Radiol Oncol 2020; 54(4): 394-408.; 54(4): 377-393. doi: 10.2478/raon-2020-0060 377 review Combining radiotherapy and immunotherapy in definitive treatment of head and neck squamous cell carcinoma: review of current clinical trials Gaber Plavc1,2, Primoz Strojan1,2 1 Department of Radiation Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia Radiol Oncol 2020; 54(4): 394-408.; 54(4): 377-393. Received 18 August 2020 Accepted 22 September 2020 Correspondence to: Assist. Gaber Plavc, M.D., Institute of Oncology Ljubljana, Department of Radiation Oncology, Zaloška cesta 2, SI-1000 Ljubljana, Slovenia. E-mail: gplavc@onko-i.si Disclosure: No potential conflicts of interest were disclosed. Background. Head and neck squamous cell carcinoma (HNSCC) presents as locally advanced disease in a major- ity 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 be- hind 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 ad- ditional 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. Key words: head and neck neoplasms; immunoradiotherapy; radiotherapy; immunotherapy Introduction 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 al- most 100% in patients with T1a glottic carcinoma to below 30% in patients with locally-advanced hy- popharyngeal 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 re- search is on treatment intensification and/or modi- fication. After intrinsic tumour suppressor mechanisms fail, further tumour progression is the result of an inefficient elimination phase or equilibrium phase Radiol Oncol 2020; 54(4): 394-408.; 54(4): 377-393. Plavc G and Strojan P / Immunoradiotherapy in definitive treatment of head and neck cancer378 of the extrinsic tumour suppression by the im- mune 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 im- munosuppressive.7 In the fight against the latter, immune checkpoint inhibitors (ICI) targeting im- mune 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 chemo- therapy regimens, an increasing number of trials are testing ICIs in the earlier stages of HNSCC.10–12 Besides a well-known immunosuppressive ef- fect of radiotherapy (RT), it can also lead to posi- tive alterations in innate and adaptive immunity.13 The same is true for the positive effects of the im- mune system on radiation efficacy, as a tumoricid- al 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 con- tributes to acquired cancer radioresistance, which could be overcome by concurrent anti-PD-1/L1.15 These intricate interactions form the basis for com- bined treatment with RT and ICIs (immunoradio- therapy). This combination was shown to cause similar toxicity compared to either RT or ICI alone across different cancer types.16 Encouraging effi- cacy of this treatment combination has also been shown in early prospective trials in metastatic malignant melanoma and non-small cell lung cancer.17–21 The first results of trials using immu- noradiotherapy in non-R/M HNSCC are now also available and many are underway. In this review we presented a biological rationale for the combi- nation 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. Role of anti-PD-1 and radiotherapy in immune rejection of 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 pres- entation, T cell exhaustion/absence, insensibility of tumours to T cells, presence of immunosuppres- sive cells, and/or presence of other inhibitory im- mune checkpoints.24 For the immune system to exert its cytotoxic function, mutant peptides, also known as tumour neoantigens (TNA) or ectopically expressed anti- gens, must be presented to antigen-presenting cells by cancer cells on major histocompatibility com- plex I (MHC I).25 Even though the tumour muta- tion burden in HNSCC is rather high with 5 muta- tions 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 recog- nition 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 re- sults 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 down- regulates 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 recog- nition receptors on the cells of innate immunity. Different types of DAMPs are exposed by differ- ent modes of cell death and even by stressed can- cer cells.37 These include membrane-bound