Elevated Levels of Serum CRP and IL-6 Are Biomarkers of Poor Prognosis in Patients Receiving Immune Checkpoint Inhibitors

According to results of exploratory retrospective analyses of patients with advanced melanoma enrolled in clinical studies of immune checkpoint inhibitor therapies, low or undetectable baseline serum levels of the acute phase reactant, C-reactive protein (CRP), and a marker of chronic inflammation that enhances liver production of CRP, interleukin-6 (IL-6), were associated with improved clinical outcomes. The findings from this study were presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting.

In this study, the serum CRP and IL-6 levels at baseline and, in some cases, on treatment for treatment-naive patients with advanced melanoma receiving immune checkpoint inhibitors nivolumab, ipilimumab, or the combination of nivolumab and ipilimumab were assessed and evaluated for their association with response and survival.

With a focus on OS results, some of the key findings from an analysis of data from the CheckMate 064 study (ClinicalTrials.gov Identifier: NCT01783938), a randomized phase 2 trial of patients with advanced or metastatic melanoma treated with either nivolumab followed by ipilimumab or ipilimumab followed by nivolumab, showed that, for patients receiving nivolumab first,  high baseline serum IL-6 level, as well as high baseline serum CRP level, were significantly associated with shorter survival (hazard ratio >7, in both cases).

Trends toward a similar association of worse survival with high baseline serum IL-6 and CRP levels were observed for patients treated with ipilimumab first, although the effect was less pronounced. At week 13 on treatment for patients receiving nivolumab followed by ipilimumab, “no patients died in the low IL-6 group [during the analysis period],” stated Dr Weber, who presented these data.

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Furthermore, findings showing an association between low baseline IL-6 level and improved survival were also observed for patients across all 3 arms of the CheckMate 067 study (ClinicalTrials.gov Identifier: NCT01844505), a randomized, phase 3 study of first-line treatment with nivolumab monotherapy, ipilimumab monotherapy,  or nivolumab in combination with ipilimumab in patients with treatment-naive advanced melanoma, as well as in a similar analysis of data from the randomized, phase 3 CheckMate 066 study (ClinicalTrials.gov Identifier: NCT01721772) of nivolumab versus dacarbazine in patients with untreated advanced melanoma.

Interestingly, patients in the CheckMate 066 study with a high baseline serum IL-6 level had shorter survival in both the immunotherapy and the chemotherapy arms.

Because the “same thing was seen for the dacarbazine arm,” [baseline IL-6 level] “is not a predictive marker [of immune checkpoint inhibitor therapy],” noted Dr Weber.

The researchers offered a possible rationale for these findings based on investigations of human T cells and dendritic cells from patients with melanoma; these analyses were performed as part of the same study. Results from this analysis showed a dose-dependent suppression of T-cell and dendritic cell function, decreased generation of antigen-specific T cells , and inhibition of calcium flux in T cells — a very early event in T-cell signaling and activation — when CRP levels were higher than 10 µg/mL.

In his concluding comments, Dr Weber stated that “blockage of IL-6 and CRP synthesis and/or activity in combination with immune checkpoint inhibitor therapy may enhance response and survival rates in patients with different cancers, including melanoma.”

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Weber JS, Tang H, Hippeli L, et al. Serum IL-6 and CRP as prognostic factors in melanoma patients receiving single agent and combination checkpoint inhibition. Presented at: 2019 American Society of Clinical Oncology (ASCO) Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 100.

This article originally appeared on Cancer Therapy Advisor