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Clinical/translational cancer immunotherapy
Original research
Long-term mortality outcomes among immunotherapy recipients treated with dupilumab for the management of cutaneous immune-related adverse events
  1. Sara Khattab1,
  2. Guihong Wan1,2,
  3. Suzanne Xu3,
  4. Cameron Moseley1,
  5. Matthew Tran1,
  6. Emma Beagles1,4,
  7. Chuck Lin1,2,
  8. Bonnie W Leung1,
  9. Marjan Azin1,
  10. Ninghui Hao1,2,
  11. Kerry L Reynolds4,5,
  12. Shadmehr Demehri1,4,
  13. Nicole R LeBoeuf6,7 and
  14. Yevgeniy R Semenov1,4
  1. 1Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA
  2. 2Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA
  3. 3Brigham and Women’s Hospital, Boston, Massachusetts, USA
  4. 4Harvard Medical School, Boston, Massachusetts, USA
  5. 5Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
  6. 6Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
  7. 7Dermatology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
  1. Correspondence to Dr Yevgeniy R Semenov; YSEMENOV{at}mgh.harvard.edu

  • SK and GW are joint first authors.

  • NRL and YRS are joint senior authors.

Abstract

Background Dupilumab has been added to National Cancer Comprehensive Network guidelines as a therapeutic strategy for managing certain cutaneous immune-related adverse events (cirAEs) from immune checkpoint blockade (ICB). However, little is known about the implications of dupilumab for cancer outcomes in this population. In this multi-institutional study, we evaluate the impact of dupilumab treatment on survival among ICB recipients.

Methods We conducted a multi-institutional retrospective cohort study of ICB recipients from the Mass General Brigham Healthcare System and Dana-Farber Cancer Institute. The dupilumab group was compared with two control groups who did not receive dupilumab: with and without cirAEs (control groups 1 and 2, respectively) that were 1:2 matched on sex, race, age at ICB initiation, Charlson Comorbidity Score, year of ICB initiation, and ICB type. Manual chart review was performed to obtain cirAE characteristics, systemic glucocorticoid use, dupilumab treatment, vital status, and last contact date. Time-varying multivariable Cox proportional hazards regressions were used to evaluate the impact of dupilumab on overall survival, adjusted for sex, race, age at ICB initiation, ICB type, Charlson Comorbidity Index score, cancer type, cancer stage at ICB initiation, and systemic glucocorticoid use.

Results A total of 53 cirAE patients treated with dupilumab were compared with two control groups of 106 patients each. Most patients receiving dupilumab demonstrated either complete or partial resolution of their cirAE (88.7%). In multivariable modeling, the overall survival of the dupilumab group was not significantly different from control group 1 (HR=0.74, 95% CI: 0.35 to 1.60, p=0.5) or control group 2 (HR=0.70, 95% CI: 0.32 to 1.51, p=0.4). However, the use of systemic glucocorticoids within 2 years after ICB initiation was associated with poorer overall survival when comparing the dupilumab group to control group 1 (HR=2.03, 95% CI: 1.04 to 3.96, p=0.039) and control group 2 (HR=2.21, 95% CI: 1.25 to 3.91, p=0.006).

Conclusions This study suggests that dupilumab is an effective therapy for recalcitrant cirAEs and does not adversely impact mortality. Due to the observed detrimental effects of systemic glucocorticoid therapy, this study suggests the need to shift away from systemic glucocorticoid immunosuppression and toward targeted immune modulators for irAE management, though prospective randomized trials are necessary to investigate this.

  • Immune Checkpoint Inhibitor
  • Immune modulatory
  • Immune related adverse event - irAE
  • Immunotherapy
  • Rash

Data availability statement

Data are available on reasonable request. Data are available on request, please contact the corresponding author, YRS. All summary data supporting the findings of this study are available within the article and/or its supplementary materials. The patient-level data generated for this study can only be shared per specific institutional review board requirements.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jitc-2024-010638

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Current guidelines recommend the use of dupilumab in the treatment of certain moderate to severe cutaneous immune-related adverse events (cirAE) and systemic glucocorticoids for others. Previous studies have shown dupilumab to be effective for steroid-refractory cirAEs; however, the impact of dupilumab on survival outcomes among recipients of immune checkpoint blockade (ICB) remains understudied.