calreti- culin, 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 cross- present antigens to naïve CD8+ T and by co-stim- ulatory signals (ligands and cytokines provided by DCs upon stimulation by DAMPs and type I interferons [IFNs]) prime these cytotoxic T lym- phocytes 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 lym- phocytes also express inhibitory receptors, such Radiol Oncol 2020; 54(4): 394-408.; 54(4): 377-393. Plavc G and Strojan P / Immunoradiotherapy in definitive treatment of head and neck cancer 379 as PD-1, with its ligand PD-L1 on host tissue and immune cells.43 The same PD-L1 expression is ex- ploited by cancer cells to escape immune surveil- lance.44 An active PD-1/PD-L1 pathway in tumour microenvironment (TME) also promotes T cell ex- haustion and differentiation of regulatory T cells (Treg).45 Primed tumour-infiltrating lymphocytes (TILs) that are suppressed due to PD-1/PD-L1 in- teraction 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 im- munogenic 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 pre- dictor of response to anti-PD-1/L1.51–53 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 in- hibit mobilisation of myeloid-derived suppressor cells (MDSC).56 Some authors also observed an en- hanced recruitment of T cells into TME after RT.57 RT-enhanced death receptor Fas expression fur- ther 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 inter- leukin-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 vascu- lature-related effect of RT is induction of cell adhe- sion molecules, for example Intercellular Adhesion Molecule 1 and E-selectin, that help leukocytes ex- travasate to TME.62 Importantly, as a part of standard treatment in HNSCC, concurrent platin-based chemoradiother- apy (CRT) was also shown to induce immunogenic cell death.47 In the in vitro model, antigen presen- tation 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 dos- es were immunosuppressive. Nevertheless, Luo et al. showed on murine cancer models that cisplatin combined with anti-PD-1 treatment enhances RT- induced 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.65–70 Activation of cGAS-STING can lead to increased concentrations of MDSC in TME and even increase cancer aggressiveness.71,72 STING ac- tivation can also lead to depletion of tryptophan in TME via upregulation of Indoleamine 2,3-di- oxygenase, resulting in reduced T cell cytotoxic- ity and increased tumour-associated macrophages and MDSCs.73,74 Even sustained type I IFN signal- ling 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 upregu- late hypoxia inducible factor-1α, leading to even- tual Treg and MDSC accumulation and DC and T cell inhibition via vascular endothelial growth fac- tor.76–80 Methods We searched PubMed and Clinicaltrials.gov da- tabases 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) Radiol Oncol 2020; 54(4): 394-408.; 54(4): 377-393. Plavc G and Strojan P / Immunoradiotherapy in definitive treatment of head and neck cancer380 AND (radiotherapy OR SBRT OR RT OR SABR OR irradiation) and with the start date of the stud- ies from 15th July 2013 to 15th July 2020. In total, 39 completed or ongoing trials were found, using con- current (chemo)radiotherapy and ICIs in primary definitive treatment of non-R/M HNSCC (non-na- sopharyngeal). Trials using anti-PD-1/L1 and radiotherapy combination in HNSCC: different approaches In completed and ongoing trials, concurrent anti- PD-1/L1 and RT was delivered either before or af- ter surgery, or as a sole definitive treatment. Few delivered anti-PD-1/L1 also as an extended con- solidative treatment. Taking the intricate relation- ship 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. Neoadjuvant immunoradiotherapy Except for the earliest stages of HNSCC, elec- tive 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 con- trol.83,84 Preclinical studies in murine cancer models clearly showed the vital role of functioning drain- ing 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 previ- ously treated patients with HNSCC.87 This speaks strongly in favour of using an immunoradiothera- py combination before surgery as compared to its postoperative application. TABLE 