Review
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Feb 10, 2017; 8(1): 37-53
Published online Feb 10, 2017. doi: 10.5306/wjco.v8.i1.37
From targeting the tumor to targeting the immune system: Transversal challenges in oncology with the inhibition of the PD-1/PD-L1 axis
Melissa Bersanelli, Sebastiano Buti
Melissa Bersanelli, Sebastiano Buti, Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy
Author contributions: Both authors equally contributed to this paper with conception and design of the study, literature review and analysis, drafting and critical revision and editing, and final approval of the final version.
Conflict-of-interest statement: No potential conflicts of interest. No financial support.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Sebastiano Buti, MD, PhD, Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy. sebabuti@libero.it
Telephone: +39-05-21702316 Fax: +39-05-21995448
Received: August 17, 2016
Peer-review started: August 18, 2016
First decision: September 28, 2016
Revised: November 9, 2016
Accepted: November 27, 2016
Article in press: November 29, 2016
Published online: February 10, 2017

Abstract

After that the era of chemotherapy in the treatment of solid tumors have been overcome by the “translational era”, with the innovation introduced by targeted therapies, medical oncology is currently looking at the dawn of a new “immunotherapy era” with the advent of immune checkpoint inhibitors (CKI) antibodies. The onset of PD-1/PD-L1 targeted therapy has demonstrated the importance of this axis in the immune escape across almost all human cancers. The new CKI allowed to significantly prolong survival and to generate durable response, demonstrating remarkable efficacy in a wide range of cancer types. The aim of this article is to review the most up to date literature about the clinical effectiveness of CKI antibodies targeting PD-1/PD-L1 axis for the treatment of advanced solid tumors and to explore transversal challenges in the immune checkpoint blockade.

Key Words: Immune checkpoint inhibitors, PD-1, PD-L1, Checkpoint inhibitors, Cancer treatment, Immune checkpoint blockade, Anti-PD-1 antibodies, Anti-PD-L1 antibodies

Core tip: The onset of PD-1/PD-L1 targeted therapy in oncology has demonstrated the importance of this axis in the immune escape across almost all human cancers. A sort of revolution has been happening with the investigation of the new immune checkpoint inhibitors in the field of anticancer therapy. The aim of this article is to review the most up to date literature about the clinical effectiveness of the antibodies targeting PD-1/PD-L1 axis for the treatment of advanced solid tumors and to explore transversal challenges in the immune checkpoint blockade.



INTRODUCTION

After that the era of chemotherapy in the treatment of solid tumors have been overcome by the “translational era”, with the innovation introduced by targeted therapies, medical oncology is currently looking at the dawn of a new “immunotherapy era” with the advent of immune checkpoint inhibitors (CKI) antibodies.

The strategy to maintain physiologic self-tolerance and to restore latent anti-tumor immunity is currently going through the whole oncology, gradually revolutionizing the standard of treatment of the most chemo-resistant tumors such as melanoma, lung and renal cancer. From the first class of antibodies against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), like ipilimumab and tremelimumab, burdened by significant autoimmune toxicity, the scenario is currently evolving in favor of the antibodies against programmed cell death protein 1 (PD-1) and its ligand PD-L1, in both cases inhibiting the PD-1/PD-L1 axis[1].

The monoclonal antibodies nivolumab and pembrolizumab (anti-PD-1), atezolizumab, durvalumab and avelumab (anti-PD-L1), have been tested against multiple cancer types in the last years and are currently under investigation in several phase II and phase III clinical trials. Further similar antibodies are currently undergoing phase I experiences, in order to compete with the first arrivals on the clinical scenario[2-4]. All the antibodies cited in the text are reported in Table 1.

Table 1 Immune-checkpoint inhibitors antibodies with their targets.
CKIMechanism of action
NivolumabAnti-PD-1
PembrolizumabAnti-PD-1
AtezolizumabAnti-PD-L1
DurvalumabAnti-PD-L1
AvelumabAnti-PD-L1
BMS936559Anti-PD-L1
PidilizumabAnti-PD-1

In all cases, the mechanism targets the inhibitory signal that contributes to the balance between co-stimulatory and inhibitory pathways in the regulation of T-cell response, starting from the antigen recognition by T-cell receptor. In fact, in contrast to other antibodies currently used for cancer therapy, CKI do not target tumor cells directly, but instead they target lymphocyte receptors or their ligands, with the aim to enhance endogenous antitumor response[5].

PD-1 belongs to the inhibitory B7-family molecules; it is upregulated and expressed by activated T-cells (but also B-cells, T regulatory and natural killer cells) and engaged through its ligands PD-L1 and PD-L2, expressed by the antigen presenting cells (APC) and by non-hematopoietic stem cells, aside from tumor cells. The role of PD-1 consists in the inhibition of the effector T-cells activity in peripheral tissues during the inflammatory response to infection and in the regulation and limitation of autoimmunity[6]. Within the tumor microenvironment, this endogenous mechanism favors immune resistance[7]. The major PD-1 ligand expressed on solid tumors cells is PD-L1, whose most important signal for induction is interferon-γ (IFN-γ), produced by T helper 1 (Th1) cells[8]. Most types of solid tumors have been demonstrated to express high levels of PD-L1 (melanoma, ovarian, lung cancer and genitourinary tumors among others), and more recently the importance of PD-L1 expression on the immune cells infiltrating the tumor also emerged, in particular on tumor-infiltrating lymphocytes (TILs). Nevertheless, the evidence about the prognostic and predictive role of these elements have not yet been clarified and it seems to be different basing on tumor type[5].

Despite these unresolved issues, the findings described above provided the rationale for the capacity of the blockade of PD-1/PD-L1 axis to enhance intratumoral immune responses in a transversal way across different tumor types, firstly encouraged by preclinical evidence and then largely satisfied by the early results of several recent clinical studies.

RESEARCH

The aim of this article is to review the most up to date literature about CKI antibodies targeting PD-1/PD-L1 axis for the treatment of advanced solid tumors, particularly considering phase III randomized trials, starting from the first performed trials on the issue. Published papers were obtained from the Medline database. The search was implemented by reviewing the most important international scientific meetings abstract databases. In addition, indirect data on the topic were achieved by reading the most recent publications related to the use of CKI in different types of solid tumors.

The ongoing trials were reached on the official website http://www.clincaltrials.gov , considering only randomized phase III studies.

RESEARCH RESULTS
Melanoma

Treatment of advanced melanoma has been radically changed by the advent of CKI. After that the anti-CTLA4 antibody ipilimumab in the last years had become the backbone of this malignant tumor treatment, where traditional chemotherapy harvested very little success, the introduction of the anti-PD-1 antibodies nivolumab and pembrolizumab further improved the therapeutic armamentarium for melanoma.

The first published phase III randomized study about PD-1/PD-L1 axis inhibition in this disease demonstrated, at the beginning of 2015, the advantage of nivolumab over chemotherapy with dacarbazine both in terms of overall survival (OS) and of progression free survival (PFS) among previously untreated patients with metastatic melanoma without BRAF mutation. Median PFS of 5.1 mo in the nivolumab group was more than doubled when compared to dacarbazine treated patients, with 2.2 mo [hazard ratio (HR) = 0.43, 95%CI: 0.34-0.56, P < 0.001]. OS was not reached in the nivolumab group, instead being 10.8 mo in the group treated with chemotherapy (HR = 0.42, 99%CI: 0.25-0.73, P < 0.001)[9].

An analogous comparison was made in patients who progressed after anti-CTLA4 treatment in the phase III randomized study CheckMate 037, reporting a response rate (RR) of 32% for nivolumab vs 11% with chemotherapy according to investigator’s choice. These findings have resulted in the inclusion of nivolumab in the new treatment options for a cancer with high unmet need[10].

In parallel, pembrolizumab was compared with ipilimumab as the new standard of care for first line treatment of advanced melanoma in a phase III randomized trial, demonstrating to prolong PFS and OS with less toxicity respect to the CTLA4 inhibitor[11].

Nevertheless, the new frontier for untreated melanoma is currently represented by the combination of anti-CTLA4 and anti-PD-L1 antibodies: Larkin et al[12] demonstrated that the association of nivolumab and ipilimumab resulted in a significantly longer PFS than ipilimumab alone, despite 55% of treatment-related adverse events (AEs) of grade 3 or 4 (G3-4) vs 16% in the nivolumab group and 27% in the ipilimumab group. This three arms phase III randomized trial closed the matter of first line ipilimumab alone, otherwise confirming good effectiveness for nivolumab monotherapy in this setting[12].

Further phase III-IV trials are currently ongoing to test different dosing schedules of CKI[13], others to verify their efficacy in particular subgroups of patients like those with brain metastases[14], or to establish the correct duration of anti-PD-1 therapy in metastatic melanoma, especially in the case of long responders[15]. Again, more others are investigating alternative combinations[16,17] or treatment sequences, like ipilimumab plus nivolumab followed or preceded by dabrafenib and trametinib in BRAF mutated patients[18].

Moreover, after the Food and Drug Administration approval of ipilimumab for the adjuvant setting for melanoma[19], as discussed below, the PD-1 and PD-L1 inhibitors are currently under investigation for the adjuvant and neoadjuvant setting also in different tumor types in several clinical trials, which results are eagerly awaited, given the lower toxicity expected from this “second generation” of CKI (Table 2)[20-31].

