ABSTRACT
The emergence of immune checkpoint inhibitors has revolutionized the landscape of cancer treatment in the modern era. However, cutaneous immune‐related adverse events (cirAEs) are common, significantly affecting patients' quality of life and often leading to treatment discontinuation, which may compromise oncological outcomes. Dupilumab, an immunoglobulin G4 (IgG4) human monoclonal antibody targeting interleukin (IL)‐4 and IL‐13 receptors, is widely used for dermatologic conditions but remains unapproved for cirAEs due to the limited and scattered supporting evidence. This review aimed to summarize the available evidence regarding the use of dupilumab for the management of cirAEs. A systematic review was conducted using MEDLINE/PubMed, Scopus, and Web of Science in adherence to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. In total, 25 publications met the eligibility criteria and were included, reporting 136 patients who were diagnosed with 140 cirAEs and were treated with dupilumab. The most frequently treated cirAEs were eczematous rashes, bullous pemphigoid, and maculopapular/morbilliform rashes. Dupilumab was found to be highly effective, with most patients achieving complete or partial responses, even when affected by two concomitant cirAEs. An acceptable safety profile was demonstrated regarding both adverse events and oncological safety, with no additional concerns to be raised. The findings may be encouraging but are limited by the relatively small number of patients treated and the nature of the included studies, with most of them being case reports and case series. More research is warranted, along with more clinical studies, prospective in design, focused on relevant clinical outcomes of this dupilumab‐treated subset of patients.
Keywords: cancer, cutaneous immune related adverse event, dupilumab, immune checkpoint inhibitor
1. Introduction
Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment landscape for various malignancies, offering increased progression‐free survival and overall survival in patients suffering from advanced melanoma, lung, renal, and colorectal carcinoma, among others [1, 2, 3, 4]. ICIs mainly act through the modulation of anticancer immune surveillance, via the inhibition of certain regulatory proteins, namely cytotoxic T lymphocyte protein 4 (CTLA‐4), programmed death (PD)‐1, and PD‐ligand (L)‐1.
Despite the significant improvements observed in oncological outcomes, ICIs have been associated with multiple immune‐related adverse events (irAEs), with cutaneous irAEs (cirAEs) being the most frequent. Such reactions can significantly impact the quality of life of those affected, and when severe, can lead to interruption and/or discontinuation of oncological treatment, potentially affecting patient survival [5, 6, 7, 8]. Such reactions can range from psoriasiform exanthems and bullous pemphigoid to eczematous‐type reactions and intractable pruritus [8, 9]. To date, most guidelines and consensus statements suggest the use of topical agents such as corticosteroids and emollients along with oral antihistamines for lower‐grade cirAEs, while systemic treatment may be advised, mostly with oral corticosteroids, for higher‐grade eruptions [5, 6, 7]. When considering systemic treatment for cirAEs, apart from the proper management of skin disease, oncological safety is the most important factor to be considered. The preferred agents should not interact with the effects of anti‐cancer therapy or affect pathways that are necessary for the survival of malignant cells. With regard to this issue, an expanded interest has been observed over the past few years regarding the increase of available novel targeted immunomodulatory and/or biological agents, which may be preferred over classic immunosuppressants which can interact with oncological treatment and have a negative effect on anti‐cancer immunity [10].
Dupilumab, an immunoglobulin G4 (IgG4) human monoclonal antibody targeting interleukin (IL)‐4 and IL‐13 receptors, is currently utilized on‐ and off‐label for the treatment of various dermatologic conditions [11, 12]. While its effectiveness and safety have been demonstrated in clinical trials and real‐world studies in non‐cancer patients, studies focusing on the use of dupilumab for the treatment of cirAEs are scattered throughout the literature. Thus, we aimed to perform a systematic review and summarize all the available evidence regarding the effectiveness, safety, and effect on oncological outcomes of dupilumab for the management of cirAEs.
2. Methods
This systematic review was prepared in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines [13]. The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO, reference number: CRD42025644581).
2.1. Search Strategy
Systematic literature searches were conducted using MEDLINE/PubMed, Web of Science, and Scopus to identify studies published up to January 2025 that reported patients diagnosed with cirAEs and have been treated with dupilumab for that specific skin disease. The following search terms were used to identify the relevant literature: (dupilumab AND cancer) OR (dupilumab AND malignancy) OR (dupilumab AND tumor) OR (dupilumab AND neoplasia) OR (dupilumab AND immune checkpoint inhibitor) OR (dupilumab AND immunotherapy) OR (dupilumab AND immune cutaneous adverse event) OR (dupilumab AND pembrolizumab) OR (dupilumab and nivolumab) OR (dupilumab AND atezolizumab) OR (dupilumab and ipilimumab) OR (dupilumab AND avelumab) OR (dupilumab AND cemiplimab). Automatic deduplication was performed using the EndNote reference manager. The exposure of interest was defined as the use of dupilumab regardless of dose and duration of treatment with the aim of reporting its effectiveness for the treatment of cirAEs, drug safety in this population, and the effect on oncological outcomes.
