Targeting PD-1/PD-L1 in lung cancer: current perspectives

Figures & data

Figure 1 Major immunological processes involved in cancer.

Notes: (A) Tumor cells produce immunosuppressive factors such as IL-10 and TGF-β that inhibit T-cell activity. Tumor cells secrete PDGF and IL-8 that activate fibroblasts (cancer-associated fibroblasts [CAFs]) that cause suppression of T-cell activity. Tumors have a peritumoral and intratumoral immune cell infiltrate consisting of macrophages, T-cells, B-cells, natural killer (NK) cells, neutrophils, dendritic cells, and eosinophils. These immunologic cells are enrolled due to the cytokine secretion by local inflammatory, stromal, and cancer cells. (B) Immunologic responses are induced by tumor-activated specific T lymphocytes CD8+ when the antigens are presented by antigen presenter cells into peptides complexed with MHC class I (MHC-I), and the positive regulator CD28 on T-cells binds to CD80 (B-7 or B7-1) and CD86 (B7-2) on dendritic cells. Expression of CTLA-4 is induced by TCR signaling allowing interaction with CD86 and CD80 to counteract CD28. The programmed cell death-1 (PD-1) receptor is another inhibitory T-cell receptor that is engaged by its ligands PD-L1 (also known as B7-H1 or CD274) and PD-L2 (also known as B7-DC or CD273). PD-1 is present in T activated cells, tumor-infiltrating T-cells, B-cells, monocytes, and NK T-cells. PD-L1 can be expressed in the tumor constitutively or as an acquired resistance mechanism. PD-1 activation inhibits CD8+ cytotoxic T lymphocyte proliferation, survival, and effector function. It can also induce apoptosis of tumor-infiltrating T-cells and promote differentiation of CD4+ T-cells into forkhead box P3-expressing (FOXP3+) regulatory T-cells. The PD-1 receptor is an inhibitory receptor engaged by its ligands PD-L1 (also known as B7-H1 or CD274) and PD-L2 (also known as B7-DC or CD273).

Table 1 Results of clinical trials with anti-PD-1 and anti-PD-L1 antibodies

Target	Drug	Authors	Phase	Line	Subtype	n	ORR (%)	PFS	OS
PD-1	Nivolumab	Brahmer et al^Citation48 Gettinger et al^Citation112	I	2nd	NSCLC	129	18–25	–	OS 2 y 24% OS 3 y 18% OS 8.2 m
		Rizvi et al^Citation50 Ramalingam et al^Citation113	II	2nd	Squamous	117	15	1.9 m PFS 1 y 20%	8.2 m OS 1 y 41%
		Rizvi et al^Citation114	I	1st	NSCLC	52	21	4 m PFS 2 y 38%	24 m
	Nivolumab + chemotherapy	Antonia et al^Citation51	I	1st	NSCLC	56	33–47	–	16 m OS 18 m 33%–86%
	Nivolumab + erlotinib	Rizvi et al^Citation104 Gettinger et al^Citation49	I	EGFRi resist	EGFR+	20	15	29 m	OS 18 m 64%
	Nivolumab + ipilimumab	Antonia et al^Citation95	I	1st	NSCLC	49	13–20 (33% squamous)	–	OS 1 y 44%–65%
	Pembrolizumab	Garon et al^Citation52	I	2nd 1st	NSCLC	194 42	21	10 m 27 m	8 m NR
		Rizvi et al^Citation115	I	1st	NSCLC PD-L1+	45	26	–	–
PD-L1	BMS-936559	Brahmer et al^Citation54	I	2nd	NSCLC	75	10	–	–
	MEDI4736	Khleif et al^Citation55	II	2nd	NSCLC	85	23	–	–
		Brahmer et al^Citation116	I	2nd	NSCLC	155		–	–
		Segal et al^Citation57	I	2nd	NSCLC	47	13	–	–
	MPDL3280A	Soria et al^Citation59	I	2nd	NSCLC	85	23	PFS 6 m 42%
CTLA-4	Ipilimumab	Lynch et al^Citation71	II	2nd	NSCLC	204	15	5 m	13 m
		Reck et al^Citation74	–	–	SCLC	104	–	–	–
	Tremelimumab	Zatloukal et al^Citation117	II	2nd	NSCLC	87	5	–	–

Abbreviations: 1st, first line; 2nd, second line; EGFRi resist, resistant to EGFR inhibitors; NR, not reported; NSCLC, non-small-cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; SCLC, small-cell lung cancer.