Table 2 Phase III randomized clinical trials currently ongoing with PD-1/PD-L1 axis blockade in adjuvant setting for solid tumors.
Trial name/NCTCancer typeImmune checkpoint inhibitorArmsPrimary endpointExpected primary completion dateNo. of patients
KEYNOTE-054[20]MelanomaPembrolizumabPembrolizumab vs placeboRFS2018900
NCT02506153[21]MelanomaPembrolizumabPembrolizumab vs high dose recombinant interferon-α-2B or ipilimumabOS20201378
KEYNOTE-091 (PEARLS)[22]NSCLCPembrolizumabPembrolizumab vs placeboDFS20211380
IMvigor010[23]Bladder cancerAtezolizumabAtezolizumab vs observationDFS2021440
IMpower010[24]NSCLCAtezolizumabAtezolizumab vs BSC after adjuvant CT1DFS20201127
NCT02768558[25]NSCLC (locally advanced)NivolumabNivolumab vs placebo (after CT1-RT)OS2022660
ANVIL[26]NSCLCNivolumabNivolumab vs observationDFS2018714
CheckMate 238[27]MelanomaNivolumabNivolumab + placebo vs ipilimumab + placeboRFS2018800
CheckMate 274[28]Urothelial cancersNivolumabNivolumab vs placeboDFS2020640
CheckMate 577[29]Esophageal or gastroesophageal junction cancer (locally advanced)NivolumabNivolumab vs placebo (after CT1-RT and surgery)DFS2019760
PACIFIC[30]NSCLC (locally advanced)DurvalumabDurvalumab vs placebo (after CT1-RT)OS2017702
NCT02273375[31]NSCLCDurvalumabDurvalumab vs placeboDFS20251100
Lung cancer

Lung cancer immunotherapy have an historical background, but it has not shown significant survival benefit until the recent advent of CKI.

Conversely to anti-CTLA4 antibodies, which demonstrated a certain efficacy only when combined with chemotherapy, the inhibition of PD-1/PD-L1 axis clearly works as single strategy in non-small cell lung cancer (NSCLC)[32].

The first step through immunotherapy for lung cancer in clinical practice was the approval of CKI monotherapy with nivolumab (and more recently with atezolizumab) for NSCLC patients pretreated with first line chemotherapy, on the basis of the first published randomized trials[33-35].

Anti-PD1 antibodies are going to radically revolutionize lung cancer treatment regardless of the histology, especially after the recently published results of KEYNOTE 024 trial[36], providing the outstanding evidence of pembrolizumab superiority compared to chemotherapy as first line treatment for NSCLC, in terms of PFS (10.3 mo vs 6 mo, P < 0.001), OS (80% vs 72% at 6 mo, P = 0.005), RR (45% vs 28%) and safety among patients bearing strong PD-L1 expression on tumor cells (at least 50% was required for enrollment). This latter evidence, despite concerned to the 30% of overall NSCLC population, will provide the rationale to radically change the therapeutic paradigm for NSCLC, shifting CKI treatment option to first line in a great subgroup of patients. The selection of patients basing on a single biomarker, despite potentially harmful, has been demonstrated to be effective in this case, as proven by the recently announced failure of the analogue phase III trial with nivolumab, whose patients were enrolled independently from PD-L1 status[37].

Several phase III studies are currently still ongoing in order to investigate further CKI antibodies in all treatment lines, in different treatment regimens and with alternative combinations targeting PD-1/PD-L1 axis in advanced NSCLC (Table 3)[37-96].

Table 3 Phase III randomized clinical trials currently ongoing with PD-1/PD-L1 axis blockade in advanced setting for solid tumors.
Trial name/NCTCancer typeImmune checkpoint inhibitorArmsTreatment linePrimary endpointExpected primary completion dateNo. of patients
STOP-GAP[15]MelanomaPD-1 inhibitor (any)Intermittent vs continuous therapyAnyOS2025550
NCT02752074[16]MelanomaPembrolizumabPembrolizumab + epacadostat vs pembrolizumab + placeboI linePFS2018600
MASTERKEY-265[17]MelanomaPembrolizumabPembrolizumab + talimogene laherparepvec vs pembrolizumab + placeboI linePFS2018660
KEYNOTE-048[82]HNSCCPembrolizumabPembrolizumab vs CT1 + pembrolizumab vs CT1I linePFS2018780
KEYNOTE-040[38]HNSCCPembrolizumabPembrolizumab vs methotrexate or docetaxel or cetuximabFrom II lineOS2017466
KEYNOTE-204[39]Hodgkin lymphomaPembrolizumabPembrolizumab vs brentuximabFrom II linePFS2019300
KEYNOTE-045[40]Urothelial cancersPembrolizumabPembrolizumab vs paclitaxel, docetaxel or vinflunineFrom II lineOS20172470
NCT02811861[41]Renal cell carcinomaPembrolizumabPembrolizumab + lenvatinib vs lenvatinib + everolimus vs sunitinibI linePFS2020735
KEYNOTE-426[102]Renal cell carcinomaPembrolizumabPembrolizumab + axitinib vs sunitinibI linePFS, OS2019840
KEYNOTE-240[42]HCCPembrolizumabPembrolizumab vs BSCII linePFS2019408
KEYNOTE-189[43]NSqNSCLCPembrolizumabPlatinum and pemetrexed ± pembrolizumabI linePFS2017570
KEYNOTE-407[44]SqNSCLCPembrolizumabCT1± pembrolizumabI linePFS2018560
KEYNOTE-042[45]NSCLC PD-L1-positivePembrolizumabPembrolizumab vs platinum based CT1I lineOS20181240
KEYNOTE-010[46]NSCLCPembrolizumabPembrolizumab vs docetaxelFrom II lineOS20191034
KEYNOTE-119[47]Triple negative breast cancerPembrolizumabPembrolizumab vs monochemotherapyII-III linePFS2017600
KEYNOTE-355[48]Triple negative breast cancerPembrolizumabCT1 + pembrolizumab vs CT1 + placeboI linePFS2019858
KEYNOTE-177[49]MSI-H or dMMR colorectal carcinomaPembrolizumabPembrolizumab vs CT1I linePFS2019270
KEYNOTE-181[50]Esophageal/esophago-gastric junction carcinomaPembrolizumabPembrolizumab vs monochemotherapy1II linePFS2018600
KEYNOTE-061[51]Esophageal/esophago-gastric junction adenocarcinomaPembrolizumabPembrolizumab vs paclitaxelII linePFS2017720
KEYNOTE-062[52]Esophageal/esophago-gastric junction carcinomaPembrolizumabPembrolizumab vs CT1 + pembrolizumab vs CT1I linePFS2019750
JAVELIN Ovarian 200[53]Ovarian cancer (platinum resistant)AvelumabAvelumab vs avelumab plus PLD vs PLDFrom II lineOS2018550
JAVELIN Ovarian 100[54]Ovarian cancerAvelumabCT1vs CT1 followed by avelumab maintenance vs CT1 + avelumab followed by avelumab maintenanceI linePFS2019951
JAVELIN Renal 101[55]Renal cell cancerAvelumabAvelumab with axitinib vs sunitinibI linePFS2018583
JAVELIN Bladder 100[56]Urothelial cancerAvelumabAvelumab vs BSC (maintenance after CT1)I line maintenanceOS2019668
JAVELIN Gastric 100[57]Adenocarcinoma of the stomach or of the gastro-esophageal junctionAvelumabCT1 continuation vs avelumab in maintenance after CT1I lineOS2018666
JAVELIN Gastric 300[58]Adenocarcinoma of the stomach or of the gastro-esophageal junctionAvelumabAvelumab + BSC vs CT1 + BSC vs BSCIII lineOS2017330
JAVELIN Lung 100[59]NSCLC (PD-L1 positive)AvelumabAvelumab vs platinum based CT1I linePFS2017420
JAVELIN Lung 200[60]NSCLC (PD-L1 positive)AvelumabAvelumab vs docetaxelFrom II lineOS2017650
OAK[61]NSqNSCLCAtezolizumabAtezolizumab vs docetaxelFrom II lineOS20171225
IMvigor211[62]Bladder cancerAtezolizumabAtezolizumab vs monochemotherapyII lineOS2017932
IMvigor130[63]Urothelial carcinoma (ineligible for cisplatin)AtezolizumabAtezolizumab + CT1vs placebo + CT1I linePFS2019435
IMpower110[64]NSqNSCLCAtezolizumabAtezolizumab vs platin + pemetrexedI linePFS2019570
IMpower111[65]SqNSCLCAtezolizumabAtezolizumab vs gemcitabine + platinI linePFS2017ND
IMpower131[66]SqNSCLCAtezolizumabAtezolizumab + nab-paclitaxel + carboplatin vs atezolizumab + paclitaxel + carboplatin vs nab-paclitaxel + carboplatinI linePFS20231200
IMpower210[67]NSCLCAtezolizumabAtezolizumab vs docetaxelII lineOS2019563
IMpower130[68]NSqNSCLCAtezolizumabAtezolizumab + nab-paclitaxel + carboplatin vs nab-paclitaxel + carboplatinI linePFS2019550
IMpower150[69]NSqNSCLCAtezolizumabAtezolizumab + carboplatin + paclitaxel ± bevacizumab vs carboplatin + paclitaxel + bevacizumabI linePFS20171200
IMpassion130[70]Triple negative breast cancerAtezolizumabAtezolizumab + nab-paclitaxel vs placebo + nab paclitaxelI linePFS2020900
IMmotion151[71]Renal cell carcinomaAtezolizumabAtezolizumab + bevacizumab vs sunitinibI linePFS2020900
IMpower133[72]SCLCAtezolizumabCarboplatin and etoposide ± atezolizumabI lineOS2019400
NCT02788279[73]Colorectal carcinomaAtezolizumabAtezolizumab + cobimetinib vs atezolizumab vs regorafenibFrom III lineOS2019360
KESTREL[74]HNSCCDurvalumabDurvalumab vs durvalumab + tremelimumab vs SOCI linePFS2017628
MYSTIC[75]NSCLCDurvalumabDurvalumab vs durvalumab + tremelimumab vs SOCI linePFS20171092
Danube[76]Bladder cancerDurvalumabDurvalumab vs durvalumab + tremelimumab vs SOC1I linePFS2017525
Lung-MAP[77]SqNSCLC (biomarker-targeted)Durvalumab, nivolumabDocetaxel vs durvalumab vs erlotinib vs AZD4547 vs ipilimumab vs palbociclib vs rilotumumab vs taselisibAnyPFS202210000
CAURAL[78]NSCLC T790M mutation positiveDurvalumabAZD9291 + durvalumab vs AZD9291II-III linePFS2018350
NCT02369874[79]HNSCCDurvalumabDurvalumab vs durvalumab + tremelimumab vs SOC1II lineOS2018720
NEPTUNE[80]NSCLCDurvalumabDurvalumab + tremelimumab vs SOC1I lineOS2018800
ARCTIC[81]NSCLCDurvalumabDurvalumab vs durvalumab + tremelimumab vs SOC1II-III lineOS2016730
NCT02224781[18]Melanoma BRAFV600 mutatedNivolumabDabrafenib + trametinib followed by ipilimumab + nivolumab vs ipilimumab + nivolumab followed by dabrafenib + trametinibI lineOS2019300
NIBIT-M2[14]Melanoma brain metastasesNivolumabFotemustine vs ipilimumab + fotemustine vs ipilimumab + nivolumabAnyOS2018168
CheckMate 026[37]NSCLC PD-L1 positive (all)NivolumabNivolumab vs CT1I linePFS20162535
CheckMate 651[83]H&N SCCNivolumabNivolumab + ipilimumab vs platinum + fluorouracil + cetuximabI lineOS2020490
CheckMate 459[84]HCCNivolumabNivolumab vs sorafenibI lineTTP2017726
NCT02267343[85]Gastric cancerNivolumabNivolumab vs placeboFrom II lineOS2017480
NCT02569242[86]Esophageal cancerNivolumabNivolumab vs docetaxel/paclitaxelFrom II lineOS2019390
CheckMate 214[87]Renal cell carcinomaNivolumabNivolumab + ipilimumab vs sunitinibI linePFS20191070
CheckMate 143[88]GlioblastomaNivolumabNivolumab vs bevacizumabII lineOS2017440
CheckMate 141[89]H&N SCCNivolumabNivolumab vs cetuximab/methotrexate/docetaxel monotherapyAnyOS2018360
CheckMate 227[90]NSCLCNivolumabNivolumab vs nivolumab + ipilimumab vs nivolumab + platinum doublet CT1I lineOS20181980
CheckMate 451[91]SCLCNivolumabNivolumab vs nivolumab + ipilimumab vs placebo after platinum based CT1Maintenance after I lineOS2018810
CheckMate 498[92]Glioblastoma (unmethylated MGMT)NivolumabNivolumab + RT vs temozolomide + RTI linePFS2019550
CheckMate 331[93]SCLCNivolumabNivolumab vs topotecan/amrubicinII lineOS2018480
CheckMate 078[94]NSCLCNivolumabNivolumab vs docetaxelFrom II lineOS2018500
NCT02339571[95]MelanomaNivolumabNivolumab + ipilimumab ± sargramostimI lineOS2021400
CheckMate 401[96]MelanomaNivolumabNivolumab + ipilimumab vs nivolumabI lineOS2021615

