma. Patients with lung cancer had significantly lower odds of xerodermia regardless of ICI type. Conclusion: The present systematic analysis indicates that pruritus and xerodermia are associated with ICI treatment of any type compared to non-immunologic therapies. There appears to be a higher incidence of these DAEs in patients with melanoma and RCC compared to patients with lung cancer. Immunotherapy cancer checkpoint inhibitors rash pruritus xerodermia systematic analysis Figures Figure 1 Introduction Immune checkpoint inhibitors (ICI) have become the mainstay of treatment of many malignancies. Their use is well known to be accompanied by increased risk of immune toxicities. Dermatologic adverse events (DAEs) are common in patients treated with ICI for cancer. The aetiology of DAEs includes inflammatory skin conditions caused by autoimmune processes induced or reinduced by ICI, and skin disorders associated with other immuno-related toxicities, mostly affecting the endocrine system. Dermatologic toxicity may lead to anticancer therapy dose modifications and/or termination, besides impairing patients’ health-related quality of life. Wide range of dermatologic toxicities have been reported, but the most common are maculopapular rash and pruritus [ 1 , 2 ]. Several authors have suggested that the occurrence on DAEs may be related to the underlying diagnosis, possibly reflecting the presence of shared antigens between some tumours and skin [ 3 – 5 ]. The aim of the present meta-analysis was to evaluate the incidence of two selected DAE, pruritus and xerodermia, reported as adverse events in phase 3 randomised clinical trials using ICI in patients with solid cancers, to compare their occurrence in patients treated with ICI to those receiving other systemic therapies, and to compare the incidence of DAEs in three types of malignancies (melanoma, lung cancer, and renal cell carcinoma) to assess the potential association of diagnosis and type of ICI treatment in developing pruritus and xerodermia. Methods Search Strategy The search was carried out in the PubMed and ClinicalTrials.gov databases using terms “cancer” and “ipilimumab or MDX-010“, “nivolumab or MDX-1106“, “avelumab or MSB0010718C“, “durvalumab or MEDI-4736“, “pembrolizumab or MK-3475“, “atezolizumab or MPDL3280A”, “tremelimumab or CP-675,206“, “cemiplimab or REGN2810“ [ 6 ]. The methodology for selecting studies is depicted in Fig. 1 and was similar to one used in our previous systematic analyses [ 6 , 7 ]. Criteria for inclusion were restricted to phase 3 clinical trials that included detailed tables of adverse events within the ClinicalTrials.gov repository. Only those studies that featured control arms not employing immunotherapy were considered. Studies were selected by a search carried out in February 2021 and data collection on pruritus and xerodermia (dry skin), was conducted during May and June 2023. This process was independently executed by two researchers, with any discrepancies resolved through collaborative discussion. The execution of this study adhered to the protocols outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [ 8 ] (Supplementary Material 1). Statistical Analysis The frequencies and corresponding confidence intervals for occurrences of pruritus and xerodermia (dry skin) were quantitatively assessed and reported for each investigated study, as well as synthesized across varying classifications of checkpoint inhibitor agents and for three distinct cancer types: melanoma, lung cancer, and renal cancer. Additionally, the odds ratio (OR) along with its confidence interval (CI) were calculated for each individual study. A random-effects model was employed for the aggregation of data across studies. Inclusion criteria for the meta-analysis encompassed studies with either two or three arms. Specifically, a three-arm study comprising two experimental arms (E1 and E2) and one control arm (C) resulted in the derivation of two pairs of comparative arms (E1 vs. C; E2 vs. C). For the analysis, data from three-arm studies were methodologically handled as per the approach suggested by Rucker et al., which involves splitting the shared control group in multi-arm trials for pairwise meta-analysis [ 9 ]. Cochrane Q statistics and I 2 statistics were used to estimate heterogeneity. Certainty of evidence was assessed per Grading of Recommendations, Assessment, Development and Evaluations (GRADE) guidelines [ 10 ]. I 2 values were used to classify heterogeneity as low ( 75%) [ 11 ]. Q-test for subgroup difference was used for type of diagnosis and types of immunotherapy. The logistic model with random effect was used to compare different classes of immunotherapy agents, i.e. those targeting PD-1, PD-L1, and CTLA-4, respectively. All statistical analyses were performed using software R version 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria) using the R package meta [ 12 ]. Results Selection of Studies A total of 8,632 records of phase 3 studies for cancer were identified in the initial step of the search. For the analysis of pruritus, 42 studies were analysed with a total of 29502 evaluable patients. The solid cancers treated in the included studies were the following: lung cancer (27 studies), melanoma (eight studies), renal cancer (seven studies). For the evaluation of xerodermia, the number of studies 23 (lung cancer 14 studies, melanoma six studies, renal cell carcinoma three studies) with 17341 patients (Figure 1). The list of the included studies is provided in Supplementary File 2 [13, 14, 23–32, 15, 33–42, 16, 43–49, 17–22]. Quality Assessment The assessment of study quality utilized the Cochrane risk of bias tool. Performance bias emerged as the primary concern, attributed to the absence of blinding among participants and personnel in certain studies, as detailed in Supplementary File 1. Given that the studies under review were all randomized phase III trials, the likelihood of encountering other forms of bias—such as those related to random sequence generation, allocation concealment, blinding of outcome assessment, incomplete outcome data, and selective reporting—was minimal. There was an unquantifiable the potential for evidence selection bias due to the potentially different specialties administering the treatment, with dermatologists and dermatooncologists treating melanoma being more perceptive to DAEs compared to physicians treating patients with renal cell carcinoma (RCC) and lung cancer. Pruritus Pruritus was significantly associated with ICI therapy with OR of 3.02 (95% CI 2.57–3.55) compared to non-immunotherapy treatments. The highest OR for pruritus was recorded in trials using anti-CTLA4 agents in monotherapy, followed by those using the combination of CTLA4 and anti-PD(L)1 therapy. The odds of pruritus in ICI versus the control arm was similar for all three selected diagnoses (Table 1). Compared to RCC treated with anti-PD1 agents (RCC/PD-1 cohort), patients with melanoma had higher odds of reporting pruritus, reaching statistical significance for the anti-PD-1 and anti-CTLA4 treatment (Table 2). In contrast, lung cancer was associated with significantly lower odds of pruritus across all ICI types (Table 2). The odds of pruritus were lower also in the control non-immunotherapy arms of lung cancer trials. Overall, as evident from Table 2, there was a clear clustering of odds depending on diagnosis rather than on type of ICI. Detailed data for comparisons across all studied subgroups defined by diagnosis and treatment are shown in Supplementary File 3. There was an intermediate heterogeneity (Table 3). Xerodermia