Table 1.

Main clinical trials exploring ICIs’ role in BC.

BC Subtype		Trial	Phase	Treatment Arms	Primary Efficacy Endpoints	Biomarker Analysis	N. Patients (Trial Status)	References
TNBC	Early TNBC	Keynote-173	I/II	Pembro + T +/− Cb > AC− > S− > pembro adj x 1yr	pCR	PT: sTILs and PD-L1 associated with pCR and ORR; and OT: sTILs associated with pCR and ORR	60 (completed)	[205]
		I-SPY 2	II	Pembro/placebo + T > AC	pCR	MHC II expression predictive of response to ICI	64 (completed)	[82]
		NeoPACT	II	Pembro + CbD	pCR	High sTILs are associated with higher pCR	117 (active, not recruiting)	[204]
		Keynote-522	III	Pembro/Placebo + CbT > AC > CH > pembro adj x 1yr	pCR + EFS	PD-L1 CPS not predictive of response to ICI	602 (completed	[12]
		NeoTRIPaPDL1	III	Atezo/placebo + NabP + Cb > S > anthracycline-based CT	EFS	pCR rate + 10% to atezo in immune-rich TME (PDL1 IC+, high/intermediate sTILs/iTILs) High expression of GATA3 and CD20, epithelial of HLA-DR and Ki67 in both epithelial and TME favors atezo arm; and PD-L1 + IDO+ APC and CD56 NE cells were associated with a higher response rate to atezo.	278 (active, not recruiting)	[83,206]
		Impassion031	III	Atezo/placebo + NabT > AC	pCR	PT: PD-L1 IC+ and TC+, sTILs, iTILs, and TLS linked to improved pCR in placebo arm; and OT: numerical increase in iTILs and PD-L1 in immune cells in patients with pCR in ICI arm; further, ICI can promote close contact of TILs to tumor nests	455 (active, not recruiting)	[207]
		NCT02489448	I/II	Durva + nab-paclitaxel > AC	pCR	IHC: sTILs associated with higher pCR, sTILs, and PD-L1 do not predict benefit in multivariate analysis; MHC II expression predicts response to ICI; and mIF: PD-L1 TC+, IC+ in the stroma and PD-L1+ CD68+ TAM compartment each associated with higher rates of pCR	69 (completed)	[82,231]
		GeparNuevo	II	Durva/placebo + nab-paclitaxel	pCR	PT: High sTILs associated with higher pCR in both arms; OT: iTILs increase = higher pCR in ICI arm; and RD: high TILs associated low rates of relapse in both arms	174 (completed)	[203,232,233,234]
	Metastatic TNBC	Keynote-119	III	Pembro/CT	OS	sTILs associated with ICI benefit, in particular in previously untreated mTNBC; and PD-L1 TC+ adds predictive power to pembro arm	622 (completed)	[26,209,210]
		Keynote-086	II	Pembro	DCR, ORR, DoR, PFS, OS	sTILs, PD-L1 CPS+, and CD8 IHC evaluation correlate with the response rate to pembro	254 (completed)	[211]
		Keynote-355	III	Pembro/placebo + NabP/T/Gem + Cb	PFS, OS	PD-L1 CPS ≥ 10 correlates with improved PFS and OS	847 (active, not recruiting)	[11]
		ENHANCE-I	Ib/II	Pembro + eribulin	ORR	PD-L1 numerically higher ORR	167 (completed)	[235]
		Impassion130	III	Atezo/placebo + NabT	PFS, OS	PD-L1 IC+ predictive of ICI benefit; and PD-L1 IC+ and either PD-L1 TC+ or 10% or more sTILs had the highest clinical activity with A + nP	902 (completed)	[10,212]
		Impassion131	III	Atezo/placebo + T	PFS	PD-L1 IC+ does not predict benefit	651 (active, not recruiting)	[28,236]