1. Neoadjuvant immunoradiotherapy trials Trial, start year Phase N Subsite and subtype Basic scheme Immunotherapy details RT details Main results NIRT-HNC, NCT03247712,89 2018 I 10 HPV+ resectable HNSCC stage I-III or CUP with clinical indications for adj. RT or TORS ineligible NIVO+SBRT 5 weeks before surgery, followed by NIVO 3x NIVO neoadj. and 3x adj. NIVO starting 4 weeks postop. SBRT to GTV+3mm; 5pts: 5x8Gy daily (A), and 5 pts: 3x8Gy (B) every other day; delivered between 1st and 2nd NIVO cycle no surgical delays; G3 postop. toxicity higher in cohort A; pCR: 100% in cohort A, and 80% in cohort B. II 11, ongoing cohort C: same as phase I, cohort D: stage III-IV HPV- resectable HNSCC cohort C: SBRT alone 5 weeks before surgery, followed by NIVO, cohort D: same as phase I cohort C: only adj. NIVO, same as in phase I cohort D: same as phase I cohort C (6pts): SBRT 3 x 8 Gy cohort D (5 pts): SBRT 3 x 8 Gy no G3-4 toxicity; major pathologic response in majority of pts NCT03635164,91 2018 I 18 HPV- resectable LAHNSCC DURVA+SBRT 3–6 weeks before surgery, followed by DURVA DURVA neoadj. with the first SBRT fraction and up to 6x DURVA postop. SBRT to gross disease only, starting dose of 2x6Gy (planned increase to 3x6Gy, cohort size of 3 patients) every other day, starting concurrently with DURVA NA NCT03618134,92 2018 I/II 82 TORS eligible HPV+ oropharyngeal HNSCC DURVA+SBRT+/- tremelimumab 5–7 weeks before TORS, followed by DURVA DURVA+/- tremelimumab neoadj. with the first SBRT fraction and on day 27, followed by up to 4x adj. DURVA SBRT in 5fx, starting concurrently with DURVA+/- tremelimumab NA adj. = adjuvant; CUP = cancer of unknown primary; DURVA = durvalumab; fx = fraction; GTV = gross tumour volume; G3 = grade 3; HNSCC = head and neck squamous cell carcinoma; HPV- = human papilloma virus negative cancer; HPV+ = human papilloma virus associated cancer; LAHNSCC = locally advanced HNSCC; N = planned number of enrolled patients, NA = not available; neoadj. = neoadjuvantly, NIVO = nivolumab; pCR = pathological complete response; postop. = postoperatively; pts = patients; RT = radiotherapy, SBRT = stereotactic body RT; TORS = transoral robotic surgery Radiol Oncol 2020; 54(4): 394-408.; 54(4): 377-393. Plavc G and Strojan P / Immunoradiotherapy in definitive treatment of head and neck cancer 381 Neoadjuvant RT is not considered a standard of care in HNSCC, therefore these “window of oppor- tunity trials” serve mostly to advance our under- standing 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 oppor- tunity” trial that reported results, no surgical de- lays were noted.89 The possibility of anti-PD-1 in- duced 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 sur- gery 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 con- current nivolumab. No grade 4 toxicity was ob- served, 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 presurgi- cal imaging evaluated by RECIST criteria, no com- plete 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 neoad- juvant 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 re- sponse rate was somewhat lower than in cohorts A and B. In-detail results are awaited. The approach to treatment was similar in HPV- negative 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-lymphocyte- associated 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 toxic- ity.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 mo- dalities are delivered concurrently in previously untreated patients with intact draining lymph nodes and no lymphopenia.85–87,95–98 Definitive im- munoradiotherapy as a sole treatment fulfils these criteria, except for nodal irradiation. If, in a neo- adjuvant 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 elec- tive 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 immu- notherapy in the neoadjuvant setting, however, the definitive setting immunoradiotherapy trials most- ly 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 atten- tion 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 ben- eficial in low doses, whereas high-dose chemother- apy 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 act- ing through targeting EGFR and dysregulating