    WHAT THIS STUDY ADDS

    • This study concludes that dupilumab is an effective modality to treat cirAEs, with 88.7% of patients responding to treatment. Additionally, this study demonstrates a 206-day average delay from cirAE onset to dupilumab treatment, suggesting the need for more timely consideration of this therapeutic option. Finally, our results demonstrated that dupilumab does not increase mortality among ICB recipients.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • The results of this study suggest that the use of dupilumab in the treatment of cirAEs is effective and does not adversely impact mortality in the cancer population. Based on these findings, clinicians should consider dupilumab treatment for cirAEs in the appropriate clinical setting. Moreover, this study provides further evidence for the use of targeted immune modulators as preferred over more commonly used broad-based glucocorticoid immunosuppression for the management of immune-related adverse events in the setting of ICB.

    Introduction

    Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment but is associated with morbid and potentially life-threatening toxicities known as immune-related adverse events (irAEs). Of these, cutaneous irAEs (cirAEs) are the most common, occurring in up to 40% of ICB recipients. Current National Cancer Comprehensive Network (NCCN) version 1.2024 guidelines for the management of cirAEs of different morphologies range from the use of topical steroids and oral antihistamines for low-grade eruptions to holding immunotherapy and initiating high-dose systemic immunosuppressive agents, typically systemic glucocorticoid therapy, for high-grade eruptions.1 Though there is not yet consensus regarding the use of systemic immunosuppression in patients receiving ICB treatment for cancer care,2–4 there is a growing body of evidence suggesting that the use of systemic glucocorticoids in ICB-treated patients is detrimental to survival outcomes,5 6 especially early in the course of ICB therapy.7 In response to this concern, increasing attention has been given to considering more targeted immune-modulating approaches for the management of irAEs8, which are hypothesized to be less likely to blunt the antitumor effect of ICB therapy than broader systemic glucocorticoid immunosuppression.

    Evidence of this approach notes the recent inclusion of dupilumab, currently approved by the US Food and Drug Administration for the management of atopic dermatitis and prurigo nodularis, in the NCCN guidelines for the management of certain cirAEs. Dupilumab is a monoclonal antibody that inhibits interleukin 4 (IL-4) and interleukin 13 (IL-13) cytokine signaling and prevents the release of downstream IgE, which plays an important role in immune-mediated allergic processes, primarily in the type 2 inflammatory pathway.9 10 Though these guidelines propose the use of dupilumab for the management of moderate to severe bullous eruptions and severe pruritus in the setting of ICB therapy,1 it has been rapidly adopted as an off-label therapeutic strategy across a wide range of cirAEs. However, though several recent studies have demonstrated the efficacy of dupilumab in the management of several specific morphologies of cirAEs, these have been limited to case reports11–14 and single institutional cohorts8 15 16 without inclusion of comparator populations and long-term follow-up to evaluate the specific impact of dupilumab on ICB outcomes. As a result, there are no available data on the long-term impact of dupilumab on mortality among ICB recipients.

    In this multi-institutional retrospective cohort study, our primary aim is to evaluate overall survival outcomes among ICB recipients treated with dupilumab. Our secondary aim includes evaluating the efficacy of dupilumab in the management of cirAEs. To our knowledge, this is the largest cohort of ICB recipients treated with dupilumab to date and the first to explicitly evaluate survival outcomes by comparison to robust non-dupilumab treated comparator populations of ICB recipients.

    Methods

    We conducted a multi-institutional retrospective cohort study of ICB recipients who received dupilumab therapy for the management of cirAEs between September 27, 2017, and December 8, 2023, at the Mass General Brigham Healthcare System and the Dana-Farber Cancer Institute (MGBD). Figure 1 presents the population included in this study. We extracted patient demographic and medical history information from the MGBD Research Patient Data Registry17 and the Enterprise Data Warehouse18 using the same approaches as in our recently published studies19–21 and in alignment with the published guidelines on defining cirAEs.22 Manual chart review was conducted to extract cirAE characteristics (cirAE status—yes or no, cirAE onset date, cirAE morphology, and cirAE severity), dupilumab variables (dupilumab status—yes or no, dupilumab indication, dupilumab start and end date, treatments before dupilumab initiation, and dupilumab response), immunosuppression variables (systemic glucocorticoid use—yes or no, start date, and indication within 24 months after ICB initiation), absolute eosinophil count before and after dupilumab start, and patient outcomes (vital status, and date of last contact). Due to the heterogeneity in causes for ICB discontinuation (eg, treatment failure, irAEs, and patient death) and the difficulty in assessing this variable (eg, immunotherapy duration recommendations vary considerably over time and by cancer indication), we defined ICB interruption as “discontinuation” if a patient received less than 3 cycles of treatment, “pause” if a patient missed or delayed at least two cycles within 1 year of ICB initiation, and “continuation” otherwise. We chose three cycles as the cut-off as this number of treatment cycles has been shown to be minimally necessary to provide a clinical benefit.23 24