Also adjuvant paradigm has been pursued in lung cancer: Table 2 summarizes all the ongoing phase III studies in this field.

Squamous cell lung cancer: Squamous cell histology had the first indication for CKI therapy, basing on the outstanding results of CheckMate 017 trial comparing nivolumab vs docetaxel in advanced squamous NSCLC (SqNSCLC) progressive to previous chemotherapy[33]. With a median OS of 9.2 mo vs 6 mo, nivolumab reduced the risk of death of 41%, with an HR of 0.59 (95%CI: 0.44-0.79), P < 0.001. The advantage was confirmed also for RR, PFS and safety profile, finally providing an unprecedented treatment option also in terms of tolerability.

Non-squamous cell lung cancer: With a slight delay and with not as brilliant but positive results, nivolumab was also approved for non-squamous NSCLC (non-SqNSCLC) treatment after failure of chemotherapy, on the basis of an analogous phase III randomized trial demonstrating an improvement of median OS from 9.4 mo with docetaxel to 12.2 mo (HR = 0.73, 95%CI: 0.59-0.89, P = 0.002)[34]. In this study, nivolumab was associated with better OS and RR but not with longer PFS compared to chemotherapy. A crossing of the PFS curves suggested a delay of the benefit with nivolumab, consistent with the results of previous immune system modulating agents, probably reflecting a pattern of response typical of immunotherapy and the use of inadequate response assessment measurements for this type of drug[97].

Other thoracic malignancies: Among other thoracic tumors, small cell lung cancer (SCLC), malignant pleural mesothelioma (MPM) and thymic epithelial tumors (TETs), under the thrust of true unmet medical needs, came across immunotherapy with CKI.

Preliminary data for PD-1/PD-L1 blockade in SCLC were encouraging and currently ongoing phase III studies are investigating CKI both in pretreated and untreated advanced SCLC patients[72,93] or as maintenance treatment after standard treatment either in extensive or in limited disease[91].

Great expectations have been made for MPM, because of the known relationship between neoplastic and inflammatory counterpart in this tumor, recognized to have a T-cell inflamed phenotype. At the moment, only preliminary data have been published and CKI are currently under proposal for further investigations in this disease. Finally, early phases studies are ongoing to test CKI immunotherapy also in TETs[98].

Renal cancer

After the pivotal trial Checkmate 025, nivolumab has vowed to became the cornerstone of previously treated metastatic renal cell carcinoma (mRCC) therapy, finally offering an OS improvement in a setting where targeted therapies have fallen short of expectation[99]. The median OS was 25 mo (95%CI: 21.8-not estimable) with nivolumab and 19.6 mo (95%CI: 17.6-23.1) with everolimus, with a HR of 0.73 and a RR of 25% vs 5% (P < 0.001). Also in terms of toxicity, nivolumab was superior to the standard treatment everolimus, with 19% vs 37% of AEs.

In the light of these results, nivolumab currently represents a new standard of treatment for mRCC after disease progression to first line antiangiogenic therapy. On this auriferous vein other phase III randomized trials have been planned and their results are eagerly awaited. Worthy of note, a phase III randomized trial with an innovative design is comparing the combination of lenvatinib and everolimus (which recently achieved great results in phase II[100]) with the combination of lenvatinib and pembrolizumab vs the standard sunitinib. Such ambitious trials will probably provide the cornerstone of the future clinical practice in RCC[41,101].

After reaching the indication for second line treatment, also first line setting has been investigated, with the planning of interesting trials currently still ongoing. In previously untreated RCC patients, atezolizumab in combination with bevacizumab is being compared to sunitinib[71]; the same standard of treatment is in turn compared to pembrolizumab combined with axitinib[102] and then to nivolumab plus ipilimumab[87]. Eventually, also avelumab plus axitinib is being investigated vs sunitinib[55]. In all cases, the control arm is represented by such a big standard of therapy (sunitinib) that, in case of positive results, the clinical practice for RCC will completely change, switching from angiogenesis inhibition to immune-checkpoint blockade.

Urothelial cancers

Since no significant improvements have been achieved in metastatic bladder cancer for long time, the impressive results of recent trials with CKI, in particular with the anti-PD-L1 atezolizumab, have given new hope to finally cure urothelial cancer[103,104].

Atezolizumab is currently been approved for treatment of urothelial cancer on the basis of a randomized phase II trial comparing this anti-PD-L1 with standard treatment, demonstrating its advantage over chemotherapy in both platinum pretreated ineligible patients and in chemotherapy pretreated patients[105]. At the same time, phase III studies in second line setting are ongoing and both atezolizumab and pembrolizumab have been compared to different second line chemotherapeutic regimens in all urothelial cancers: The trial with pembrolizumab has been recently early stopped due to the meeting of the primary endpoint (OS)[40,62]. Also avelumab and durvalumab reached phase III investigation in bladder cancer, but in the first line setting; the latter combined with the anti-CTLA4 tremelimumab vs standard first line chemotherapy[56,76]. A further interesting study in metastatic urothelial cancer is recruiting naive patients ineligible to cisplatin to receive atezolizumab in combination with chemotherapy (gemcitabine and carboplatin) as first line treatment[63].

Not less significant the promising evidence about the role of CKI in the adjuvant setting of urothelial cancer: Atezolizumab is under investigation vs only observation after cystectomy in PD-L1 positive high risk muscle-invasive bladder cancer[23] and also nivolumab is being tested in this setting[28].

