Immunotherapy combinations and chemotherapy sparing schemes in first line non-small cell lung cancer

Table 1 Main programed death ligand-1 and cytotoxic T lymphocyte–associated antigen 4 pathways

Checkpoint pathways	Anti-PD-L1 pathway	Anti-CTLA-4 pathway
Receptor expression	Activated T-cells	Activated T-cells, B-cells and NK cells
Ligands	B 7.1 (CD80); B7.2 (CD86)	PD-L1 (B7-H1), PD-L2 (B7-DC)
Mechanism of immune modulation	T-cell activation at initial stage; Competition with co-stimulatory receptor CD-28 for ligand binding; Down regulation of helper T cells CD4 activity; Enhancement Tregs-cells immunosuppressive activity	Suppresses activated T cells in tissues and tumor environment; Express in Tregs-cells may enhance immunosuppressive activity; Limits of B-cells and NK- cells activity; PD-L1 interact with CD-80 to down-modulate T-cells activity

NK: Natural killer; PD-L1: Programed death ligand-1; CTLA-4: Cytotoxic T lymphocyte–associated antigen 4.

Table 2 Summary of the main Phase III studies of IT combinations

Trial	Ph1	Drugs	Endpoints/outcome	PD-L1/TMB
				Population
				Subgroups
Checkmate 227	III	NI vs N vs CT1	OS PD-L1 > 1% and in non-selected population	PD-L1 ≥ 1%: NI 17 m vs CT 14.9 m, P = 0.007
			NI vs CT	PD-L1 < 1%: NI 17 m vs CT 12.2 m, P =0.007
			17 m vs 13.9 m
MYSTIC	III	DT vs D vs CT1	OS D vs CT OS and PFS DT vs CT PD-L1 > 25% population	PD-L1 > 25%: D vs CT1
				16 m vs 12 m, P = 0.04
				DT vs CT1 11.9 vs 12 m, P = 0.2
				TMB > 20
				DT vs CT1 21 m vs 10 m
Checkmate9LA	III	NI + CT1 X2 vs CT1 X4	OS in non selected population	NA
			OS NI-CT 15.6 m vs CT 10.9 m, P = 0.0006
CCTG BR.34	III	DT+ CT1 x 4 vs Durvalumab + tremelimumab (DT)	OS in non selected population	PD-L1 TPS ≥ 50%, DT-CT vs DT (HR 0.64, 95%CI: 0.40-1.04, P = 0.07). Plasma TMB < 20 mut/Mb was associated with shorter survival in both treatment groups (HR 1.99, 95%CI: 1.3-3.1)
			16.6 m DT-CT vs 14 m DT
CITYSCAPE	II	TA vs PA	ORR and PFS en PD-L1 > 1% PFS TA 7.7 m vs PA 3.2 m	PD-L1 > 50%
			ORR TA 37% vs PA 20%	PFS TA NA vs PA 4.1
				ORR TA 66 % vs PA 24%

¹Ph; Phase.

NI: Nivolumab + Ipilimumab; N: Nivo; DT: Tremelimumab + Durvalumab; D: Durvalumab; PD-1: Programed death-1; TMB: Tumor mutational burden; HR: Hazard ratio; CI: Confidence interval; TA: Tiragolumab + atezolizumab; PA: Placebo + atezolizumab; NA: Not available; CT: Chemotherapy.

Table 3 Summary of the main toxicities in each of the studies on immunotherapy combinations or immunotherapy ± chemotherapy

Phase II-III studies	G3-4 toxicity (%)		Treatment discontinuation (%)
	Exp arm	Control arm	Exp arm	Control arm
CM 227	32.8 NI	33.8 CT	9.4 NI	3.4 CT
MYSTIC	22.9 DT	36 CT	12.3 DT	4.9 CT
CM9LA	47 NI-CT	38 CT	16 NI-CT	9 CT
CCTG-BG-34	82 DT-CT	70 DT	NA	NA
CITYSCAPE	19 ATir	14 PA	10.3 ATir	7.5 PlA
KEYNOTE-189	67 P-CT	65.8 CT	13.8 P-CT	7.9 CT

NI: Nivolumab + ipilimumab; DT: Durvalumab+ tremelimumab; CT: Chemotherapy; Tir: Tirogolumab; A: Atezolizumab; PL: Placebo; P-CT: Pembrolizumab + chemotherapy; NA: Not available.