Metabolomic correlates of response in nivolumab-treated renal cell carcinoma and melanoma patients

3036 Background: Immune-checkpoint inhibition has been shown to be effective in a variety of cancers, including renal cell carcinoma (RCC) and melanoma. However, only a subset of patients with RCC and melanoma respond to anti-PD1 therapy. Given the importance of metabolism in the tumor immune microenvironment, we performed serum metabolomics in nivolumab-treated patients towards identifying novel non-invasive correlates of response and progression-free survival in immunotherapy-treated patients. Methods: We performed liquid chromatography-mass spectrometry on pre- and on-treatment serum samples from 79 patients with advanced melanoma (CA209-038 study) and 82 patients with metastatic RCC (CA209-009 study) receiving nivolumab. We precisely measured more than one-hundred named metabolites at baseline (prior to starting nivolumab), at 4 weeks and at 6 (melanoma) or 9 weeks (RCC) after initiation of treatment and correlated these with best overall response as well as progression-free survival (PFS). Results: In melanoma patients treated with nivolumab, the difference in mean levels of kynurenine (the product of IDO / TDO activity in tryptophan catabolism) between weeks 4 and 6 compared to baseline was significantly different between responders and non-responders (t-test with unequal variance p-value = 0.043 and p-value = 0.044 respectively). In RCC patients, we observed that patients with no response to nivolumab had significantly higher adenosine levels, than those who responded, at baseline and at 4 weeks after initiation of treatment (158% and 138% higher, t-test p-value = 0.0019 and p-value = 0.0011 respectively). RCC nivolumab-treated patients with higher (top quartile) baseline adenosine levels also had a significantly worse PFS (log rank test p-value = 0.004). Conclusions: In this first-of-its kind metabolomic analysis of peripheral blood from nivolumab-treated patients, we find that the change in kynurenine levels in melanoma patients correlates to response. In addition, higher baseline levels of adenosine in RCC patients are associated with worse PFS and lack of response to nivolumab. These results suggest a possible role for serum metabolites as biomarkers of benefit to PD1 inhibition.