Peripheral blood clinical laboratory variables associated with outcomes following combination nivolumab and ipilimumab immunotherapy in melanoma

Abstract

Both the combination of nivolumab + ipilimumab and single‐agent anti‐PD‐1 immunotherapy have demonstrated survival benefit for patients with advanced melanoma. As the combination has a high rate of serious side effects, further analyses in randomized trials of combination versus anti‐PD‐1 immunotherapy are needed to understand who benefits most from the combination. Clinical laboratory values that were routinely collected in randomized studies may provide information on the relative benefit of combination immunotherapy. To prioritize which clinical laboratory factors to ultimately explore in these randomized studies, we performed a single‐center, retrospective analysis of patients with advanced melanoma who received nivolumab + ipilimumab either as part of a clinical trial (n = 122) or commercial use (n = 87). Baseline routine laboratory values were correlated with overall survival (OS) and overall response rate (ORR). Kaplan–Meier estimation and Cox regression were performed. Median OS was 44.4 months, 95% CI (32.9, Not Reached). A total of 110 patients (53%) responded (CR/PR). Significant independent variables for favorable OS included the following: high relative eosinophils, high relative basophils, low absolute monocytes, low LDH, and a low neutrophil‐to‐lymphocyte ratio. These newly identified factors, along with those previously reported to be associated with anti‐PD‐1 monotherapy outcomes, should be studied in the randomized trials of nivolumab + ipilimumab versus anti‐PD‐1 monotherapies to determine whether they help define the patients who benefit most from the combination versus anti‐PD‐1 alone.

High neutrophil‐to‐lymphocyte ratio (NLR) is associated with treatment failure and death in patients who have melanoma treated with PD‐1 inhibitor monotherapy

“…B). These findings are consistent with other studies of the NLR in the setting of checkpoint inhibition, which find that an elevated baseline NLR alone does not appear to have sufficient prognostic magnitude to merit withholding PD‐1 inhibitor therapy . Rather, an elevated NLR may identify a patient population of particular interest for clinical trials testing PD‐1 inhibition in combination with additional agents.…”

“…We show that a baseline NLR ≥5 is independently prognostic for both TTF and OS in patients with stage IV metastatic melanoma undergoing initial PD‐1 inhibition. These findings are consistent with the prognostic significance of the NLR, particularly in melanoma . Despite the large clinical magnitude of the difference in survival and its independent significance, an elevated baseline NLR does not preclude long‐term survival (30% of patients with an elevated baseline NLR survived for >3 years) (Fig.…”

“…Indeed, PFS or ORR would be preferred measures of treatment efficacy in the prospective setting, but retrospective assessment of these outcomes is fraught with challenges, especially when Response Evaluation Criteria for Solid Tumors (RECIST)‐defined or Immune‐Related RECIST (irRECIST)‐defined progression are not recorded, as in our institutional database . Other studies have found that the baseline NLR was associated with PFS and/or ORR in patients with melanoma who received treatment with a checkpoint inhibitor, but it remains to be determined whether a change in the NLR during treatment would be similarly associated.…”

“…The prognostic significance of this immune‐based marker is particularly interesting in light of the clinical success of immunotherapy in melanoma. Recent studies have demonstrated that an elevated baseline NLR is prognostic for worse overall survival (OS) and progression‐free survival (PFS) before checkpoint inhibitor therapy with CTLA‐4 and/or PD‐1 blockade . Although the prognostic value of the NLR is clear, how this translates into clinical utility remains undefined.…”

Pretreatment hematological markers predict clinical outcome in cancer patients receiving immune checkpoint inhibitors: A meta‐analysis

“…The following information was extracted from each study: first author's name, publication year, country of origin, number of patients, therapeutic regimen, cancer type, and clinical factors. HRs and 95% CIs were used to combine these data, they were obtained directly from 13 articles when described in text or tables, or calculated from available numerical data using methods reported by Tierney et al .,or by emailing the authors . Multivariate data were preferable to univariate data if both were provided; however, univariate data were acceptable if multivariate results were not presented.…”