key: cord-0809800-5s5iktle
authors: Plavc, Gaber; Strojan, Primoz
title: Combining Radiotherapy and Immunotherapy in Definitive Treatment of Head and Neck Squamous Cell Carcinoma: Review of Current Clinical Trials
date: 2020-10-11
journal: Radiol Oncol
DOI: 10.2478/raon-2020-0060
sha: e1754767b1bb69cc9ad921694b4141474c57eae7
doc_id: 809800
cord_uid: 5s5iktle

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) presents as locally advanced disease in a majority of patients and is prone to relapse despite aggressive treatment. Since immune checkpoint inhibitors (ICI) have shown clinically significant efficacy in patients with recurrent/metastatic HNSCC (R/M HNSCC), a plethora of trials are investigating their role in earlier stages of disease. At the same time, preclinical data showed the synergistic role of concurrently administered radiotherapy and ICIs (immunoradiotherapy) and explained several mechanisms behind it. Therefore, this approach is prospectively tested in a neoadjuvant, definitive, or adjuvant setting in non-R/M HNSCC patients. Due to the intricate relationship between host, immunotherapy, chemotherapy, and radiotherapy, each of these approaches has its advantages and disadvantages. In this narrative review we present the biological background of immunoradiotherapy, as well as a rationale for, and possible flaws of, each treatment approach, and provide readers with a critical summary of completed and ongoing trials. CONCLUSIONS: While immunotherapy with ICIs has already become a standard part of treatment in patients with R/M HNSCC, its efficacy in a non-R/M HNSCC setting is still the subject of extensive clinical testing. Irradiation can overcome some of the cancer’s immune evasive manoeuvres and can lead to a synergistic effect with ICIs, with possible additional benefits of concurrent platinum-based chemotherapy. However, the efficacy of this combination is not robust and details in trial design and treatment delivery seem to be of unprecedented importance.

Head and neck squamous cell carcinoma (HNSCC) accounts for more than 800,000 new cancer cases and over 400,000 deaths each year worldwide. 1 Despite aggressive therapeutic approaches the outcomes are still highly dependent on disease burden. Five-year disease control ranges from almost 100% in patients with T1a glottic carcinoma to below 30% in patients with locally-advanced hypopharyngeal cancer. 2, 3 More than 60% of all cases are locally-advanced at diagnosis with a 50% rate of relapse in the first two years, despite the use of multimodal state-of-the-art treatment. 4 Therefore, while treatment-related toxicity is now of primary concern in early stage HNSCC and low-risk human papilloma virus (HPV) mediated oropharyngeal carcinomas, with 3-year overall survival rates in excess of 90% 5, 6 , in other patients the focus of research is on treatment intensification and/or modification.

After intrinsic tumour suppressor mechanisms fail, further tumour progression is the result of an inefficient elimination phase or equilibrium phase of the extrinsic tumour suppression by the immune system. 7 Genetically unstable cancer cells under constant immune selection pressure evade immune recognition and destruction. Thus, they become invisible to immune cells by reducing the presentation of tumour antigens, decreasing their sensitivity to the cytotoxic effects of immune cells, and rendering their microenvironment immunosuppressive. 7 In the fight against the latter, immune checkpoint inhibitors (ICI) targeting immune checkpoint programmed cell death protein 1 (anti-PD-1) are now considered standard care in recurrent and metastatic HNSCC (R/M HNSCC). 8, 9 Because of their proven efficacy and significantly improved toxicity profile as well as positive effect on quality of life as compared to standard chemotherapy regimens, an increasing number of trials are testing ICIs in the earlier stages of HNSCC. [10] [11] [12] Besides a well-known immunosuppressive effect of radiotherapy (RT), it can also lead to positive alterations in innate and adaptive immunity. 13 The same is true for the positive effects of the immune system on radiation efficacy, as a tumoricidal effect of RT is dependent on functional T cells, even at ablative doses. 14 Furthermore, RT induces programmed death-ligand 1 (PD-L1) expression in dendritic cells (DCs) and cancer cells which contributes to acquired cancer radioresistance, which could be overcome by concurrent anti-PD-1/L1. 15 These intricate interactions form the basis for combined treatment with RT and ICIs (immunoradiotherapy). This combination was shown to cause similar toxicity compared to either RT or ICI alone across different cancer types. 16 Encouraging efficacy of this treatment combination has also been shown in early prospective trials in metastatic malignant melanoma and non-small cell lung cancer. [17] [18] [19] [20] [21] The first results of trials using immunoradiotherapy in non-R/M HNSCC are now also available and many are underway. In this review we presented a biological rationale for the combination of RT and anti-PD-1/L1 and performed a systematic search for, and critical assessment of, completed and ongoing trials using a combination in non-R/M HNSCC.