Xerodermia was more commont in the ICI arms of the randomised trial (OR 1.44, 95% CI 1.15–1.82). It was more common in patients receiving anti-PDL-1 therapies compared to other types of ICI. (Table 4) The odds of xerodermia in ICI versus the control arm was statistically significant only in lung cancer. With RCC/PD-1 used as a reference, there was a trend to higher incidence of xerodermia in patients with melanoma, especially patients treated with anti-PDL1 agents. As with pruritus, patients with lung cancer had significantly lower odds of xerodermia regardless of ICI type. The incidence of xerodermia was also significantly lower than the reference in the non-immunotherapy control arms in trials for lung cancer (Table 5). There was an intermediate heterogeneity (Table 6). Comparisons between all studied subgroups defined by diagnosis and ICI type are shown in Supplementary File 3. Discussion The results of the present extensive meta-analysis of phase III trials indicate that there is a clear association of both pruritus and xerodermia reported as adverse events with ICI treatment for cancer. Xerodermia and pruritus are closely interrelated and may represent a diffuse skin inflammation of lower intensity than rash. While the occurence of rash in patients treated with immunotherapy has been the subject of several systemic analyses, many types of rash are reported in clinical trials per Common Terminology Criteria for Adverse Events classification, and thus it may be problematic to establish the true incidence of the symptom. Therefore, pruritus and xerodermia, which are unequivocally coded, were selected for the present analysis. Several systematic analyses have been published concerning DAEs. In 2016 Belum et al have mapped the incidence of DAEs in randomised clinical trials with PD-1/L1 inhibitors [ 50 ]. At that time, only one phase 3 trial in non-small cell lung cancer (NSCLC) and three such studies in melanoma could be included, the rest of the meta-analysis comprised of phase 1 and 2 studies. The incidence of pruritus was 20.2% for pembrolizumab and 13.2% for nivolumab. Ge et al. (2021) conducted a meta-analysis of 50 randomized controlled trials (RCTs) involving 29,941 patients to investigate the risk of pruritus and rash from ICIs [ 4 ]. The study found that the risk of developing pruritus and rash from CTLA-4 or PD-1/-L1 inhibitors was significantly increased compared to placebo with relative risks of 2.15 and 4.21 for pruritus. Combining PD-1/-L1 with CTLA-4 inhibitors led to higher risks of pruritus (relative risk of 1.76) compared to monotherapy with either. PD-1/-L1 inhibitors had significantly lower risks of pruritus compared to CTLA-4 inhibitors. The rash associated with ipilimumab, an immune checkpoint inhibitor, is likened to common maculopapular rashes and atopic dermatitis. The incidence and severity of pruritus from ipilimumab have shown similar rates for the 3-mg/kg and 10-mg/kg dose. In this analysis, data also suggested that the risk of rash was independent of tumour type, based on analysis of patients with metastatic melanoma and other tumour types [ 51 ]. In 2021, Han et al. conducted a comprehensive meta-analysis of 46 RCTs involving 28,569 patients to assess DAE associated with ICI therapy, finding these events to be dose-independent, agent-specific, and more prevalent with CTLA-4 blockade compared to PD-(L)1 blockade [ 5 ]. Specifically, melanoma patients had the highest overall incidence of cutaneous immune-related adverse events (irAEs), with rates of 23.1% for rash and 25.3% for pruritus, while patients with squamous carcinoma of the head and neck experienced the lowest risk. The present analysis expands the findings of Khoja and collaborators published in 2017 [ 3 ]. A comparison irAEs among melanoma, NSCLC, and RCC patients in trials studying anti-PD-1 ICI revealed that melanoma patients exhibited higher frequencies of gastrointestinal and skin irAEs, and lower pneumonitis compared to NSCLC. However, the numbers of patients (6938 patients in 48 trials) that could be analysed were understandably much lower owing to rapid publication of many studies since. None of the above systematic studies analysed xerodermia in the context of ICI therapy. Although xerodermia is non-fatal and rarely if ever leads to treatment discontinuation, it is an exceedingly common problem in cancer patients. The underlying pathophysiology of xerodermia is the dysfunction of corneal layer, impairing the barrier function of the skin. Pruritus is the most common associated symptom [ 52 ]. The principal weakness of the metaanalysis is the potential evidence selection bias influenced by the varying specialties of the treating clinicians. Dermatologists participate in or administer the treatment for melanoma, and they may be more receptive to DAEs compared to cancer physicians with other subspecialization. Similar bias may be present in other systematic analysis comparing the incidence of organ-specific adverse events between different types of tumour. However, RCC treated with PD-1 was as the reference for all comparisons in our study and the bias is unlikely to be responsible for the differences between RCC and lung cancer. In conclusion, the present systematic analysis suggests that pruritus and xerodermia are clearly associated with ICI treatment of any type. There appears to be higher incidence of these DAEs in patients with melanoma and RCC compared to patients with lung cancer, suggesting that the occurrence of DAEs is diagnosis-specific. Abbreviations GRADE: Grading Of Recommendations, Assessment, Development And Evaluations ICIs: Immune Checkpoint Inhibitors irAEs: Immune-Related Adverse Events PD-1: Programmed Death PD-L1: Programmed Death 1 Ligand PRISMA: Preferred Reporting Items For Systematic Reviews And Meta-Analyses RCC: Renal Cell Carcinoma RCTs: Randomized Controlled Trials Declarations Statement of Ethics Ethical approval and consent were not required as this study was based on publicly available data. Data Availability Statement The raw data used for the analysis will be made available by the authors upon request. Author Contribution TB had the right to deal with all the data and was responsible for the decision to submit the manuscript for publication. IK, MK and TB had the data of all included clinical trials. TB, BB and KH retrieved the data. MK carried out the statistical analysis. LB extensively revised the manuscript and provided interpretation of the statistical methods and results. TB, IK and BB were responsible for checking and evaluating the quality of the collected data. All authors contributed to the article and approved the submitted version. Funding None Conflict of Interest IK has received research support and honoraria from Roche, Bristol Myers Squibb, Merck Sharp Dohme, Merck, and Servier, all unrelated to the present paper. TB has received research support and honoraria from Roche, Bristol Myers Squibb, Merck Sharp Dohme, Merck, and AstraZeneca, all unrelated to the present paper. Other authors declare no conflicts of interest. References Sibaud V (2018) Dermatologic Reactions to Immune Checkpoint Inhibitors : Skin Toxicities and Immunotherapy. Am J Clin Dermatol 19:345–361. https://doi.org/10.1007/s40257-017-0336-3 Wang Y, Zhou S, Yang F, et al (2019) Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-analysis. JAMA Oncol 5:1008–1019. https://doi.org/10.1001/jamaoncol.2019.0393 Khoja L, Day D, Wei-Wu Chen T, et al (2017) Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review. Ann Oncol Off J Eur Soc Med Oncol 28:2377–2385. https://doi.org/10.1093/annonc/mdx286 Ge Y, Zhang H, Weygant N, Yao J (2021) Differential Dermatologic Adverse Events Associated With Checkpoint Inhibitor Monotherapy and Combination Therapy: A Meta-Analysis of Randomized Control Trials. Front Pharmacol 12:640099. https://doi.org/10.3389/fphar.2021.640099 Han Y, Wang J, Xu B (2021) Cutaneous adverse events associated with immune checkpoint blockade: A systematic review and meta-analysis. Crit Rev Oncol Hematol 163:103376. https://doi.org/10.1016/j.critrevonc.2021.103376 Kiss I, Kuhn M, Hrusak K, Buchler T (2022) Incidence of fatigue associated with immune checkpoint inhibitors in patients with cancer: a meta-analysis. ESMO Open 7:100474 Kiss I, Kuhn M, Hrusak K, et al (2022) Insomnia in patients treated with checkpoint inhibitors for cancer: A meta-analysis. Front. Oncol. 