Immunotherapy with PD-1 Inhibitor Nivolumab in Recurrent/Metastatic Platinum Refractory Head and Neck Cancers: The Early Experience of Two Academic Center

1. Introduction

Head and neck squamous cell carcinoma (HNSCC) is associated with a poor prognosis and lower survival rates in the advanced stages of the disease even if a multimodal treatment is administered according to the current standards. The improvement of diagnostic and therapeutic performances brought minimal benefits in the HNSCC prognosis. As confirmed by preclinical data, immunosuppression and the ability to escape from immunosurveillance by the accumulation of genetic mutations during carcinogenesis or by disease progression are responsible for the therapeutic failure of HNSCC. In this context, the identification of some strategies to restore the antitumor immune response could bring benefit in term of treatment response with longer survival rates. Nivolumab, an anti–programmed death 1 (PD-1) monoclonal antibody, brought long-term overall survival (OS) benefits in platinum-refractory HNSCC cases compared to single agent chemotherapy treatment in the phase III CheckMate 141 trial. Scientific efforts are focused on identication of predictive biomarkers for favorable response to immunotherapy, head and neck tumors being associated with a tumor microenvironment (TME) considered highly immunosuppressive. Programmed death ligand-1 (PD-L1), combined positive score (CPS), tumor mutation burden (TMB), neutrophil to lymphocyte ratio (NLR), but also more recently radiomics biomarkers based on artificial intelligence applied to medical imaging are evaluated in order to identify cases that will have a long term response to immune checkpoint inhibitors (ICI) [1,2,3,4,5,6,7,8].

The aim of the study was to present the early experience of two academic center with the PD-1 inhibitor Nivolumab in relapsed/metastatic head and neck cancers (HNC) refractory to platinum agents.

2. Materials and methods

The cases of locoregional repalpse or metastatic HNC treated with Nivolumab were identified from the database of the Oncology Clinic of the Craiova County Emergency Hospital, “Saint Nectarie” Oncological Hospital and Euroclinic Oncological Center Iași. Biological, clinical and therapeutic data of the patients as well as outcomes were analyzed. The follow-up since initiation of Nivolumab therapy has varied between 3 months and 25 months.

3. Results

18 cases of locoreginal relapsed or metastatic HNC refractory to platinum-based chemotherapy treated with Nivolumab between January 2020 and March 2023 were identified. 17 (94,4%) of the 18 cases are squamous cell carcinomas and 1 (5,5%) case is an adenoid cystic carcinoma. 5 cases (27,5%) were anatomically located in the oropharynx (tonsils and tongue base), 5 cases (27,5%) were treated for oral cavity (tongue and floor of the mouth) cancers, 3 (16,5%) and 1 (5,5%) cases were treated for laryngeal respectively hipopharynx cancer. 2 cases were treated with Nivolumab for salivary gland—1 case (5.55) respectively sinonasal cancer—1 case (5.5%). 14 cases (77%) were initially staged—8 cases (44%) stage III, 5 cases (27,5%) stage IVA and 1 case (5,5%) stage IVB (lung metastases). Only 2 case (11%) received curative surgical treatment, 1 patient (5,5%) was treated with salvage surgery after relapsed and 1 case (5,5%) was treated with surgery for residual disease after a response to immunotherapy. The median age of the patients included in the study was 58,9 years (52 to 65 years) and 16 cases (85.7%) being male. 15 cased (82,5%) benefited from radiotherapy, 2 case (11%) for adjuvant purpose and 11 cases (60,5%) as definitive treatment, 2 cases (11%) were treted with re-irradiation (11%) and 1 case (5,5%) were treated with palliative purpose a in total doses ranging between 30Gy in 10 fractions and 70Gy in 35 or 33 fractions (simultaneous integrated bost). Poly-chemotherapy or single agent chemotherapy was also administered in all cases, the number of cycles varying between 1 and 10. Chemotherapy regimens included platinum base doublet or triple combination including Cisplatin, Carboplatin, 5-Fluorouracil, Docetaxel. Single agent chemotherapy with Capecitabine and Metotrexat and Carboplatin was also used. The median duration of immunotherapy treatment was 5.6 months (1 to 14 months) and 4 patient (22%) died up to 3 months after initiation of Nivolumab therapy. The median DFS was 34 months (0 to 84 months). Most of the failures were loco-regional recurrences, but in 4 cases (16.5%) the failure was due to lung metastasis (2 cases), mediastinal lymph node metastases (1 case) and both locoregional and lung reccurence (1 case) (Table 1 and Table 2) 2. Infectious episodes were reported in 3 cases (16,5%) during treatment, Klebsiella species, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA) being mentioned as pathogens. Only one case was diagnosed with metachronous pancreatic cancer. Two of the cases meet the criteria of second primary malignancy (SPM). In both cases the initial disease free survival (DFS) was longer than 10 years. For the case that benefited from re-irradiation with a dose of 50 Gy in 25 daily fraction (both initial treatment and re-irradiation being delivered with an Rokus-M40 former Soviet Union Cobalt-60 machine without image guided treatment capability), OS after the initiation of Nivolumab was 16 months. The other SPM case treated with radiotherapy only for the first malignancy, but heavily treated with chemotherapy and Cetuximab had an OS of 3 months after the initiation of immunotherapy. It should be mentioned that this case required the administration of corticosteroids and antibiotics after the initiation of Nivolumab. No immune related adverse events (AEs) ≥ grade 3 were recorded. One death associated with admission to the emergency room for respiratory failure was not related to immune-mediated pneumonitis. Median nadir neutrophil to lymphocyte ratio (NLR) was 2.72 (1.43 to 8.27) and median NLR during the treatment was 6.01 (2.91 to 16.08). Much higher values of NLR during treatment are observed in patients who died early during immunotherapy. The median monthly delta-NLR variation was calculated in these cases, a positive dynamic of 13.07 per month being identified.

