Long-term mortality outcomes among immunotherapy recipients treated with dupilumab for the management of cutaneous immune-related adverse events.

Background: Dupilumab has been added to National Cancer Comprehensive Network (NCCN) guidelines as a therapeutic strategy for managing certain cutaneous immune-related adverse events (cirAEs) from immune checkpoint inhibitor (ICI) therapy. 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 ICI recipients.

Methods: We conducted a muti-institutional retrospective cohort study of ICI recipients from the Mass General Brigham Healthcare System and Dana-Farber Cancer Institute. The dupilumab group was compared to 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 ICI initiation, Charlson Comorbidity Score, year of ICI initiation, and ICI 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 ICI initiation, ICI type, Charlson Comorbidity Index score, cancer type, cancer stage at ICI initiation, and systemic glucocorticoid use.

Results: A total of 53 cirAE patients treated with dupilumab were compared to 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:0.35-1.60, p=0.5) or control group 2 (HR=0.70, 95% CI:0.32-1.51, p=0.4). However, the use of systemic glucocorticoids within two 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, p=0.039) and control group 2 (HR=2.21, 95% CI:1.25-3.91, p=0.006).

Conclusions: This study suggests that dupilumab is an effective therapeutic option for recalcitrant cirAEs and does not adversely impact mortality. Due to the observed detrimental effects of systemic glucocorticoid therapy, this study supports the need to shift away from systemic glucocorticoid immunosuppression and towards targeted immune modulators for irAE management that are less detrimental to ICI response.

• 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; ¹ however, the impact dupilumab on survival outcomes among recipients of immune checkpoint inhibitor therapy (ICI) remains under studied.

• 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 ICI recipients.

• how this study might affect research practice or policy: The results of this study suggest that 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 utilized broad-based glucocorticoid immunosuppression for the management of immune related adverse events in the setting of ICI therapy.