Table 3.

Current investigational liquid biomarkers of ICB response

Marker	Drug	Malignancy	End-point results	References
LDH	Ipilimumab Pembrolizumab Nivolumab	Melanoma	Elevated baseline LDH = lower ORR P = 0.0292 Elevated baseline LDH = decreased response rate of 22.3, 95% CI (17.1–28.1) compared to 42.0, 95% CI (36.6–47.5)	Diem et al. [153] Ribas et al. [8]
Neutrophil-lymphocyte ratio (NLR)	Nivolumab	NSCLC	Baseline NLR > 3 shorter PFS predictive marker at 2 and 4 weeks P = 0.484 2 weeks P = 0.00528 4 weeks P = 0.00515	Nakaya et al. [154]
	Ipilimumab	Melanoma	Baseline NLR > 5 worse PFS and OS PFS P = 0.0006 OS P < 0.0001	Ferrucci et al. [155]
Absolute eosinophil count	Pembrolizumab	Melanoma	High count–low response rate P < 0.001	Weide et al. [126]
	Ipilimumab	Melanoma	High count–low response rate P < 0.0001	Ferrucci et al. [127]
Monocyte count and myeloid derived suppressor cells (MDSCs)	Ipilimumab	Melanoma	Low baseline levels show a favorable response P < 0.001	Martens et al. [147]
T-cell markers and sPD-L1	Ipilimumab	Melanoma	High CD4(+)CD25(+)FoxP3(+)-Treg better survival P < 0.001	Martens et al. [147]
	Ipilimumab	Melanoma	Increased baseline T-cell receptor diversity associated with improved response, no survival difference P = 0.01	Postow et al. [156]
	Nivolumab	NSCLC	Increased SOX-2 reactive T-cells in periphery better response P = 0.04	Dhodapkar et al. [157]
	PD-1 and PD-L1 Antibodies	NSCLC	Increased PD-1, Ki-67 + CD8 T-cells 4 weeks into treatment correlated with clinical benefit. P < 0.0001	Kamphorst et al. [158]
	PD-1 and PD-L1 Antibodies	NSCLC	Baseline elevated PD-L1 as a poor prognostic marker P = 0.002	Boffa et al. [159]
	PD-1 and PD-L1 Antibodies	OSCC	Elevated PD-L1 mRNA expression in peripheral blood could contribute to increased metastatic behavior (higher grade cancer, node positive status) P < 0.05	Weber et al. [160]
	Ipilimumab Pembrolizumab	Melanoma	High pretreatment levels of sPD-L1 were associated with increased likelihood of progressive disease P = 0.0015	Zhou et al. [50]
B cell-antibody markers	Ipilimumab	Melanoma	NYESO antibody seropositive have better ORR P = 0.02	Yuan et al. [161]
	Ipilimumab	Melanoma	Soluble CTLA4 antibody associated with improved response P = 0.02	Leung et al. [162]
Soluble CD25	Ipilimumab	Melanoma	Elevated baseline CD25 associated with shorter OS P = 0.056	Hannani et al. [144]
bTMB	Atezolizumab	NSCLC	bTMB correlated with TMB, bTMB correlated with PFS, bTMB did not associate with high PD-L1 expression bTMB P = 0.035 PD-L1 P = 0.160	Gandara et al. [41]

NSCLC non-small cell lung carcinoma, LDH lactate dehydrogenase, OSCC oral squamous cell cancer, ORR objective response rate, OS overall survival, PFS progression-free survival, bTMB blood–tumor mutational burden, sPD-L1 soluble PD-L1