4. Discussions

4.1. Immunotherapy in HNC—the challenges of a revolution

Locally-advanced HNSCC is characterized by a recurrence rate >50% within 3 years, survival in relapsed/metastatic cases refractory to platinum being generally less than 6 months, with limited therapeutic options in this context. Considering that disease progression, invasion and metastasis are associated with programmed death ligands (PD-L1 and PD-L2) and with Programmed cell death Protein 1 (PD-1) expressed on the surface of T lymphocytes, the use of immune checkpoint inhibitors was evaluated in multiple preclinical and clinical studies. PD-1 inhibitor Nivolumab was evaluated at a dose of 3 mg per kilogram every 2 weeks in comparison with a single agent of systemic therapy, including cases treated with Methotrexate, Docetaxel, or Cetuximab. The study that included 361 patients had OS as its main objective. Progression free survival (PFS), objective response rate (ORR), quality of life and safety profile were also assessed. 7.5 months versus 5.1 months were the median OS rates in the Nivolumab respectively monotherapy group (investigator choice). The treatment response rate was 13.3% versus 5.8% in favor of the patient lot treated with immune checkpoint inhibitors (ICI), with a significantly better toxicity profile (adverse events of grade 3 or 4) for Nivolumab (13.1% versus 35.1%) [9,10,11].

In a subgroup analysis, Gillison and collaborators demonstrate long-term outcomes in patients with recurrent/metastatic HNSCC who received Nivolumab in the first line. The authors mention a median overall survival (OS) at 2 years for patients who received first-line immunotherapy of 20.4%, in contrast to only 3.8% in the group that received the treatment chosen by the investigator. Thus, a clear benefit for immunotherapy in the first line for recurrent or metastatic HNSCC is highlighted. EXTREME regimen including Cetuximab, platinum and 5-Fluorouracil and, later, TPEx regimen including Cetuximab, platinum salts and Docetaxel were the preferred therapeutic options before ICI therapy entered the therapeutic spectrum of recurrent/metastatic HNSCC [12].

Combined positive score (CPS)>1 was proposed to stratify patients between Pembrolizumab monotherapy (for CPS ≥ 1) and Pembrolizmumab in combination with platinum or fluorouracil. The double association between a Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4) inhibitor, Ipilimumab and Nivolumab did not demonstrate a benefit in OS compared to the EXTREME regimen for cases with CPS>1 [1,9,13].

The KEYNOTE-040 trial, a phase III trial that included 247 patients from 97 medical centers (20 countries) demonstrated a benefit of 1.5 months in OS in the intention-to-treat population compared to standard treatment based on Methotrexate, Docetaxel, or Cetuximab in metastatic/recurring HNSCC when platinum-based chemotherapy was associated with Pembrolizumab. The use of immunotherapy in the first line of treatment for patients with high expression of PD-L1 was anticipated as early as 2019 by Saada-Bouzid et al. which mentions the prospects of immunotherapy with Pemrolizumab to become the first-line treatment in recurrent and metastatic HNSCC as a unique treatment for patients with high PD-L1 levels [14].