Head and neck cancer

Head and neck squamous cell carcinoma (HNSCC) undoubtedly a promising candidate for CKI because of the profound immune suppression from which is characterized. As the matter of fact, a phase III randomized study comparing nivolumab to the standard of treatment in pretreated HNSCC patients was early stopped after the clear demonstration of an improvement in terms of OS for nivolumab[89]. This trial provided very promising results in platinum refractory disease, encouraging the planning of further phase III studies, currently ongoing, also for pembrolizumab[38,82] and early phases trials with durvalumab and avelumab[106].

Despite an apparently not so favorable toxicity profile, also anti-CTLA4 antibodies are being tested in combination with anti-PD-1 or anti-PD-L1 agents in HNSCC. Phase III studies with this therapeutic strategy are currently ongoing both in pretreated patients and in first line setting[74,79].

Other tumors

The PD-1/D-L1 axis has been targeted in other tumor types than those cited above, with an interesting rationale and supported by phase I-II experiences, despite still remaining in shadow waiting for phase III results.

In ovarian cancer, despite several early phase studies currently ongoing with nivolumab, pembrolizumab, BMS936559 (an anti-PD-L1) and avelumab, the emerged response rates are relatively low, in front of a manageable safety profile[53,54,107].

Pembrolizumab, aside from early investigations in soft tissue and bone sarcomas[108], is currently under phase III investigation in hepatocellular carcinoma[42], in esophageal and gastric carcinoma[50-52], in Hodgkin and non-Hodgkin lymphoma[39].

In these latter malignancies also nivolumab and pidilizumab, anti-PD-1 antibodies, besides from atezolizumab and durvalumab, anti-PD-L1 antibodies, are being evaluated in early phases[109]. Furthermore, different treatment lines of advanced gastric cancer are being tested with avelumab[57,58].

Some initial encouraging data are emerging from ongoing studies in favor of the employment of CKI also in central nervous system (CNS) malignancies, such as glioblastoma, where unmet clinical needs are leading to new investigations[88,92]. Disappointing results were instead obtained for pancreatic cancer, despite a certain evidence for durvalumab[110].

About colorectal cancer, despite the initial evidence to be not responsive to nivolumab, a subset of patients has been identified as potentially best responders to pembrolizumab, revealing that the mismatch repair (MMR) status can predict clinical benefit with enhanced responsiveness in tumors with microsatellite instability (MSI)[111]. With this rationale, phase III randomized studies have been initiated in order to compare standard therapy with pembrolizumab in MSI colorectal cancer patients[49]. Furthermore, atezolizumab is currently under investigation alone or in combination with cobimetinib (mitogen activate protein kinase-inhibitor) vs regorafenib (antiangiogenic multi-kinase inhibitor) in all advanced colorectal tumors[73].

Eventually, a great interest for PD-1/PD-L1 blockade is represented by triple negative breast cancer: Phase III trials are currently ongoing with pembrolizumab compared to chemotherapy and with atezolizumab combined with nab-paclitaxel both in neo-adjuvant and advanced setting[47,48,70,112].

Transversal challenges

Immune-related toxicity: The management of the “new toxicities” of CKI is transversal to all malignancies and to all cited antibodies, unavoidably involving other specialists beyond the oncologist, such as the endocrinologist and the immunologist in first line.

These immune-related adverse events (irAEs) are due to the infiltration of tissues by activated T-lymphocytes responsible of autoimmunity. As a consequence, the block of the immune-checkpoint can amplify any immune response in all organs: Skin, gastrointestinal tract, endocrine glands, lung, CNS, liver, kidney, hematological cells, muscular-articular system, heart and eyes can all be affected. Nevertheless, most of these irAEs are rare and only fatigue, rash, pruritus, diarrhea, nausea and arthralgia occurs in > 10% of cases. On the other hand, despite being rare, interstitial pneumonitis is the main life-threatening toxicity for anti PD-1/PD-L1 agents[113].

Potentially predisposing conditions for irAEs development could be represented by personal or family history of autoimmune disease (genetic determinants), by underlying silent autoimmunity, chronic viral infections or other personal ecological factors (such as the microbiome in the case of enterocolitis)[114].

The prevention, the anticipation, the detection and then the treatment (with multidisciplinary approach) and monitoring of irAEs are the principles of their correct clinical management. Depending on their severity, irAEs require temporary or permanent discontinuation of CKI therapy, use of high doses corticosteroids or, in severe cases, of anti-TNF treatment with infliximab. The current management guidelines are based on recent expert consensus recommendations published about the issue[115].

Response assessment: RECIST vs immune-related criteria: Based on survival analysis, traditional response evaluation criteria in solid tumors (RECIST) might underestimate the benefit of CKI[116].

The pattern of response of immunotherapy, radically different from those of standard chemotherapy and also of antiangiogenic agents, is frequently not captured by the conventional RECIST[117]. This led to the development of the immune-related response criteria (irRC)[118], assessing tumor burden as a continuous variable and evaluating percentage changes in several target lesions overtime. In this system, the appearance of new lesions does not mean progressive disease but it is considered and reassessed in the context of a dynamic evaluation. Moreover, the thresholds to determine progression or response (25% increase and 50% decrease) are higher than those of RECIST (20% increase and 30% decrease)[119]. Given the reported evidence, modified criteria are undoubtedly mandatory in the response assessment to the new immunotherapy, in order to prevent premature discontinuation of treatment.

PD-L1 expression as response predictor: In the context of solid tumors treated with PD-1/PD-L1 inhibitors, the predictive role of PD-L1 expression on tumor cells and, as more recently discovered, on immune infiltrating cells, represents an actual issue of great interest and constitutes a significant cue of discussion for clinical researchers[120].

Currently, on the basis of the state of art, the predictive value of PD-L1 on tumor cells is limited to NSCLC and melanoma, especially for anti-PD-1 antibodies, whilst a more predictive significance of PD-L1 expression on the immune cells infiltrating the tumor seems to emerge for urothelial cancers in the case of anti-PD-L1 antibodies[121,122]. Nevertheless, a great limit of such speculations is represented by the scarce reliance and reproducibility of the different methods used for the biomarker’s detection, with controversial results depending on the staining technique, on the different anti-PD-L1 antibodies and finally on the sample used for immune-histochemical assay (primary tumor vs metastases samples, with the challenge of heterogeneity). Moreover, confusing data emerged from the use (and the lack of validation) of different cut-off for PD-L1 expression, from 1%, to 5%, to 50% threshold in different trials[120].

Aside from PD-L1 expression, further multiple factors have been explored and are currently undergoing investigations as predictive elements for response to CKI: Among these, an increasing interest is being acquired by the micro-environmental features of the tumor, such as the infiltrating immune cells sub-populations and their biomarkers expression[123].

Microsatellite instability and hyper-mutational status: The MSI phenotype, as a consequence of a defective DNA-MMR system, characterizes a subgroup of tumors harboring a large number of somatic mutations (high mutational load). Since these mutations have the potential to encode a great number of immunogenic neoantigens, a particular susceptibility of MSI-hyper-mutated cancers to PD-1/PD-L1 axis blockade have been hypothesized and more recently proven[124]. As the matter of fact, MSI tumors have a microenvironment characterized by abundant T-cell infiltrate, with activated CD8+ cytotoxic T lymphocyte (CTL) and activated Th1 producing IFN-γ, high expression of PD-L1 (in particular by TILs and myeloid cells infiltrating the tumor) and great overexpression of immune-checkpoint related proteins[125]. All these elements configure the elective candidate cancer for immune-checkpoint inhibition and suggest to investigate CKI in all cancer types with MMR defects.

Additionally, tumors with polymerase E (POLE) mutations, despite stable microsatellites, have been demonstrated to contain a high mutational load. Also these POLE-ultra-mutated cancers are characterized by an active Th1/CTL microenvironment and upregulated immune checkpoints, constituting an ideal target for CKI therapy as well as MSI tumors[126].

In conclusion, among apparently resistant cancer types (such as colon cancer), CKI have been proven to exert an effect in case of MMR defects and trials on this selected population are currently ongoing to investigate the efficacy of anti-PD-1 antibodies[49].

Immune system modulation with sequential or association strategies: Given the great benefit in terms of OS and the long lasting impact of CKI therapy on patients’ survival in the responding cases, probably due to immunological memory, two major issues remain to be addressed: The sensitization of non-responders and the disease control in patients initially pseudo-progressive. With these aims, combination strategies have been planned and investigated in the last years, either combining immunotherapy with chemotherapy, radiotherapy and targeted agents or associating different CKI[127].

The strategy to increase the immunogenicity of tumors can be pursued through the enhancement of antigen presentation (boosting antigens release or stimulating APC function), the stimulation of major histocompatibility complex (MHC) class I expression, the down-regulation of the T-reg cells and the stimulation of the T-cells infiltration. Some of these mechanisms can be achieved with promising combination strategies.

Chemotherapeutic agents are capable to induce immunogenic cancer death, generating a strong immune stimulation. Among these, cyclophosphamide have additionally been shown to reduce the number of circulating T-reg cells, removing a key element of immunosuppression, and moreover to sensitize tumor cells to T-cell mediated apoptosis, potentially boosting the effect of the immune checkpoint blockade[128-130]. Considering the criticism of a combination between CKI and chemotherapy, given expected short term immunosuppressive effect of the latter, in our opinion a sequential strategy could represent a good opportunity to take advantage of cell death and antigen release caused by an induction chemotherapy, in order to prepare a more immunogenic environment for the subsequent CKI[131].