    Figure 1
    Figure 1

    The study population and data collection. This study identified all ICB recipients who developed cirAEs and received dupilumab for managing cirAEs as the case group (the dupilumab group). To demonstrate the robustness of this study, the dupilumab group was compared with two control groups that were identified using 1:2 matching based on sex, race, age at ICB initiation, Charlson Comorbidity Score, year of ICB start, and ICB type. The first control group included 106 ICB recipients who developed cirAEs and were not treated with dupilumab; the second control group included 106 ICB recipients who did not experience cirAEs and were not treated with dupilumab. CirAE, cutaneous immune-related adverse event; ICB, immune checkpoint blockade.

    Manual chart review to identify cirAEs was conducted in accordance with our previously published approaches.19–21 Briefly, a likelihood score between one to four was assigned to each cutaneous eruption in the setting of ICB use, with 1 representing that the eruption is highly unlikely to be secondary to ICB treatment and 4 representing that the eruption is highly likely to be secondary to ICB treatment. Cutaneous eruptions with a likelihood score of 3 or 4 were considered as cirAEs in this study.

    High-dose systemic glucocorticoid use was defined as treatment with a glucocorticoid of 10 mg prednisone equivalent daily for at least seven consecutive days, which is consistent with prior literature.25 Reasons for high-dose systemic glucocorticoid use were classified into four groups: cirAEs, other irAEs, cancer palliation, and other. The other irAEs group included patients who received systemic glucocorticoids for managing other non-cutaneous irAEs, such as colitis.

    CirAE severity was graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.26 CirAE morphology was documented based on clinical and histologic confirmation, whenever available. If histologic confirmation was not available, the morphology was documented based on clinical assessment by the dermatology team. Response to dupilumab was measured by comparing the CTCAE grade of the cirAE before and after the use of dupilumab. Patients whose cirAE became grade 0 were considered complete responders. Patients whose cirAE became grade 1 were considered partial responders. Both complete responders and partial responders were categorized as responders.

    Patients who did not ultimately receive dupilumab treatment or who were given dupilumab for treatment of a condition besides a cirAE were excluded from the study population. The retained ICB recipients who were treated with dupilumab for management of cirAEs (dupilumab group) were then compared with two control groups that were identified by 1:2 best matching based on sex, race, age at ICB initiation, Charlson Comorbidity Score (CCS), year of ICB start, and ICB type using the “matchControls” function in the R package e1071 V.1.7-14. The first control group included ICB recipients who developed cirAEs but were not treated with dupilumab (control group 1). The second group included ICB recipients who did not experience cirAEs and were not treated with dupilumab (control group 2). Because the development of cirAEs has been associated with improved survival in the setting of ICB therapy,19 25 27 we controlled for the presence of cirAEs by matching with patients who developed cirAEs but did not use dupilumab (control group 1). The second control group was used to examine the impact of dupilumab on overall survival independent of the presence of cirAEs.

    We used Pearson’s χ2 test for categorical variables and t-test for continuous variables to compare groups. We used an alpha of 0.05 as the significance threshold. To account for immortal time bias,28 we performed time-varying Cox proportional hazards modeling, adjusting for sex, race, age at ICB initiation, ICB type, CCS, cancer type, cancer stage at ICB initiation, and systemic glucocorticoid use within 2 years after ICB initiation. Both dupilumab and high-dose systemic glucocorticoid use were considered as time-varying covariates. We also conducted sensitivity analyses by additionally adjusting for ICB interruption and duration status. The proportional hazards assumption was examined using the “cox.zph” function in the R package survival V.3.5-7. All statistical analyses were conducted in R V.4.3.2.