A meta-analysis and systematic review aims to investigate the efficacy of anti-PD-1- vs. anti-PD-L1-based therapy in patients with relapsed or metastatic HNSCC, including data from the Keynote 040, Keynote 048, Eagle, Condor, Checkmate 141 including 3001 patients. The study compares PD-L1-based, PD-1-based and chemotherapy treatments. The data analysis did not highlight major differences between the studied groups in terms of treatment results, but anti-PD-1 administration was associated with better results in smokers and in HPV negative patients. Anti-PD-L1 was associated with favorable response in female patients and smokers. The results of the meta-analysis could help to stratify patients for the choice of the type of immune checkpoint inhibitors (ICI) [15].

A post hoc analysis that evaluated patients included in the CheckMate 141 trial evaluated Nivolumab in recurrent or metastatic HNSCC for cases treated beyond first RECIST-defined progression (TBP). Among the 60 patients who fulfilled this criterion, 25% of the cases associated a reduction in the size of the target lesions. 5% of these cases, were associated with a >30% reduction in tumor size. Haddad et al. also mentions the need to identify biomarkers of response beyond disease progression [16].

Salvage chemotherapy (SCT) after Nivolumab is considered a therapeutic option for recurrent/metastatic HNSCC. ORR and disease control rate were evaluated on a group of 21 cases that received SCT after Nivolumab. PFS and median OS were also evaluated. Values of 52.4% and 81.0% for ORR and disease control rate, as well as a median OS of 12.9 months and a median PFS of 5.4 months advocate for the possibility of using salvage chemotherapy in cases of relapsed and metastatic HNSCC after ICI treatment. Positive PD-L1 expression could be considered a prognostic factor of response to SCT [17].

The efficacy and safety of Nivolumab for the category of patients with relapsed and metastatic HNSCC sensitive to platinum was evaluated in a single institution prospective study in Japan. Cases were included based on the criterion of relapse or metastasis at least 6 months after therapy or chemoradiotherapy based on platinum salts. In the group of 22 platinum sensitive patients, the median OS was 17.4 months and the survival at 1 year was 73%. With an ORR of 36% and no adverse events (AEs) of grade 4 and 5 related to treatment, the regimen is considered safe and feasible. The retrospective study proposed by Okada and collaborators demonstrates on a group of 88 patients (60 platinum refractory cases), similar results of treatment with Nivolumab in metastatic or relapsed HNSCC cases, both in platinum sensitive and refractory cases [18].

Gavrielatou et al. analyzes the response of NNSCC to ICI treatment, evaluating and classifying biomarkers in 3 categories: tumor related biomarkers, host related biomarkers and other biomarkers related to the tumor microenvironment (TME). In the first category, PD-L1 or CPS, Interferon gamma (IFN-γ) signature genes and TMB are mentioned. An “inflamed” microenvironment is an immune environment including increased values of CD3 and CD8 lymphocytes, forkhead box P3 (FOXP3), T cell clonality, M1 macrophages and tertiary lymphoid structures (TLS). HPV positive status and microbiome including Akkermansia muciniphila and Enterococcus hirae are associated with positive response to immunotherapy [19].

4.2. Neutrophil to lymphocytes ratio (NLR)—towards a new biomarker

NLR as a hematological marker of inflammation and the modified Glasgow prognostic score (mGPS) were evaluated for their predictive potential of response to treatment with Nivolumab was evaluated in HNSCC in the Japanese multi-institutional study that included 88 eligible patients. The values increased pre-treatment NLR and mGPS (=2) were associated with reduced survival. Thus, the increased NLR value was correlated with OS at 1 year and OS at one year: 45.3% vs. 16.3% for cases with reduced NLR. Also mGPS low (=0) and mGPS higher (=2) was correlated with OS at 1 year of 37.4% and 26.1%, respectively. Another Japanese cohort study identifies high NLR values and a cut-off value of 5 for NLR as predictive for discontinuation of immunotherapy and treatment switch to “best supportive care” but also for unfavorable response to treatment. The authors propose the use of NLR as a biomarker for evaluating the effectiveness of immunotherapy with Nivolumab [5,6,20,21].

