Serum interleukin-6 and C-reactive protein are associated with survival in melanoma patients receiving immune checkpoint inhibition

Abstract

BackgroundInflammatory mediators, including acute phase reactants and cytokines, have been reported to be associated with clinical efficacy in patients with melanoma and other cancers receiving immune checkpoint inhibitors (ICI). Analyses of patient sera from three large phase II/III randomized ICI trials, one of which included a chemotherapy arm, were performed to assess whether baseline levels of C-reactive protein (CRP), interleukin-6 (IL-6) or neutrophil/lymphocyte (N/L) ratios were prognostic or predictive.Patients and methodsBaseline and on-treatment sera were analyzed by multiplex protein assays from immunotherapy-naïve patients with metastatic melanoma randomized 1:1 on the Checkmate-064 phase II trial of sequential administration of nivolumab followed by ipilimumab or the reverse sequence. Baseline sera, and peripheral blood mononuclear cells using automated cell counting, were analyzed from treatment-naïve patients who were BRAF wild-type and randomly allocated 1:1 to receive nivolumab or dacarbazine on the phase III Checkmate-066 trial, and from treatment-naïve patients allocated 1:1:1 to receive nivolumab, ipilimumab or both ipilimumab and nivolumab on the phase III Checkmate-067 trial.ResultsHigher baseline levels of IL-6 and the N/L ratio, and to a lesser degree, CRP were associated with shorter survival in patients receiving ICI or chemotherapy. Increased on-treatment levels of IL-6 in patients on the Checkmate-064 study were also associated with shorter survival. IL-6 levels from patients on Checkmate-064, Checkmate-066 and Checkmate-067 were highly correlated with levels of CRP and the N/L ratio.ConclusionIL-6, CRP and the N/L ratio are prognostic factors with higher levels associated with shorter overall survival in patients with metastatic melanoma receiving ICI or chemotherapy in large randomized trials. In a multi-variable analysis of the randomized phase III Checkmate-067 study, IL-6 was a significant prognostic factor for survival.

Clinical utility of the C‐reactive protein:albumin ratio in non‐small cell lung cancer patients treated with nivolumab

“…Therefore, modified GPS and CAR might represent markers of systemic inflammation, as well as the dynamics associated with the tumorigenic inflammatory response. This suggests that a higher modified GPS and CAR reflect upregulation of proinflammatory cytokine levels (IL‐6 and IL‐1) reportedly involved in tumorigenic inflammation and associated with resistance to anticancer agents 23,24 …”

Predictive impact of C-reactive protein to albumin ratio for recurrent or metastatic head and neck squamous cell carcinoma receiving nivolumab

“…Furthermore, IL-6 also induces cachexia by altering the metabolism of lipids and proteins 36 . Recently, the correlation between the baseline IL-6 and CRP in melanoma treated with immune checkpoint inhibitors (ICIs) or chemotherapy was demonstrated, and higher levels of IL-6 were significantly associated with poor survival 37 . On the other hand, no significant change of systemic levels of IL-6 during ICI treatment has been observed in the studies of melanoma 38 and gastric cancer 39 .…”

Living with Metastatic Cancer: A Roadmap for Future Research

“…Notably, there is a large body of research in humans and animals indicating that biological changes due to cancer and its treatment (e.g., inflammation) can cause short- and long-term psychological and behavioral changes. Inflammation is a well-established driver of metastatic disease in breast cancer and melanoma [ 74 ]. For example, neutrophils produce a wide variety of proteins that stimulate tumorigenesis as well as tumor cell proliferation, migration, and invasion [ 75 ].…”

“…Melanoma is characterized by high immunogenicity and chronic inflammation in the tumor microenvironment [ 77 ]. Higher circulating levels of CRP and IL-6 prior to treatment with ICIs appear to be poor prognostic indicators among patients with metastatic melanoma [ 74 , 78 , 79 ], although evidence is mixed [ 80 ]. These findings are consistent with a large body of research demonstrating high levels of inflammation and associated behavioral changes (e.g., depression, fatigue) prior to surgery and systemic therapy for a variety of cancer types [ 81 ].…”