12:946307 Liberati A, Altman DG, Tetzlaff J, et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700. https://doi.org/10.1136/bmj.b2700 Rücker G, Cates CJ, Schwarzer G (2017) Methods for including information from multi-arm trials in pairwise meta-analysis. Res Synth Methods 8:392–403. https://doi.org/10.1002/jrsm.1259 Balshem H, Helfand M, Schünemann HJ, et al (2011) GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 64:401–406. https://doi.org/10.1016/j.jclinepi.2010.07.015 Higgins JPT, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560. https://doi.org/10.1136/bmj.327.7414.557 Balduzzi S, Rücker G, Schwarzer G (2019) How to perform a meta-analysis with R: a practical tutorial. Evid Based Ment Health 22:153–160. https://doi.org/10.1136/ebmental-2019-300117 Hodi FS, O’Day SJ, McDermott DF, et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723. https://doi.org/10.1056/NEJMoa1003466 Robert C, Thomas L, Bondarenko I, et al (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526. https://doi.org/10.1056/NEJMoa1104621 Borghaei H, Paz-Ares L, Horn L, et al (2015) Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 373:1627–1639. https://doi.org/10.1056/NEJMoa1507643 Brahmer J, Reckamp KL, Baas P, et al (2015) Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 373:123–135. https://doi.org/10.1056/NEJMoa1504627 Motzer RJ, Escudier B, McDermott DF, et al (2015) Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 373:1803–1813. https://doi.org/10.1056/NEJMoa1510665 Eggermont AMM, Chiarion-Sileni V, Grob J-J, et al (2016) Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med 375:1845–1855. https://doi.org/10.1056/NEJMoa1611299 Herbst RS, Baas P, Kim D-W, et al (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet (London, England) 387:1540–1550. https://doi.org/10.1016/S0140-6736(15)01281-7 Reck M, Rodríguez-Abreu D, Robinson AG, et al (2016) Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 375:1823–1833. https://doi.org/10.1056/NEJMoa1606774 Reck M, Luft A, Szczesna A, et al (2016) Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol Off J Am Soc Clin Oncol 34:3740–3748. https://doi.org/10.1200/JCO.2016.67.6601 Antonia SJ, Villegas A, Daniel D, et al (2017) Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 377:1919–1929. https://doi.org/10.1056/NEJMoa1709937 Paz-Ares L, Ciuleanu T-E, Cobo M, et al (2021) First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol 22:198–211. https://doi.org/10.1016/S1470-2045(20)30641-0 Rittmeyer A, Barlesi F, Waterkamp D, et al (2017) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet (London, England) 389:255–265. https://doi.org/10.1016/S0140-6736(16)32517-X Socinski MA, Jotte RM, Cappuzzo F, et al (2018) Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med 378:2288–2301. https://doi.org/10.1056/NEJMoa1716948 Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al (2018) Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med 378:2078–2092. https://doi.org/10.1056/NEJMoa1801005 Horn L, Mansfield AS, Szczęsna A, et al (2018) First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med 379:2220–2229. https://doi.org/10.1056/NEJMoa1809064 Larkin J, Minor D, D’Angelo S, et al (2018) Overall Survival in Patients With Advanced Melanoma Who Received Nivolumab Versus Investigator’s Choice Chemotherapy in CheckMate 037: A Randomized, Controlled, Open-Label Phase III Trial. J Clin Oncol Off J Am Soc Clin Oncol 36:383–390. https://doi.org/10.1200/JCO.2016.71.8023 Motzer RJ, Tannir NM, McDermott DF, et al (2018) Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 378:1277–1290. https://doi.org/10.1056/NEJMoa1712126 Paz-Ares L, Luft A, Vicente D, et al (2018) Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med 379:2040–2051. https://doi.org/10.1056/NEJMoa1810865 Mok TSK, Wu Y-L, Kudaba I, et al (2019) Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet (London, England) 393:1819–1830. https://doi.org/10.1016/S0140-6736(18)32409-7 Rini BI, Plimack ER, Stus V, et al (2019) Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. https://doi.org/10.1056/NEJMoa1816714 Rini BI, Powles T, Atkins MB, et al (2019) Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet (London, England) 393:2404–2415. https://doi.org/10.1016/S0140-6736(19)30723-8 West H, McCleod M, Hussein M, et al (2019) Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 tri. Lancet Oncol 20:924–937. https://doi.org/10.1016/S1470-2045(19)30167-6 Gutzmer R, Stroyakovskiy D, Gogas H, et al (2020) Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAF(V600) mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (London, England) 395:1835–1844. https://doi.org/10.1016/S0140-6736(20)30934-X Herbst RS, Giaccone G, de Marinis F, et al (2020) Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med 383:1328–1339. https://doi.org/10.1056/NEJMoa1917346 Jotte R, Cappuzzo F, Vynnychenko I, et al (2020) Atezolizumab in Combination With Carboplatin and Nab-Paclitaxel in Advanced Squamous NSCLC (IMpower131): Results From a Randomized Phase III Trial. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 15:1351–1360. https://doi.org/10.1016/j.jtho.2020.03.028 Rizvi NA, Cho BC, Reinmuth N, et al (2020) Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial. JAMA Oncol 6:661–674. https://doi.org/10.1001/jamaoncol.2020.0237 Rudin CM, Awad MM, Navarro A, et al (2020) Pembrolizumab or Placebo Plus Etoposide and Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer: Randomized, Double-Blind, Phase III KEYNOTE-604 Study. J Clin Oncol Off J Am Soc Clin Oncol 38:2369–2379. https://doi.org/10.1200/JCO.20.00793 Motzer R, Alekseev B, Rha S-Y, et al (2021) Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med 384:1289–1300. https://doi.org/10.1056/NEJMoa2035716 Owonikoko TK, Park K, Govindan R, et al (2021) Nivolumab and Ipilimumab as Maintenance Therapy in Extensive-Disease Small-Cell Lung Cancer: CheckMate 451. J Clin Oncol Off J Am Soc Clin Oncol 39:1349–1359. https://doi.org/10.1200/JCO.20.02212 Paz-Ares L, Dvorkin M, Chen Y, et al (2019) Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet (London, England) 394:1929–1939. https://doi.org/10.1016/S0140-6736(19)32222-6 Choueiri TK, Powles T, Burotto M, et al (2021) Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 384:829–841. https://doi.org/10.1056/NEJMoa2026982 Wu Y-L, Lu S, Cheng Y, et al (2019) Nivolumab Versus Docetaxel in a Predominantly Chinese Patient Population With Previously Treated Advanced NSCLC: CheckMate 078 Randomized Phase III Clinical Trial. