Combining radiotherapy and immunotherapy in definitive treatment of head and neck squamous cell carcinoma: review of current clinical trials

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 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 These two ICIs provide complementary effects, albeit at the expense of increased toxicity.93,94

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 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 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 ineligible 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 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 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 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 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 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 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 increase 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 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 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 compared 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. These 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 unnecessary 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