The efficacy of anti-PD1 therapy in HNSCC is poor with less than 20% of responding patients. 8, 22, 23 These high rates of primary or acquired resistance in R/M HNSCC to anti-PD1 agents are a result of absent antigenic proteins, defective antigen presentation, T cell exhaustion/absence, insensibility of tumours to T cells, presence of immunosuppressive cells, and/or presence of other inhibitory immune checkpoints. 24 For the immune system to exert its cytotoxic function, mutant peptides, also known as tumour neoantigens (TNA) or ectopically expressed antigens, must be presented to antigen-presenting cells by cancer cells on major histocompatibility complex I (MHC I). 25 Even though the tumour mutation burden in HNSCC is rather high with 5 mutations per million base pairs, a proper presentation is needed for them to elicit an immune response. 26, 27 A vital role of antigen processing machinery in this step is evident by the absence of CD8 + T cell recognition of HNSCC in the case of defective antigen processing machinery (defect present in 20-80% of HNSCCs). 28-30 The next step is presentation of the TNA by MHC I. The complete loss of MHC I results in natural killer (NK) cells' activation, while aberrant expression is beneficial for cancer cells and is present in up to 60% of HNSCCs. 31-33 Up to 80% of HNSCC patients overexpress the epidermal growth factor receptor (EGFR), which also downregulates MHC I. 34 Treatment with anti-PD-1 was shown to be less efficient in cancers with aberrant MHC I. 35, 36 Yet tumour antigenicity is not enough to elicit immune response by itself. TNA presentation must be put in context by accompanying adjuvants in the form of danger-associated molecular patterns (DAMP) which are recognised by pattern recognition receptors on the cells of innate immunity. Different types of DAMPs are exposed by different modes of cell death and even by stressed cancer cells. 37 These include membrane-bound calreticulin, emitted ATP, and passively released nuclear high-mobility group box protein 1 (HMGB1). This leads to the recruitment and activation of dendritic (DCs) and other mononuclear cells. 38, 39 DCs crosspresent antigens to naïve CD8 + T and by co-stimulatory signals (ligands and cytokines provided by DCs upon stimulation by DAMPs and type I interferons [IFNs]) prime these cytotoxic T lymphocytes in regional lymph nodes. 40 Type I IFN is produced by cancer cells as a result of a stimulator of interferon genes (STING) responding to DNA in the cytosol of cancer cell, which is a consequence of cancer's unstable genome. 41, 42 To prevent unnecessary damage to surrounding tissue in their fight against viruses, CD8 + T lymphocytes also express inhibitory receptors, such as PD-1, with its ligand PD-L1 on host tissue and immune cells. 43 The same PD-L1 expression is exploited by cancer cells to escape immune surveillance. 44 An active PD-1/PD-L1 pathway in tumour microenvironment (TME) also promotes T cell exhaustion and differentiation of regulatory T cells (Treg). 45 Primed tumour-infiltrating lymphocytes (TILs) that are suppressed due to PD-1/PD-L1 interaction are vital for anti-PD-1 efficacy, which also tips the balance from differentiation of exhausted T cells and Tregs towards generation of effector T cells. 45, 46 Immunostimulatory effect of RT depends a great deal on inducing the above-described immunogenic cell death, with dose-dependent (from 2 to 20 Gy) increase in concentrations of DAMPs calreticulin, HMGB1, and ATP. 47 RT also produces free cytosolic DNA which is more pronounced in cancers with a loss of p53 function, as is the case in the majority of HNSCC. 48, 49 Cytosolic DNA is sensed by various pattern recognition receptors with STING being a central connecting protein.

Activation of the cyclic GMP-AMP synthase-STING (cGAS-STING) pathway by free cytosolic DNA leads to type I IFN production in cancer and DCs. 41, 50 Regarding antigenicity, RT increases MHC I expression and diversifies the tumour-infiltrating T cell receptor repertoire which is a positive predictor of response to anti-PD-1/L1. [51] [52] [53] Previously silent mutated genes can be expressed by RT, thus leading to presentation of these TNAs by MHC I. 54, 55 RT also induces some constituents of antigen processing machinery by enhancing degradation of proteins into peptides. 51 The positive effects of RT are also apparent in TME. By reducing tumour hypoxia and consequently reducing the expression of vascular endothelial growth factor , SBRT can inhibit mobilisation of myeloid-derived suppressor cells (MDSC). 56 Some authors also observed an enhanced recruitment of T cells into TME after RT. 57 RT-enhanced death receptor Fas expression further promotes the antitumour activity of recruited T cells. 58, 59 Furthermore, RT promotes the function and differentiation of cytotoxic T cells by inducing interleukin-1B, tumour necrosis factor-α, and interleukin-6. 13 Considering vasculature, low dose RT increases the ratio of antitumoural macrophages type 1 and tumour-promoting macrophages type 2, which leads to vascular normalisation and T cell recruitment. 60 Besides, low dose RT also appears to decrease TME's immunosuppressive cells such as Tregs and MDSCs. 61 Another beneficial vasculature-related effect of RT is induction of cell adhesion molecules, for example Intercellular Adhesion Molecule 1 and E-selectin, that help leukocytes extravasate to TME. 62 Importantly, as a part of standard treatment in HNSCC, concurrent platin-based chemoradiotherapy (CRT) was also shown to induce immunogenic cell death. 47 In the in vitro model, antigen presentation and T cell cytotoxicity were enhanced by moderate doses of cisplatin. In the in vivo mouse model synergism of cisplatin and anti-PD-1 was observed. 63 However, cisplatin also resulted in PD-L1 upregulation on cancer cells and higher doses were immunosuppressive. Nevertheless, Luo et al. showed on murine cancer models that cisplatin combined with anti-PD-1 treatment enhances RTinduced abscopal effect in non-irradiated nodes. 64 It should be noted that all the above-mentioned effects of RT were observed in preclinical studies and are not universally beneficial, as was shown in clinical setting. Release of DAMPs HMGB1 and ATP, which is degraded into extracellular adenosine, can have many immunosuppressive effects. [65] [66] [67] [68] [69] [70] Activation of cGAS-STING can lead to increased concentrations of MDSC in TME and even increase cancer aggressiveness. 71,72 STING activation can also lead to depletion of tryptophan in TME via upregulation of Indoleamine 2,3-dioxygenase, resulting in reduced T cell cytotoxicity and increased tumour-associated macrophages and MDSCs. 73, 74 Even sustained type I IFN signalling is detrimental as it results in increased Treg and MDSC concentrations in TME and enhanced expression of PD-1. 75 Besides, RT increases tumour growth factor beta concentration which was shown to promote tumour-promoting macrophages type 2 differentiation and inhibit DCs and cytotoxic T cells. 13 In addition, RT was shown to even upregulate hypoxia inducible factor-1α, leading to eventual Treg and MDSC accumulation and DC and T cell inhibition via vascular endothelial growth factor. [76] [77] [78] [79] [80] 

We searched PubMed and Clinicaltrials.gov databases with search terms ((immunoradiotherapy OR radioimmunotherapy) OR ((head and neck) OR (oral cavity) OR (oropharyngeal) OR (oropharynx) OR (larynx) OR (laryngeal) OR (hypopharynx) OR (hypopharyngeal)) AND (immunotherapy OR checkpoint OR pembrolizumab OR avelumab OR atezolizumab OR camrelizumab OR durvalumab OR avelumab OR nivolumab OR toripalimab OR PD-1 OR PD-L1 OR tremelimumab OR CTLA-4) AND (radiotherapy OR SBRT OR RT OR SABR OR irradiation) and with the start date of the studies from 15 th July 2013 to 15 th July 2020. In total, 39 completed or ongoing trials were found, using concurrent (chemo)radiotherapy and ICIs in primary definitive treatment of non-R/M HNSCC (non-nasopharyngeal).