    Results

    A total of 53 ICB recipients who received dupilumab for the management of cirAEs were included and were matched to 106 ICB recipients with cirAEs but no dupilumab treatment and 106 ICB recipients without cirAEs and without dupilumab therapy (figure 1). The characteristics of the dupilumab group and the two control groups are presented in table 1. Comparing the dupilumab group and the control group 1, there were no significant differences in mortality status, follow-up duration, sex, race, age at ICB initiation, year of ICB initiation, ICB type, CCS, cancer stage at ICB initiation, and high-dose systemic glucocorticoid use within 2 years after initiation of ICB therapy (p>0.05). Comparing the dupilumab group and the control group 2, there were significant differences in mortality status (18.9% vs 55.7%, p<0.001), follow-up duration (median: 961 vs 416 days, p<0.001), CCS (median: 1 vs 2, p=0.023), and high-dose systemic glucocorticoid use within 2 years after initiation of ICB therapy (71.7% vs 48.1%, p=0.008). Among the 38 patients who received high-dose systemic glucocorticoids within 2 years after initiation of ICB therapy in the dupilumab group, 81.6% (31 patients) received systemic glucocorticoids before dupilumab treatment to manage either cutaneous irAEs (24 patients) or non-cutaneous irAEs (7 patients). The remaining 18.4% (seven patients) who were treated with high-dose systemic glucocorticoids received it after initiating dupilumab therapy, for the management of either cutaneous irAEs (three patients), non-cutaneous irAEs (one patient), cerebral edema from brain metastases (two patients), or worsening pre-existing cough (one patient). All patients started on dupilumab after ICB initiation. However, some patients received dupilumab while on ICB (26/53) while the remainder (27/53) received dupilumab after stopping ICB, defined as ≥42 days from final ICB infusion.

    View this table:
    Table 1

    Characteristics of the study population

    Supplemental material

    Among the dupilumab group, 30.2% (16/53) of patients developed an initial cirAE presentation before a subsequent cirAE for which treatment with dupilumab was indicated. Among these 16 patients, dupilumab-treated cirAEs had more morphologic specificity (eight patients from unspecific rash to eczematous dermatitis, lichenoid dermatitis, or bullous pemphigoid; four patients from pruritus to eczematous dermatitis or lichenoid dermatitis; three patients from maculopapular eruption to bullous pemphigoid or sclerodermoid reaction with morphea-profunda; and one patient from lichenoid dermatitis to lichenoid dermatitis and bullous pemphigoid) and the grade was higher (greater than grade 1: 98.1% vs 75.5%, p=0.003) by comparison to the first cirAE presentation. Table 2 presents the cirAE severity and morphologies. Moreover, compared with control group 1, the first cirAE presentation for the dupilumab group was more severe (greater than grade 1: 75.5% vs 50.9%, p=0.012). Among all 53 dupilumab-treated patients, 22 (41.5%) had eczematous dermatitis, 14 (26.4%) had bullous pemphigoid, 7 (13.2%) had lichenoid dermatitis, 5 (9.4%) had maculopapular drug eruptions, 3 (5.7%) had mixed morphology (which consisted of lichenoid dermatitis/maculopapular drug eruption, lichenoid dermatitis/bullous pemphigoid, and lichenoid dermatitis/eczematous dermatitis), and 2 (3.8%) had other morphologies (radiation-induced ICB exacerbated morphea and sclerodermoid reaction with morphea profunda) (table 2). The median time from ICB start to first cirAE onset was 63 vs 54.5 days (p=0.395) for dupilumab and control group 1 cohorts, respectively. Online supplemental table S2 presents the median time from ICB start to the first cirAE stratified by morphology. The median duration from ICB start to the onset of dupilumab-treated cirAEs and to the initiation of dupilumab treatment was 146 and 352 days, respectively. The median duration of dupilumab treatment was 230 days.

    View this table:
    Table 2

    Severity and morphology of cirAEs and eosinophil count

    Of the 53 patients treated with dupilumab, 33 (62.3%) were complete responders, 14 (26.4%) were partial responders, and 6 (11.3%) were non-responders (online supplemental table S3). Among single morphologies of cirAEs that were treated with dupilumab, complete response was highest for maculopapular drug eruptions (80%), followed by eczematous eruptions (63.6%). Non-response was highest for bullous pemphigoid (21.4%). All patients with lichenoid eruptions and other eruptions in this cohort had either a complete response or partial response to dupilumab. Therefore, the response rate to dupilumab treatment was 88.7% (47/53). There was a significant decrease in absolute eosinophil count before and after dupilumab treatment (median: 0.39 vs 0.16, p<0.001) (table 2).

    All patients who received dupilumab had failed prior first-line therapy for the management of their cirAE. Table 3 presents the details of treatments patients received before starting dupilumab for managing cirAEs. In the dupilumab group, 100% (53 patients) received topical treatments, 69.8% (37 patients) were treated with antihistamines, and 66.0% (35 patients) received high-dose (24 patients) or low-dose (11 patients) systemic glucocorticoids for managing cirAEs before the initiation of dupilumab therapy. In the multivariable time-varying Cox proportional hazards models (table 4), the overall survival of the dupilumab group was not significantly different from control group 1 (HR=0.74, 95% CI: 0.35 to 1.60, p=0.5) or control group 2 (HR=0.70, 95% CI: 0.32 to 1.51, p=0.4). The use of high-dose systemic glucocorticoids within 2 years following ICB initiation was associated with poorer overall survival (HR=2.03, 95% CI: 1.04 to 3.96, p=0.039) in the regression comparing the dupilumab group to the control group one and (HR=2.21, 95% CI: 1.25 to 3.91, p=0.006) in the regression comparing the dupilumab group to the control group 2. Cox modeling assumptions held globally and separately for each covariate in the two models (p>0.05). After further adjusting for ICB interruption (online supplemental table S4) and duration (online supplemental table S5), dupilumab exposure did not significantly increase the risk of mortality as in the primary analyses, with the coefficient tending toward a protective effect.