Table 2 Ongoing clinical trials with anti-PD-1 and anti-PD-L1 drugs

Drug	Phase	Setting	Combination	Status	NCT number
Nivolumab (BMS-936558)	III	Squamous 2nd	–	Completed	0164200
	III	Non-squamous 2nd	–	Completed	01673867
	III	PD-L1+ 1st	–	Ongoing	02041533
	I	NSCLC	Ipilimumab, Avastin, erlotinib, chemotherapy	Ongoing	01454102
	I	SCLC, breast	Ipilimumab	Ongoing	01928394
	I	NSCLC, breast, pancreas	Abraxane/CBDCA	Planned	02309177
	I	Solid	Lirilumab (anti-KIR)	Ongoing	01714739
	I	Solid	BMS986016 (anti-LAG-3)	Ongoing	01968109
Pembrolizumab (MK3475)	II/III	PD-L1+ 2nd	Chemotherapy	Ongoing	01905657
	III	PD-L1+ 1st	–	Ongoing	02220894
	III	PD-L1+ 1st	–	Ongoing	02142738
	II	CNS metastases 1st	–	Ongoing	02085070
	I	PD-L1+ 2nd	–	Completed	02007070
	I	1st	Ipilimumab, chemotherapy + Avastin, erlotinib, gefitinib	Ongoing	02039674
MEDI0680 (AMP-514)	I	Solid	–	Ongoing	02013804
	I	Solid	MEDI4736	Ongoing	02118337
AMP-224	I (NCI)	Solid CRC	Radiotherapy	Ongoing	01352884
MEDI4736	III	Adjuvant	–	Ongoing	01693562
	III	3rd PD-L1+/PD-L1−	Tremelimumab (PD-L1+) vs single (PD-L1−) vs chemotherapy (unselected)	Ongoing	02453282
	II	3rd	–	Ongoing	02087423
	Ib–II	1st	Sequential: tremelimumab, gefitinib, AZD9291, selumetinib	Ongoing	02179671
	Ib	EGFR+ 2nd	AZD9291	Ongoing	02143466
	I	EGFR+ 2nd	Gefitinib	Ongoing	02088112
	I	Solid	–	Ongoing	01693562
	Ib	Solid	Tremelimumab	Ongoing	02000947
	Ib	NSCLC	Tremelimumab	Ongoing	02261220
MPDL3280A (RG7446)	II	PD-L1+ 1st	–	Completed	01846416
	II	2nd	–	Completed	01903993
	III	2nd	–	Ongoing	02008227
	I	EGFR+	Tarceva	Ongoing	02013219
	II	PD-L1+ 2nd	–	Ongoing	02031458
	I	NSCLC, melanoma, CRC	Cobimetinib	Ongoing	01988896
	Ib	NSCLC, TN, CRC	Avastin	Planned	01633970
MSB0010718C (EMD Serono)	I	Solid	–	Ongoing	01772004

Abbreviations: 1st, first line; 2nd, second line; 3rd, third line; SCLC, small-cell lung cancer; CNS, central nervous system; CRC, colorectal cancer; NCI, ; NSCLC, non-small-cell lung cancer; TN, triple negative breast cancer.

Table 3 Correlation of PD-L1 expression by IHC analysis and anti-tumoral activity

Authors, year	Drug	IHC Aba	Cellb	Cut-offc	n	PD-L1+ pt (%)	ORR (%) PD-L1+d	ORR (%) PD-L1−e	ORR (%) unselected	PFS (m)	OS (m)	Tumor type
Daud et al,^Citation118 2014 Kefford et al,^Citation119 2014	Pembrolizumab	22C3	Tumor	1%	125	71	49	13	40	10 vs 3	–	Melanoma
Garon et al,^Citation53 2014	Pembrolizumab	22C3	Tumor	1%	236	80	23	9	21	–	–	Lung
Gandhi et al,^Citation60 2014				50%	129		37	10	22	HR 0.52 (0.33–0.8)	9 vs 7
Seiwert et al,^Citation120 2014	Pembrolizumab	22C3	Tumor	1%	55	78	46	11	20	–	–	Head/neck
Weber et al,^Citation121 2013	Nivolumab	DAKO 28-8	Tumor	5% (1%)	44	27	66	19	32	–	–	Melanoma
Motzer et al,^Citation122 2015	Nivolumab	DAKO 28-8	Tumor	5% (1%)	107	27	31	18	20	5 vs 3	–	Renal
Topalian et al,^Citation2 2012	Nivolumab	SH1 clone	Tumor	5%	42	59	36	0	21	–	–	Solid
Gettinger et al,^Citation112 2014	Nivolumab	SH1 clone	Tumor	5%	68	48	15	14	17	3 vs 1.8	7.8 vs 1	Lung 2nd line
Antonia et al,^Citation51 2014	Nivolumab	SH1 clone	Tumor	5%	44	38	53	41	47–53	–	88 vs 83	Lung 1st line
Ramalingam et al,^Citation113 2014 Rizvi et al,^Citation50 2015	Nivolumab	SH1 clone	Tumor	5%	76	33	24	14	15	–	–	Lung 2nd line
Rizvi et al,^Citation114 2014	Nivolumab	SH1 clone	Tumor	5%	47	55	31	10	25	15 vs 10	NR vs 9.8	Lung 1st line
Grosso et al,^Citation123 2013	Nivolumab	SH1 clone	Tumor	5%	27	37	44	17	20	–	–	Melanoma
Hodi et al,^Citation124 2014	Nivolumab	DAKO 28-8	Tumor	5% (1%)	41	44	44	13	32	9 vs 2	NR vs 13	Melanoma
Robert et al,^Citation125 2015	Nivolumab	DAKO 28-8	Tumor	5%	418	35	53	33	40	–	ns	Melanoma
Powles et al,^Citation126 2014	MPDL3280A	Roche	TIL tumor	5% 5%	205	27 11	43	4	26	–	–	Bladder
Herbst et al,^Citation62 2014	MPDL3280A	Roche	TIL tumor	5% 5%	184	26 24	83 40	15 24	36	–	–	Lung
Hamid et al,^Citation127 2013	MPDL3280A	Roche	TIL	5%	30	–	27	20	26	–	–	Melanoma
Brahmer et al,^Citation64 2014	MEDI4736	VentSP263	–	–	49	41	25	3	16	–	–	Lung
Segal et al,^Citation57 2014	MEDI4736	VentSP263	–	–	47	–	39	5	13	–	–	Lung
Segal et al,^Citation57 2014	MEDI4736	VentSP263	–	–	179	–	22	4	11	–	–	Solid

Notes:

a Ab used for immunohistochemical analysis;

b cells considered for immunohistochemical analysis;

c cut-off level considered as positive/negative for PD-L1 expression;

d objective response rate in PD-L1-positive patients;

e objective response rate in PD-L1-negative patients.

Abbreviations: Ab, antibody; HR, hazard ratio; IHC, immunohistochemistry; NR, not reported; ns, not significant; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; pt, patient; TIL, tumor infiltrating lymphocytes.

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