A great interest for the potential stimulation of the immune-response through radiotherapy has been suggested by the evidence about the immune-mediated abscopal effect[132]. Aside from interesting case reports, clinical trials in this field are currently in early phases and eagerly awaited[133].

Targeted therapy combinations with immunotherapy are currently under investigation, in early phases, with interesting results[127]. The rationale of such strategies could be represented by the aim to obtain a more rapid RR and to boost PFS with the targeted agent, in expectation of the long-term effect on survival of the CKI.

Finally, the combination of anti-PD-1 and anti-CTLA4 antibodies, despite the increased immune-related toxicity, has been shown to improve the outcomes in a phase III randomized trial in metastatic melanoma, early changing the standard of treatment a few years after the onset of the new immunotherapy with ipilimumab[134]. Several trials investigating such association of CKI are currently ongoing: The management of irAEs will probably represent the main criticism of such strategies[127].

Targeting PD-1/PD-L1 axis in adjuvant setting: The rationale for the PD-1/PD-L1 axis inhibition for adjuvant purposes is in the concept of “immunological memory”, generated by the cancer-immunity cycle, starting from the release of cancer cell antigens also in the early phases of tumorigenesis. After the APC migration in the lymph nodes and the presentation of antigens in the context of MHC-I molecules to CD8+ T cells, aside from effector T-lymphocytes capable of activation against cancer neo-antigens, memory T-cells are also generated. These quiescent lymphocytes are appointed to the subsequent immune-response and could contribute to avoid disease relapse[135].

Considering the widely acceptable toxicity profile of CKI, the proposal of using them as adjuvant therapy, to prevent relapses after surgery of early disease while maintaining a good quality of life, appears very favorable. In support of this, we have the approval of the CTLA4 inhibitor ipilimumab for adjuvant treatment in melanoma, on the basis of a recent pivotal trial[136]. For PD-1/PD-L1 axis inhibitors, nevertheless, the investigation in adjuvant setting is quite early, in spite of a more favorable safety management. A noteworthy issue about immune-adjuvant treatment with these compounds (unlike the case of ipilimumab) is the correct duration of therapy, ranging from one to more years in different planned trials. The currently ongoing studies are reported in Table 2.

PERSPECTIVES

Considering the wide range of settings and combinations covered by the ongoing clinical trials with CKI treatment, we think that the future directions for immunotherapy are still to be written and they are probably different basing on cancer types. The reason of this latter statement, not so obvious as it may seem, is likely due to the other different therapies to whom immune-checkpoint blockade needs to be sequenced and alternated in each tumor, more than to a real difference in the target, which is always represented by the immune system and by its relationship with the tumor rather than by the tumor itself.

From this point of view, a key issue could be represented by the immunomodulating potential of the current standard of treatment in each case, sometimes widely unknown and rarely explored before the “immunotherapy era”[137].

The great advantage of anti-PD-1/PD-L1 agents is undoubtedly represented by their very favorable safety profile, with large tolerability in almost all patients. Combinations of CKI with standard chemotherapy or targeted therapies, despite possibly more effective, have the risk of became unsustainable both in terms of costs and of toxicity, significantly impacting on the final outcome. Nevertheless, alternating targeted and immunotherapy might permit to modulate tumor metabolism, inflammation and immune infiltration, allowing to modify the relationship between cancer and immune system.

Thus, in order to fully take advantage of its potential, the winning strategy with immune-checkpoint blockade could be represented by an ingenious sequence, exploiting the immunomodulating properties of previous and subsequent drugs with the aim of boosting immune system activation against the tumor.

CONCLUSION

The onset of PD-1/PD-L1 targeted therapy has demonstrated the importance of this axis in the immune escape across almost all human cancers. Despite being burdened by some issues not still addressed, such as the correct duration of therapy in the responsive patients, the new CKI allowed to significantly prolong survival and to generate durable response, demonstrating remarkable efficacy in a wide range of cancer types. However, such benefit is not extended to all patients, and some of them experienced immune escape despite therapy. The investigation about mechanisms leading to the development of primary or secondary immune escape must represent the key element of future studies in the whole immuno-oncology, with the aim of resensitize these patients to the immune checkpoint blockade. The future approach to the problem may be represented by a personalized cancer immunotherapy, allowed only by multiparameter biomarkers approaches, as interestingly suggested by Kim et al[138] in a recent review about the “step to success (or failure)” to PD-1/PD-L1 blockade. In their proposal, a hypothetical algorithm could provide the assessment of specific immune-related biomarkers in each patient’s tumor, allowing to create a personal mapping according to which characteristics the oncologist could chose (or exclude) the optimal immunotherapy or immunotherapeutic combination for each single case.

Waiting for the possible realization of such sophistication of therapy, the immune checkpoint blockade in oncology is currently experiencing promising huge advances, shifting the classical paradigm of anticancer treatment from targeting the tumor to targeting the immune system and increasing our hopes to gain the immune control of oncological disease.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Oncology

Country of origin: Italy

Peer-review report classification

Grade A (Excellent): 0

Grade B (Very good): B, B, B

Grade C (Good): C, C

Grade D (Fair): 0

Grade E (Poor): 0

P- Reviewer: Qin JM, Tirumani SH, Tomizawa M, Tsikouras PPT, Zhang L S- Editor: Ji FF L- Editor: A E- Editor: Wu HL

