From targeting the tumor to targeting the immune system: Transversal challenges in oncology with the inhibition of the PD-1/PD-L1 axis

Table 1 Immune-checkpoint inhibitors antibodies with their targets

CKI	Mechanism of action
Nivolumab	Anti-PD-1
Pembrolizumab	Anti-PD-1
Atezolizumab	Anti-PD-L1
Durvalumab	Anti-PD-L1
Avelumab	Anti-PD-L1
BMS936559	Anti-PD-L1
Pidilizumab	Anti-PD-1

CKI: Checkpoint inhibitors.

Table 2 Phase III randomized clinical trials currently ongoing with PD-1/PD-L1 axis blockade in adjuvant setting for solid tumors

Trial name/NCT	Cancer type	Immune checkpoint inhibitor	Arms	Primary endpoint	Expected primary completion date	No. of patients
KEYNOTE-054[20]	Melanoma	Pembrolizumab	Pembrolizumab vs placebo	RFS	2018	900
NCT02506153[21]	Melanoma	Pembrolizumab	Pembrolizumab vs high dose recombinant interferon-α-2B or ipilimumab	OS	2020	1378
KEYNOTE-091 (PEARLS)[22]	NSCLC	Pembrolizumab	Pembrolizumab vs placebo	DFS	2021	1380
IMvigor010[23]	Bladder cancer	Atezolizumab	Atezolizumab vs observation	DFS	2021	440
IMpower010[24]	NSCLC	Atezolizumab	Atezolizumab vs BSC after adjuvant CT1	DFS	2020	1127
NCT02768558[25]	NSCLC (locally advanced)	Nivolumab	Nivolumab vs placebo (after CT1-RT)	OS	2022	660
ANVIL[26]	NSCLC	Nivolumab	Nivolumab vs observation	DFS	2018	714
CheckMate 238[27]	Melanoma	Nivolumab	Nivolumab + placebo vs ipilimumab + placebo	RFS	2018	800
CheckMate 274[28]	Urothelial cancers	Nivolumab	Nivolumab vs placebo	DFS	2020	640
CheckMate 577[29]	Esophageal or gastroesophageal junction cancer (locally advanced)	Nivolumab	Nivolumab vs placebo (after CT1-RT and surgery)	DFS	2019	760
PACIFIC[30]	NSCLC (locally advanced)	Durvalumab	Durvalumab vs placebo (after CT1-RT)	OS	2017	702
NCT02273375[31]	NSCLC	Durvalumab	Durvalumab vs placebo	DFS	2025	1100

¹According to the standard of care and basing on the choice of the investigator. RFS: Recurrence free survival; NSCLC: Non-small cell lung cancer; DFS: Disease free survival; CT: Chemotherapy; OS: Overall survival; RT: Radiotherapy.

Table 3 Phase III randomized clinical trials currently ongoing with PD-1/PD-L1 axis blockade in advanced setting for solid tumors

