Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes

Abstract

Purpose Retrospective analysis of irAEs in melanoma patients treated with nivolumab. Experimental Design Data were pooled from 148 patients (33 resected, 115 unresectable) treated with nivolumab plus peptide vaccine or nivolumab alone every 2 weeks for 12 weeks. Patients with stable disease or regression received an additional 12-week cycle, then nivolumab alone every 12 weeks for up to 2 additional years. Frequency, grade, and characteristics of irAEs were analyzed. A 12-week landmark survival analysis using a multivariate time-dependent Cox proportional hazard model assessed difference in OS in the presence or absence of irAEs. Results IrAEs of any grade were observed in 68.2% of patients (101 of 148). Grade III/IV irAEs were infrequent: 3 (2%) had Grade III rash, 2 (1.35%) had asymptomatic Grade III elevation in amylase/lipase, and 2 (1.35%) had Grade III colitis. A statistically significant OS difference was noted amongst patients with any grade of irAE versus those without (p=<0.001), and OS benefit was noted in patients who reported 3 or more irAE events (p=<0.001). Subset analyses showed statistically significant OS differences with rash (p=0.001 [HR 0.423, 95% CI 0.243 to 0.735]) and vitiligo (p=0.012 [HR 0.184, 95% CI 0.036 to 0.94]). Rash and vitiligo also correlated with statistically significant OS differences in patients with metastatic disease (p=0.004 and p=0.028, respectively). No significant survival differences were seen with other irAEs (endocrinopathies, colitis, or pneumonitis). Conclusions Cutaneous irAEs are associated with improved survival in melanoma patients treated with nivolumab, and clinical benefit should be validated in larger prospective analyses.

Characterization of nivolumab-associated skin reactions in patients with metastatic non-small cell lung cancer

“…4,5,7,8 An association between appearance of skin irAEs and OS in melanoma has been reported. [13][14][15]17 Similarly, our data suggest an association between skin irAEs and tumor response. The histological analysis of the rashes on the one hand allowed us to rule out clinical differential diagnoses of eczema and psoriasis and on the other hand revealed that the rashes were characterized by an inflammation rich in CD3C T-lymphocytes.…”

Cytotoxic Cutaneous Adverse Drug Reactions during Anti-PD-1 Therapy

“…Interestingly, both vitiligo and/or cutaneous reactions emerging during nivolumab treatment in patients with melanoma have recently been reported to be associated with overall survival (23). As a consequence, cutaneous reactions during anti-PD-1 treatment could potentially be used as biomarkers in the therapy.…”

Treating tumors with immune checkpoint inhibitors: Rationale and limitations

“…It should be noted that patients may still respond to immune checkpoint blockade despite the development of adverse events, the administration of corticosteroids or the cessation of treatment [44] . Intriguingly, the development of immune-related adverse events, particularly rash and vitiligo, has even been associated with improved disease outcome in melanoma patients treated with anti-PD-1 [47] , suggesting that the breaking of tolerance to local (auto-) antigens may also lead to improved anti-tumor immune responses. Figure 1 shows the visualization of treatmentassociated adverse events and their anatomical sites in melanoma patients treated with anti-PD-1 and/or anti-CTLA-4, as reported by Larkin and colleagues [37] .…”

“…Th1-and CTLA-4-related gene expressions within the tumor prior to treatment have been linked to subsequent response to anti-PDL-1 [47] . In another study, melanoma patients responding successfully to anti-PD-1 treatment were more likely to display high [37] TGF-β levels pre-treatment and an expanded IL-9 producing CD4 + T (Th9) cell compartment posttreatment [52] .…”