References
1.  Lee CS, Cragg M, Glennie M, Johnson P. Novel antibodies targeting immune regulatory checkpoints for cancer therapy. Br J Clin Pharmacol. 2013;76:233-247.  [PubMed]  [DOI]
2.  Naing A, Gelderblom H, Gainor J, Forde PM, Butler M, Lin CC, Sharma S, Ochoa de Olza M, Schellens JHM, Soria JC. A first-in-human phase I study of the anti-PD-1 antibody PDR001 in patients with advanced solid tumors. 2016 ASCO Annual Meeting, Poster Discussion. J Clin Oncol. 2016;34 Suppl:abstr 3060.  [PubMed]  [DOI]
3.  Eli Lilly and Company. A study of anti-PD-L1 checkpoint antibody (LY3300054) alone and in combination in participants with advanced refractory solid tumors (PACT). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02791334.  [PubMed]  [DOI]
4.  Bristol-Myers Squibb. Study of Urelumab in Subjects With Advanced and/or Metastatic Malignant Tumors. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02534506.  [PubMed]  [DOI]
5.  Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252-264.  [PubMed]  [DOI]
6.  Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11:3887-3895.  [PubMed]  [DOI]
7.  Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8:467-477.  [PubMed]  [DOI]
8.  Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793-800.  [PubMed]  [DOI]
9.  Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320-330.  [PubMed]  [DOI]
10.  Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH, Lao CD. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16:375-384.  [PubMed]  [DOI]
11.  Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372:2521-2532.  [PubMed]  [DOI]
12.  Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373:23-34.  [PubMed]  [DOI]
13.  Bristol-Myers Squibb. A study of two different dose combinations of nivolumab in combination with ipilimumab in subjects with previously untreated, unresectable or metastatic melanoma. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https: //clinicaltrials.gov/ct2/show/NCT02714218.  [PubMed]  [DOI]
14.  Italian Network for Tumor Biotherapy Foundation. A study of fotemustine (FTM) vs FTM and ipilimumab (IPI) or IPI an nivolumab in melanoma brain metastasis (NIBIT-M2). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https: //clinicaltrials.gov/ct2/show/NCT02460068.  [PubMed]  [DOI]
15.  Canadian Cancer Trials Group. Duration of anti-PD-1 therapy in metastatic melanoma (STOP-GAP). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02821013.  [PubMed]  [DOI]
16.  Incyte Corporation. A phase 3 study of pembrolizumab epacadostat or placebo in subjects with unresectable or metastatic melanoma. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02752074.  [PubMed]  [DOI]
17.  Amgen. Pembrolizumab with or without talimogene laherparepvec or talimogene laherparepvec placebo in unresected melanoma (MASTERKEY-265). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02263508.  [PubMed]  [DOI]
18.  National Cancer Institute (NCI). A randomized phase III trial of dabrafenib trametinib followed by ipilimumab nivolumab at progression vs ipilimumab nivolumab followed by dabrafenib trametinib at progression in patients with advanced BRAFV600 mutant melanoma. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02224781.  [PubMed]  [DOI]
19.  FDA approves Yervoy to reduce the risk of melanoma returning after surgery. [released 2015 Oct 28].  Available from: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm469944.htm.  [PubMed]  [DOI]
20.  Merck Sharp & Dohme Corp. Study of Pembrolizumab (MK-3475) Versus Placebo After Complete Resection of High-Risk Stage III Melanoma (MK-3475-054/KEYNOTE-054). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02362594.  [PubMed]  [DOI]
21.  National Cancer Institute (NCI). High-Dose Recombinant Interferon Alfa-2B, Ipilimumab, or Pembrolizumab in Treating Patients With Stage III-IV High Risk Melanoma That Has Been Removed by Surgery. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02506153.  [PubMed]  [DOI]
22.  Merck Sharp & Dohme Corp. Study of Pembrolizumab (MK-3475) vs Placebo for Participants With Non-small Cell Lung Cancer After Resection With or Without Standard Adjuvant Therapy (MK-3475-091/KEYNOTE-091) (PEARLS). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02504372.  [PubMed]  [DOI]
23.  Hoffmann-La Roche. A Phase III Study of Atezolizumab Treatment Versus Observation as Adjuvant Therapy in Patients With PD-L1 Positive, High Risk Muscle Invasive Bladder Cancer After Cystectomy [IMvigor010]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02450331.  [PubMed]  [DOI]
24.  Hoffmann-La Roche. Study to Assess Safety and Efficacy of Atezolizumab (MPDL3280A) Compared to Best Supportive Care Following Chemotherapy in Patients With Lung Cancer [IMpower010]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02486718.  [PubMed]  [DOI]
25.  RTOG Foundation, Inc. Cisplatin and Etoposide Plus Radiation Followed By Nivolumab/Placebo For Locally Advanced NSCLC. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02768558.  [PubMed]  [DOI]
26.  National Cancer Institute (NCI). Nivolumab After Surgery and Chemotherapy in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer (ANVIL). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02595944.  [PubMed]  [DOI]
27.  Bristol-Myers Squibb. Efficacy Study of Nivolumab Compared to Ipilimumab in Prevention of Recurrence of Melanoma After Complete Resection of Stage IIIb/c or Stage IV Melanoma (CheckMate 238). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02388906.  [PubMed]  [DOI]
28.  Bristol-Myers Squibb. A Study of Nivolumab, Compared to Placebo, in Patients With Bladder or Upper Urinary Tract Cancer, Following Surgery to Remove the Cancer (CheckMate 274). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02632409.  [PubMed]  [DOI]
29.  Bristol-Myers Squibb. Study of Adjuvant Nivolumab or Placebo in Subjects With Resected Esophageal or Gastroesophageal Junction Cancer (CheckMate 577). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02743494.  [PubMed]  [DOI]
30.  AstraZeneca. A Global Study to Assess the Effects of MEDI4736 Following Concurrent Chemoradiation in Patients With Stage III Unresectable Non-Small Cell Lung Cancer (PACIFIC). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02125461.  [PubMed]  [DOI]
31.  Canadian Cancer Trials Group. Double Blind Placebo Controlled Controlled Study of Adjuvant MEDI4736 In Completely Resected NSCLC. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02273375.  [PubMed]  [DOI]
32.  Steven A, Fisher SA, Robinson BW. Immunotherapy for lung cancer. Respirology. 2016;21:821-833.  [PubMed]  [DOI]
33.  Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373:123-135.  [PubMed]  [DOI]
34.  Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373:1627-1639.  [PubMed]  [DOI]
35.  ESMO 2016 Press Release. Significant survival gains with atezolizumab vs docetaxel for non-small cell lung cancer [updated 2016 Oct 9].  Available from: https://www.esmo.org.  [PubMed]  [DOI]
36.  Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375:1823-1833.  [PubMed]  [DOI]
37.  Bristol-Myers Squibb. An Open-Label, Randomized, Phase 3 Trial of Nivolumab Versus Investigator’s Choice Chemotherapy as First-Line Therapy for Stage IV or Recurrent PD-L1 Non-Small Cell Lung Cancer (CheckMate 026). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02041533.  [PubMed]  [DOI]
38.  Merck Sharp & Dohme Corp. Pembrolizumab (MK-3475) Versus Standard Treatment for Recurrent or Metastatic Head and Neck Cancer (MK-3475-040/KEYNOTE-040). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https: //clinicaltrials.gov/ct2/show/NCT02252042.  [PubMed]  [DOI]
39.  Merck Sharp & Dohme Corp. Study of Pembrolizumab (MK-3475) vs. Brentuximab Vedotin in Participants With Relapsed or Refractory Classical Hodgkin Lymphoma (MK-3475-204/KEYNOTE-204). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02684292.  [PubMed]  [DOI]
40.  Merck Sharp & Dohme Corp. A Study of Pembrolizumab (MK-3475) Versus Paclitaxel, Docetaxel, or Vinflunine for Participants With Advanced Urothelial Cancer (MK-3475-045/KEYNOTE-045). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https: //clinicaltrials.gov/ct2/show/NCT02256436.  [PubMed]  [DOI]
41.  Eisai Inc. Lenvatinib/Everolimus or Lenvatinib/Pembrolizumab Versus Sunitinib Alone as Treatment of Advanced Renal Cell Carcinoma. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02811861.  [PubMed]  [DOI]
42.  Merck Sharp & Dohme Corp. Study of Pembrolizumab (MK-3475) vs. Best Supportive Care in Participants With Previously Systemically Treated Advanced Hepatocellular Carcinoma (MK-3475-240/KEYNOTE-240). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02702401.  [PubMed]  [DOI]
43.  Merck Sharp & Dohme Corp. tudy of Platinum Pemetrexed Chemotherapy With or Without Pembrolizumab (MK-3475) in Participants With First Line Metastatic Non-squamous Non-small Cell Lung Cancer (MK-3475-189/KEYNOTE-189). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02578680.  [PubMed]  [DOI]
44.  Merck Sharp & Dohme Corp. A Study of Carboplatin-Paclitaxel/Nab-Paclitaxel Chemotherapy With or Without Pembrolizumab (MK-3475) in Adults With First Line Metastatic Squamous Non-small Cell Lung Cancer (MK-3475-407/KEYNOTE-407). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02775435.  [PubMed]  [DOI]
45.  Merck Sharp & Dohme Corp. Study of MK-3475 (Pembrolizumab) Versus Platinum-based Chemotherapy for Participants With PD-L1-positive Advanced or Metastatic Non-small Cell Lung Cancer (MK-3475-042/KEYNOTE-042). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02220894.  [PubMed]  [DOI]
46.  Merck Sharp & Dohme Corp. Study of Two Doses of MK-3475 (Pembrolizumab) Versus Docetaxel in Previously-Treated Participants With Non-Small Cell Lung Cancer (MK-3475-010/KEYNOTE-010). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT01905657.  [PubMed]  [DOI]
47.  Merck Sharp & Dohme Corp. Study of Single Agent Pembrolizumab (MK-3475) Versus Single Agent Chemotherapy for Metastatic Triple Negative Breast Cancer (MK-3475-119/KEYNOTE-119). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02555657.  [PubMed]  [DOI]