Trial name/NCT	Cancer type	Immune checkpoint inhibitor	Arms	Treatment line	Primary endpoint	Expected primary completion date	No. of patients
STOP-GAP[15]	Melanoma	PD-1 inhibitor (any)	Intermittent vs continuous therapy	Any	OS	2025	550
NCT02752074[16]	Melanoma	Pembrolizumab	Pembrolizumab + epacadostat vs pembrolizumab + placebo	I line	PFS	2018	600
MASTERKEY-265[17]	Melanoma	Pembrolizumab	Pembrolizumab + talimogene laherparepvec vs pembrolizumab + placebo	I line	PFS	2018	660
KEYNOTE-048[82]	HNSCC	Pembrolizumab	Pembrolizumab vs CT1 + pembrolizumab vs CT1	I line	PFS	2018	780
KEYNOTE-040[38]	HNSCC	Pembrolizumab	Pembrolizumab vs methotrexate or docetaxel or cetuximab	From II line	OS	2017	466
KEYNOTE-204[39]	Hodgkin lymphoma	Pembrolizumab	Pembrolizumab vs brentuximab	From II line	PFS	2019	300
KEYNOTE-045[40]	Urothelial cancers	Pembrolizumab	Pembrolizumab vs paclitaxel, docetaxel or vinflunine	From II line	OS	20172	470
NCT02811861[41]	Renal cell carcinoma	Pembrolizumab	Pembrolizumab + lenvatinib vs lenvatinib + everolimus vs sunitinib	I line	PFS	2020	735
KEYNOTE-426[102]	Renal cell carcinoma	Pembrolizumab	Pembrolizumab + axitinib vs sunitinib	I line	PFS, OS	2019	840
KEYNOTE-240[42]	HCC	Pembrolizumab	Pembrolizumab vs BSC	II line	PFS	2019	408
KEYNOTE-189[43]	NSqNSCLC	Pembrolizumab	Platinum and pemetrexed ± pembrolizumab	I line	PFS	2017	570
KEYNOTE-407[44]	SqNSCLC	Pembrolizumab	CT1± pembrolizumab	I line	PFS	2018	560
KEYNOTE-042[45]	NSCLC PD-L1-positive	Pembrolizumab	Pembrolizumab vs platinum based CT1	I line	OS	2018	1240
KEYNOTE-010[46]	NSCLC	Pembrolizumab	Pembrolizumab vs docetaxel	From II line	OS	2019	1034
KEYNOTE-119[47]	Triple negative breast cancer	Pembrolizumab	Pembrolizumab vs monochemotherapy	II-III line	PFS	2017	600
KEYNOTE-355[48]	Triple negative breast cancer	Pembrolizumab	CT1 + pembrolizumab vs CT1 + placebo	I line	PFS	2019	858
KEYNOTE-177[49]	MSI-H or dMMR colorectal carcinoma	Pembrolizumab	Pembrolizumab vs CT1	I line	PFS	2019	270
KEYNOTE-181[50]	Esophageal/esophago-gastric junction carcinoma	Pembrolizumab	Pembrolizumab vs monochemotherapy1	II line	PFS	2018	600
KEYNOTE-061[51]	Esophageal/esophago-gastric junction adenocarcinoma	Pembrolizumab	Pembrolizumab vs paclitaxel	II line	PFS	2017	720
KEYNOTE-062[52]	Esophageal/esophago-gastric junction carcinoma	Pembrolizumab	Pembrolizumab vs CT1 + pembrolizumab vs CT1	I line	PFS	2019	750
JAVELIN Ovarian 200[53]	Ovarian cancer (platinum resistant)	Avelumab	Avelumab vs avelumab plus PLD vs PLD	From II line	OS	2018	550
JAVELIN Ovarian 100[54]	Ovarian cancer	Avelumab	CT1vs CT1 followed by avelumab maintenance vs CT1 + avelumab followed by avelumab maintenance	I line	PFS	2019	951
JAVELIN Renal 101[55]	Renal cell cancer	Avelumab	Avelumab with axitinib vs sunitinib	I line	PFS	2018	583
JAVELIN Bladder 100[56]	Urothelial cancer	Avelumab	Avelumab vs BSC (maintenance after CT1)	I line maintenance	OS	2019	668
JAVELIN Gastric 100[57]	Adenocarcinoma of the stomach or of the gastro-esophageal junction	Avelumab	CT1 continuation vs avelumab in maintenance after CT1	I line	OS	2018	666
JAVELIN Gastric 300[58]	Adenocarcinoma of the stomach or of the gastro-esophageal junction	Avelumab	Avelumab + BSC vs CT1 + BSC vs BSC	III line	OS	2017	330
JAVELIN Lung 100[59]	NSCLC (PD-L1 positive)	Avelumab	Avelumab vs platinum based CT1	I line	PFS	2017	420
JAVELIN Lung 200[60]	NSCLC (PD-L1 positive)	Avelumab	Avelumab vs docetaxel	From II line	OS	2017	650
OAK[61]	NSqNSCLC	Atezolizumab	Atezolizumab vs docetaxel	From II line	OS	2017	1225
IMvigor211[62]	Bladder cancer	Atezolizumab	Atezolizumab vs monochemotherapy	II line	OS	2017	932
IMvigor130[63]	Urothelial carcinoma (ineligible for cisplatin)	Atezolizumab	Atezolizumab + CT1vs placebo + CT1	I line	PFS	2019	435
IMpower110[64]	NSqNSCLC	Atezolizumab	Atezolizumab vs platin + pemetrexed	I line	PFS	2019	570
IMpower111[65]	SqNSCLC	Atezolizumab	Atezolizumab vs gemcitabine + platin	I line	PFS	2017	ND
IMpower131[66]	SqNSCLC	Atezolizumab	Atezolizumab + nab-paclitaxel + carboplatin vs atezolizumab + paclitaxel + carboplatin vs nab-paclitaxel + carboplatin	I line	PFS	2023	1200