2.2. Study Selection
A study was considered eligible if (1) it was an interventional, prospective, or retrospective observational study or case report/series that (2) evaluated the effectiveness and safety of dupilumab in treating cirAEs, and (3) a population with any underlying malignancy or history of malignancy for which ICIs are utilized. Studies were excluded if (a) not involve human subjects, (b) not present original data (e.g., review articles, editorials, reports, comments, or guidelines), or (c) they addressed interventions other than the use of dupilumab. No restrictions were imposed regarding geographical location or publication date. Only studies in English were accepted. The titles, abstracts, and full texts of studies identified in the original search were reviewed independently by two authors (I.‐A.K. and A.N.) in accordance with the inclusion and exclusion criteria. Disagreements at any stage of study selection were resolved after discussion involving a third author (V.N.). The literature search was complemented by back and forward citation tracking of eligible papers.
2.3. Data Extraction
Three authors (I.‐A.K., A.N., and V.N.) independently extracted the information using a standardized data collection form. The following data were extracted: (1) study characteristics (participating authors, study design, publication year), (2) sample characteristics (country, study cohort, sex, age, sample size, underlying malignancy type), (3) exposure characteristics (type of ICI associated with the cirAE, type of cirAEs, dupilumab duration and follow‐up when reported), (4) outcome characteristics (associated to skin disease, drug safety and malignancy‐associated outcomes).
3. Results
In total, 1988 articles were originally identified in the three databases, and after the removal of duplicates using the EndNote reference manager, 1396 were screened based on title and abstract. Full‐text screening was performed for 140 articles, from which 25 [14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38] met the eligibility criteria and were included in the systematic review (Figure 1, Table S1). All general characteristics of the included studies are summarized in Table 1, while detailed relevant information extracted from each study is summarized in Table S1. Eligible studies included 136 patients (87 males, 44 females, 5 not specified) who were diagnosed with 140 cirAEs and were treated with dupilumab. Among the cirAEs treated, the most common were eczema/eczematous rashes (35%), followed by bullous pemphigoid (30.7%), maculopapular/morbilliform rashes (15.7%), and lichenoid dermatitis (8.6%). Other cirAEs treated included transient acantholytic dermatosis (Grover disease) (1.4%), lichen planus (1.4%), pruritus without evident skin disease/rash (0.7%), expansion of radiation‐induced morphea (0.7%), and sclerodermoid reaction with morphea‐profunda (0.7%). The most common underlying malignancies treated with ICIs were melanoma/non‐melanoma skin cancers (30.2%), followed by genitourinary cancers (27.3%) and thoracic/lung cancers (14.4%). Regarding the most frequently utilized ICI class associated with cirAEs in these cases, anti PD‐1/anti‐PD‐L1 (76.5%) regimens were the most common, followed by anti CTLA‐4 + anti PD‐1/anti‐PD‐L1 (19.1%) combination regimens, while only one patient reportedly received anti CTLA‐4 monotherapy (0.7%). In 5 (3.7%) cases, the exact ICIs associated with cirAEs were not specified. The various cirAEs treated with dupilumab and the number of patients classified as complete/partial responders, or non‐responders, are graphically represented in Figure 2.
FIGURE 1.
Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) 2020 flow diagram of the studies screened for eligibility, including searches of databases and registers only.
TABLE 1.
Basic characteristics of the studies included in the systematic review.