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 14:867–875. https://doi.org/10.1016/j.jtho.2019.01.006 Ribas A, Kefford R, Marshall MA, et al (2013) Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol Off J Am Soc Clin Oncol 31:616–622. https://doi.org/10.1200/JCO.2012.44.6112 Robert C, Long G V, Brady B, et al (2015) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320–330. https://doi.org/10.1056/NEJMoa1412082 Govindan R, Szczesna A, Ahn M-J, et al (2017) Phase III Trial of Ipilimumab Combined With Paclitaxel and Carboplatin in Advanced Squamous Non-Small-Cell Lung Cancer. J Clin Oncol Off J Am Soc Clin Oncol 35:3449–3457. https://doi.org/10.1200/JCO.2016.71.7629 Nishio M, Barlesi F, West H, et al (2021) Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 16:653–664. https://doi.org/10.1016/j.jtho.2020.11.025 Ren S, Feng J, Ma S, et al (2023) KEYNOTE-033: Randomized phase 3 study of pembrolizumab vs docetaxel in previously treated, PD-L1-positive, advanced NSCLC. Int J cancer 153:623–634. https://doi.org/10.1002/ijc.34532 Belum VR, Benhuri B, Postow MA, et al (2016) Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer 60:12–25. https://doi.org/10.1016/j.ejca.2016.02.010 Lacouture ME, Wolchok JD, Yosipovitch G, et al (2014) Ipilimumab in patients with cancer and the management of dermatologic adverse events. J Am Acad Dermatol 71:161–169. https://doi.org/10.1016/j.jaad.2014.02.035 Pons-Guiraud A (2007) Dry skin in dermatology: a complex physiopathology. J Eur Acad Dermatol Venereol 21 Suppl 2:1–4. https://doi.org/10.1111/j.1468-3083.2007.02379.x Tables Tables 1-6 are available in the Supplementary Files section. Additional Declarations Competing interest reported. IK has received research support and honoraria from Roche, Bristol Myers Squibb, Merck Sharp Dohme, Merck, and Servier, all unrelated to the present paper. TB has received research support and honoraria from Roche, Bristol Myers Squibb, Merck Sharp Dohme, Merck, and AstraZeneca, all unrelated to the present paper. Other authors declare no conflicts of interest. Supplementary Files supplementaryfile1PRISMA2020checklist2122024.docx Supplementary File 1. PRISMA checklist. supplementaryfile2studylist21022024.docx Supplementary File 2. List of included studies. SupplementaryFile3.xlsx Supplementary File 3. Odds ratio tables for individual tumour and immunotherapy types. Tables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4480556","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":311452420,"identity":"253167dc-e6f3-41d5-9cea-876b22f0b84d","order_by":0,"name":"Igor Kiss","email":"","orcid":"","institution":"Masaryk University","correspondingAuthor":false,"prefix":"","firstName":"Igor","middleName":"","lastName":"Kiss","suffix":""},{"id":311452421,"identity":"1aefb2c7-64c3-48b3-811c-5863b9b8d7bc","order_by":1,"name":"Michal Svoboda","email":"","orcid":"","institution":"Institute of Biostatistics and Analyses","correspondingAuthor":false,"prefix":"","firstName":"Michal","middleName":"","lastName":"Svoboda","suffix":""},{"id":311452422,"identity":"2455ab39-f6f8-4b1c-8c58-72e44b414624","order_by":2,"name":"Cecilie Horska","email":"","orcid":"","institution":"Charles University and Motol University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Cecilie","middleName":"","lastName":"Horska","suffix":""},{"id":311452423,"identity":"2c8adc59-d4a9-4be3-ad1d-5232fce78a67","order_by":3,"name":"Samuel Buchler","email":"","orcid":"","institution":"Charles University and Motol University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Samuel","middleName":"","lastName":"Buchler","suffix":""},{"id":311452424,"identity":"2b4488ad-6ebd-44ff-9078-543649b5cdc0","order_by":4,"name":"Tomas Buchler","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8klEQVRIiWNgGAWjYPCCAwwMEswNDAwVchD+AzxqeRBaGIFazhgDOcwMDAlEa2FsI0KLPXt34scfDHcS+2c3Nj6unGeQp9vef/BBAoOdPU5beM5uluZheJY4487BZsOz2wyKzc4cZjZIYEhmxqlFIneDNAPD4cQNEoltko3b/iRuu5HMJpHAcIANj5bNP39AtLT/bJxjANfCg0fLNgkeqC2MjQ0ILRI4tZw5u82ax+CZ8Ywbic2SDceAWs4cNjZIMEg2wKWFvb13880fFXdk+2ckH/zYUAPUcrzx4YMPFbhDDAIwTcRpxygYBaNgFIwCYgAAGJ5athT8e9sAAAAASUVORK5CYII=","orcid":"","institution":"Charles University and Motol University Hospital","correspondingAuthor":true,"prefix":"","firstName":"Tomas","middleName":"","lastName":"Buchler","suffix":""}],"badges":[],"createdAt":"2024-05-26 14:59:37","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4480556/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4480556/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":58169256,"identity":"d82cbed2-2644-4d3d-a8d0-ec20e47b0410","added_by":"auto","created_at":"2024-06-12 03:29:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":106725,"visible":true,"origin":"","legend":"\u003cp\u003eSelection process of the studies used in meta-analysis.\u003c/p\u003e","description":"","filename":"Figure1pruritusrash3324.png","url":"https://assets-eu.researchsquare.com/files/rs-4480556/v1/68afb4e545c9d998f14340ea.png"},{"id":60341938,"identity":"af4daa25-1c34-4fcc-933c-40b638a54321","added_by":"auto","created_at":"2024-07-15 18:48:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":416627,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4480556/v1/9c5cf8ee-d204-4c99-8850-10bf3961b821.pdf"},{"id":58169258,"identity":"27e5f1f0-ca51-44e2-83bb-8fb94f1435e3","added_by":"auto","created_at":"2024-06-12 03:29:56","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":32436,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary File 1. PRISMA checklist.\u003c/p\u003e","description":"","filename":"supplementaryfile1PRISMA2020checklist2122024.docx","url":"https://assets-eu.researchsquare.com/files/rs-4480556/v1/ce3415c448c82c1ec1121e41.docx"},{"id":58170268,"identity":"e9703dc6-dfe6-48f5-9931-143f1f067d3e","added_by":"auto","created_at":"2024-06-12 03:37:57","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":23254,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary File 2. List of included studies.\u003c/p\u003e","description":"","filename":"supplementaryfile2studylist21022024.docx","url":"https://assets-eu.researchsquare.com/files/rs-4480556/v1/fd7a03a6eb75efa4769f4892.docx"},{"id":58170267,"identity":"4a1b4b77-eb30-493a-b64b-602190d3fc35","added_by":"auto","created_at":"2024-06-12 03:37:56","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":51499,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary File 3. Odds ratio tables for individual tumour and immunotherapy types.\u003c/p\u003e","description":"","filename":"SupplementaryFile3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4480556/v1/5c18276c138d00c1e3b74c22.xlsx"},{"id":58169259,"identity":"d130203d-1002-4b66-9f98-5babdce91396","added_by":"auto","created_at":"2024-06-12 03:29:56","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":186195,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-4480556/v1/e2db4ce54f49b803e128b9dc.docx"}],"financialInterests":"Competing interest reported. IK has received research support and honoraria from Roche, Bristol Myers Squibb, Merck Sharp Dohme, Merck, and Servier, all unrelated to the present paper. TB has received research support and honoraria from Roche, Bristol Myers Squibb, Merck Sharp Dohme, Merck, and AstraZeneca, all unrelated to the present paper. Other authors declare no conflicts of interest.","formattedTitle":"Pruritus and xerodermia in patients treated with checkpoint inhibitors for melanoma, lung and renal cancer: a meta-analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eImmune checkpoint inhibitors (ICI) have become the mainstay of treatment of many malignancies. Their use is well known to be accompanied by increased risk of immune toxicities. Dermatologic adverse events (DAEs) are common in patients treated with ICI for cancer. The aetiology of DAEs includes inflammatory skin conditions caused by autoimmune processes induced or reinduced by ICI, and skin disorders associated with other immuno-related toxicities, mostly