In completed and ongoing trials, concurrent anti-PD-1/L1 and RT was delivered either before or after surgery, or as a sole definitive treatment. Few delivered anti-PD-1/L1 also as an extended consolidative treatment. Taking the intricate relationship between the immune system and therapy into account, attention to the below-described caveats should help shed light on the pros and cons of these research approaches.

Except for the earliest stages of HNSCC, elective neck treatment either by lymphadenectomy or irradiation is part of the standard treatment. 81 Lymph nodes are also one of the places where DCs cross-prime CD8 + T lymphocytes. 82 Even though the immediate treatment effect of concurrent anti-PD-1 and RT depends primarily on TILs already present in the primary tumour, T cells from lymph nodes are responsible for long-lasting tumour control. 83, 84 Preclinical studies in murine cancer models clearly showed the vital role of functioning draining lymph nodes for RT efficacy with or without concurrent ICI. 85, 86 Removal of draining lymph nodes or elective nodal irradiation led to reduced tumour-specific TILs. 85, 86 Furthermore, clinical data show reduced efficacy of anti-PD-1 in previously treated patients with HNSCC. 87 This speaks strongly in favour of using an immunoradiotherapy combination before surgery as compared to its postoperative application. Neoadjuvant RT is not considered a standard of care in HNSCC, therefore these "window of opportunity trials" serve mostly to advance our understanding of the underlying mechanisms and to lay the ground for further studies. 88 Special attention must be therefore given to patient safety. In the, so far only, immunoradiotherapy "window of opportunity" trial that reported results, no surgical delays were noted. 89 The possibility of anti-PD-1 induced hyperprogression must nevertheless be kept in mind as it was reported in up to 29% of patients with R/M HNSCC. 90 The ongoing trials are presented in detail in Table 1 . Leidner et al. completed phase I of their phase I/II trial and already provided intriguing results. 89 In the first phase, 10 patients with stage I-III HPV associated HNSCC or cancer of unknown primary with clinical indications for adjuvant RT or who were ineligible for transoral robotic surgery were accrued. Two cohorts were formed of which five patients received neoadjuvant SBRT with 5x8 Gy (A cohort), and another five patients had SBRT with 3x8 Gy (B cohort), both with concurrent nivolumab. No grade 4 toxicity was observed, with somewhat higher grade 3 toxicity in the A cohort. Notably, grade 2 renal insufficiency was observed in 50% of patients. Both fractionation regimens were shown to be effective with 100% and 80% complete pathological responses in the A and B cohort, respectively. However, on presurgical imaging evaluated by RECIST criteria, no complete responses were found. Recently, preliminary results of their phase II cohort expansion were also presented. 91 Only the SBRT fractionation of the B cohort was further pursued. In cohort C inclusion criteria were the same as in cohorts A and B, while these six patients were treated with only neoadjuvant SBRT, followed by surgery and adjuvant nivolumab. Cohort D included only patients with HPV-negative HNSCC, and these five patients were treated the same as those in cohort B (SBRT with 3x8 Gy concurrently with nivolumab). Results were so far only vaguely described: there was no limiting toxicity, but the complete pathological response rate was somewhat lower than in cohorts A and B. In-detail results are awaited.

The approach to treatment was similar in HPVnegative HNSCC patients in the NCT03635164 trial, with the difference that anti-PD-L1 agent durvalumab was used instead of nivolumab. 91 The third ongoing trial (NCT03618134) with a similar approach is testing whether the addition of tremelimumab, an anti-cytotoxic T-lymphocyteassociated protein 4 (anti-CTLA-4), to durvalumab can improve the outcome in HPV-positive HNSCC patients. 92 T hese two ICIs provide complementary effects, albeit at the expense of increased toxicity. 93, 94 Definitive immunoradiotherapy

Considering only non-cancer/TME-related factors, synergism between anti-PD-1 and RT is probably most pronounced when these two treatment modalities are delivered concurrently in previously untreated patients with intact draining lymph nodes and no lymphopenia. [85] [86] [87] [95] [96] [97] [98] Definitive immunoradiotherapy as a sole treatment fulfils these criteria, except for nodal irradiation. If, in a neoadjuvant setting, elective nodal irradiation is not mandatory, its omission would be ill-advised in a definitive (chemo)radiotherapy setting based on our current knowledge. 81 However, advancement in diagnostic imaging and treatment (e.g. sentinel lymph node biopsy) provides the basis for ongoing trials testing reduced dose and/or volume of elective nodal irradiation which would be welcomed in immunoradiotherapy as well. 99 Preclinical studies also provide rather strong support for greater efficacy of hypofractionated RT compared to conventionally fractionated RT. 56, 100, 101 In contrast to all the above-listed trials with immunotherapy in the neoadjuvant setting, however, the definitive setting immunoradiotherapy trials mostly utilise conventionally fractionated RT courses as compared to hypofractionated SBRT. This could be an important outcome-defining factor.

Concurrent chemoradiotherapy with cisplatin causes severe radiomucositis (grade 3-4) in around 40% of HNSCC patients. 102, 103 Even though anti-PD-1/L1 induced oral mucositis or stomatitis occurs in less than 3% of patients and is usually mild, it can nevertheless occasionally be severe. 104 Special attention should be paid to this when using an approach with combined CRT and anti-PD-1/L1, despite the fact that pertinent trials have so far not reported exacerbated toxicity in oral mucosa (see below). Another important aspect of concurrent CRT and immunotherapy is the effect of chemotherapy on immunotherapy's efficacy which seems to be beneficial in low doses, whereas high-dose chemotherapy is known to cause myelosuppression and could be detrimental to the efficacy of immunotherapy. 63, 64 Several trials use ICI combined with cetuximab, an anti-EGFR agent. Cetuximab is a mouse/human chimeric monoclonal IgG1 antibody. 105 Besides acting through targeting EGFR and dysregulating its signaling pathway, it also stimulates NK cells anti-tumour activity, activates DCs, and recruits cytotoxic CD8 + T cells. 105 Cetuximab's ability to prime adaptive and innate immunity is met with regulatory immunosuppressive mechanisms. Targeting these immunosuppressive mechanisms (induction of Tregs, MDSC, PD-1, PD-L1, CTLA-4) by immunotherapy such as ICI has great potential and is still being tested in several trials. 106 A prospective trial using anti-PD-1 combined with cetuximab in 33 patients with platinum-refractory/ineligible R/M HNSCC showed a 41% response rate. About a third of patients experienced treatment-related grade 3 toxicity. 107 Furthermore, retrospectively gathered data on a triple combination of cetuximab, chemotherapy and anti-PD-1 used in 15 patients with R/M HNSCC was presented in 2018 by Lin et al. 108 The combination seemed effective with 58% partial responses and acceptable toxicity.