its signaling pathway, it also stimulates NK cells anti- Radiol Oncol 2020; 54(4): 394-408.; 54(4): 377-393. Plavc G and Strojan P / Immunoradiotherapy in definitive treatment of head and neck cancer382 tumour activity, activates DCs, and recruits cyto- toxic CD8+ T cells.105 Cetuximab’s ability to prime adaptive and innate immunity is met with regula- tory immunosuppressive mechanisms. Targeting these immunosuppressive mechanisms (induction of Tregs, MDSC, PD-1, PD-L1, CTLA-4) by immu- notherapy 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, chemo- therapy 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 re- sponses and acceptable toxicity. Completed and ongoing trials treating patients with non-R/M HNSCC with a definitive immuno- radiotherapy 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) fol- lowed 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 pro- gression-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 pa- tients fit for high-dose cisplatin, and RT with con- current cetuximab in a cohort of patients unfit for high-dose cisplatin) were compared to experimen- tal arms with the same RT regimen and concur- rent 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 in- eligible for high-dose cisplatin), and in 5/41 (12%) patients in standard arms (14% in high-dose cispl- atin 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-ineli- gible 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 present- ed 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 dys- phagia (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 re- cently 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 concurrent- ly 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 pembroli- zumab doses. Toxicities were mild with a major exception being grade 3–4 lymphopenia, which oc- curred in 59% of patients, however, absolute lym- phopenia 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 rela- tively 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 Radiol Oncol 2020; 54(4): 394-408.; 54(4): 377-393. Plavc G and Strojan P / Immunoradiotherapy in definitive treatment of head and neck cancer 383 TABLE 2. Definitive immunoradiotherapy trials Trial, start year Phase N Subsite and subtype Basic scheme Immunotherapy details RT details Main results NCT02586207,117 2015 I 59 LAHNSCC eligible for CRT (34 pts HPV + and 23 pts HPV-) PEMBRO + CRT, followed by PEMBRO PEMBRO on days -7 (before CRT), 15 and 36 (conc. with CRT), and adj. for 5 cycles starting on day 1: CRT with IMRT 70 Gy (2Gy/fx) and LD-CDDP for 6 cycles HPV + : 85% CR 12 weeks after CRT; HPV-: 78% CR 12 weeks after CRT; HPV + : 2-year OS 97% and PFS 93%; HPV-: 1-year OS 87% and PFS 73% GORTEC 2015-01 “PembroRad” (NCT02707588),114 2016 II, rand. 133 LAHNSCC ineligible for CDDP arm A: CETUX + RT; arm B: PEMBRO + RT arm A: CETUX during RT; arm B: PEMBRO during RT IMRT (69.99Gy/33fx) arm A: 94% grade 3 toxicity, 57% grade 3 mucositis, 86% received full RT; arm B: 78% grade 3 toxicity, 24% grade 3 mucositis, 88% received full RT KEYNOTE-412 (NCT03040999),124 2017 III, rand. 780 LAHNSCC eligible for CRT arm A: PEMBRO + CRT, followed by PEMBRO; arm B: placebo + CRT, followed by placebo arm A: priming dose of PEMBRO followed by 2x PEMBRO + CRT, followed by 14x maint. PEMBRO; arm B: placebo instead of PEMBRO CRT (70Gy/35fx) and HD-CDDP NA NCT02759575,131 2016 I/II 47 LAHNSCC of larynx PEMBRO + CRT PEMBRO starting 3 weeks before CRT, maximum 4x CRT (70Gy/35fx) and HD-CDDP NA NCT02609503,116 2016 II 29 LAHNSCC ineligible for CDDP PEMBRO + RT, followed by PEMBRO PEMBRO conc. with RT and 3 adj. cycles IMRT (70Gy/35fx) 2-year OS 75% and PFS 71%; 59% grade 3–4 lymphopenia NCT02777385,130 2016 II, rand. 90 LAHNSCC arm A: PEMBRO + CRT; arm B: CRT followed by PEMBRO arm A: 8x PEMBRO 1 week prior to RT; arm B: 8x PEMBRO beginning in week 10 CRT with IMRT (70Gy/35fx) and LD-CDDP NA NCT03532737,132 2018 II 50 LAHNSCC PEMBRO + CRT or PEMBRO + CETUX + RT PEMBRO starting 3 weeks before (C)RT and during CRT or during RT + CETUX CRT with IMRT (66–70Gy/30–35fx) and HD-CDDP or conc. CETUX NA KEYCHAIN (NCT03383094),133 2018 II, rand. 114 HPV + LAHNSCC arm A: PEMBRO + RT; arm B: CRT arm A: conc. and adj. PEMBRO for 20 cycles; arm B: CDDP-based CRT IMRT (70Gy/33– 35fx) (arm A) and HD-CDDP in arm B NA PEACH (NCT02819752),134 2017 I 36 LAHNSCC PEMBRO + CRT, followed by PEMBRO pre-loading dose of PEMBRO (dose- escalation trial, 100–200mg) and conc. CRT and PEMBRO and 4x adj. PEMBRO standard CRT NA NCT04369937,127 2020 II 50 IR HPV + HNSCC HPV-16 vaccination (ISA101b) + PEMBRO + CRT 3x ISA101b starting 1 week prior to PEMBRO and two weeks prior to CRT CRT with IMRT (70Gy/35fx) and HD-CDDP NA RTOG 3504 (NCT02764593),120 2016 I 40 IR-HR LAHNSCC conc. and adj. NIVO added to each of 4 (C)RT cohorts conc. NIVO starting 2 weeks before (C)RT and adj. NIVO starting 3 months after CRT all cohorts: IMRT (70Gy/35fx); cohort 1: CRT with LD-CDDP; cohort 2: CRT with HD- CDDP; cohort 3: RT + CETUX; cohort 4: RT adj. NIVO infeasible after HD-CDDP or in CDDP-ineligible pts; low rates of NIVO DLT NCT03349710,125 2017 III, rand. 1046 LAHNSCC NIVO + RT vs. CETUX + RT vs. NIVO + CRT vs. CRT Closed due to slow accrual Radiol Oncol 2020; 54(4): 394-408.; 54(4): 377-393. Plavc G and Strojan P / Immunoradiotherapy in definitive treatment of head and neck cancer384 Trial, start year Phase N Subsite and subtype Basic scheme Immunotherapy details RT details Main results NCT03162731,121 2017 I 24 HR LAHNSCC NIVO + ipilimumab + RT 17x NIVO and 6x ipilimumab, both starting 2 weeks before RT IMRT (70Gy/35fx) first 12 pts: grade 3 in-RT- field toxicity in 50% of pts, 3 pts discontinued therapy >3 months post-RT, 1 grade 3 colitis, 1 grade 5 bleeding, irAE in 50% of pts NCT03894891,135 2019 II 70 LAHNSCC of larynx and hypopharynx induction docetaxel + CDDP + NIVO, followed by NIVO + RT standard institutional dosing standard institutional dosing NA NCT03829722,136 2019 II 40 HR HPV + OP cancer NIVO + CRT, followed by adj. NIVO 4x NIVO before and conc. with CRT, followed by 4x NIVO CRT (70Gy/35fx) and carboplatin + paclitaxel combination once per week NA (temporarily suspended due to COVID-19) NRG-HN005 (NCT03952585),126 2019 II/III, rand. 711 early-stage HPV + OP cancer arm A: NIVO + deescalated RT; arm B: CRT arm C: deescalated CRT 6x NIVO, starting 1 week prior to RT IMRT, CRT with HD- CDDP NA NCT03799445,137 2019 II 180 low- intermediate volume HPV + OP cancer NIVO + ipilimumab + RT NIVO on days 1, 15, 29, and ipilimumab on day 1; for 2 cycles IMRT 50–66Gy starting on day 1 of 2. cycle of NIVO + ipilimumab NA GORTEC 2017- 01 “REACH” (NCT02999087),138 2017 III, rand. 688 LAHNSCC Cohort 1 (fit for CDDP): CRT with CDDP (arm 1A), RT + AVEL + CETUX (arm 1B); Cohort 2 (unfit for CDDP); RT + CETUX (arm 2A), RT + AVEL + CETUX (arm 2B) AVEL and CETUX starting 1 week prior to RT, followed by AVEL maint. for 12 months IMRT 69.96Gy with either HD-CDDP or CETUX first 82 pts: thresholds of the safety monitoring rule not crossed; trial continues JAVELIN HEAD AND NECK 100 (NCT02952586),110 2016 III, rand. 697 LAHNSCC arm A: AVEL + CRT; arm B: placebo + CRT AVEL starting 1 week prior to CRT, followed by maint. AVEL for 12 months CRT with IMRT (70Gy/35fx) and HD-CDDP preplanned interim analysis: unlikely to show improvement, terminated NCT02938273,122 2017 I 10 LAHNSCC ineligible for CDDP AVEL + CETUX + RT AVEL starting 1 week prior to RT, followed by maint. AVEL for 4 months; CETUX conc. VMAT (70Gy/35fx) tumour recurrence in 50% after a median follow up of 12months; transient and manageable irAE DUCRO-HN (NCT03051906),139 2018 I/II 69 LAHNSCC DURVA + CETUX + RT DURVA and CETUX, both conc. with RT, followed by adj. DURVA for 6 months IMRT (69.9Gy/33fx) NA DURTRE-RAD (NCT03624231),115 2018 II, rand. 120 HPV- LAHNSCC arm A: DURVA + TREM + RT; arm B: DURVA + RT DURVA started 2 weeks prior to RT and TREM started with RT, followed by DURVA for up to 9 cycles RT (70Gy/35fx) first 16 patients: in arm A 5/6 stopped treatment due to toxicity -> terminated; in arm B 1/10 patients stopped treatment CheckRad-CD8 (NCT03426657),123 2018 II 120 LAHNSCC induction DURVA + TREM + CDDP + docetaxel and in case of increased CD8 + TILs compared to pre-treatment Bx -> DURVA + TREM + RT after induction: DURVA with RT and TREM with RT, followed by DURVA for up to 12 cycles RT (70Gy/35fx) first 10pts after induction (re- biopsies): pCR in 8/10pts, 2 grade 3 + toxicities Radiol Oncol 2020; 54(4): 394-408.; 54(4): 377-393. Plavc G and Strojan P / Immunoradiotherapy in definitive treatment of head and neck cancer 385 related causes in 12% after CRT. The goal cisplatin dose of 200 mg/m2 or more was received by 88% of patients and 98% of patients received all 70 Gy of RT. 76% of patients received all eight planned pembrolizumab cycles. Grade 4 toxicities were solely hematologic and electrolyte abnormalities. Outcomes are described in Table 2. In the RTOG 3504, a phase I trial enrolling 40 pa- tients with intermediate risk (HPV-associated oro- pharyngeal 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.118–120 RT was delivered with either a weekly low-dose or three-weekly high- dose 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 af- ter 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), re- spectively. However, adjuvant administration of nivolumab was infeasible after (C)RT in cisplatin- ineligible patients or in those who received high- dose 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 ineligi- ble patients with LAHNSCC that received avelum- ab and cetuximab in conjunction with RT, followed by avelumab as a maintenance therapy for an addi- tional four months (Table 2).122 After a median fol- low-up of 12 months disease recurred in 50% of the patients. The majority of adverse effects were re- lated 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, tremelimum- ab, 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 pre- sented in 2019. After induction therapy re-biopsies showed a complete pathological response in 8/10 patients with another two patients showing an in- Trial, start year Phase N Subsite and subtype Basic scheme Immunotherapy details RT details Main results NRG-HN004 (NCT03258554),113 2017 II/III, rand. 523 LAHNSCC ineligible for CDDP arm A: DURVA + RT; arm B: CETUX + RT DURVA started 2 weeks prior to RT for 7 cycles; CETUX conc. RT (70Gy/35fx) lead-in trial, 10 pts: all received arm A treatment, all completed RT, 8/10 received all doses of DURVA CITHARE (NCT03623646),140 2019 II, rand. 66 early-stage HPV + OP cancer arm A: DURVA + RT; arm B: CRT DURVA conc. with RT RT 70Gy with CDDP in arm B NA REWRITe (NCT03726775),129 2018 II 73 HNSCC T1-2 or HNSCC T3-4 and not eligible for CRT/CETUX + RT DURVA + RT, followed by additional 6 months of DURVA DURVA conc. with RT, followed by 6 months of DURVA RT to only primary tumour and immediately adjacent nodal level without extended neck irradiation NA NCT04405154,141 2020 II 32 LAHNSCC CRT + camrelizumab camrelizumab conc. with CRT and after for total of 8 cycles CRT with IMRT/VMAT (66–70Gy/33–35fx) and HD-CDDP NA adj. = adjuvantly; AVEL = avelumab; CETUX = cetuximab; ,; CDDP = cisplatin; conc. = concurrently; CR = complete response; CRT = chemoradiotherapy; DLT = dose-limiting toxicity; DURVA = durvalumab; , fx = fractions; HD-CDDP = high dose cisplatin 100 mg/m2 every three weeks during RT; HR = high-risk; HPV+ = human papilloma virus associated cancer, HPV- = human papilloma virus negative cancer; IMRT = intensity modulated RT; IR = intermediate-risk; irAE – immune-related adverse effects; LAHNSCC = locally advanced head and neck squamous cell carcinoma; LD-CDDP = low dose cisplatin 40 mg/m2 every week during RT; maint. = maintenance; N = planned enrolment; NA = not available; NIVO = nivolumab; OP = oropharyngeal; OS = overall survival; PEMBRO = pembrolizumab; PFS = progression-free survival; RT = radiotherapy, TILs = tumour infiltrating lymphocytes; TREM – tremelimumab; VMAT = volumetric modulated arc therapy Radiol Oncol 2020; 54(4): 394-408.; 54(4): 377-393. Plavc G and Strojan P / Immunoradiotherapy in definitive treatment of head and neck cancer386 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 em- ploying 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 pembrolizum- ab given concomitantly with CRT and as a main- tenance 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 simi- lar 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 addi- tional phase III trial, NRG-HN005, is a non-inferior- ity trial, testing treatment de-escalation in patients with early stage HPV-positive oropharyngeal car- cinoma.