affecting the endocrine system. Dermatologic toxicity may lead to anticancer therapy dose modifications and/or termination, besides impairing patients\u0026rsquo; health-related quality of life. Wide range of dermatologic toxicities have been reported, but the most common are maculopapular rash and pruritus [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Several authors have suggested that the occurrence on DAEs may be related to the underlying diagnosis, possibly reflecting the presence of shared antigens between some tumours and skin [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe aim of the present meta-analysis was to evaluate the incidence of two selected DAE, pruritus and xerodermia, reported as adverse events in phase 3 randomised clinical trials using ICI in patients with solid cancers, to compare their occurrence in patients treated with ICI to those receiving other systemic therapies, and to compare the incidence of DAEs in three types of malignancies (melanoma, lung cancer, and renal cell carcinoma) to assess the potential association of diagnosis and type of ICI treatment in developing pruritus and xerodermia.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSearch Strategy\u003c/h2\u003e \u003cp\u003eThe search was carried out in the PubMed and ClinicalTrials.gov databases using terms \u0026ldquo;cancer\u0026rdquo; and \u0026ldquo;ipilimumab or MDX-010\u0026ldquo;, \u0026ldquo;nivolumab or MDX-1106\u0026ldquo;, \u0026ldquo;avelumab or MSB0010718C\u0026ldquo;, \u0026ldquo;durvalumab or MEDI-4736\u0026ldquo;, \u0026ldquo;pembrolizumab or MK-3475\u0026ldquo;, \u0026ldquo;atezolizumab or MPDL3280A\u0026rdquo;, \u0026ldquo;tremelimumab or CP-675,206\u0026ldquo;, \u0026ldquo;cemiplimab or REGN2810\u0026ldquo; [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The methodology for selecting studies is depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and was similar to one used in our previous systematic analyses [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Criteria for inclusion were restricted to phase 3 clinical trials that included detailed tables of adverse events within the ClinicalTrials.gov repository. Only those studies that featured control arms not employing immunotherapy were considered. Studies were selected by a search carried out in February 2021 and data collection on pruritus and xerodermia (dry skin), was conducted during May and June 2023. This process was independently executed by two researchers, with any discrepancies resolved through collaborative discussion. The execution of this study adhered to the protocols outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] (Supplementary Material 1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eThe frequencies and corresponding confidence intervals for occurrences of pruritus and xerodermia (dry skin) were quantitatively assessed and reported for each investigated study, as well as synthesized across varying classifications of checkpoint inhibitor agents and for three distinct cancer types: melanoma, lung cancer, and renal cancer. Additionally, the odds ratio (OR) along with its confidence interval (CI) were calculated for each individual study. A random-effects model was employed for the aggregation of data across studies. Inclusion criteria for the meta-analysis encompassed studies with either two or three arms. Specifically, a three-arm study comprising two experimental arms (E1 and E2) and one control arm (C) resulted in the derivation of two pairs of comparative arms (E1 vs. C; E2 vs. C). For the analysis, data from three-arm studies were methodologically handled as per the approach suggested by Rucker et al., which involves splitting the shared control group in multi-arm trials for pairwise meta-analysis [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCochrane Q statistics and I\u003csup\u003e2\u003c/sup\u003e statistics were used to estimate heterogeneity. Certainty of evidence was assessed per Grading of Recommendations, Assessment, Development and Evaluations (GRADE) guidelines [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. I\u003csup\u003e2\u003c/sup\u003e values were used to classify heterogeneity as low (\u0026lt;\u0026thinsp;25%), intermediate (25\u0026ndash;75%), or high (\u0026gt;\u0026thinsp;75%) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Q-test for subgroup difference was used for type of diagnosis and types of immunotherapy. The logistic model with random effect was used to compare different classes of immunotherapy agents, i.e. those targeting PD-1, PD-L1, and CTLA-4, respectively. All statistical analyses were performed using software R version 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria) using the R package meta [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSelection of Studies\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 8,632 records of phase 3 studies for cancer were identified in the initial step of the search. \u0026nbsp;For the analysis of pruritus, 42 studies were analysed with a total of 29502 evaluable patients. \u0026nbsp;The solid cancers treated in the included studies were the following: \u0026nbsp;lung cancer (27 studies), melanoma (eight studies), renal cancer (seven studies). For the evaluation of xerodermia, the number of studies 23 (lung cancer 14 studies, melanoma six studies, renal cell carcinoma three studies) with\u0026nbsp;17341 patients\u0026nbsp;(Figure 1). \u0026nbsp;The list of the included studies \u0026nbsp;is provided in Supplementary File 2\u0026nbsp;[13, 14, 23–32, 15, 33–42, 16, 43–49, 17–22].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eQuality Assessment\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe assessment of study quality utilized the Cochrane risk of bias tool. Performance bias emerged as the primary concern, attributed to the absence of blinding among participants and personnel in certain studies, as detailed in Supplementary File 1. Given that the studies under review were all randomized phase III trials, the likelihood of encountering other forms of bias—such as those related to random sequence generation, allocation concealment, blinding of outcome assessment, incomplete outcome data, and selective reporting—was minimal. There was an unquantifiable the potential for evidence selection bias due to the potentially different specialties administering the treatment, with dermatologists and dermatooncologists treating melanoma being more perceptive to DAEs compared to physicians treating patients with renal cell carcinoma (RCC) and lung cancer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePruritus\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePruritus was significantly associated with ICI therapy with OR of\u0026nbsp;3.02 (95% CI 2.57–3.55) compared to non-immunotherapy treatments. The highest OR for pruritus was recorded in trials using anti-CTLA4 agents in monotherapy, followed by those using the combination of CTLA4 and anti-PD(L)1 therapy. The odds of pruritus in ICI versus the control arm was similar for all three selected diagnoses (Table 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCompared to RCC treated with anti-PD1 agents (RCC/PD-1 cohort), patients with melanoma had higher odds of reporting pruritus, reaching statistical significance for the anti-PD-1 and anti-CTLA4 treatment (Table 2). In contrast, lung cancer was associated with significantly lower odds of pruritus across all ICI types (Table 2). The odds of pruritus were lower also in the control non-immunotherapy arms of lung cancer trials. Overall, as evident from Table 2, there was a clear clustering of odds depending on diagnosis rather than on type of ICI.