Background Melanoma mortality has steadily decreased since the introduction of immune checkpoint inhibitors (ICIs) to manage advanced-stage disease (stage III/IV).¹ Although ICIs have prolonged survival, this therapeutic class is associated with toxicities, of which cutaneous immune-related adverse events (cirAEs) are the most common² and may serve as early biomarkers of therapeutic efficacy.^{3 4} The recent approval of adjuvant ICI therapy for patients with stage IIB/IIC melanoma raises concerns about the appropriateness and timing of immunotherapy in this population,⁵ especially when most patients will not experience disease recurrence following surgical resection alone.⁶ In this study, we compare cirAE development and overall survival in patients with early-stage (stage I/II) primary cutaneous melanoma that recurred at an advanced stage (recurred) as compared to those with advanced-stage melanoma at time of diagnosis (advanced).

Methods We identified 134 ICI recipients with recurrent melanoma and 134 matched ICI recipients with advanced melanoma from the Mass General Brigham and Dana-Farber Cancer Institute. Manual chart reviews were conducted to ascertain the presence of cirAEs.³ Pearson’s chi-squared test for categorical variables and t-test for continuous variables were used for comparisons. Cox proportional hazards (CoxPH) modeling was performed, adjusted for demographics, Charlson comorbidity score (CCS), ICI type, melanoma stage at ICI initiation, histologic type, primary melanoma anatomic site, presence of ulceration, and presence of tumor-infiltrating lymphocytes within the primary melanoma.

Results Table 1 presents the characteristics of the study population. CoxPH models demonstrated no differences in cirAE development (HR:0.68; 95% CI:0.39–1.20; p=0.2) and overall survival (HR:1.21; 95% CI:0.69–2.12; p=0.5) (table 2).

Conclusions Our study shows that patients with recurrent early-stage primary melanoma are as likely to develop cirAEs (an early biomarker of therapeutic efficacy in this population) and experience similar overall survival as patients with advanced-stage melanoma at the time of diagnosis. Given that most stage IIB and IIC melanomas do not recur after excision and the high risk of ICI toxicities, adoption of adjuvant immunotherapy in this population has been slow, particularly in the absence of accurate biomarkers for identification of high-risk patients. Our findings are, however, reassuring that ICI response is similar among early-stage patients who experience recurrence and the advanced-stage melanoma population in which ICI therapy has been used more extensively. Given these observations, it is important to inform patients of the potential benefits and risks of delaying ICI therapy in the setting of early-stage disease and the expected response to ICI therapy in the event of melanoma recurrence.

References

1. Naik PP. Current Trends of Immunotherapy in the Treatment of Cutaneous Melanoma: A Review. Dermatol Ther (Heidelb). 2021;11(5):1481–1496. doi:10.1007/s13555-021-00583-z

2. Tattersall IW, Leventhal JS. Focus: Skin: Cutaneous Toxicities of Immune Checkpoint Inhibitors: The Role of the Dermatologist. The Yale Journal of Biology and Medicine. 2020;93(1):123.

3. Zhang S, Tang K, 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. Journal of the American Academy of Dermatology. Jan 31, 2023; doi:10.1016/j.jaad.2022.12.048

4. Nguyen N, Wan G, 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(6):1308–1316. doi:10.1016/j.jaad.2023.02.014

5. FDA Center for Drug Evaluation and Research. FDA approves pembrolizumab for adjuvant treatment of Stage IIB or IIC melanoma. FDA.gov. Published December 6, 2021. Accessed December 11, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-adjuvant-treatment-stage-iib-or-iic-melanoma

6. Bleicher J, Swords DS, Mali ME, et al. Recurrence patterns in patients with Stage II melanoma: The evolving role of routine imaging for surveillance. Journal of Surgical Oncology. 2020;122(8):1770–1777. doi:10.1002/jso.26214

Ethics Approval Reviewed and exempted by Mass General Brigham IRB (Protocol #2020P002179).