Completed and ongoing trials treating patients with non-R/M HNSCC with a definitive immunoradiotherapy combination are presented in Table 2 , while important details are presented below.

JAVELIN Head and Neck 100 (NCT02952586) is the first randomised phase III trial combining CRT with concomitant ICI in patients with LAHNSCC to be terminated due to inefficiency. 109 Concurrent administration of a PD-L1 inhibitor avelumab and standard CRT (70 Gy and high-dose cisplatin) followed by maintenance avelumab for 12 months was compared to a placebo arm receiving the same CRT but with placebo instead of avelumab in 697 high-risk LAHNSCC patients. 110 A pre-planned interim analysis showed that this combination is unlikely to show a significant improvement in progression-free survival and the trial was therefore terminated. Detailed study findings are awaited.

In a GORTEC 2017-01 REACH trial (NCT02999087), two standard arms (CRT with a three-weekly high-dose cisplatin in a cohort of patients fit for high-dose cisplatin, and RT with concurrent cetuximab in a cohort of patients unfit for high-dose cisplatin) were compared to experimental arms with the same RT regimen and concurrent avelumab and cetuximab (preliminary results, Table 2 ). 111, 112 All patients completed RT except for one cisplatin-ineligible patient receiving RT concurrently with avelumab and cetuximab. 88% and 76% of patients received all planned doses of avelumab and cetuximab, respectively. A grade ≥4 adverse effect occurred in 5/41 (12%) patients in experimental arms (all in the cohort of patients ineligible for high-dose cisplatin), and in 5/41 (12%) patients in standard arms (14% in high-dose cisplatin eligible and 10% in high-dose cisplatin ineli-gible patients) where one grade 5 toxicity was also observed. The trial continues.

In 2019, results of the lead-in phase of randomised phase II/III trial NRG-HN004 (NCT03258554) were presented. Ten out of a planned 523 cisplatin-ineligible patients received durvalumab concomitantly with RT and all completed RT as planned, while 8/10 patients received all the planned durvalumab cycles. Randomisation will continue to either RT with durvalumab or RT with cetuximab. 113 The GORTEC 2015-01 PembroRad randomised phase II trial's safety-related results were presented in 2018. 114 In 133 cisplatin ineligible patients with LAHNSCC cetuximab or pembrolizumab were added to conventional RT, which resulted in a similar completion rate of RT (86 vs. 88%) and dysphagia (34 vs. 39%). However, mucositis was more prevalent in the cetuximab arm and the same goes for dermatitis (49 vs. 17%) ( Table 2 ). Final results are still awaited.

The results of the first 16 randomised patients of the planned 120 patients with HPV-LAHNSCC in a DURTRE-RAD trial (NCT03624231) were recently presented. 115 Among the first six patients treated with a combination of RT, durvalumab and tremelimumab (arm A), five patients (83%) stopped treatment due to immune-related adverse effects (irAE), of which one was grade 5. This arm was terminated due to excessive toxicity. Arm B with only durvalumab added to RT, which resulted in only 1/10 patients stopping treatment due to irAE, is continuing to enrol. Weiss et al. (NCT02609503) presented the results of their phase II trial after a median follow-up of 21 months. 116 In 29 cisplatin ineligible patients with LAHNSCC pembrolizumab was given concurrently with definitive RT and for an additional three adjuvant cycles ( Table 2 ). The estimated two-year overall and progression-free survival was 75% and 71% respectively. RT was delivered in full in 28/29 patients, and 25/29 patients received all pembrolizumab doses. Toxicities were mild with a major exception being grade 3-4 lymphopenia, which occurred in 59% of patients, however, absolute lymphopenia did not predict for progression. Further characterisation of this unexpected lymphopenia showed declines in blood concentrations of B cells and CD4 + T cells, whereas CD8 + T cells were relatively preserved. 116 Powel et al. presented results from their phase I trial (NCT02586207), testing pembrolizumab with chemoradiotherapy in 59 patients with LAHNSCC. 117 Pembrolizumab was discontinued due to irAE in 9% during CRT and for non-irAE In the RTOG 3504, a phase I trial enrolling 40 patients with intermediate risk (HPV-associated oropharyngeal HNSCC, T1-2N2b-N3/T3-4N0-3, >10 pack-years or T4N0-N3, T1-3N3 ≤10 pack-years) or high-risk LAHNSCC (oral cavity, laryngeal, hypopharyngeal, or HPV-negative oropharyngeal HNSCC, T1-2N2a-N3 or T3-4N0-3), nivolumab was added to each of four (C)RT cohorts in a concurrent and adjuvant setting. [118] [119] [120] RT was delivered with either a weekly low-dose or three-weekly highdose cisplatin, with cetuximab, or as monotherapy ( Table 2) . T he addition of nivolumab concurrently to all four (C)RT regimens was found safe. Levels of dose-limiting toxicity were acceptable and after 17, 16, 10, and 6 months of median follow-up in each of the four RT cohorts there were 0/10 (RT plus weekly cisplatin), 1/9 (RT plus three-weekly cisplatin), 1/10 (RT plus cetuximab), and 3/10 (RT only) events (i.e. death or disease progression), respectively. However, adjuvant administration of nivolumab was infeasible after (C)RT in cisplatinineligible patients or in those who received highdose three-weekly concurrent cisplatin. Data from the first 12 patients (planning to enrol 24 patients) from the NCT03162731 phase I trial, adding nivolumab and ipilimumab to standard RT in high-risk LAHNSCC, were also presented. 121 After a follow-up of 7.2-18.4 months, 10 of the 12 patients are alive with no evidence of disease. Major toxicities are presented in Table 2 .