| Number of patients | 136 (100%) |
| Males, n (%) | 87 (63.9%) |
| Females, n (%) | 44 (32.4%) |
| Not specified | 5 (3.7%) |
| Cutaneous immune‐related adverse events, n (%) | |
| Total a | 140 (100%) |
| Eczema/eczematous rash b | 49 (35%) |
| Bullous pemphigoid | 43 (30.7%) |
| Maculopapular/morbilliform rash | 22 (15.7%) |
| Lichenoid dermatitis | 12 (8.6%) |
| Non‐classified/Other c | 7 (5%) |
| Transient acantholytic dermatosis (grover disease) | 2 (1.4%) |
| Lichen planus | 2 (1.4%) |
| Pruritus without evident skin disease/rash | 1 (0.7%) |
| Expansion of radiation induced morphoea d | 1 (0.7%) |
| Sclerodermoid reaction with morphea‐profunda | 1 (0.7%) |
| Immune checkpoint inhibitor class, n (%) | |
| Total | 136 (100%) |
| Anti PD‐1/anti‐PD‐L1 | 104 (76.5%) |
| Anti CTLA‐4 + anti PD‐1/anti‐PD‐L1 | 26 (19.1%) |
| Anti CTLA‐4 monotherapy | 1 (0.7%) |
| Not specified | 5 (3.7%) |
| Underlying malignancies, n (%) | |
| Total e | 139 (100%) |
| Melanoma/non‐melanoma skin cancer e | 42 (30.2%) |
| Genitourinary cancers | 38 (27.3%) |
| Thoracic/lung cancer | 20 (14.4%) |
| Head and neck cancers | 15 (10.8%) |
| Non‐classified/other f | 13 (9.4%) |
| Sarcoma | 5 (3.6%) |
| Gastrointestinal cancer | 5 (3.6%) |
| Breast cancer | 1 (0.7%) |
Abbreviations: CTLA‐4, cytotoxic T‐lymphocyte associated protein 4; n, number; PD‐1, programmed cell death protein 1; PD‐L1, programmed death‐ligand 1.
Four patients suffered from an additional cirAE: one patient from both bullous pemphigoid and transient acantholytic dermatosis, one patient from bullous pemphigoid and lichenoid dermatitis, one patient from lichenoid dermatitis and eczematous dermatitis, and one patient from lichenoid dermatitis and morbilliform drug eruption.
One patient was reported to experience a significant worsening of pre‐existing atopic dermatitis.
One study did not classify 7 patients according to their skin disease.
One patient was reported twice (in two separate publications).
Two patients suffered from more than two skin cancers: one patient from melanoma and squamous cell carcinoma, and one patient from melanoma, squamous cell carcinoma, and basal cell carcinoma.
Two studies did not classify 13 malignancies.
FIGURE 2.
The Sankey diagram of the various cutaneous immune‐related adverse events managed with dupilumab and the classification of patients according to response. The diagram was created using SankeyMATIC. Seven cutaneous immune‐related adverse events were not classified.
3.1. Eczematous Rashes
In total, 9 publications reported 49 patients suffering from ICI‐associated eczematous rashes, with one patient suffering from concomitant lichenoid dermatitis. Complete/partial responses were observed in 45/49 (91.8%) patients, with the remaining classified as non‐responders. The patient with the concomitant lichenoid dermatitis experienced a complete response for both diseases.
3.2. Bullous Pemphigoid
In total, 13 publications reported 43 patients with ICI‐induced bullous pemphigoid. Complete/partial responses were achieved by 40/43 patients (93%). In all case reports/case series, complete/partial responses were observed during dupilumab treatment, with two cases reporting patients who experienced disease flares when dupilumab doses were missed. In the study by Khattab et al., among 15 bullous pemphigoids treated with dupilumab, 9 patients were classified as complete responders, 3 as partial responders, and 3 as non‐responders [23]. In the same study, one of the patients was reported to experience both lichenoid dermatitis and bullous pemphigoid, achieving a complete response with dupilumab in both [23]. In the retrospective study by Bur et al., dupilumab was classified as successful for all 8 patients with ICI‐associated bullous pemphigoid [18]. In one case report, a patient developed both bullous pemphigoid and Grover's disease under nivolumab while achieving complete clinical responses for both diseases [24]. Interestingly, the study by Shipman et al. demonstrated that IL‐4 and IL‐13 mRNAs were elevated in lesional ICI‐bullous pemphigoid and conventional bullous pemphigoid skin and expressed at levels indistinguishable from one another, with the magnitude of expression comparable to that of AD skin [34]. Regarding clinical effectiveness, both groups displayed significant improvements with dupilumab [34].
3.3. Maculopapular/Morbilliform Rash
Two publications reported 22 patients with maculopapular/morbilliform rashes, with one patient suffering from concomitant lichenoid dermatitis. Complete/partial responses were achieved by 21/22 (95.5%) of the evaluated patients, including the patient with lichenoid dermatitis, who achieved complete responses for both diseases.
3.4. Lichenoid Dermatitis
Two publications reported 12 patients suffering from lichenoid dermatitis. As mentioned above, 3 patients also suffered, one each, from bullous pemphigoid, an eczematous rash, and a maculopapular rash, all associated with ICI treatment. All 12 (100%) patients reported complete/partial responses, along with complete responses for the patients with the other concomitant cirAEs.