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 knowl- edge from the de-escalation trials in patients with HPV-positive HNSCC. A somewhat different approach will be exam- ined in the NCT04369937.127 HPV-16 E6/E7-specific therapeutic vaccination (ISA101b) will be adminis- tered to 50 patients with intermediate risk of HPV+ HNSCC one week prior to the start of pembroli- zumab and two weeks prior to the start of CRT with cisplatin (Table 2). The combination of ISA101 and nivolumab was already examined in a single- arm 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 dura- tion of response of 10.3 months and a median over- all 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 elec- tive nodal irradiation when combining RT with im- munotherapy. In this trial, patients with early stage T1–2 HNSCC or those with T3–4 disease and who are ineligible for cisplatin or cetuximab concurrent- ly with RT will simultaneously receive durvalum- ab 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 ran- domise 90 patients with LAHNSCC to either con- current CRT with cisplatin and pembrolizumab or to CRT followed by pembrolizumab (Table 2).130 It will hopefully help to answer if concurrent appli- cation is better than sequential or vice versa. Adjuvant (postoperative) immunoradiotherapy 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 radio- therapy in patients with resected draining lymph nodes or after intensive treatment. Two trials testing the potentials of adjuvant im- munoradiotherapy 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 adju- vant pembrolizumab in combination with RT or CRT. The pathological response to priming appli- cation of pembrolizumab was seen in 47% and was correlated with increased TILs. Adjuvant combina- tion 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 sched- ule for a phase II study. The tested regimen con- sisted 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 pur- suing. 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 combi- nations 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- Radiol Oncol 2020; 54(4): 394-408.; 54(4): 377-393. Plavc G and Strojan P / Immunoradiotherapy in definitive treatment of head and neck cancer 387 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 metasta- ses.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 ad- juvant 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 patho- logical 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 ac- tivity of radioimmunotherapy. A major drawback of adding immunotherapeutics to RT in postopera- tive setting could be the absence of regional lymph nodes that could hinder the efficacy of this com- bination. 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. A djuvant/maintenance therapy with immune checkpoint inhibitor 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 TABLE 3. Trials utilizing adjuvant immunoradiotherapy Trial, start year Phase N Subsite and subtype Basic scheme Immunotherapy details RT details Main results NCT02641093,142 2016 II 80 LAHNSCC neoadj. PEMBRO followed by resection, followed by PEMBRO + (C)RT PEMBRO 1 week prior to surgery and conc. with RT for total of 7 doses IMRT (60–66Gy/30fx) + /- LD-CDDP (if ECE + /R1) first 23 pts (lead- in phase): 47% pathological response, no DLT, 2 pts recurred NRG-HN003 (NCT02775812),143 2016 I 34 resected R1/ECE + HPV- HNSCC adj. PEMBRO + CRT 3 different schedules aimed to determine phase II schedule CRT with IMRT (60Gy/30fx) and LD-CDDP No irAE unacceptably delayed RT, 50% got all 8 doses of PEMBRO KEYNOTE-689 (NCT03765918),144,145 2018 III, rand. 600 resected LAHNSCC arm A: neoadj. PEMBRO followed by resection then PEMBRO + (C)RT; arm B: resection then (C)RT arm A: 2x neoadj. PEMBRO and PEMBRO conc. with adj. (C) RT, followed by PEMBRO for up to 15 cycles (C)RT 60–70Gy/30–35fx + /- HD-CDDP depending on risk factors NA GORTEC 2018-01 “NIVOPOSTOP” (NCT03576417),146 2018 III, rand. 680 resected R1/ECE + LAHNSCC arm A: adj. NIVO + CRT; arm B: adj. CRT NIVO starting 3 weeks before CRT for total of 4 doses CRT with IMRT (66Gy/33fx) and