Elbers et al. recently reported results from their phase I trial (NCT02938273) in 10 cisplatin ineligible patients with LAHNSCC that received avelumab and cetuximab in conjunction with RT, followed by avelumab as a maintenance therapy for an additional four months (Table 2) . 122 After a median follow-up of 12 months disease recurred in 50% of the patients. The majority of adverse effects were related to RT and cetuximab; grade 3 irAE occurred in four patients and were successfully managed.

An innovative approach is used in the CheckRad-CD8 phase II trial (NCT03426657) in which 120 patients with LAHNSCC have a second biopsy after induction durvalumab, tremelimumab, cisplatin, and docetaxel therapy. In the case of increased CD8 + TILs compared to pre-treatment biopsy, patients receive concurrent durvalumab, tremelimumab, and RT. Non-responders continue with standard therapy outside of the trial. The interim analysis for the first 10 patients was presented in 2019. After induction therapy re-biopsies showed a complete pathological response in 8/10 patients with another two patients showing an in- crease in CD8 + TILs. There were two cases of grade III-IV toxicity: hepatitis and infectious diarrhoea. 123 Further results are awaited.

There are an additional 16 ongoing trials employing a combination of RT and ICIs that have not presented their results yet. Two of these are randomized phase III studies. The first one, KEYNOTE-412, will hopefully provide robust data to clarify the role of anti-PD-1 agent pembrolizumab given concomitantly with CRT and as a maintenance therapy in patients with locally advanced HNSCC. 124 The interpretation of the results could be hindered by the inability to discern the distinct effects of the priming, concurrent, and maintenance applications of pembrolizumab. Notably, a similar international phase III trial has previously been terminated due to slow accrual, and another similar trial, JAVELIN Head and Neck 100, testing the addition of anti-PD-L1 agent to CRT in LAHNSCC was terminated due to inefficiency. 109, 125 An additional phase III trial, NRG-HN005, is a non-inferiority trial, testing treatment de-escalation in patients with early stage HPV-positive oropharyngeal carcinoma. 126 A reduced dose RT, concurrently with either cisplatin or nivolumab, will be compared to standard CRT with cisplatin. The results will add valuable information to expanding pool of knowledge from the de-escalation trials in patients with HPV-positive HNSCC.

A somewhat different approach will be examined in the NCT04369937. 127 HPV-16 E6/E7-specific therapeutic vaccination (ISA101b) will be administered to 50 patients with intermediate risk of HPV+ HNSCC one week prior to the start of pembrolizumab and two weeks prior to the start of CRT with cisplatin ( Table 2 ). The combination of ISA101 and nivolumab was already examined in a singlearm phase II trial where 24 patients with incurable HPV-positive cancers (22 oropharyngeal and one cervical and one anal cancer) were enrolled. An overall response rate of 33% with a median duration of response of 10.3 months and a median overall survival of 17.5 months seemed promising. 128 REWRITe (NCT03726775), a phase II trial that started in 2018, follows the recommendations from preclinical studies about omitting extended elective nodal irradiation when combining RT with immunotherapy. In this trial, patients with early stage T1-2 HNSCC or those with T3-4 disease and who are ineligible for cisplatin or cetuximab concurrently with RT will simultaneously receive durvalumab and RT to the primary tumour and immediately adjacent lymph nodes only. This will be followed by six months of maintenance durvalumab. 129 NCT02777385 is a phase II trial, planning to randomise 90 patients with LAHNSCC to either concurrent CRT with cisplatin and pembrolizumab or to CRT followed by pembrolizumab (Table 2) . 130 It will hopefully help to answer if concurrent application is better than sequential or vice versa.

Testing novel treatments in an adjuvant setting offers a unique opportunity to stratify operated patients by risk of recurrence based on a detailed histopathological report, and therefore to avoid overtreatment. However, one should be aware of the above-described disadvantages when using immunotherapy with or without concurrent radiotherapy in patients with resected draining lymph nodes or after intensive treatment.

Two trials testing the potentials of adjuvant immunoradiotherapy reported early results. Wise-Draper et al. presented results of the lead-in stage of their phase II trial (NCT02641093). One to three weeks before planned surgery, patients who were clinically at high risk (cT3/4 stage and/or ≥2 +LNs) had one priming application of pembrolizumab followed by risk adjusted administration of adjuvant pembrolizumab in combination with RT or CRT. The pathological response to priming application of pembrolizumab was seen in 47% and was correlated with increased TILs. Adjuvant combination treatment with pembrolizumab and RT/CRT has an acceptable safety profile (Table 3) . 142 The other trial is a phase I NRG-HN003 trial that was conducted with the aim of determining a schedule for a phase II study. The tested regimen consisted of pembrolizumab added to adjuvant RT in patients with previously resected HPV-negative HNSCC with microscopically positive margins or an extracapsular extension of nodal metastases. 143 Pembrolizumab administered every three weeks in a dose of 200 mg for eight doses, starting the week before adjuvant CRT, was declared as worth pursuing. irAE were rare and non-significant (Table 3) .

Beside these, there are six more ongoing trials registered in the international databases delivering different concurrent immunoradiotherapy combinations in an adjuvant setting and three of them are randomised phase 3 trials. The experimental arm in KEYNOTE-689 (NCT03765918) is similar to the one in trial by Wise-Draper et al., except that two cycles of neoadjuvant pembrolizumab will be administered and longer maintenance therapy with pembrolizumab is planned. This will be com-pared to standard adjuvant CRT in LAHNSCC patients with either more than one pathological lymph node, microscopically positive margins or an extracapsular extension of nodal metastases. 144, 145 The two other randomised phase III trials, GORTEC 2018-01 (NCT03576417, also known as NIVOPOSTOP) 146 and ADHERE (NCT03673735) 147 , will both enrol patients with resected high-risk HNSCC and randomise them to either adjuvant CRT with concurrent nivolumab (NIVOPOSTOP)/ durvalumab (ADHERE), or to standard of care adjuvant CRT. Th ese three phase III trials could set ground for the new era in the setting of adjuvant treatment of a high-risk HNSCC based on pathological data (microscopically positive margins or extracapsular extension of nodal metastases). Currently, with adjuvant CRT locoregional relapse rates as well as distant metastases rates at five years are around 20% in these patients. 102, 148 Based on the preclinical data described above, it would be reasonable to expect a synergistic locoregional activity of radioimmunotherapy. A major drawback of adding immunotherapeutics to RT in postoperative setting could be the absence of regional lymph nodes that could hinder the efficacy of this combination. Nevertheless, ICIs will be delivered in doses that were shown to be effective systemically, therefore, it is justified to expect improved distant control of the disease. 8, 10 The other three phase I and phase II trials are presented in Table 3 .