    View this table:
    Table 3

    Treatments for cirAEs before dupilumab

    View this table:
    Table 4

    Time-varying cox proportional hazards models for overall survival

    Discussion

    This multi-institutional retrospective cohort study suggests that dupilumab is an effective treatment modality for recalcitrant cirAEs of various morphologies and that its use does not adversely impact mortality among ICB recipients. Notably, the survival trend associated with dupilumab was protective of mortality but did not reach statistical significance in this study due to insufficient sample size of the dupilumab population to demonstrate this protective effect. Interestingly, a recent study has suggested that dupilumab may enhance response to ICB treatment in ICB-resistant cancers; in six patients with non-small cell lung cancer with progressive disease while on PD-1 or PDL-1 receptor inhibiting immunotherapy, patients were given adjunct dupilumab in addition to their continued ICB regimens.29 One of the six patients experienced near-complete response following the addition of dupilumab.29 Similarly, though not reaching statistical significance, our results suggest that the use of dupilumab for cirAE management may be associated with a protective mechanism in the ICB population. Additional prospective randomized clinical trials with larger cohorts are necessary to further elucidate this potential relationship. Our study demonstrates that dupilumab does not increase the risk of mortality in this population and adds valuable data to aid oncologists and dermatologists in guiding their therapeutic selection and counseling patients about the long-term implications of dupilumab use in the setting of ICB therapy. Additionally, this is the largest study of dupilumab efficacy in the ICB-treated population and the first study to explicitly explore its long-term safety profile in an ICB-treated population.

    The utility of dupilumab in the management of cirAEs has previously been reported, and our conclusions confirm these findings.8 Our results demonstrated an 88.7% response rate to dupilumab therapy among ICB recipients across a broad range of cirAE morphologies, demonstrating that this therapeutic strategy is highly effective. Prior studies have reported an 87% cirAE response rate to dupilumab use,8 which our findings independently validate in a larger multi-institutional cohort. We also further stratified responders by cirAE morphology and found that although dupilumab is effective for the management of multiple different morphologies of cirAEs, its efficacy varies across morphologies. For instance, among individual morphologies of cirAEs, dupilumab demonstrated the highest non-response for the management of bullous eruptions and the highest complete response rate for the management of maculopapular drug eruptions (though our sample size is limited and further studies into this population are necessary), followed by eczematous eruptions. Interestingly, all patients with lichenoid and other eruptions achieved partial or complete response with a 90% rate of complete response in patients with mixed morphologies. It is important to note that morbilliform drug eruption is equivalent to maculopapular rash. As a result, this study suggests that the use of dupilumab in the treatment of lichenoid, other, and mixed morphologies could also be useful and that clinicians should consider broadening the indications for which they use dupilumab, despite the current absence of these morphologies in the NCCN guidelines for the management of irAEs.1

    Additionally, these results suggest that the use of high-dose systemic glucocorticoid immunosuppression within 2 years of immunotherapy initiation may be associated with detrimental effects on overall survival, which previous studies have also reported, though prospective randomized clinical trials are necessary to further explore this association.5 30 It is important to note that, unlike other classes of biologics such as tumor necrosis factor (TNF) inhibitors or interleukin 17 and 23 inhibitors,31–33 dupilumab is considered a more targeted form of immunosuppression and does not require the same degree of laboratory monitoring as the aforementioned biologic classes.34 Additionally, dupilumab has been approved for use in children as young as 6 months of age.35 Our findings also indicate a significant delay from the time of dupilumab-treated cirAE start to dupilumab initiation of 206 days. We suspect that this delay may be due to several issues, including time to dermatology referral and insurance approval of dupilumab. Based on these findings, we encourage early referral to dermatology for patients experiencing cirAEs.