48.  Merck Sharp & Dohme Corp. Study of Pembrolizumab (MK-3475) Plus Chemotherapy vs. Placebo Plus Chemotherapy for Previously Untreated Locally Recurrent Inoperable or Metastatic Triple Negative Breast Cancer (MK-3475-355/KEYNOTE-355). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02819518.  [PubMed]  [DOI]
49.  Merck Sharp & Dohme Corp. Study of Pembrolizumab (MK-3475) vs Standard Therapy in Participants With Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Carcinoma (MK-3475-177/KEYNOTE-177). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02563002.  [PubMed]  [DOI]
50.  Merck Sharp & Dohme Corp. Study of Pembrolizumab (MK-3475) Versus Investigator’s Choice Standard Therapy for Participants With Advanced Esophageal/Esophagogastric Junction Carcinoma That Progressed After First-Line Therapy (MK-3475-181/KEYNOTE-181). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02564263.  [PubMed]  [DOI]
51.  Merck Sharp & Dohme Corp. A Study of Pembrolizumab (MK-3475) Versus Paclitaxel for Participants With Advanced Gastric/Gastroesophageal Junction Adenocarcinoma That Progressed After Therapy With Platinum and Fluoropyrimidine (MK-3475-061/KEYNOTE-061). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02370498.  [PubMed]  [DOI]
52.  Merck Sharp & Dohme Corp. Study of Pembrolizumab (MK-3475) as First-Line Monotherapy and Combination Therapy for Treatment of Advanced Gastric or Gastroesophageal Junction Adenocarcinoma (MK-3475-062/KEYNOTE-062). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02494583.  [PubMed]  [DOI]
53.  Pfizer. A Study Of Avelumab Alone Or In Combination With Pegylated Liposomal Doxorubicin Versus Pegylated Liposomal Doxorubicin Alone In Patients With Platinum Resistant/Refractory Ovarian Cancer (JAVELIN Ovarian 200). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02580058.  [PubMed]  [DOI]
54.  Pfizer. Avelumab in Previously Untreated Patients With Epithelial Ovarian Cancer (JAVELIN OVARIAN 100). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02718417.  [PubMed]  [DOI]
55.  Pfizer. A Study of Avelumab With Axitinib Versus Sunitinib In Advanced Renal Cell Cancer (JAVELIN Renal 101). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02684006.  [PubMed]  [DOI]
56.  Pfizer. A Study Of Avelumab In Patients With Locally Advanced Or Metastatic Urothelial Cancer (JAVELIN Bladder 100). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02603432.  [PubMed]  [DOI]
57.  EMD Serono Research & Development Institute, Inc. Avelumab in First-Line Gastric Cancer (JAVELIN Gastric 100). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02625610.  [PubMed]  [DOI]
58.  EMD Serono Research & Development Institute, Inc. Avelumab in Third-Line Gastric Cancer (JAVELIN Gastric 300). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02625623.  [PubMed]  [DOI]
59.  EMD Serono Research & Development Institute, Inc. Avelumab in First-line Non-Small Cell Lung Cancer (JAVELIN Lung 100). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02576574.  [PubMed]  [DOI]
60.  EMD Serono Research & Development Institute, Inc. Avelumab in Non-Small Cell Lung Cancer (JAVELIN Lung 200). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https: //clinicaltrials.gov/ct2/show/NCT02395172.  [PubMed]  [DOI]
61.  Hoffmann-La Roche. A Randomized Phase 3 Study of Atezolizumab (an Engineered Anti-PDL1 Antibody) Compared to Docetaxel in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Have Failed Platinum Therapy - “OAK”. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02008227.  [PubMed]  [DOI]
62.  Hoffmann-La Roche. A Study of Atezolizumab Compared With Chemotherapy in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer (IMvigor211). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02302807.  [PubMed]  [DOI]
63.  Hoffmann-La Roche. The Effect of Atezolizumab in Combination With Gemcitabine/Carboplatin and Gemcitabine/Carboplatin Alone in Participants With Untreated Locally Advanced or Metastatic Urothelial Carcinoma Who Are Ineligible for Cisplatin-based Therapy [IMvigor130]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02807636.  [PubMed]  [DOI]
64.  Hoffmann-La Roche. A Study of Atezolizumab (MPDL3280A) Compared With a Platinum Agent (Cisplatin or Carboplatin) (Pemetrexed or Gemcitabine) in Participants With Stage IV Non-Squamous or Squamous Non-Small Cell Lung Cancer (NSCLC) [IMpower110]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02409342.  [PubMed]  [DOI]
65.  Hoffmann-La Roche. A Study of Atezolizumab (MPDL3280A) Compared With Gemcitabine Cisplatin or Carboplatin in Patients With Stage IV Squamous Non-Small Cell Lung Cancer [IMpower111]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02409355.  [PubMed]  [DOI]
66.  Hoffmann-La Roche. A Study of Atezolizumab in Combination With Carboplatin Paclitaxel or Carboplatin Nab-paclitaxel Compared With Carboplatin Nab-paclitaxel in Participants With Stage IV Squamous Non-small Cell Lung Cancer (NSCLC) [IMpower 131]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02367794.  [PubMed]  [DOI]
67.  Hoffmann-La Roche. A Study of Atezolizumab Compared With Docetaxel in Non-Small Cell Lung Cancer (NSCLC) After Failure With Platinum-Containing Chemotherapy [IMpower210]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02813785.  [PubMed]  [DOI]
68.  Hoffmann-La Roche. A Phase III Study of MPDL3280A (Anti-PD-L1 Antibody) in Combination With Non-Squamous Non-Small Cell Lung Cancer (IMpower130). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02367781.  [PubMed]  [DOI]
69.  Hoffmann-La Roche. A Phase III Study of MPDL3280A (Anti-PD-L1 Antibody) In Combination With Carboplatin Paclitaxel With or Without Bevacizumab in Patients With Stage IV Non-Squamous Non-Small Cell Lung Cancer (NSCLC) (IMpower150). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02366143.  [PubMed]  [DOI]
70.  Hoffmann-La Roche. A Study of Atezolizumab (Anti-PD-L1 Antibody) in Combination With Nab Paclitaxel Compared With Placebo With Nab Paclitaxel for Patients With Previously Untreated Metastatic Triple Negative Breast Cancer (IMpassion130). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02425891.  [PubMed]  [DOI]
71.  Hoffmann-La Roche. A Study Of Atezolizumab (Anti-PD-L1 Antibody) in Combination With Bevacizumab Versus Sunitinib in Patients With Untreated Advanced Renal Cell Carcinoma. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02420821.  [PubMed]  [DOI]
72.  Hoffmann-La Roche. A Study of Carboplatin Plus Etoposide With or Without Atezolizumab in Participants With Untreated Extensive-Stage Small Cell Lung Cancer (IMpower133). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02763579.  [PubMed]  [DOI]
73.  Hoffmann-La Roche. A Study to Investigate Efficacy and Safety of Cobimetinib Plus Atezolizumab and Atezolizumab Monotherapy Versus Regorafenib in Participants With Metastatic Colorectal Adenocarcinoma. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02788279.  [PubMed]  [DOI]
74.  AstraZeneca. Phase III Open-label Study of MEDI4736 With/Without Tremelimumab Versus Standard of Care (SOC) in Recurrent/Metastatic Head and Neck Cancer (KESTREL). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02551159.  [PubMed]  [DOI]
75.  AstraZeneca. Phase III Open Label First Line Therapy Study of MEDI 4736 (Durvalumab) With or Without Tremelimumab Versus SOC in Non Small-Cell Lung Cancer (NSCLC). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02453282.  [PubMed]  [DOI]
76.  AstraZeneca. Study of MEDI4736 With or Without Tremelimumab Versus Standard of Care Chemotherapy in Urothelial Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02516241.  [PubMed]  [DOI]
77.  Southwest Oncology Group. Lung-MAP: Biomarker-Targeted Second-Line Therapy in Treating Patients With Recurrent Stage IV Squamous Cell Lung Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02154490.  [PubMed]  [DOI]
78.  AstraZeneca. Study of AZD9291 Plus MEDI4736 Versus AZD9291 Monotherapy in NSCLC After Previous EGFR TKI Therapy in T790M Mutation Positive Tumours (CAURAL). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02454933.  [PubMed]  [DOI]
79.  AstraZeneca. Study of MEDI4736 Monotherapy and in Combination With Tremelimumab Versus Standard of Care Therapy in Patients With Head and Neck Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02369874.  [PubMed]  [DOI]
80.  AstraZeneca. Study of 1st Line Therapy Study of MEDI4736 With Tremelimumab Versus SoC in Non Small-Cell Lung Cancer (NSCLC) (NEPTUNE). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02542293.  [PubMed]  [DOI]
81.  AstraZeneca. A Global Study to Assess the Effects of MEDI4736, Given as Monotherapy or in Combination With Tremelimumab Determined by PD-L1 Expression Versus Standard of Care in Patients With Locally Advanced or Metastatic Non Small Cell Lung Cancer (ARCTIC). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02352948.  [PubMed]  [DOI]
82.  Merck Sharp & Dohme Corp. A Study of Pembrolizumab (MK-3475) for First Line Treatment of Recurrent or Metastatic Squamous Cell Cancer of the Head and Neck (MK-3475-048/KEYNOTE-048). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https: //clinicaltrials.gov/ct2/show/NCT02358031.  [PubMed]  [DOI]
83.  Bristol-Myers Squibb. Study of Nivolumab in Combination With Ipilimumab Compared to the Standard of Care (Extreme Study Regimen) as First Line Treatment in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (CheckMate 651). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02741570.  [PubMed]  [DOI]
84.  Bristol-Myers Squibb. A Study of Nivolumab Compared to Sorafenib as a Primary Treatment in Patients With Advanced Hepatocellular Carcinoma. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02576509.  [PubMed]  [DOI]
85.  Ono Pharmaceutical Co. Ltd. Study of ONO-4538 in Unresectable Advanced or Recurrent Gastric Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02576509.  [PubMed]  [DOI]
86.  Ono Pharmaceutical Co. Ltd. Study of ONO-4538 in Unresectable Advanced or Recurrent Esophageal Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02569242.  [PubMed]  [DOI]
87.  Bristol-Myers Squibb. Nivolumab Combined With Ipilimumab Versus Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (CheckMate 214). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02231749.  [PubMed]  [DOI]