In several of the above-described trials anti-PD-1/ L1 therapy is also applied as a prolonged adjuvant or maintenance therapy. Support for this approach comes from two other tumour types. In patients with unresectable locally-advanced non-squamous cell carcinoma lung cancer (NSCLC) without progression after definitive CRT, consolidation durvalumab was shown to prolong survival. 152 Also, after a complete resection of stage III melanoma, adjuvant ipilimumab prolonged overall survival compared to placebo, while adjuvant nivolumab compared head-to-head to adjuvant ipilimumab showed better relapse-free survival and less toxicity. Long-term data of the latter study are not yet available. 153, 154 Besides differences in tumour-intrinsic factors and the composition of their TME, another important aspect to consider is the different recurrence pattern of these tumours. While melanoma and NSCLC are prone to dissemination, HNSCC tends to recur more often locoregionally in previously treated tissue. After resection alone, stage III melanoma spreads to distant sites in more than 60% of cases, and stage III NSCLC relapses distantly after CRT alone in up to 50% of cases. 154, 155 On the other hand, the risk of distant metastases is around 15% in HNSCC, whereas isolated locoregional relapses are much more common. 4, 156 Whether consolidation anti-PD-1/L1 agents can decrease rates of distant metastases as well as locoregional relapses in HNSCC is still to be determined. Another important consideration in prolonged treatment with anti-PD-1/L1 agents is toxicity. Even though the overall effect on the quality of life with anti-PD-1 agents in R/M HNSCC was found to be positive and there were fewer adverse effects compared to standard chemotherapy, irAE nevertheless occurred in around 60% of patients with 17% of them experiencing a grade 3 or higher toxic event. 22, 157 Prolonged treatment with anti-PD-1/L1 agents should therefore be approached carefully and weighted against its toxicity. It should not be ignored that there is also financial toxicity associated with these treatments. It was estimated that in CheckMate 141 the incremental cost-effectiveness ratio per quality-adjusted life year for nivolumab was around 90,000 euros. 158 Even if the methods used in such calculations had some flaws, the financial burden of these new drugs is obvious and therefore special attention should already be paid in trial design. 158 Importantly, with the above-described trials it will be hard to discern the benefit of concurrent immunoradiotherapy from the benefit of maintenance immunotherapy as none of these trials compares this extended adjuvant treatment to a comparator arm without it. In either case, careful patient selection for immunotherapy, probably biomarker driven, will help to prevent unneces-sary additional toxicity and the financial burden of this treatment. Potential biomarkers for immunotherapy in HNSCC have recently been extensively reviewed by Gavrielatou et al. 159 

Researchers pursue different strategies in using a RT-ICI combination in a non-R/M HNSCC setting and the first results are already available. Window of opportunity trials are most welcomed since biological mechanisms behind the synergistic effect of combined immunoradiotherapy are not fully understood and reliable criteria for patient selection are lacking. The first results of these trials that use immunoradiotherapy neoadjuvantly are encouraging. In a definitive setting results are more varied. A large phase III trial employing concurrent and maintenance avelumab for 12 months post-chemoradiotherapy was terminated because of inefficacy. Prolonged RT courses with large treatment fields and high doses of concomitant chemotherapy agents could be detrimental to the success of immunotherapy. In an adjuvant setting it is hard to overlook factors such as a changed anatomy of lymphatics and a changed microenvironment of possible remaining cancer cells due to previous surgery, which could both adversely affect the effectiveness of immunoradiotherapy. Additionally, many of these trials administer anti-PD-1/L1 agents not only concurrently with RT but also as prolonged adjuvant treatment, without a comparator arm for proper evaluation of this approach. However, immunoradiotherapy is evolving rapidly in HNSCC and final results of the herein presented ongoing trials are eagerly awaited. 

Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Trends in treatment, incidence and survival of hypopharynx cancer: a 20-year population-based study in the Netherlands

Cordectomy by CO2 laser or radiotherapy for small T1a glottic carcinomas: Costs, local control, survival, quality of life, and voice quality

Head and neck cancer

Management of locally advanced HPV-related oropharyngeal squamous cell carcinoma: where are we?

Human papillomavirus and survival of patients with oropharyngeal cancer

Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion

Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study

Nivolumab for recurrent squamous-cell carcinoma of the head and neck

Nivolumab versus investigator's choice in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: efficacy and safety in CheckMate 141 by age

Rationale for neoadjuvant immunotherapy in head and neck squamous cell carcinoma

Nivolumab versus standard, single-agent therapy of investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial

Effects of radiation on the tumor microenvironment

Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment

Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice

Toxicity in combination immune checkpoint inhibitor and radiation therapy: a systematic review and meta-analysis

A prospective clinical trial combining radiation therapy with systemic immunotherapy in metastatic melanoma

Phase 1 dose escalation trial of ipilimumab and stereotactic body radiation therapy in metastatic melanoma

Final results of a phase II prospective trial evaluating the combination of stereotactic body radiotherapy (SBRT) with concurrent pembrolizumab in patients with metastatic non-small cell lung cancer (NSCLC)

Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer

Randomized phase I trial to evaluate Concurrent or Sequential Ipilimumab, Nivolumab, and stereotactic body Radiotherapy in patients with stage IV non-small cell lung cancer (COSINR Study)

Nivolumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: efficacy and safety in CheckMate 141 by prior cetuximab use

Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study

Primary, adaptive, and acquired resistance to cancer immunotherapy

Recent advances in antigen processing and presentation

Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden

Neoantigens in cancer immunotherapy

Decoding cell death signals in inflammation and immunity

Immunogenic cell death in cancer therapy

Antigen cross-presentation and T-cell crosspriming in cancer immunology and immunotherapy