    Our study suggests that dupilumab can be used in the management of treatment-refractory cirAEs) without impacting survival. Clinicians should consider using dupilumab in treating cirAEs not responsive to topical therapies as a safer alternative to the more commonly used systemic glucocorticoid immunosuppression and can counsel patients that this therapeutic strategy does not adversely impact their ICB outcomes. Additionally, this study demonstrates a favorable response to dupilumab treatment across several cirAE morphologies, including non-specific morphologies, and clinicians should discuss this treatment option with their cirAE patients with difficult-to-classify rashes. This study provides further support for the need to shift the paradigm of irAE management from reliance on systemic glucocorticoid immunosuppression, which may dampen the desired immune response in the setting of ICB treatment, toward more targeted forms of immunomodulation, with the goal of uncoupling toxicity from the therapeutic effect of ICBs. Additional studies exploring the use of other biologic and targeted immunosuppressive treatment modalities for the management of cirAEs and irAEs more broadly are necessary.

    Limitations of this study include its retrospective nature and limited sample size of the dupilumab-treated cohort. However, this is the largest study of dupilumab-treated cirAEs to date and the first to include robust comparator cohorts to investigate the impact of dupilumab on mortality in the ICB population. Future studies should confirm these findings among larger cohorts of ICB recipients and investigate the optimal time, dosing, and frequency for dupilumab therapeutic intervention in this population.

    Data availability statement

    Data are available on reasonable request. Data are available on request, please contact the corresponding author, YRS. All summary data supporting the findings of this study are available within the article and/or its supplementary materials. The patient-level data generated for this study can only be shared per specific institutional review board requirements.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study received approval from the Massachusetts General Brigham Institutional Review Board under protocol number 2020P002307.