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDetailed data for comparisons across all studied subgroups defined by diagnosis and treatment are shown in Supplementary File 3. \u0026nbsp;There was an intermediate heterogeneity (Table 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eXerodermia\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXerodermia was more commont in the ICI arms of the randomised trial (OR\u0026nbsp;1.44, 95% CI 1.15–1.82).\u0026nbsp;\u0026nbsp;It was more common in patients receiving anti-PDL-1 therapies compared to other types of ICI.\u0026nbsp;(Table 4)\u0026nbsp;The odds of xerodermia in ICI versus the control arm was statistically significant only in lung cancer. \u0026nbsp;With RCC/PD-1 used as a reference, there was a trend to higher incidence of xerodermia in patients with melanoma, especially patients treated with anti-PDL1 agents. As with pruritus, patients with lung cancer had significantly lower odds of xerodermia regardless of \u0026nbsp;ICI type. The incidence of xerodermia was also significantly lower than the reference in the non-immunotherapy control arms in trials for lung cancer (Table 5). \u0026nbsp;There was an intermediate heterogeneity (Table 6).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eComparisons between all studied subgroups defined by diagnosis and ICI type are shown in Supplementary File 3.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe results of the present extensive meta-analysis of phase III trials indicate that there is a clear association of both pruritus and xerodermia reported as adverse events with ICI treatment for cancer. Xerodermia and pruritus are closely interrelated and may represent a diffuse skin inflammation of lower intensity than rash. While the occurence of rash in patients treated with immunotherapy has been the subject of several systemic analyses, many types of rash are reported in clinical trials per Common Terminology Criteria for Adverse Events classification, and thus it may be problematic to establish the true incidence of the symptom. Therefore, pruritus and xerodermia, which are unequivocally coded, were selected for the present analysis.\u003c/p\u003e \u003cp\u003eSeveral systematic analyses have been published concerning DAEs. In 2016 Belum et al have mapped the incidence of DAEs in randomised clinical trials with PD-1/L1 inhibitors [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. At that time, only one phase 3 trial in non-small cell lung cancer (NSCLC) and three such studies in melanoma could be included, the rest of the meta-analysis comprised of phase 1 and 2 studies. The incidence of pruritus was 20.2% for pembrolizumab and 13.2% for nivolumab. Ge et al. (2021) conducted a meta-analysis of 50 randomized controlled trials (RCTs) involving 29,941 patients to investigate the risk of pruritus and rash from ICIs [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The study found that the risk of developing pruritus and rash from CTLA-4 or PD-1/-L1 inhibitors was significantly increased compared to placebo with relative risks of 2.15 and 4.21 for pruritus. Combining PD-1/-L1 with CTLA-4 inhibitors led to higher risks of pruritus (relative risk of 1.76) compared to monotherapy with either. PD-1/-L1 inhibitors had significantly lower risks of pruritus compared to CTLA-4 inhibitors.\u003c/p\u003e \u003cp\u003eThe rash associated with ipilimumab, an immune checkpoint inhibitor, is likened to common maculopapular rashes and atopic dermatitis. The incidence and severity of pruritus from ipilimumab have shown similar rates for the 3-mg/kg and 10-mg/kg dose. In this analysis, data also suggested that the risk of rash was independent of tumour type, based on analysis of patients with metastatic melanoma and other tumour types [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn 2021, Han et al. conducted a comprehensive meta-analysis of 46 RCTs involving 28,569 patients to assess DAE associated with ICI therapy, finding these events to be dose-independent, agent-specific, and more prevalent with CTLA-4 blockade compared to PD-(L)1 blockade [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Specifically, melanoma patients had the highest overall incidence of cutaneous immune-related adverse events (irAEs), with rates of 23.1% for rash and 25.3% for pruritus, while patients with squamous carcinoma of the head and neck experienced the lowest risk.\u003c/p\u003e \u003cp\u003eThe present analysis expands the findings of Khoja and collaborators published in 2017 [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. A comparison irAEs among melanoma, NSCLC, and RCC patients in trials studying anti-PD-1 ICI revealed that melanoma patients exhibited higher frequencies of gastrointestinal and skin irAEs, and lower pneumonitis compared to NSCLC. However, the numbers of patients (6938 patients in 48 trials) that could be analysed were understandably much lower owing to rapid publication of many studies since.\u003c/p\u003e \u003cp\u003eNone of the above systematic studies analysed xerodermia in the context of ICI therapy. Although xerodermia is non-fatal and rarely if ever leads to treatment discontinuation, it is an exceedingly common problem in cancer patients. The underlying pathophysiology of xerodermia is the dysfunction of corneal layer, impairing the barrier function of the skin. Pruritus is the most common associated symptom [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe principal weakness of the metaanalysis is the potential evidence selection bias influenced by the varying specialties of the treating clinicians. Dermatologists participate in or administer the treatment for melanoma, and they may be more receptive to DAEs compared to cancer physicians with other subspecialization. Similar bias may be present in other systematic analysis comparing the incidence of organ-specific adverse events between different types of tumour. However, RCC treated with PD-1 was as the reference for all comparisons in our study and the bias is unlikely to be responsible for the differences between RCC and lung cancer.\u003c/p\u003e \u003cp\u003eIn conclusion, the present systematic analysis suggests that pruritus and xerodermia are clearly associated with ICI treatment of any type. There appears to be higher incidence of these DAEs in patients with melanoma and RCC compared to patients with lung cancer, suggesting that the occurrence of DAEs is diagnosis-specific.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eGRADE: Grading Of Recommendations, Assessment, Development And Evaluations\u003c/p\u003e\n\u003cp\u003eICIs: Immune Checkpoint Inhibitors\u003c/p\u003e\n\u003cp\u003eirAEs: Immune-Related Adverse Events\u003c/p\u003e\n\u003cp\u003ePD-1: Programmed Death\u003c/p\u003e\n\u003cp\u003ePD-L1: Programmed Death 1 Ligand\u003c/p\u003e\n\u003cp\u003ePRISMA: Preferred Reporting Items For Systematic Reviews And Meta-Analyses\u003c/p\u003e\n\u003cp\u003eRCC: Renal Cell Carcinoma\u003c/p\u003e\n\u003cp\u003eRCTs: Randomized Controlled Trials\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eStatement of Ethics\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval and consent were not required as this study was based on publicly available data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe raw data used for the analysis will be made available by the authors upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTB had the right to deal with all the data and was responsible for the decision to submit the manuscript for publication. IK, MK and TB had the data of all included clinical trials. TB, BB and KH retrieved the data. MK carried out the statistical analysis. LB extensively revised the manuscript and provided interpretation of the statistical methods and results. TB, IK and BB were responsible for checking and evaluating the quality of the collected data. All authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIK has received research support and honoraria from Roche, Bristol Myers Squibb, Merck Sharp Dohme, Merck, and Servier, all unrelated to the present paper. TB has received research support and honoraria from Roche, Bristol Myers Squibb, Merck Sharp Dohme, Merck, and AstraZeneca, all unrelated to the present paper. Other authors declare no conflicts of interest.