Type I interferons in anticancer immunity

Catastrophic nuclear envelope collapse in cancer cell micronuclei

Balancing immune protection and immune pathology by CD8+ T-cell responses to influenza infection

Engagement of the PD-1 mmunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation

The PD1:PD-L1/2 pathway from discovery to clinical implementation

PD-1 blockade induces responses by inhibiting adaptive immune resistance

Radiation fosters dose-dependent and chemotherapyinduced immunogenic cell death

Comprehensive genomic characterization of head and neck squamous cell carcinomas

Radiation-induced chromosomal aberrations and immunotherapy: micronuclei, cytosolic DNA, and interferon-production pathway

Cytosolic DNA Sensing in organismal tumor control

Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy

Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer

TCR repertoire diversity of peripheral PD-1 + CD8 + T cells predicts clinical outcomes after immunotherapy in patients with non-small cell lung cancer

Cutting edge: neosynthesis is required for the presentation of a T cell epitope from a long-lived viral protein

Radiation induction of immediate early genes: Effectors of the radiation-stress response

Targeting myeloid-derived suppressor cells and programmed death ligand 1 confers therapeutic advantage of ablative hypofractionated radiation therapy compared with conventional fractionated radiation therapy

Radiation-induced CXCL16 release by breast cancer cells attracts effector T cells

Irradiation of tumor cells up-regulates Fas and enhances CTL lytic activity and CTL adoptive immunotherapy

External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing

Low-dose irradiation programs macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy

Postablation modulation after single high-dose radiation therapy improves tumor control via enhanced immunomodulation

Cell adhesion molecules mediate radiation-induced leukocyte adhesion to the vascular endothelium

Cisplatin alters antitumor immunity and synergizes with PD-1/PD-L1 inhibition in head and neck squamous cell carcinoma

Cisplatin facilitates radiation-induced abscopal effects in conjunction with PD-1 checkpoint blockade through CXCR3/CXCL10-mediated T-cell recruitment

CXCR1 and CXCR2 Chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity

Abstract 3743: Neutrophil extracellular traps and their implication with radioresistance in muscle invasive bladder cancer

Ectonucleotidases as regulators of purinergic signaling in thrombosis, inflammation, and immunity

The development and immunosuppressive functions of CD4+ CD25+ FoxP3+ regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway

Suppression of inflammatory and immune responses by the A 2A adenosine receptor: an introduction

Myeloid expression of adenosine a2A receptor suppresses T and NK cell responses in the solid tumor microenvironment

Host STINGdependent MDSC mobilization drives extrinsic radiation resistance

Chromosomal instability drives metastasis through a cytosolic DNA response

STING promotes the growth of tumors characterized by low antigenicity via IDO activation

Blocking indolamine-2,3-dioxygenase rebound immune suppression boosts antitumor effects of radio-immunotherapy in murine models and spontaneous canine malignancies

Sustained Type I interferon signaling as a mechanism of resistance to PD-1 blockade

Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors

HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment

VEGFR2 is selectively expressed by FOXP3high CD4+ Treg

Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo

Expression of vascular endothelial growth factor in ovarian cancer inhibits tumor immunity through the accumulation of myeloid-derived suppressor cells

National Comprehensive Cancer Network (NCCN)

Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells

Tumor cure by radiation therapy and checkpoint inhibitors depends on pre-existing immunity

An antitumor immune response is evoked by partial-volume single-dose radiation in 2 murine models

Local radiation therapy inhibits tumor growth through the generation of tumor-specific CTL: its potentiation by combination with TH1 cell therapy

Elective nodal irradiation attenuates the combinatorial efficacy of stereotactic radiation therapy and immunotherapy

The impact of locoregional treatment on response to nivolumab in advanced platinum refractory head and neck cancer: The need trial

Window studies in squamous cell carcinoma of the head and neck: values and limits

Abstract CT182: Neoadjuvant immuno-radiotherapy (NIRT) in head and neck cancer: Phase I/Ib study of combined PD-1/SBRT prior to surgical resection

Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma

Cohort expansion study of neoadjvuant immunoradiotherapy in locoregionally advanced HPV+ and HPV-head and neck squamous cell carcinoma

Stereotactic body radiation therapy and Durvalumab with or without Tremelimumab before surgery in treating participants with human papillomavirus positive oropharyngeal squamous cell cancer

The promise of immunotherapy in head and neck squamous cell carcinoma: combinatorial immunotherapy approaches

Immunotherapies and combination strategies for immuno-oncology

Relationships between lymphocyte counts and treatment-related toxicities and clinical responses in patients with solid tumors treated with PD-1 checkpoint inhibitors

Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade

Interaction between lymphopenia, radiotherapy technique, dosimetry, and survival outcomes in lung cancer patients receiving combined immunotherapy and radiotherapy

Association between pretreatment lymphocyte count and response to PD1 inhibitors in head and neck squamous cell carcinomas

Advances in cancer imaging require renewed radiotherapy dose and target volume concepts

Optimized fractionated radiotherapy with anti-PD-L1 and anti-TIGIT: a promising new combination

Ablative tumor radiation can change the tumor immune cell microenvironment to induce durable complete remissions

Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer

Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer

Pembrolizumab-induced severe oral mucositis in a patient with squamous cell carcinoma of the lung: a case study

Distinguishing features of Cetuximab and Panitumumab in colorectal cancer and other solid tumors

Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation

An openlabel, non-randomized, multi-arm, phase II trial evaluating pembrolizumab combined with cetuximab in patients (pts) with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): updated results of cohort 1 analysis

Triple combination treatment of cetuximab, chemotherapy, and anti-PD1 check-point inhibitor for recurrent and/or metastatic head and neck squamous cell carcinoma: a single institute experience

Pfizer provide update on phase III JAVELIN Head and Neck 100 Study

JAVELIN Head and Neck 100: a Phase III trial of avelumab and chemoradiation for locally advanced head and neck cancer

Avelumabcetuximab-radiotherapy (RT) versus standards of care (SoC) in locally advanced squamous cell carcinoma of the head and neck (SCCHN): safety phase of the randomized trial GORTEC 2017-01 (REACH)