    References

    1. ↵
    2. ↵
      1. Goodman RS,
      2. Johnson DB,
      3. Balko JM
      . Corticosteroids and Cancer Immunotherapy. Clin Cancer Res 2023;29:2580–7. doi:10.1158/1078-0432.CCR-22-3181
      OpenUrlPubMed
    3. ↵
      1. Horvat TZ,
      2. Adel NG,
      3. Dang T-O, et al
      . Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol 2015;33:3193–8. doi:10.1200/JCO.2015.60.8448
      OpenUrlAbstract/FREE Full Text
    4. ↵
      1. Riudavets M,
      2. Mosquera J,
      3. Garcia-Campelo R, et al
      . Immune-Related Adverse Events and Corticosteroid Use for Cancer-Related Symptoms Are Associated With Efficacy in Patients With Non-small Cell Lung Cancer Receiving Anti-PD-(L)1 Blockade Agents. Front Oncol 2020;10:1677. doi:10.3389/fonc.2020.01677
      OpenUrlCrossRefPubMed
    5. ↵
      1. Faje AT,
      2. Lawrence D,
      3. Flaherty K, et al
      . High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma. Cancer 2018;124:3706–14. doi:10.1002/cncr.31629
      OpenUrlCrossRefPubMed
    6. ↵
      1. Bruera S,
      2. Suarez-Almazor ME
      . The effects of glucocorticoids and immunosuppressants on cancer outcomes in checkpoint inhibitor therapy. Front Oncol 2022;12:928390. doi:10.3389/fonc.2022.928390
      OpenUrl
    7. ↵
      1. Bai X,
      2. Hu J,
      3. Betof Warner A, et al
      . Early Use of High-Dose Glucocorticoid for the Management of irAE Is Associated with Poorer Survival in Patients with Advanced Melanoma Treated with Anti-PD-1 Monotherapy. Clin Cancer Res 2021;27:5993–6000. doi:10.1158/1078-0432.CCR-21-1283
      OpenUrlAbstract/FREE Full Text
    8. ↵
      1. Kuo AM-S,
      2. Gu S,
      3. Stoll J, et al
      . Management of immune-related cutaneous adverse events with dupilumab. J Immunother Cancer 2023;11:e007324. doi:10.1136/jitc-2023-007324
    9. ↵
      1. D’Ippolito D,
      2. Pisano M
      . Dupilumab (Dupixent): An Interleukin-4 Receptor Antagonist for Atopic Dermatitis. P T 2018;43:532–5.
      OpenUrl
    10. ↵
      1. Wollenberg A,
      2. Thomsen SF,
      3. Lacour J-P, et al
      . Targeting immunoglobulin E in atopic dermatitis: A review of the existing evidence. World Allergy Organ J 2021;14:100519. doi:10.1016/j.waojou.2021.100519
      OpenUrl
    11. ↵
      1. Klepper EM,
      2. Robinson HN
      . Dupilumab for the treatment of nivolumab-induced bullous pemphigoid: a case report and review of the literature. Dermatol Online J 2021;27:1–6. doi:10.5070/D327955136
      OpenUrl
    12. ↵
      1. Bruni M,
      2. Moar A,
      3. Schena D, et al
      . A case of nivolumab-induced bullous pemphigoid successfully treated with dupilumab. Dermatol Online J 2022;28:1–4. doi:10.5070/D328257396
      OpenUrl
    13. ↵
      1. Pop SR,
      2. Strock D,
      3. Smith RJ
      . Dupilumab for the treatment of pembrolizumab-induced bullous pemphigoid: A case report. Dermatol Ther 2022;35:e15623. doi:10.1111/dth.15623
    14. ↵
      1. Fournier C,
      2. Hirsch I,
      3. Spreafico A, et al
      . Dupilumab as a treatment for cutaneous immune-related adverse events induced by immune checkpoint inhibitors: A case series and review of the literature. SAGE Open Med Case Rep 2023;11. doi:10.1177/2050313X231195462
    15. ↵
      1. Bur D,
      2. Patel AB,
      3. Nelson K, et al
      . A retrospective case series of 20 patients with immunotherapy-induced bullous pemphigoid with emphasis on management outcomes. J Am Acad Dermatol 2022;87:1394–5. doi:10.1016/j.jaad.2022.08.001
      OpenUrlPubMed
    16. ↵
      1. Said JT,
      2. Talia J,
      3. Wei E, et al
      . Impact of biologic therapy on cancer outcomes in patients with immune checkpoint inhibitor-induced bullous pemphigoid. J Am Acad Dermatol 2023;88:670–1. doi:10.1016/j.jaad.2022.06.1186
      OpenUrlPubMed
    17. ↵
      Research patient data registry. Available: https://rc.partners.org/about/who-we-are-risc/research-patient-data-registry [Accessed 18 Jun 2024].
    18. ↵
    19. ↵
      1. Zhang S,
      2. Tang K,
      3. Wan G, et al
      . Cutaneous immune-related adverse events are associated with longer overall survival in advanced cancer patients on immune checkpoint inhibitors: A multi-institutional cohort study. J Am Acad Dermatol 2023;88:1024–32. doi:10.1016/j.jaad.2022.12.048
      OpenUrlPubMed
    20. ↵
      1. Nguyen N,
      2. Wan G,
      3. Ugwu-Dike P, et al
      . Influence of melanoma type on incidence and downstream implications of cutaneous immune-related adverse events in the setting of immune checkpoint inhibitor therapy. J Am Acad Dermatol 2023;88:1308–16. doi:10.1016/j.jaad.2023.02.014
      OpenUrlPubMed
    21. ↵
      1. Wan G,
      2. Khattab S,
      3. Leung BW, et al
      . Cancer type and histology influence cutaneous immunotherapy toxicities: a multi-institutional cohort study. Br J Dermatol 2024;191:117–24. doi:10.1093/bjd/ljae053
      OpenUrl
    22. ↵
      1. Chen ST,
      2. Semenov YR,
      3. Alloo A, et al
      . Defining D-irAEs: consensus-based disease definitions for the diagnosis of dermatologic adverse events from immune checkpoint inhibitor therapy. J Immunother Cancer 2024;12:e007675. doi:10.1136/jitc-2023-007675
    23. ↵
      1. Kang SP,
      2. Gergich K,
      3. Lubiniecki GM, et al
      . Pembrolizumab KEYNOTE-001: an adaptive study leading to accelerated approval for two indications and a companion diagnostic. Ann Oncol 2017;28:1388–98. doi:10.1093/annonc/mdx076
      OpenUrlPubMed
    24. ↵
      1. Postow MA,
      2. Chesney J,
      3. Pavlick AC, et al
      . Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015;372:2006–17. doi:10.1056/NEJMoa1414428
      OpenUrlCrossRefPubMed
    25. ↵
      1. Wan G,
      2. Chen W,
      3. Khattab S, et al
      . Multi-organ immune-related adverse events from immune checkpoint inhibitors and their downstream implications: a retrospective multicohort study. Lancet Oncol 2024;25:1053–69. doi:10.1016/S1470-2045(24)00278-X
      OpenUrl
    26. ↵
      1. National Cancer Institute
      . Common terminology criteria for adverse events (CTCAE). Cancer Therapy Evaluation Program (CTEP); 2020.
    27. ↵
      1. Tang K,
      2. Seo J,
      3. Tiu BC, et al
      . Association of Cutaneous Immune-Related Adverse Events With Increased Survival in Patients Treated With Anti-Programmed Cell Death 1 and Anti-Programmed Cell Death Ligand 1 Therapy. JAMA Dermatol 2022;158:189–93. doi:10.1001/jamadermatol.2021.5476
      OpenUrl
    28. ↵
      1. Lévesque LE,
      2. Hanley JA,
      3. Kezouh A, et al
      . Problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes. BMJ 2010;340. doi:10.1136/bmj.b5087
    29. ↵
      1. LaMarche NM,
      2. Hegde S,
      3. Park MD, et al
      . An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis. Nature New Biol 2024;625:166–74. doi:10.1038/s41586-023-06797-9
      OpenUrl
    30. ↵
      1. Verheijden RJ,
      2. Burgers FH,
      3. Janssen JC, et al
      . Corticosteroids and other immunosuppressants for immune-related adverse events and checkpoint inhibitor effectiveness in melanoma. Eur J Cancer 2024;207:114172. doi:10.1016/j.ejca.2024.114172
      OpenUrlPubMed
    31. ↵
      1. Madani AN,
      2. Al-Saif FM,
      3. Alzamil LR, et al
      . Monitoring the effect of TNF-alpha inhibitors on laboratory parameters and adverse effects in different diseases: a retrospective, single-center study. Ann Saudi Med 2022;42:309–18. doi:10.5144/0256-4947.2022.309
      OpenUrl
    32. ↵
      1. Yang K,
      2. Oak ASW,
      3. Elewski BE
      . Use of IL-23 Inhibitors for the Treatment of Plaque Psoriasis and Psoriatic Arthritis: A Comprehensive Review. Am J Clin Dermatol 2021;22:173–92. doi:10.1007/s40257-020-00578-0
      OpenUrlCrossRefPubMed
    33. ↵
      1. Kearns DG,
      2. Uppal S,
      3. Chat VS, et al
      . Comparison of Guidelines for the Use of Interleukin-17 Inhibitors for Psoriasis in the United States, Britain, and Europe: A Critical Appraisal and Comprehensive Review. J Clin Aesthet Dermatol 2021;14:55–9.
      OpenUrl
    34. ↵
      1. Wollenberg A,
      2. Beck LA,
      3. Blauvelt A, et al
      . Laboratory safety of dupilumab in moderate-to-severe atopic dermatitis: results from three phase III trials (LIBERTY AD SOLO 1, LIBERTY AD SOLO 2, LIBERTY AD CHRONOS). Br J Dermatol 2020;182:1120–35. doi:10.1111/bjd.18434
      OpenUrl
    35. ↵
      1. Paller AS,
      2. Simpson EL,
      3. Siegfried EC, et al
      . Dupilumab in children aged 6 months to younger than 6 years with uncontrolled atopic dermatitis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2022;400:908–19. doi:10.1016/S0140-6736(22)01539-2
      OpenUrlCrossRef

