Dronca, Roxana

9535 Background: A broad understanding of baseline immunity is needed in order to predict responses to PD-1 blockade. We previously reported in a preclinical model that elevated Th1 signature cytokines are present after successful therapy with PD-1 blockade. In this study we evaluated serum cytokines as biomarkers of response in a cohort of patients with metastatic melanoma undergoing anti-PD1 therapy. Methods: 27 pts diagnosed with metastatic melanoma (MM) received anti-PD-1 therapy and had peripheral blood collected prior to anti-PD-1 therapy start and 12 weeks after; 55 proinflammatory-related serum cytokines were analyzed at both times using the Meso Scale Discovery (MSD) assay. At week 12, we identified 15 pts who had radiographic complete or partial response (TR) and 12 had progressive disease (PD) using RECIST criteria. Spearman rank correlation coefficients (rho) were used to assess association between pre-treatment serum cytokine levels. For each cytokine, differences in pretreatment serum levels and the ratio of the 12 week to pre-treatment serum levels between TR and PD groups were assessed using Wilcoxon rank sum tests. Results: Pretreatment serum IL-12p40 and MIP3a (CCL20) were moderately correlated (rho=0.3944). Pretreatment IL-12p40 and was found to be significantly higher (p=0.0025) in the TR group (median=48.5; 25th to 75th percentile [IQR]:25.3-63.8) relative to the PD group (median=17.3; IQR: 8.6-30.3). Pretreatment MIP3a was also found to be significantly higher (p=0.0359) in the TR group (median=1.72; IQR: 1.41-2.65) relative to the PD group (median=1.33; IQR: 1.09-1.98). The 12th week pretreatment IL-12p40 ratio (median=1.98; IQR: 1.4-11.3) in the TR group was greater than that (median=0.64; IQR: 0.23-1.61) in the PD group (p=0.0029); we identified that baseline serum levels >15pg/ml of IL12p40 prior to immunotherapy were associated with significantly prolonged event free survival (p=0.001). Conclusions: Measurements of IL-12p40 and MIP-3a levels before immunotherapy may help to select patients who are likely to benefit from anti-PD1 therapy. Additionally, exploration of combination therapies that increase IL-12P40 and MIP3 prior or during immunotherapy should be undertaken.

Abstract Background Immune-related adverse events (irAEs) have emerged as a serious clinical issue in the use of immune checkpoint inhibitors (ICIs). Risk factors for irAEs remain controversial. Therefore, we studied sex differences in irAEs in patients treated with anti-programmed cell death protein 1 (PD-1) therapy. Materials and Methods All patients with metastatic melanoma and non-small cell lung cancer (NSCLC) treated with anti-PD-1 therapy at Mayo Clinic Rochester and Florida from 2015 to 2018 were reviewed. Kaplan-Meier method and log-rank test was used for time-to-event analysis. Results In 245 patients with metastatic melanoma, premenopausal women were more likely to experience irAEs (all grades) compared with postmenopausal women and men (67% vs. 60% vs. 46%), primarily because of an increase in endocrinopathies (33% vs. 12% vs. 10%, respectively). In patients with NSCLC (231 patients), women (all ages) were also more likely to develop irAEs of all grades (48% vs. 31%). Women with NSCLC were more likely to develop pneumonitis (11% vs. 4%) and endocrinopathies (14% vs. 5%). No differences in grade ≥3 toxicities were seen across sexes in both cohorts, but women were more likely to receive systemic steroids for the treatment of irAEs compared with men. Better progression-free-survival was observed in women with NSCLC and irAEs (10 months vs. 3.3 months) compared with women without irAEs. Conclusion Women with metastatic melanoma and NSCLC are more likely to experience irAEs compared with men. We also observed differences between sexes in the frequency of certain irAEs. Larger studies are needed to investigate the mechanisms underlying these associations. Implications for Practice The results of this study suggest that women may be at a higher risk for immune-related adverse events (irAEs) compared with men when treated with anti-programmed cell death protein 1 therapy. In addition, women were more likely to develop certain irAEs, including endocrinopathies and pneumonitis. Close follow-up of women undergoing treatment with immune checkpoint inhibitors will allow clinicians to diagnose these treatment-related complications early, potentially reducing their associated morbidity and mortality. In addition, a possible association between irAEs and response to therapy was observed.