Pretreatment Blood Parameters Predict Efficacy from Immunotherapy Agents in Early Phase Clinical Trials

Abstract

Background Peripheral blood parameters are correlated to immune‐checkpoint inhibitor efficacy in solid tumors, such as melanoma and non‐small cell lung cancer. Few data are currently available on the prognostic role of these immune‐inflammatory biomarkers for other solid tumors and immunotherapy combinations. Material and Methods From August 2014 to May 2019, 153 patients with metastatic solid tumors were enrolled in phase I clinical trials testing immunotherapy both as single agents and as combinations. Primary endpoint was to evaluate the impact of baseline blood parameters on progression‐free survival (PFS) and overall survival (OS). Results The most common tumor types were gastrointestinal, breast, and gynecological cancers (22.9%, 22.2%, and 15.0%, respectively). Higher lactate dehydrogenase (LDH) and derived neutrophil‐to‐lymphocyte ratio (dNLR) were independently associated with reduced PFS (hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.30–2.99; p = .001, and HR, 2.29; 95% CI, 1.39–3.77; p = .001, respectively) and reduced OS (HR, 2.04; 95% CI, 1.26–3.28; p = .004, and HR, 2.06; 95% CI, 1.12–3.79; p = .02, respectively). In the subgroup analysis, (single agent vs. combination), patients at “good” (dNLR <3 and LDH < upper limit of normal [ULN]) and “intermediate and poor” (dNLR >3 and/or LDH > ULN) risk had higher and lower PFS, respectively (p for interaction = .002). Conversely, patients receiving monotherapy presented statistically significant difference in OS according to the risk group, whereas this effect was not observed for those treated with combinations (p for interaction = .004). Conclusion Elevated LDH and dNLR are associated with poorer survival outcomes in patients treated with immunotherapy in phase I clinical trials, regardless of tumor type. These parameters represent an easy tool that might be considered as stratification factors in immunotherapy‐based clinical trials. Implications for Practice In this retrospective cohort study of 153 patients with metastatic solid tumors treated with immunotherapy in the context of phase I clinical trials, elevated baseline lactate dehydrogenase and derived neutrophil‐to‐lymphocyte ratio were associated with reduced survival regardless of tumor subtype. If prospectively validated, these parameters might represent low‐cost and easy biomarkers that could help patient selection for early phase immunotherapy trials and be applied as a stratification factor in randomized studies testing immunotherapy agents.

Prognostic Performance of the Derived Neutrophil-to-Lymphocyte Ratio in Stage IV Melanoma Patients Treated with Immune Checkpoint Inhibitors

“…We could confirm the data of many previous studies on CM and other solid cancers that NLR is a potent independent predictor for response to ICI in metastatic CM patients. In line with the present work focusing on the impact of dNLR in stage IV melanoma, Chriscitiello et al [23] recently demonstrated that dNLR may be more accurate in predicting poor outcome than NLR for patients with solid cancers treated with ICI in the context of phase I trials. Moreover, Ferrucci et al [25] reported for the first time similar prospective data for 720 patients under ipilimumab treatment.…”

“…The derived NLR (dNLR), composed of white cell counts (WBC) and absolute neutrophil counts (ANC), has been proposed as a simple alternative to NLR for those studies in which only WBC and ANC have been recorded. Indeed, the absolute lymphocyte count has not been determined in some studies [18][19][20][21][22][23][24][25]. In the present study, we aimed to evaluate the prognostic performance of the dNLR in patients with metastatic CM treated with immune checkpoint inhibitors (ICI).…”

The Gustave Roussy Immune (GRIm)-Score Variation Is an Early-on-Treatment Biomarker of Outcome in Advanced Non-Small Cell Lung Cancer (NSCLC) Patients Treated with First-Line Pembrolizumab

“…Elevated LDH and NLR results are associated with poorer survival outcomes in patients treated with immunotherapy in phase I clinical trials, regardless of tumor type [ 32 ].…”

Harnessing Liquid Biopsies to Guide Immune Checkpoint Inhibitor Therapy

“…Several studies have demonstrated high neutrophil to lymphocyte ratio (NLR) as a predictor for poor response to IO. Criscitiello et al [ 115 ] demonstrated that a higher derived neutrophil to lymphocyte ratio was associated with reduced PFS (HR 2.29, p = 0.001) and reduced OS (HR 2.06, p = 0.02). A meta-analysis of 14 retrospective studies with 1225 non-small cell lung cancer patients [ 116 ] further provides evidence for a higher baseline NLR being associated with poor PFS (HR 1.44, p < 0.05) and OS (HR 1.75, p < 0.05), following treatment with nivolumab.…”