    Footnotes

    • X @CaImmunoprevent, @EugeneSemenovMD

    • Contributors Study concept and design: GW, SK, NRL and YRS. Data collection: SK, GW, SX, CM, MT, EB, CL and BWL. Data analysis: GW, SK and YRS. Data interpretation: SK, GW, SX, CM, MT, EB, CL, BWL, MA, NH, KLR, SD, NRL and YRS. Drafting of the manuscript: GW, SK, NRL and YRS. Administrative, technical, or material support: YRS. Study supervision: NRL and YRS. GW, SK, NRL and YRS directly accessed and verified the underlying data reported in the manuscript. All authors had access to the summary data reported in the study. This manuscript was written by the lead investigators and was reviewed and approved for publication by all coauthors. YRS is the guarantor of this study. YRS, the guarantor of this manuscript, agrees to the license to publish in the Journal of ImmunoTherapy of Cancer (JITC) on behalf of all authors.

    • Funding YRS is supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (award number K23AR080791), the Department of Defense (award number W81XWH2110819), and the Melanoma Research Alliance Young Investigator Award. GW is supported by the National Cancer Institute of the National Institutes of Health (award number K99CA286966).

    • Competing interests YRS is an advisory board member or consultant and has received honoraria from Pfizer, Incyte Corporation, Sanofi, Galderma, Castle Biosciences, and Iovance Biotherapeutics. KLR is an advisory board member to SAGA Diagnostics, has received speaker fees from CMEOutfitters, MedScape, and BMS, and provides institutional support for the ATRIUM clinical trial. NRL is a consultant and has received honoraria from Bayer, Silverback, Fortress Biotech, and Synox Therapeutics outside the scope of the submitted work.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.