3.5. Other cirAEs
One patient suffered from pruritus, without an exanthem, which appeared after initiation of nivolumab‐ipilimumab and managed to achieve almost complete cessation of itch [35]. In this case, the patient received only five doses of dupilumab, due to technical regulations, with a recurrence of pruritus after discontinuation [35]. One patient suffered from pembrolizumab‐associated expansion of radiation‐induced morphea, which was significantly improved with dupilumab, an effect maintained during treatment [32]. A sclerodermoid reaction with morphea‐profunda was observed in another patient, which was clinically resolved after dupilumab treatment [23]. Two patients were treated with dupilumab for ICI‐associated Grover's disease, one diagnosed also with bullous pemphigoid as discussed above, achieving complete clinical responses [24, 33]. Two patients were diagnosed with nivolumab‐induced lichen planus, and both achieved almost complete resolution under dupilumab treatment [15, 38].
3.6. Adverse Events
Regarding dupilumab's adverse events, among the case reports and case series examined, in one case, a psoriasiform exanthem appeared under dupilumab treatment (2.5 months after) [14]. Also, adverse events were reported in the study by Kuo et al., in which 1/39 (2.6%) patients experienced site injection reaction and discontinued dupilumab, while 2/39 (5.1%) patients reported eye irritation but continued medication [27]. Another publication reported adverse events, with one conjunctivitis, which resolved with over‐the‐counter eye drops, and one patient experiencing eosinophilia and associated fatigue, dizziness, and low mood, resulting in two doses of dupilumab being held [26]. No other publication included in the systematic review reported adverse events associated with dupilumab use in this population.
3.7. Oncological Outcomes
Regarding oncological outcomes, among the case reports and case series examined, disease progression was noted in 5/39 (12.8%) patients. Four experienced disease progression after ICI discontinuation due to cirAE severity, with two of them re‐initiating treatment with ICI after the cirAEs were adequately managed with dupilumab. The patient who died due to cancer progression had also discontinued ICI treatment during a bullous pemphigoid flare and restarted shortly after [21]. It should be noted that those case series and case reports were not designed to assess oncological outcomes and have limited follow‐up periods, not allowing for proper assessment of survival, among other oncological outcomes. In one small retrospective study reporting 5 patients who received dupilumab for their cirAEs, no cancer progression was observed [26]. The two larger retrospective studies are discussed separately as follows.
The study by Khattab et al. compared the mortality outcomes of 53 cirAE patients treated with dupilumab with those of two control groups (group 1: no dupilumab + cirAE, group 2: no dupilumab + no cirAE) of 106 patients each. According to the multivariable model utilized, the overall survival of the dupilumab group was not significantly different from control group 1 [hazard ratio (HR) = 0.74, 95% confidence interval (CI): 0.35–1.60, p = 0.5] or control group 2 (HR = 0.70, 95% CI: 0.32–1.51, p = 0.4). Interestingly, the use of systemic corticosteroids within 2 years after ICI initiation was associated with poorer overall survival when comparing the dupilumab group to control group 1 (HR = 2.03, 95% CI: 1.04–3.96, 95 p = 0.039) and control group 2 (HR = 2.21, 95% CI: 1.25–3.91, p = 0.006) [23].
In the retrospective study by Kuo et al., 17/39 (43.6%) patients experienced progression of their cancer at any point after dupilumab initiation. Of these patients, 12 had previously received systemic steroids for their cirAEs. All but one of these patients suffered from metastatic disease at baseline; 52.9% had ongoing tumor progression prior to initiation of dupilumab, and 70.6% of those who progressed had also previously received systemic steroids [27].
4. Discussion
ICIs have transformed the treatment landscape in oncology and are now administered to a growing number of patients for prolonged periods. However, the effective therapeutic progress of patients is often interrupted by the onset of dermatologic toxicities. Systemic corticosteroids have been traditionally the cornerstone of cirAE management, as most cirAEs are steroid responsive. However, emerging evidence suggests that high doses of corticosteroids, particularly when administered early in the course of immunotherapy, may exert unfavorable effects on tumor response to ICI therapy. Furthermore, cirAEs exhibit substantial variability in clinical presentation. While some cutaneous reactions benefit from systemic corticosteroids, others demonstrate limited responsiveness or may benefit more from targeted immunomodulatory approaches. Given these challenges, there is growing interest in exploring alternative therapeutic strategies for managing cirAEs. Biological agents, such as IL‐4 and IL‐13 inhibitors, have shown promise in managing cirAEs more effectively by offering a targeted approach. Our systematic review indicates that, based on available evidence, dupilumab may be a viable treatment option, particularly for cases where topical treatments are inadequate or when systemic therapy is warranted.