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSibaud V (2018) Dermatologic Reactions to Immune Checkpoint Inhibitors : Skin Toxicities and Immunotherapy. Am J Clin Dermatol 19:345\u0026ndash;361. https://doi.org/10.1007/s40257-017-0336-3\u003c/li\u003e\n\u003cli\u003eWang Y, Zhou S, Yang F, et al (2019) Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-analysis. JAMA Oncol 5:1008\u0026ndash;1019. https://doi.org/10.1001/jamaoncol.2019.0393\u003c/li\u003e\n\u003cli\u003eKhoja L, Day D, Wei-Wu Chen T, et al (2017) Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review. Ann Oncol Off J Eur Soc Med Oncol 28:2377\u0026ndash;2385. https://doi.org/10.1093/annonc/mdx286\u003c/li\u003e\n\u003cli\u003eGe Y, Zhang H, Weygant N, Yao J (2021) Differential Dermatologic Adverse Events Associated With Checkpoint Inhibitor Monotherapy and Combination Therapy: A Meta-Analysis of Randomized Control Trials. Front Pharmacol 12:640099. https://doi.org/10.3389/fphar.2021.640099\u003c/li\u003e\n\u003cli\u003eHan Y, Wang J, Xu B (2021) Cutaneous adverse events associated with immune checkpoint blockade: A systematic review and meta-analysis. Crit Rev Oncol Hematol 163:103376. https://doi.org/10.1016/j.critrevonc.2021.103376\u003c/li\u003e\n\u003cli\u003eKiss I, Kuhn M, Hrusak K, Buchler T (2022) Incidence of fatigue associated with immune checkpoint inhibitors in patients with cancer: a meta-analysis. ESMO Open 7:100474\u003c/li\u003e\n\u003cli\u003eKiss I, Kuhn M, Hrusak K, et al (2022) Insomnia in patients treated with checkpoint inhibitors for cancer: A meta-analysis. Front. Oncol. 12:946307\u003c/li\u003e\n\u003cli\u003eLiberati A, Altman DG, Tetzlaff J, et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700. https://doi.org/10.1136/bmj.b2700\u003c/li\u003e\n\u003cli\u003eR\u0026uuml;cker G, Cates CJ, Schwarzer G (2017) Methods for including information from multi-arm trials in pairwise meta-analysis. Res Synth Methods 8:392\u0026ndash;403. https://doi.org/10.1002/jrsm.1259\u003c/li\u003e\n\u003cli\u003eBalshem H, Helfand M, Sch\u0026uuml;nemann HJ, et al (2011) GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 64:401\u0026ndash;406. https://doi.org/10.1016/j.jclinepi.2010.07.015\u003c/li\u003e\n\u003cli\u003eHiggins JPT, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557\u0026ndash;560. https://doi.org/10.1136/bmj.327.7414.557\u003c/li\u003e\n\u003cli\u003eBalduzzi S, R\u0026uuml;cker G, Schwarzer G (2019) How to perform a meta-analysis with R: a practical tutorial. Evid Based Ment Health 22:153\u0026ndash;160. https://doi.org/10.1136/ebmental-2019-300117\u003c/li\u003e\n\u003cli\u003eHodi FS, O\u0026rsquo;Day SJ, McDermott DF, et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711\u0026ndash;723. https://doi.org/10.1056/NEJMoa1003466\u003c/li\u003e\n\u003cli\u003eRobert C, Thomas L, Bondarenko I, et al (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517\u0026ndash;2526. https://doi.org/10.1056/NEJMoa1104621\u003c/li\u003e\n\u003cli\u003eBorghaei H, Paz-Ares L, Horn L, et al (2015) Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 373:1627\u0026ndash;1639. https://doi.org/10.1056/NEJMoa1507643\u003c/li\u003e\n\u003cli\u003eBrahmer J, Reckamp KL, Baas P, et al (2015) Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 373:123\u0026ndash;135. https://doi.org/10.1056/NEJMoa1504627\u003c/li\u003e\n\u003cli\u003eMotzer RJ, Escudier B, McDermott DF, et al (2015) Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 373:1803\u0026ndash;1813. https://doi.org/10.1056/NEJMoa1510665\u003c/li\u003e\n\u003cli\u003eEggermont AMM, Chiarion-Sileni V, Grob J-J, et al (2016) Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med 375:1845\u0026ndash;1855. https://doi.org/10.1056/NEJMoa1611299\u003c/li\u003e\n\u003cli\u003eHerbst RS, Baas P, Kim D-W, et al (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet (London, England) 387:1540\u0026ndash;1550. https://doi.org/10.1016/S0140-6736(15)01281-7\u003c/li\u003e\n\u003cli\u003eReck M, Rodr\u0026iacute;guez-Abreu D, Robinson AG, et al (2016) Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 375:1823\u0026ndash;1833. https://doi.org/10.1056/NEJMoa1606774\u003c/li\u003e\n\u003cli\u003eReck M, Luft A, Szczesna A, et al (2016) Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol Off J Am Soc Clin Oncol 34:3740\u0026ndash;3748. https://doi.org/10.1200/JCO.2016.67.6601\u003c/li\u003e\n\u003cli\u003eAntonia SJ, Villegas A, Daniel D, et al (2017) Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 377:1919\u0026ndash;1929. https://doi.org/10.1056/NEJMoa1709937\u003c/li\u003e\n\u003cli\u003ePaz-Ares L, Ciuleanu T-E, Cobo M, et al (2021) First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol 22:198\u0026ndash;211. https://doi.org/10.1016/S1470-2045(20)30641-0\u003c/li\u003e\n\u003cli\u003eRittmeyer A, Barlesi F, Waterkamp D, et al (2017) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet (London, England) 389:255\u0026ndash;265. https://doi.org/10.1016/S0140-6736(16)32517-X\u003c/li\u003e\n\u003cli\u003eSocinski MA, Jotte RM, Cappuzzo F, et al (2018) Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med 378:2288\u0026ndash;2301. https://doi.org/10.1056/NEJMoa1716948\u003c/li\u003e\n\u003cli\u003eGandhi L, Rodr\u0026iacute;guez-Abreu D, Gadgeel S, et al (2018) Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med 378:2078\u0026ndash;2092. https://doi.org/10.1056/NEJMoa1801005\u003c/li\u003e\n\u003cli\u003eHorn L, Mansfield AS, Szczęsna A, et al (2018) First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med 379:2220\u0026ndash;2229. https://doi.org/10.1056/NEJMoa1809064\u003c/li\u003e\n\u003cli\u003eLarkin J, Minor D, D\u0026rsquo;Angelo S, et al (2018) Overall Survival in Patients With Advanced Melanoma Who Received Nivolumab Versus Investigator\u0026rsquo;s Choice Chemotherapy in CheckMate 037: A Randomized, Controlled, Open-Label Phase III Trial. J Clin Oncol Off J Am Soc Clin Oncol 36:383\u0026ndash;390. https://doi.org/10.1200/JCO.2016.71.8023\u003c/li\u003e\n\u003cli\u003eMotzer RJ, Tannir NM, McDermott DF, et al (2018) Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 378:1277\u0026ndash;1290. https://doi.org/10.1056/NEJMoa1712126\u003c/li\u003e\n\u003cli\u003ePaz-Ares L, Luft A, Vicente D, et al (2018) Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med 379:2040\u0026ndash;2051. https://doi.org/10.1056/NEJMoa1810865\u003c/li\u003e\n\u003cli\u003eMok TSK, Wu Y-L, Kudaba I, et al (2019) Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet (London, England) 393:1819\u0026ndash;1830. https://doi.org/10.1016/S0140-6736(18)32409-7\u003c/li\u003e\n\u003cli\u003eRini BI, Plimack ER, Stus V, et al (2019) Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. https://doi.org/10.1056/NEJMoa1816714\u003c/li\u003e\n\u003cli\u003eRini BI, Powles T, Atkins MB, et al (2019) Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet (London, England) 393:2404\u0026ndash;2415. https://doi.org/10.1016/S0140-6736(19)30723-8\u003c/li\u003e\n\u003cli\u003eWest H, McCleod M, Hussein M, et al (2019) Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 tri. Lancet Oncol 20:924\u0026ndash;937. https://doi.org/10.1016/S1470-2045(19)30167-6\u003c/li\u003e\n\u003cli\u003eGutzmer R, Stroyakovskiy D, Gogas H, et al (2020) Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAF(V600) mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (London, England) 395:1835\u0026ndash;1844. https://doi.org/10.1016/S0140-6736(20)30934-X\u003c/li\u003e\n\u003cli\u003eHerbst RS, Giaccone G, de Marinis F, et al (2020) Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med 383:1328\u0026ndash;1339. https://doi.org/10.1056/NEJMoa1917346\u003c/li\u003e\n\u003cli\u003eJotte R, Cappuzzo F, Vynnychenko I, et al (2020) Atezolizumab in Combination With Carboplatin and Nab-Paclitaxel in Advanced Squamous NSCLC (IMpower131): Results From a Randomized Phase III Trial. