Despite the proven efficacy of immune checkpoint inhibitor (ICI) therapy in treating solid tumors, there is still a need to identify reliable response biomarkers.1 The S1400I study was a randomized phase 3 trial of nivolumab plus ipilimumab versus nivolumab alone that included ICI-naïve patients with previously treated stage IV or recurrent squamous-cell lung cancer. Gonzalez-Kozlova and colleagues presented an analysis of circulating serum proteins in serial blood specimens from enrolled patients to determine if changes in serum protein levels could serve as response biomarkers to ICI therapy.2
A total of 561 serial blood specimens (baseline, weeks 3, 7, 9, and progression) from 160 of 252 eligible patients enrolled in the study were analyzed for 92 immuno-oncology analytes with the Olink proximity extension assay. Protein levels were normalized using internal controls and quantified as log2 protein expression (denoted as NPX). Linear mixed models evaluated change in expression from baseline at each time point (weeks 3, 7, and 9 and progression) and NPX differences at baseline, week 3, and progression based on the best objective response. A Cox model was used to evaluate the association between baseline NPX and survival.2
The level of serum proteins, PCDC1, CXCL9, and CXCL10, were increased from baseline at weeks 3, 7, and 9 and at the time of progression. In addition, the CCL19 protein level was increased at weeks 3 and 7 but not at week 9 or at progression. IL-10 and IFNγ were increased at week 3 but subsequently returned to baseline. Interestingly, patients treated with nivolumab plus ipilimumab had larger changes in CXCL13 protein level from baseline to progression compared with those treated with nivolumab alone. In addition, baseline levels of CCL23, CSF-1, IL-6, and MUC-16 were correlated with shorter survival (hazard ratio [HR] >1). Joint modeling of survival with cytokines showed an increased risk of death (HR >1) with higher longitudinal serum levels of CXCL13, MMP12, CSF-1, and IL-8. Patients achieving an objective response had higher IL-4 and LAMP3 and lower IL-6 and IL-8 at baseline and week 3 than nonresponders.
In conclusion, analyzing blood circulating soluble proteins represents an easily accessible noninvasive approach to predict treatment outcomes, which warrants further investigation in prospective trials.
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