Correlation between cutaneous adverse events and prognosis in patients with melanoma treated with nivolumab: A single institutional retrospective study

Abstract

Treatment for patients with unresectable melanoma has been dramatically changed by the use of immunocheckpoint inhibitors (ICI). In this study, we reviewed patients with unresectable stage III/IV melanoma, who were treated with nivolumab between and retrospectively recorded cutaneous adverse events (cAE), development of vitiligo, clinical characteristics and clinical responses. We identified 128 patients, 61 (47.7%) of whom showed cAE, including 30 (23.4%) with development or exacerbation of vitiligo. The prognosis of patients with melanoma treated with ICI correlated with cAE, including development of vitiligo. Patients with cAE showed better objective responses (41.0% vs 6.0%, P < 0.001), progression-free survival (PFS) (377 vs 61 days, P < 0.001) and overall survival (OS) (763 vs 209 days, P < 0.001) than did patients without cAE. Patients who developed vitiligo showed better objective responses (53.3% vs 29.0% vs 6.0%, P < 0.001), PFS (median, not reached vs 317 vs 65 days, P < 0.001) and OS (not reached vs 689 vs 209 days, P < 0.001) than did patients with other cAE and patients without cAE. Landmark analysis showed development of vitiligo starting 20 weeks after starting nivolumab correlated with better OS. In multivariate analysis, OS correlated with performance status, number of metastasized organs, cAE other than vitiligo and development of vitiligo. Despite the fact that the correlation between other cAE and OS was less than that of vitiligo, cAE may be a simple marker of favorable prognosis.

Resistance to anti-PD1 therapies in patients with advanced melanoma: systematic literature review and application of the Society for Immunotherapy of Cancer Immunotherapy Resistance Taskforce anti-PD1 resistance definitions

“…3), including acral ( n = 2) [42,44], mucosal ( n = 1) [37,42], or uveal ( n = 1) [29]. Three additional studies [31,32,38] did not specify histology but were conducted in Asia, where acral or mucosal melanoma is the dominant subtype.…”

“…Figure 4a describes resistance by treatment regimen and country/region. In the studies with cohorts in Asia, where patients are predominantly acral and mucosal melanoma [47], the median primary resistance for patients treated with anti-PD-1 monotherapy overall (line of therapy not specified) was 50.78% (35.53-66.67%; n = 4) [31,32,38,44]. In the studies conducted in Europe, one study assessed primary resistance in first-line monotherapy (39.13%) [21]; the median primary resistance for patients treated in second-line was 41.54% (30.0-56.41%; n = 3) [23][24][25]; in the studies that did not specify line of therapy, the median primary resistance was 48.32% (28.57-81.25%; n = 9) [24,26,29,33,36,40,41,43,48].…”

“…In the studies that did not specify line of therapy, the median proportion of primary resistance was 50.78% (28.74-81.25%; n = 7) [26][27][28][29][30][31][32] for nivolumab monotherapy, 39.93% (25.04-75.47%; n = 9) [12,22,24,29,31,[33][34][35][36] for pembrolizumab monotherapy, and 49.13% (28.85-57.32%; n = 9) [37][38][39][40][41][42][43][44][45] for studies that did not specify which type of anti-PD1 monotherapy. Overall the median proportion of primary resistance was 47.50% (25.04-81.25%; n = 23) for anti-PD1 monotherapy in studies that did not specify line of therapy [12,22,24,[26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44]…”

“…In observational studies, patients receiving first-line pembrolizumab had a primary resistance of 39.13% (n = 1) [21], 30.30% (n = 1) [25] for second-line or higher pembrolizumab, and 56.41% (n = 1) [25] for second-line or higher nivolumab or pembrolizumab. Patients enrolled in observational studies that did not specify line of therapy who received either nivolumab or pembrolizumab had an overall median resistance of 49.13% (28.57-81.25%; n = 19) [24,26,29,[31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]48].…”

Checkpoint Inhibitors in Melanoma Patients with Underlying Autoimmune Disease

“…There is a well-documented relationship between checkpoint-inhibitor induced cutaneous toxicity, specifically vitiligo, and improved tumor response. [21][22][23] A retrospective study of 346 patients with melanoma showed that those who developed gastrointestinal immune adverse events had a statistically significant improvement in progression-free and overall survival compared to those who did not. 24 Moreover, the severity of the irAE appeared to correlate with benefit: patients who developed higher-grade diarrhea had a statistically significant improvement in overall survival.…”