88.  Bristol-Myers Squibb. A Study of the Effectiveness and Safety of Nivolumab Compared to Bevacizumab and of Nivolumab With or Without Ipilimumab in Glioblastoma Patients (CheckMate 143). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02017717.  [PubMed]  [DOI]
89.  Bristol-Myers Squibb. Trial of Nivolumab vs Therapy of Investigator’s Choice in Recurrent or Metastatic Head and Neck Carcinoma (CheckMate 141). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02105636.  [PubMed]  [DOI]
90.  Bristol-Myers Squibb. A Trial of Nivolumab, or Nivolumab Plus Ipilimumab, or Nivolumab Plus Platinum-doublet Chemotherapy, Compared to Platinum Doublet Chemotherapy in Patients With Stage IV Non-Small Cell Lung Cancer (NSCLC) (CheckMate 227). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02477826.  [PubMed]  [DOI]
91.  Bristol-Myers Squibb. A Study of Nivolumab, or Nivolumab in Combination With Ipilimumab, or Placebo in Patients With Extensive-Stage Disease Small Cell Lung Cancer (ED-SCLC) After Completion of Platinum-based Chemotherapy (CheckMate 451). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02538666.  [PubMed]  [DOI]
92.  Bristol-Myers Squibb. Study of Nivolumab Compared to Temozolomide, Given With Radiation Therapy, for Newly-diagnosed Patients With Glioblastoma (GBM, a Malignant Brain Cancer) (CheckMate 498). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02617589.  [PubMed]  [DOI]
93.  Bristol-Myers Squibb. Effectiveness Study of Nivolumab Compared to Chemotherapy in Patients With Relapsed Small-cell Lung Cancer (CheckMate331). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02481830.  [PubMed]  [DOI]
94.  Bristol-Myers Squibb. Efficacy Study of Nivolumab Compared to Docetaxel in Subjects Previously Treated With Advanced or Metastatic Non Small Cell Lung Cancer (CheckMate 078). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02613507.  [PubMed]  [DOI]
95.  National Cancer Institute (NCI). Nivolumab and Ipilimumab With or Without Sargramostim in Treating Patients With Stage III-IV Melanoma That Cannot Be Removed by Surgery. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02339571.  [PubMed]  [DOI]
96.  Bristol-Myers Squibb. Nivolumab Combined With Ipilimumab Followed by Nivolumab Monotherapy as First-Line Treatment for Patients With Advanced Melanoma (CheckMate 401). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).  Available from: https://clinicaltrials.gov/ct2/show/NCT02599402.  [PubMed]  [DOI]
97.  Buti S, Bersanelli M. The ‘nivolution’ in renal cell carcinoma: behind the scenes of clinical trials. Future Oncol. 2016;12:2061-2063.  [PubMed]  [DOI]
98.  Facchinetti F, Marabelle A, Rossi G, Soria JC, Besse B, Tiseo M. Moving Immune Checkpoint Blockade in Thoracic Tumors beyond NSCLC. J Thorac Oncol. 2016;11:1819-1836.  [PubMed]  [DOI]
99.  Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373:1803-1813.  [PubMed]  [DOI]
100.  Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16:1473-1482.  [PubMed]  [DOI]
101.  Buti S, Bersanelli M. Combination therapy in kidney cancer: the next revolution? Lancet Oncol. 2015;16:1441-1442.  [PubMed]  [DOI]
102.  A Phase III Randomized, Open-label Study to Evaluate Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Axitinib Versus Sunitinib Monotherapy as a First-line Treatment for Locally Advanced or Metastatic Renal Cell Carcinoma (mRCC) (KEYNOTE-426)  NCT02853331.  [PubMed]  [DOI]
103.  Kim J. Immune checkpoint blockade therapy for bladder cancer treatment. Investig Clin Urol. 2016;57 Suppl 1:S98-S105.  [PubMed]  [DOI]
104.  Fahmy O, Khairul-Asri MG, Stenzl A, Gakis G. The current status of checkpoint inhibitors in metastatic bladder cancer. Clin Exp Metastasis. 2016;33:629-635.  [PubMed]  [DOI]
105.  Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O’Donnell PH, Balmanoukian A, Loriot Y. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387:1909-1920.  [PubMed]  [DOI]
106.  Economopoulou P, Kotsantis I, Psyrri A. Checkpoint Inhibitors in Head and Neck Cancer: Rationale, Clinical Activity, and Potential Biomarkers. Curr Treat Options Oncol. 2016;17:40.  [PubMed]  [DOI]
107.  Hamanishi J, Mandai M, Konishi I. Immune checkpoint inhibition in ovarian cancer. Int Immunol. 2016;28:339-348.  [PubMed]  [DOI]
108.  Burgess M, Gorantla V, Weiss K, Tawbi H. Immunotherapy in Sarcoma: Future Horizons. Curr Oncol Rep. 2015;17:52.  [PubMed]  [DOI]
109.  Matsuki E, Younes A. Checkpoint Inhibitors and Other Immune Therapies for Hodgkin and Non-Hodgkin Lymphoma. Curr Treat Options Oncol. 2016;17:31.  [PubMed]  [DOI]
110.  Kunk PR, Bauer TW, Slingluff CL, Rahma OE. From bench to bedside a comprehensive review of pancreatic cancer immunotherapy. J Immunother Cancer. 2016;4:14.  [PubMed]  [DOI]
111.  Sanchez-Castañón M, Er TK, Bujanda L, Herreros-Villanueva M. Immunotherapy in colorectal cancer: What have we learned so far? Clin Chim Acta. 2016;460:78-87.  [PubMed]  [DOI]
112.  Bedognetti D, Maccalli C, Bader SB, Marincola FM, Seliger B. Checkpoint Inhibitors and Their Application in Breast Cancer. Breast Care (Basel). 2016;11:108-115.  [PubMed]  [DOI]
113.  Helissey C, Vicier C, Champiat S. The development of immunotherapy in older adults: New treatments, new toxicities? J Geriatr Oncol. 2016;7:325-333.  [PubMed]  [DOI]
114.  Abdel-Wahab N, Shah M, Suarez-Almazor ME. Adverse Events Associated with Immune Checkpoint Blockade in Patients with Cancer: A Systematic Review of Case Reports. PLoS One. 2016;11:e0160221.  [PubMed]  [DOI]
115.  Champiat S, Lambotte O, Barreau E, Belkhir R, Berdelou A, Carbonnel F, Cauquil C, Chanson P, Collins M, Durrbach A. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol. 2016;27:559-574.  [PubMed]  [DOI]
116.  Hodi FS, Hwu WJ, Kefford R, Weber JS, Daud A, Hamid O, Patnaik A, Ribas A, Robert C, Gangadhar TC. Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With Advanced Melanoma Treated With Pembrolizumab. J Clin Oncol. 2016;34:1510-1517.  [PubMed]  [DOI]
117.  Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.  [PubMed]  [DOI]
118.  Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, Maio M, Binder M, Bohnsack O, Nichol G. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412-7420.  [PubMed]  [DOI]
119.  Ades F, Yamaguchi N. WHO, RECIST, and immune-related response criteria: is it time to revisit pembrolizumab results? Ecancermedicalscience. 2015;9:604.  [PubMed]  [DOI]
120.  Carbognin L, Pilotto S, Milella M, Vaccaro V, Brunelli M, Caliò A, Cuppone F, Sperduti I, Giannarelli D, Chilosi M. Differential Activity of Nivolumab, Pembrolizumab and MPDL3280A according to the Tumor Expression of Programmed Death-Ligand-1 (PD-L1): Sensitivity Analysis of Trials in Melanoma, Lung and Genitourinary Cancers. PLoS One. 2015;10:e0130142.  [PubMed]  [DOI]
121.  Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563-567.  [PubMed]  [DOI]
122.  McDermott DF, Sosman JA, Sznol M, Massard C, Gordon MS, Hamid O, Powderly JD, Infante JR, Fassò M, Wang YV. Atezolizumab, an Anti-Programmed Death-Ligand 1 Antibody, in Metastatic Renal Cell Carcinoma: Long-Term Safety, Clinical Activity, and Immune Correlates From a Phase Ia Study. J Clin Oncol. 2016;34:833-842.  [PubMed]  [DOI]
123.  Taube JM, Young GD, McMiller TL, Chen S, Salas JT, Pritchard TS, Xu H, Meeker AK, Fan J, Cheadle C. Differential Expression of Immune-Regulatory Genes Associated with PD-L1 Display in Melanoma: Implications for PD-1 Pathway Blockade. Clin Cancer Res. 2015;21:3969-3976.  [PubMed]  [DOI]
124.  Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015;372:2509-2520.  [PubMed]  [DOI]
125.  Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, Blosser RL, Fan H, Wang H, Luber BS. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015;5:43-51.  [PubMed]  [DOI]
126.  Howitt BE, Shukla SA, Sholl LM, Ritterhouse LL, Watkins JC, Rodig S, Stover E, Strickland KC, D’Andrea AD, Wu CJ. Association of Polymerase e-Mutated and Microsatellite-Instable Endometrial Cancers With Neoantigen Load, Number of Tumor-Infiltrating Lymphocytes, and Expression of PD-1 and PD-L1. JAMA Oncol. 2015;1:1319-1323.  [PubMed]  [DOI]
127.  Harris SJ, Brown J, Lopez J, Yap TA. Immuno-oncology combinations: raising the tail of the survival curve. Cancer Biol Med. 2016;13:171-193.  [PubMed]  [DOI]
128.  van der Most RG, Currie AJ, Mahendran S, Prosser A, Darabi A, Robinson BW, Nowak AK, Lake RA. Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy. Cancer Immunol Immunother. 2009;58:1219-1228.  [PubMed]  [DOI]
129.  van der Most RG, Currie AJ, Cleaver AL, Salmons J, Nowak AK, Mahendran S, Larma I, Prosser A, Robinson BW, Smyth MJ. Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-dependent CD8 T cell-mediated immune attack resulting in suppression of tumor growth. PLoS One. 2009;4:e6982.  [PubMed]  [DOI]
130.  Kroemer G, Senovilla L, Galluzzi L, André F, Zitvogel L. Natural and therapy-induced immunosurveillance in breast cancer. Nat Med. 2015;21:1128-1138.  [PubMed]  [DOI]
131.  Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G. Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. Cancer Cell. 2015;28:690-714.  [PubMed]  [DOI]
132.  Demaria S, Ng B, Devitt ML, Babb JS, Kawashima N, Liebes L, Formenti SC. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys. 2004;58:862-870.  [PubMed]  [DOI]
133.  Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, Mu Z, Rasalan T, Adamow M, Ritter E. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:925-931.  [PubMed]  [DOI]
134.  Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373:1270-1271.  [PubMed]  [DOI]
135.  Abbas AK, Lichtman AH, Pober JS.   Cellular and molecular immunology. 8th ed. Elsevier. ISBN-13 987-0323222754.  [PubMed]  [DOI]
136.  Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16:522-530.  [PubMed]  [DOI]
137.  van der Most RG, Currie AJ, Robinson BW, Lake RA. Decoding dangerous death: how cytotoxic chemotherapy invokes inflammation, immunity or nothing at all. Cell Death Differ. 2008;15:13-20.  [PubMed]  [DOI]
138.  Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27:1492-1504.  [PubMed]  [DOI]