IMpower210[67]	NSCLC	Atezolizumab	Atezolizumab vs docetaxel	II line	OS	2019	563
IMpower130[68]	NSqNSCLC	Atezolizumab	Atezolizumab + nab-paclitaxel + carboplatin vs nab-paclitaxel + carboplatin	I line	PFS	2019	550
IMpower150[69]	NSqNSCLC	Atezolizumab	Atezolizumab + carboplatin + paclitaxel ± bevacizumab vs carboplatin + paclitaxel + bevacizumab	I line	PFS	2017	1200
IMpassion130[70]	Triple negative breast cancer	Atezolizumab	Atezolizumab + nab-paclitaxel vs placebo + nab paclitaxel	I line	PFS	2020	900
IMmotion151[71]	Renal cell carcinoma	Atezolizumab	Atezolizumab + bevacizumab vs sunitinib	I line	PFS	2020	900
IMpower133[72]	SCLC	Atezolizumab	Carboplatin and etoposide ± atezolizumab	I line	OS	2019	400
NCT02788279[73]	Colorectal carcinoma	Atezolizumab	Atezolizumab + cobimetinib vs atezolizumab vs regorafenib	From III line	OS	2019	360
KESTREL[74]	HNSCC	Durvalumab	Durvalumab vs durvalumab + tremelimumab vs SOC	I line	PFS	2017	628
MYSTIC[75]	NSCLC	Durvalumab	Durvalumab vs durvalumab + tremelimumab vs SOC	I line	PFS	2017	1092
Danube[76]	Bladder cancer	Durvalumab	Durvalumab vs durvalumab + tremelimumab vs SOC1	I line	PFS	2017	525
Lung-MAP[77]	SqNSCLC (biomarker-targeted)	Durvalumab, nivolumab	Docetaxel vs durvalumab vs erlotinib vs AZD4547 vs ipilimumab vs palbociclib vs rilotumumab vs taselisib	Any	PFS	2022	10000
CAURAL[78]	NSCLC T790M mutation positive	Durvalumab	AZD9291 + durvalumab vs AZD9291	II-III line	PFS	2018	350
NCT02369874[79]	HNSCC	Durvalumab	Durvalumab vs durvalumab + tremelimumab vs SOC1	II line	OS	2018	720
NEPTUNE[80]	NSCLC	Durvalumab	Durvalumab + tremelimumab vs SOC1	I line	OS	2018	800
ARCTIC[81]	NSCLC	Durvalumab	Durvalumab vs durvalumab + tremelimumab vs SOC1	II-III line	OS	2016	730
NCT02224781[18]	Melanoma BRAFV600 mutated	Nivolumab	Dabrafenib + trametinib followed by ipilimumab + nivolumab vs ipilimumab + nivolumab followed by dabrafenib + trametinib	I line	OS	2019	300
NIBIT-M2[14]	Melanoma brain metastases	Nivolumab	Fotemustine vs ipilimumab + fotemustine vs ipilimumab + nivolumab	Any	OS	2018	168
CheckMate 026[37]	NSCLC PD-L1 positive (all)	Nivolumab	Nivolumab vs CT1	I line	PFS	20162	535
CheckMate 651[83]	H&N SCC	Nivolumab	Nivolumab + ipilimumab vs platinum + fluorouracil + cetuximab	I line	OS	2020	490
CheckMate 459[84]	HCC	Nivolumab	Nivolumab vs sorafenib	I line	TTP	2017	726
NCT02267343[85]	Gastric cancer	Nivolumab	Nivolumab vs placebo	From II line	OS	2017	480
NCT02569242[86]	Esophageal cancer	Nivolumab	Nivolumab vs docetaxel/paclitaxel	From II line	OS	2019	390
CheckMate 214[87]	Renal cell carcinoma	Nivolumab	Nivolumab + ipilimumab vs sunitinib	I line	PFS	2019	1070
CheckMate 143[88]	Glioblastoma	Nivolumab	Nivolumab vs bevacizumab	II line	OS	2017	440
CheckMate 141[89]	H&N SCC	Nivolumab	Nivolumab vs cetuximab/methotrexate/docetaxel monotherapy	Any	OS	2018	360
CheckMate 227[90]	NSCLC	Nivolumab	Nivolumab vs nivolumab + ipilimumab vs nivolumab + platinum doublet CT1	I line	OS	2018	1980
CheckMate 451[91]	SCLC	Nivolumab	Nivolumab vs nivolumab + ipilimumab vs placebo after platinum based CT1	Maintenance after I line	OS	2018	810
CheckMate 498[92]	Glioblastoma (unmethylated MGMT)	Nivolumab	Nivolumab + RT vs temozolomide + RT	I line	PFS	2019	550
CheckMate 331[93]	SCLC	Nivolumab	Nivolumab vs topotecan/amrubicin	II line	OS	2018	480
CheckMate 078[94]	NSCLC	Nivolumab	Nivolumab vs docetaxel	From II line	OS	2018	500
NCT02339571[95]	Melanoma	Nivolumab	Nivolumab + ipilimumab ± sargramostim	I line	OS	2021	400
CheckMate 401[96]	Melanoma	Nivolumab	Nivolumab + ipilimumab vs nivolumab	I line	OS	2021	615

¹According to the standard of care and basing on the choice of the investigator;

²The trial has results but it is still unpublished. OS: Overall survival; PFS: Progression free survival; HNSCC: Head and neck squamous cell carcinoma; HCC: Hepatocarcinoma; NSqNSCLC: Non-squamous non-small cell lung cancer; SqNSCLC: Squamous non-small cell lung cancer; CT: Chemotherapy; NSCLC: Non-small cell lung cancer; MSI-H: High microsatellite instability; dMMR: Deficient mismatch repair; PLD: Pegylated liposomal doxorubicin; SCLC: Small cell lung cancer; TTP: Time to progression; ORR: Objective response rate.