Serum IL-6 and CRP as prognostic factors in melanoma patients receiving single agent and combination checkpoint inhibition.

Abstract

100 Background: Acute phase reactants including C-reactive protein (CRP), and chronic inflammatory proteins including IL-6, which induces production of CRP from the liver, have been associated with a poor outcome in a variety of cancers. Methods: Sera from the CheckMate 064, 066 and 067 studies were assessed at baseline and on treatment for levels of IL-6 and CRP by Luminex. Associations between IL-6 and/or CRP levels and response or survival were determined. Purified endotoxin- and azide-free CRP was also tested for its immune effects in vitro using human T cells. Results: In patients receiving sequential nivolumab then ipilimumab in CheckMate 064 (cohort A), baseline serum IL-6 was associated with response (p = 0.03); serum IL-6 at week 12 after nivolumab alone (cohort A) or ipilimumab alone (cohort B), was also associated with response (p = 0.004 and 0.006, respectively). Baseline IL-6 above the median was associated with shorter survival in cohort A (p = 0.003) and cohort B (p = 0.0001). Serum CRP above the median was associated with shorter survival in cohort A (p = 0.001). Baseline IL-6 and CRP in cohort A were associated with one another, rho = 0.71 and p < 0.0001 In the randomized CheckMate 067 study, higher baseline serum CRP above the median was associated with shorter survival for ipilimumab, nivolumab or the combination with p < 0.0001, p < 0.11, and p = 0.0034, respectively. In the randomized CheckMate 066 study, higher baseline serum CRP was associated with shorter survival for nivolumab or dacarbazine (p = 0.131 and P < 0.0001 respectively). CRP suppressed T cell immunity and function, and levels above 10 micrograms/mL suppressed T cell proliferation (p = 0.005) and altered T cell signaling as well as calcium flux (p = 0.01), suggesting that CRP affected the earliest steps in T cell signaling and activation. Conclusions: High levels of CRP and IL-6 at baseline were associated with a poor response and shorter survival after nivolumab alone, and CRP with ipilimumab alone or the combination of both drugs. High levels of CRP were also associated with shorter overall survival in the randomized CheckMate 066 study of chemotherapy compared to nivolumab. CRP and IL-6 are prognostic factors for checkpoint inhibition.