More specifically, dupilumab may be beneficial for various cirAEs, including eczematous rashes, bullous pemphigoid, maculopapular/morbilliform rashes, and lichenoid dermatitis. Recently, Lacouture et al. conducted a study involving 200 patients on ICIs, aiming to characterize the clinical presentation and immunologic endotypes of cirAEs by measuring cytokine profiles in skin specimens and plasma. Their findings revealed elevated skin and plasma IL‐4 levels in pruritus and increased IL‐13 in eczema, suggesting that targeting these cytokines could be a rational therapeutic approach [39]. Moreover, our systematic review demonstrated the high effectiveness of dupilumab in patients suffering from eczematous and pruritic cirAEs.
Similarly, positive results were observed for bullous pemphigoid, where dupilumab exhibited favorable clinical outcomes in more than 90% of the cases examined, either achieving complete or partial responses, with only a small percentage of patients classified as non‐responders. ICI‐induced bullous pemphigoid is a particularly challenging toxicity that often manifests several months after treatment initiation and is one of the few cutaneous toxicities that may necessitate oncologic treatment discontinuation. Given the severity of this condition, early intervention with dupilumab could be considered to allow for immunotherapy to be continued without interruption. Regarding morbilliform rashes, transient acantholytic dermatosis (Grover's disease), and lichen planus, robust evidence is currently lacking. Our systematic review demonstrated that the existing literature primarily consists of case reports and small case series documenting few patients treated with dupilumab. However, the available data seem encouraging and suggest dupilumab as a promising option even in such cases.
Despite these findings, the available evidence remains limited by the nature of the included studies, which are predominantly case reports and small case series, with only a few larger retrospective analyses. Moreover, due to the heterogeneity of the presentation of available results from each eligible study, the process of meta‐analysis was hindered, along with the inability to strictly and uniformly classify patients as complete or partial responders in many publications.
In the examined patient population, dupilumab demonstrated high tolerability, with no novel adverse events reported and minimal treatment discontinuations. Regarding oncological safety, no concerns were raised about its impact on cancer treatment, and according to the retrospective studies examined, dupilumab did not negatively affect patient survival. While data on the long‐term oncologic safety of dupilumab in patients suffering from cirAEs remain scarce, studies evaluating its potential association with cancer risk have been reassuring. A five‐year retrospective cohort study by Owji et al. found no correlation between dupilumab use and the development of primary or recurrent malignancies in atopic dermatitis patients [40]. Similarly, an analysis of the World Health Organization's VigiBase database found no strong link between anti‐IL‐5 and anti‐IL‐4Ra biologics and increased cancer risk [41].
Nonetheless, the impact of IL‐4 and IL‐13 blockade on a patient's immune response to cancer remains uncertain. Emerging data have suggested a potential increased risk of cutaneous T‐cell lymphoma (CTCL) emergence and/or progression in patients with atopic dermatitis treated with dupilumab, based on retrospective studies and large database analyses [42]. A study by Cabrera‐Perez et al. proposed that dupilumab may contribute to CTCL progression by unmasking pre‐existing disease, primarily through IL‐13 receptor blockade, which could stimulate CTCL proliferation [42, 43]. However, while IL‐4 and IL‐13 blockade may influence CTCL development, preclinical models indicate that these cytokines promote tumor survival, progression, and metastasis in other malignancies [44, 45, 46]. The blockade of these pathways may therefore have potential anticancer effects, though definitive clinical evidence is currently lacking.
5. Conclusion
This systematic review highlights dupilumab's strong clinical effectiveness in managing various cirAEs while maintaining a favorable safety profile regarding both adverse events and oncologic outcomes. Based on current evidence, dupilumab emerges as a promising alternative to systemic corticosteroids for the successful management of various cirAEs. However, due to the heterogeneity of the available evidence and the predominance of case reports and case series in the literature, larger prospective studies specifically designed to evaluate dupilumab in cancer patients with cirAEs are warranted. Comprehensive patient evaluation, accurate diagnosis, and close monitoring throughout treatment remain essential to optimize patient care.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Table S1. General patient characteristics, effectiveness, safety, and oncological outcomes of dupilumab extracted from each eligible study.
Funding: The authors received no specific funding for this work.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. General patient characteristics, effectiveness, safety, and oncological outcomes of dupilumab extracted from each eligible study.