Heterogeneous response and irAE patterns in advanced melanoma patients treated with anti-PD-1 monotherapy from different ethnic groups: Subtype distribution discrepancy and beyond.

10020 Background: Programmed cell death receptor-1 (PD-1) monotherapy is the standard first line therapy for advanced cutaneous melanoma, with efficacy, toxicity, and their correlations well established. Yet these remain poorly characterized for non-Caucasians and for certain rarer melanoma subtypes. Methods: Clinical data from melanoma patients treated with anti-PD-1 monotherapy between 2009 and 2018 was collected retrospectively from three independent institutions from the US and China. Tumor response, survival outcome, and organ/system-specific immune-related adverse effects (irAEs) were directly compared between different subgroups. Results: Among 626 patients, 411 were Caucasian, 214 non-Caucasian; 369 had cutaneous melanoma, and 257 other subtypes. Both ethnicity and melanoma subtype were independently associated with benefit and irAEs. In multivariate analyses, Caucasians had significantly higher objective response rate (ORR) (OR 2.0, 95% CI 1.1-3.5), but this did not translate into a survival advantage (PFS, HR 0.8, 95% CI 0.6-1.1; OS, HR 1.0, 95% CI 0.7-1.4); melanoma of unknown primary shared similar response and survival profile with cutaneous, while acral (ORR, OR 0.4, 95% CI 0.2-0.9; PFS, HR 1.6, 95% CI 1.1-2.2; OS, HR 1.3, 95% CI 0.8-1.9), mucosal (ORR, OR 0.4, 95% CI 0.2-0.9; PFS, HR 1.4, 95% CI 1.0-2.0; OS, HR 1.7, 95% CI 1.1-2.6) and ocular (ORR, OR 0.1, 95% CI 0-0.6; PFS, HR 2.3, 95% CI 1.4-3.6; OS, HR 2.2, 95% CI 1.3-3.6) melanomas had inferior outcomes. Non-Caucasian cutaneous patients had a significantly worse ORR than Caucasians with cutaneous melanoma (P < .01). Distinct irAE patterns were observed, exemplified by lower incidence of most irAEs (although more frequent pneumonitis) in Caucasians, and higher and lower liver irAE incidence in ocular and mucosal melanomas, respectively. Endocrine, musculoskeletal and skin irAEs were associated with improved PFS and OS across ethnicities and nearly all melanoma subtypes, whereas heterogeneity existed for other irAE types. Conclusions: Ethnicity and melanoma subtype are associated with distinct response patterns, survival outcomes, and irAE profiles in the setting of anti-PD-1 monotherapy. More research is needed to elucidate the molecular and immunologic determinants of these variable outcomes.