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 15:1351\u0026ndash;1360. https://doi.org/10.1016/j.jtho.2020.03.028\u003c/li\u003e\n\u003cli\u003eRizvi NA, Cho BC, Reinmuth N, et al (2020) Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial. JAMA Oncol 6:661\u0026ndash;674. https://doi.org/10.1001/jamaoncol.2020.0237\u003c/li\u003e\n\u003cli\u003eRudin CM, Awad MM, Navarro A, et al (2020) Pembrolizumab or Placebo Plus Etoposide and Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer: Randomized, Double-Blind, Phase III KEYNOTE-604 Study. J Clin Oncol Off J Am Soc Clin Oncol 38:2369\u0026ndash;2379. https://doi.org/10.1200/JCO.20.00793\u003c/li\u003e\n\u003cli\u003eMotzer R, Alekseev B, Rha S-Y, et al (2021) Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med 384:1289\u0026ndash;1300. https://doi.org/10.1056/NEJMoa2035716\u003c/li\u003e\n\u003cli\u003eOwonikoko TK, Park K, Govindan R, et al (2021) Nivolumab and Ipilimumab as Maintenance Therapy in Extensive-Disease Small-Cell Lung Cancer: CheckMate 451. J Clin Oncol Off J Am Soc Clin Oncol 39:1349\u0026ndash;1359. https://doi.org/10.1200/JCO.20.02212\u003c/li\u003e\n\u003cli\u003ePaz-Ares L, Dvorkin M, Chen Y, et al (2019) Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet (London, England) 394:1929\u0026ndash;1939. https://doi.org/10.1016/S0140-6736(19)32222-6\u003c/li\u003e\n\u003cli\u003eChoueiri TK, Powles T, Burotto M, et al (2021) Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 384:829\u0026ndash;841. https://doi.org/10.1056/NEJMoa2026982\u003c/li\u003e\n\u003cli\u003eWu Y-L, Lu S, Cheng Y, et al (2019) Nivolumab Versus Docetaxel in a Predominantly Chinese Patient Population With Previously Treated Advanced NSCLC: CheckMate 078 Randomized Phase III Clinical Trial. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 14:867\u0026ndash;875. https://doi.org/10.1016/j.jtho.2019.01.006\u003c/li\u003e\n\u003cli\u003eRibas A, Kefford R, Marshall MA, et al (2013) Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol Off J Am Soc Clin Oncol 31:616\u0026ndash;622. https://doi.org/10.1200/JCO.2012.44.6112\u003c/li\u003e\n\u003cli\u003eRobert C, Long G V, Brady B, et al (2015) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320\u0026ndash;330. https://doi.org/10.1056/NEJMoa1412082\u003c/li\u003e\n\u003cli\u003eGovindan R, Szczesna A, Ahn M-J, et al (2017) Phase III Trial of Ipilimumab Combined With Paclitaxel and Carboplatin in Advanced Squamous Non-Small-Cell Lung Cancer. J Clin Oncol Off J Am Soc Clin Oncol 35:3449\u0026ndash;3457. https://doi.org/10.1200/JCO.2016.71.7629\u003c/li\u003e\n\u003cli\u003eNishio M, Barlesi F, West H, et al (2021) Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 16:653\u0026ndash;664. https://doi.org/10.1016/j.jtho.2020.11.025\u003c/li\u003e\n\u003cli\u003eRen S, Feng J, Ma S, et al (2023) KEYNOTE-033: Randomized phase 3 study of pembrolizumab vs docetaxel in previously treated, PD-L1-positive, advanced NSCLC. Int J cancer 153:623\u0026ndash;634. https://doi.org/10.1002/ijc.34532\u003c/li\u003e\n\u003cli\u003eBelum VR, Benhuri B, Postow MA, et al (2016) Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer 60:12\u0026ndash;25. https://doi.org/10.1016/j.ejca.2016.02.010\u003c/li\u003e\n\u003cli\u003eLacouture ME, Wolchok JD, Yosipovitch G, et al (2014) Ipilimumab in patients with cancer and the management of dermatologic adverse events. J Am Acad Dermatol 71:161\u0026ndash;169. https://doi.org/10.1016/j.jaad.2014.02.035\u003c/li\u003e\n\u003cli\u003ePons-Guiraud A (2007) Dry skin in dermatology: a complex physiopathology. J Eur Acad Dermatol Venereol 21 Suppl 2:1\u0026ndash;4. https://doi.org/10.1111/j.1468-3083.2007.02379.x\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1-6 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Immunotherapy, cancer, checkpoint inhibitors, rash, pruritus, xerodermia, systematic analysis","lastPublishedDoi":"10.21203/rs.3.rs-4480556/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4480556/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eDermatologic adverse events (DAEs) are common in patients treated with immune checkpoint inhibitors (ICI) for cancer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e To evaluate the incidence of two selected dermatologic adverse events (DAEs), pruritus and xerodermia, reported as adverse events in phase 3 randomised clinical trials using ICI in patients with lung cancer, renal cancer, and melanoma.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Phase 3 studies where treatment included an ICI in the experimental arm were analysed. For pruritus, 42 studies were analysed with a total of 29,502 evaluable patients. For xerodermia, the number of studies was 23 with 17,341 patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e. Pruritus was associated with ICI therapy with OR of 3.02 (95% CI 2.57–3.55). Compared to renal cell carcinoma (RCC) treated with anti-programmed death (PD-1) agents, patients with melanoma had higher odds of reporting pruritus, reaching statistical significance for the anti-PD-1 and anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) treatment. Patient with lung cancer had significantly lower odds of pruritus across all ICI types compared to other analysed tumour types. Xerodermia was also associated with ICI treatment. \u0026nbsp;Using RCC/PD-1 as a reference, there was a trend to higher incidence of xerodermia in patients with melanoma. Patients with lung cancer had significantly lower odds of xerodermia regardless of ICI type.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e The present systematic analysis indicates that pruritus and xerodermia are associated with ICI treatment of any type compared to non-immunologic therapies. There appears to be a higher incidence of these DAEs in patients with melanoma and RCC compared to patients with lung cancer.\u003c/p\u003e","manuscriptTitle":"Pruritus and xerodermia in patients treated with checkpoint inhibitors for melanoma, lung and renal cancer: a meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-12 03:29:52","doi":"10.21203/rs.3.rs-4480556/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d8ad79f1-f05d-4218-855e-d53e5a100cad","owner":[],"postedDate":"June 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-21T11:38:25+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-12 03:29:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4480556","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4480556","identity":"rs-4480556","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}