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.

Malignant melanoma is a significant public health problem; according to 2013 Surveillance, Epidemiology, and End Results data, its average incidence rate rose 2.6% each year for the last decade, and it is now the fifth most common cancer diagnosis in the United States. The rising incidence and historical poor response to chemotherapy have led to intense investigation of novel treatments for melanoma, including therapies to improve the immune-mediated destruction of cancer cells. Among the hallmarks of malignancy is the ability to evade this process: while early stages of tumor growth can induce functional CD8+ T-cell responses, cancer cells become increasingly embedded in an immune-suppressive tumor stroma. In the tumor microenvironment, T-cell proliferation and effector function are impaired due to engagement of T-cell programmed death receptor 1 (PD-1) with programmed death receptor ligand (PD-L1) expressed by cancer cells and antigen-presenting cells, which blocks T-cell-mediated cytotoxicity. This receptor-ligand engagement thereby inhibits immunity, allows the tumor to continue to grow, and contributes to the phenomenon of 'T-cell exhaustion'. One immunotherapy strategy currently under investigation is inhibition of the interaction between PD-L1 and PD-1, thereby overcoming a critical immune checkpoint to facilitate destruction of cancer cells. In this review we discuss the preclinical rationale for PD-1 pathway inhibition in cancer, recent results of clinical trials targeting PD-1 and PD-L1, and evaluate its potential as a future anticancer therapy.

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<p>Supplemental Table 1: Detailed patient characteristics of each cohort, including age, gender, race, disease stage, whether CNS disease was present, and what dose of nivolumab and/or vaccine was allocated. Supplemental Table 2: The relationship of overall response rate (ORR, PR + CR vs SD + PD) to vitiligo and rash. The authors found a statistically significant relationship between ORR and rash (p=0.03) and vitiligo (p=0.009).</p>