Published online Feb 10, 2017. doi: 10.5306/wjco.v8.i1.37
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
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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.
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.
- Citation: Bersanelli M, Buti S. From targeting the tumor to targeting the immune system: Transversal challenges in oncology with the inhibition of the PD-1/PD-L1 axis. World J Clin Oncol 2017; 8(1): 37-53
- URL: https://www.wjgnet.com/2218-4333/full/v8/i1/37.htm
- DOI: https://dx.doi.org/10.5306/wjco.v8.i1.37
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.
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 |
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.
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.
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].
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 |
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].
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 |
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].
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.
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 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].
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].
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.
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.
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.
Manuscript source: Invited manuscript
Specialty type: Oncology
Country of origin: Italy
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P- Reviewer: Qin JM, Tirumani SH, Tomizawa M, Tsikouras PPT, Zhang L S- Editor: Ji FF L- Editor: A E- Editor: Wu HL
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