		TONIC	II	Nivo/nivo after induction with CT or RT	PFS	PD-L1 IC+, sTILs, and CD8+ higher in responders	67 (active, not recruiting)	[109]
HER2	Early HER2+ BC	Impassion-050	III	Atezo/placebo + THP + AC > S > atezo/placebo + HP	pCR	PD-L1 IC+ does not predict pCR	454 (active, not recruiting)	[237]
	LABC/Metastatic HER2+ BC	NCT02605915	Ib	In LABC: Atezo + HP or atezo/T-DM1 > THP + Cb In mBC: Atezo with trastuzumab/pertuzumab, atezo with T-DM1, or atezo with THP	ORR + DoR	PT: No correlation between response and PD-L1 IC+, TC+, sTILs, and CD8+ T-cell density in central tumor area and immune phenotypes (ID, IE, or IN); OT: increase in PD-L1 IC+ in both cohorts, no association with response; and LABC: significant increase in CD8+ T cells density in the central tumoral area, but not correlated with pCR, no increase in mBC	76 (completed)	[238]
	Metastatic HER2+ BC	PANACEA	I/II	Pembro + trastuzumab	ORR	sTILs correlate with ORR and disease control, as well as higher clinical benefit in PD-L1 + CPS	58 (completed)	[239]
		KATE-2	II	Atezo/placebo + T-DM1	PFS	High CD8 T cells at invasive margins favor atezo arm in subgroup analysis	1486 (completed)	[220]
HR+	Early HR+ BC	GIADA	II	Nivo + exemestane + triptorelin + EC	pCR	PT: in pCR patients higher in sTILs, iTILs (iCD4, I CD8, and iCD4+ FOXP3+), and TAMs (intratumoral); TAMs: stromal CD68+ CD163+ TAMs) immune-checkpoints co-expression: PD-1+ on T cells, and PD-L1 on TAMs (CD68+ PD-L1+ and CD68+ CD163+ PD-L1) higher in pCR; OT after CT: sTILs increase, increase in CD8+ T cells, decrease in FOXP3+ CD4+ T cells, and CD68+ CD163+ TAMs; and OT after Nivo: increase in intratumoral and stromal CD8+, CD8+ Granzyme+ T cells and stromal CD4+ Granzyme B+ T cells.	43 (completed)	[23]
		ISPY-2	II	Pembro/placebo + T > AC	pCR	MHC II expression predicts response to ICI	89 (completed)	[82]
	Metastatic HR+ BC	Keynote-028	Ib	Pembro	ORR	sTILs do not predict PFS	83 (completed)	[240]
		KELLY	II	Pembro + eribulin	CBR	PD-L1 does not predict benefit	44 (completed)	[241]
		NCT03051659	II	Pembro + eribulin	PFS	sTILs and PD-L1 do not predict benefit	88 (active, not recruiting)	[242]
		NCT03044730	II	Pembro + capecitabine	PFS	sTILs and PD-L1 do not predict benefit	14 (completed)	[243]
		NIMBUS	II	Pembro + nivo in TMB-H	ORR	sTILs and PD-L1 do not predict benefit	20 (active, not recruiting)	[28]

PT = pre-treatment; OT = on-treatment; mBC: metastatic BC; LABC: locally advanced BC; S = surgery, CT = chemotherapy; ICI = immune checkpoint inhibitors; Atezo = atezolizumab; Durva = durva; Pembro = pembrolizumab; D = docetaxel; E = epirubicin; C = cyclophosphamide; T = taxane; Gem = gemcitabine; H = trastuzumab; P = pertuzumab; Cb = carboplatin; ORR = objective response rate; PFS = progression-free survival; OS = overall survival; pCR = pathological complete response; EFS = event-free survival; DoR = duration of response; DCR = disease control rate; CBR = clinical benefit rate; IC = immune cells; TC = tumoral cells; CPS = combined positive score; ID = immune desert; IE = immune excluded; and IN = immune inflamed.