Avelumabcetuximab-radiotherapy versus standards of care in locally advanced squamous cell carcinoma of the head and neck: safety phase of the randomized phase III trial GORTEC 2017-01 REACH

Safety of radiotherapy with concurrent and adjuvant MEDI4736 (durvalumab) in patients with locoregionally advanced head and neck cancer with a contraindication to cisplatin: NRG-HN004

A phase II randomized trial of pembrolizumab versus cetuximab, concomitant with radiotherapy (RT) in locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN): first results of the GORTEC 2015-01 "PembroRad" trial

DURTRERAD: a phase II open-label study evaluating feasibility and efficacy of durvalumab (D) and durvalumab and tremelimumab (DT) in combination with radiotherapy (RT) in non-resectable locally advanced HPV-negative HNSCC -results of the preplanned feasibi

Concurrent definitive immunoradiotherapy for patients with stage III-IV head and neck cancer and cisplatin contraindication

Safety and efficacy of pembrolizumab with chemoradiotherapy in locally advanced head and neck squamous cell carcinoma: a phase IB study

Safety evaluation of nivolumab concomitant with platinum-based chemoradiation therapy for intermediate and high-risk local-regionally advanced head and neck squamous cell carcinoma: RTOG foundation 3504

Safety evaluation of nivolumab (Nivo) concomitant with cetuximab-radiotherapy for intermediate (IR) and high-risk (HR) local-regionally advanced head and neck squamous cell carcinoma (HNSCC): RTOG 3504

Safety and disease control achieved with the addition of nivolumab (Nivo) to chemoradiotherapy (CRT) for intermediate (IR) and high-risk (HR) localregionally advanced head and neck squamous cell carcinoma (HNSCC): RTOG Foundation 3504

Safety of nivolumab and ipilimumab in combination with radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN)

Immuno-radiotherapy with cetuximab and avelumab for advanced stage head and neck squamous cell carcinoma: results from a phase-I trial

Single cycle induction treatment with cisplatin/docetaxel plus durvalumab/ tremelimumab in stage III-IVB head and neck squamous cell cancer (CheckRad-CD8 trial)

Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412

Nivolumab or nivolumab plus cisplatin, in combination with radiotherapy in patients with cisplatin-ineligible or eligible locally advanced squamous cell head and neck cancer

De-intensified radiation therapy with chemotherapy (cisplatin) or immunotherapy (nivolumab) in treating patients with early-stage, HPVpositive, non-smoking associated oropharyngeal cancer

HPV-16 Vaccination and pembrolizumab plus cisplatin for "intermediate risk" HPV-16-associated head and neck squamous cell carcinoma

Combining immune checkpoint blockade and tumor-specific vaccine for patients with incurable human papillomavirus 16-related cancer

Trial evaluating the tolerance and safety of durvalumab -RT combination for treatment in SCCHN (REWRITe)

Pembrolizumab in combination with cisplatin and intensity modulated radiotherapy (IMRT) in head and neck cancer

A study of chemoradiation plus pembrolizumab for locally advanced laryngeal squamous cell carcinoma

Concomitant immune check point inhibitor with radiochemotherapy in head and neck cancer

Chemoradiation vs immunotherapy and radiation for head and neck cancer

Pembrolizumab combined with chemoradiotherapy in squamous cell carcinoma of the head and neck (PEACH)

Induction TPN followed by nivolumab with radiation in locoregionally advanced laryngeal and hypopharyngeal cancer

Radiotherapy, carboplatin/paclitaxel and nivolumab for high risk HPV-related head and neck cancer

Ipilimumab, nivolumab, and radiation therapy in treating patients with HPV positive advanced oropharyngeal squamous cell carcinoma

Avelumabcetuximab-radiotherapy versus standards of care in locally advanced squamous cell carcinoma of the head and neck: safety phase of the randomized phase III trial GORTEC 2017-01 REACH

Anti PD-L1 durvalumab combined with cetuximab and radiotherapy in locally advanced squamous cell carcinoma of the head and neck: a phase I/II study (DUCRO)

Cisplatin or immunotgerapy in association with definitive radiotherapy in HPV-related oropharyngEal squamous cell carcinoma: a randomized phase II trial. (CITHARE)

A study of concomitant camrelizumab with chemoradiation for locally advanced head and neck cancer

Phase II multi-site investigation of neoadjuvant pembrolizumab and adjuvant concurrent radiation and pembrolizumab with or without cisplatin in resected head and neck squamous cell carcinoma

NRG-HN003: Phase I and expansion cohort study of adjuvant cisplatin, intensity-modulated radiation therapy (IMRT), and MK-3475 (pembrolizumab) in high-risk head and neck squamous cell carcinoma (HNSCC)

KEYNOTE-689: Phase 3 study of adjuvant and neoadjuvant pembrolizumab combined with standard of care (SOC) in patients with resectable, locally advanced head and neck squamous cell carcinoma

KEYNOTE-689: phase 3 study of neoadjuvant and adjuvant pembrolizumab combined with standard of care in patients with resectable, locally advanced head and neck squamous cell carcinoma

A trial evaluating the addition of nivolumab to cisplatin-RT for treatment of cancers of the head and neck (NIVOPOSTOP)

Maintenance immune check-point inhibitor following post-operative chemo-radiation in subjects with HPV-negative HNSCC (ADHERE)

Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck

Postoperative aRCH with cisplatin versus aRCH with cisplatin and pembrolizumab in locally advanced head and neck squamous cell carcinoma

Adjuvant de-escalated radiation + adjuvant nivolumab for intermediate-high risk P16+ oropharynx cancer

Durvalumab with radiotherapy for adjuvant treatment of intermediate risk SCCHN

Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC

Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: updated results from a phase III trial (CheckMate 238)

Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial

Comparison of concurrent use of thoracic radiation with either carboplatin-paclitaxel or cisplatin-etoposide for patients with stage III nonsmall-cell lung cancer

Distant metastases in head and neck cancer

Immune checkpoint inhibitor toxicity in head and neck cancer: from identification to management

Immunotherapy for head and neck cancer in the era of exponentially increasing health care expenditure

Biomarkers for immunotherapy response in head and neck cancer

This study was funded by the Slovenian Research Agency (program no. P3-0307).