HD-CDDP NA ADHERE (NCT03673735),147 2019 III, rand. 650 resected HR HPV- HNSCC arm A: adj. DURVA + CRT; arm B: adj. CRT 1 dose of DURVA 1 week prior to CRT and maint. DURVA for 6 doses CRT 66Gy/33fx and HD-CDDP NA ADRISK (NCT03480672),149 2018 II, rand. 240 resected LAHNSCC with >1LN/ECE + /R1 arm A: adj. PEMBRO + CRT; arm B: adj. CRT PEMBRO conc. with RT and for up to 12 months CRT with CDDP NA NCT03715946,150 2018 II 135 resected IR- HR HPV + oropharyngeal cancer adj. NIVO + deescalated RT NIVO conc. with RT and for additional 6 doses after RT RT (45–50Gy/25fx) NA NCT03529422,151 2019 II 33 resected IR HNSCC adj. DURVA + RT DURVA starting conc. with RT for total of 6 cycles IMRT (60Gy/30fx) NA adj. = adjuvant; CDDP = cisplatin; conc. = concurrent; CRT = chemoradiotherapy; DLT = dose-limiting toxicity; DURVA = durvalumab; ECE+ = extracapsular extension of metastasis in lymph node; fx = fractions; HD-CDDP = high dose cisplatin 100 mg/m2 every three weeks during RT; HPV+ = human papilloma virus associated cancer; HPV- = human papilloma virus negative cancer; HR = high-risk; IMRT = intensity modulated RT; IR = intermediate-risk; irAE = immune-related adverse effects; LAHNSCC = locally advanced head and neck squamous cell carcinoma; LD-CDDP = low dose cisplatin 40 mg/m2 every week during RT; N = planned enrolment; neoadj. = neoadjuvant; NIVO = nivolumab; PEMBRO = pembrolizumab; RT = radiotherapy; R1 = microscopically positive resection margin, LN = lymph node; NA = not available Radiol Oncol 2020; 54(4): 394-408.; 54(4): 377-393. Plavc G and Strojan P / Immunoradiotherapy in definitive treatment of head and neck cancer388 comes from two other tumour types. In patients with unresectable locally-advanced non-squamous cell carcinoma lung cancer (NSCLC) without pro- gression after definitive CRT, consolidation dur- valumab 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 toxic- ity. Long-term data of the latter study are not yet available.153,154 Besides differences in tumour-in- trinsic factors and the composition of their TME, another important aspect to consider is the dif- ferent 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 lo- coregional relapses are much more common.4,156 Whether consolidation anti-PD-1/L1 agents can de- crease rates of distant metastases as well as locore- gional 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 never- theless 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 associ- ated 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 fi- nancial burden of these new drugs is obvious and therefore special attention should already be paid in trial design.158 Importantly, with the above-de- scribed 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, care- ful 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 immuno- therapy in HNSCC have recently been extensively reviewed by Gavrielatou et al.159 Conclusions 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 bio- logical mechanisms behind the synergistic effect of combined immunoradiotherapy are not fully un- derstood and reliable criteria for patient selection are lacking. The first results of these trials that use immunoradiotherapy neoadjuvantly are encourag- ing. In a definitive setting results are more varied. A large phase III trial employing concurrent and maintenance avelumab for 12 months post-chemo- radiotherapy 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 im- munotherapy. In an adjuvant setting it is hard to overlook factors such as a changed anatomy of lym- phatics and a changed microenvironment of possi- ble remaining cancer cells due to previous surgery, which could both adversely affect the effective- ness 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, im- munoradiotherapy is evolving rapidly in HNSCC and final results of the herein presented ongoing trials are eagerly awaited. Acknowledgments This study was funded by the Slovenian Research Agency (program no. P3-0307). References 1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality world- wide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68: 394-424. doi: 10.3322/caac.21492 2. 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