Neutrophil-lymphocytes (NLR) as a hematological marker of inflammation and the modified Glasgow prognostic score (mGPS) were evaluated for their predictive potential of response to treatment with Nivolumab was evaluated in HNSCC in the Japanese multi-institutional study that included 88 eligible patients. The values increased pre-treatment NLR and mGPS (=2) were associated with worst prognosis. Thus, the increased NLR value was correlated with OS at 1 year of 45.3% vs. 16.3% for cases with low NLR. Also mGPS low (=0) and mGPS higher (=2) was correlated with OS at 1 year of 37.4% and 26.1%, respectively. Another Japanese cohort study identifies high NLR values and a cut-off value of 5 for NLR as predictive for discontinuation of immunotherapy and treatment switch to “best supportive care”, but also for unfavorable response to treatment. The authors propose the use of NLR as a biomarker for evaluating the effectiveness of immunotherapy with Nivolumab [22,23,24].

The association of neutrophils with cancer progression and treatment outcomes is controversial. The association of NLR or tumor-associated neutrophils (TAN) and cancer prognosis was evaluated in a systematic reviews and meta-analyses including observational studies published in the MEDLINE, Embase and Cochrane databases. 204 meta-analyses from 86 studies met the inclusion criteria. 29% of these meta-analyses presented consistent evidence supporting the correlation between NLR and TAN and an unfavorable cancer prognosis, however, it is necessary to mention the heterogeneity of the studies including the inclusion of some cases treated with immunotherapy [25].

Immune dysfunction in relation to NLR is evaluated not only in cancer but also in space flight, a low gravity medium being associated with increased NLR values and lymphocyte dysfunctions. The study demonstrated that increased NLR values were associated with oxidative stress and the release of inflammatory cytokines triggered by simulated microgravity in laboratory mice [26].

A higher NLR ratio was significantly correlated with an unfavorable response to treatment overall survival and reduced progression-free survival in patients treated with ICI for various types of cancer. A combination of NLR with tumor mutational burden (TMB) can increase the predictive power. Thus, low NLR and high TMB associate a favorable response to ICI, while an increased NLR and a low TMB can be a biomarker for immunotherapy failure [27].The prognostic role of NLR in esophageal cancer patients treated with anti-PD-1 agents is evaluated on a group of 140 patients with unresectable or metastatic tumors treated with immunotherapy. In these cases, using Kaplan-Meier and the log-rank test, OS and progression free survival (PFS) were evaluated between patient groups. The multivariate Cox method was used to test the prognostic value of NLR. The study proposed a follow-up period of 20 months and a threshold value of NLR of 5. Pretreatment values of NLR ≥5 were associated with overall response rate (ORR), PFS and higher OS compared to cases with NLR<5 , of 46.7%, 10 months and 22 months respectively 12.1%, 3.5 months and 4.9 months. The study demonstrates that the pretreatment value of NLR can be used as a predictive biomarker of treatment response and prognosis in unresectable and metastatic esophageal cancer treated with anti-PD-1 immunotherapy [28].The association of NLR with the outcome of treatment with Nivolumab for recurrent or metastatic oral squamous cell carcinoma (OSCC) was evaluated on 13 cases in an observational study. The complete and partial response rates were 38.5% and 0%, respectively, and the rates of stable disease and progressive disease in non-responders were 77% and 53.8%, respectively. The study demonstrated a decrease in NLR in responders from a median value of 4.1 to 3.3. In the case of non-responders, the median NLR increased from 5.6 pre-treatment to 9.4 during treatment. Also, a post-treatment value of NLR >10 was associated with an unfavorable response to post-Nivolumab salvage chemotherapy. And the cuttof value of 5 was identified as significant for unfavorable OS in the case of post-Nivoluamb NLR>5 values. The authors note the possibility of using NLR as a predictor of salvage chemotherapy post-Nivolumab [29].

The predictive and prognostic power of NLR, platelet-lymphocyte ratio (PLR), but also the dynamics of these biomarkers during treatment with programmed death-ligand 1 (PD-L1) inhibitors, as second-line treatment for non-small cell lung cancer (NSCLC) was analyzed in a study that identified the NLR value = 5 as the cutoff for the PFS and OS endpoints. A PFS of 6.86 months vs. 18.82 months was identified in cases with pretreatment NLR > 5 vs. NLR ≤ 5. In a multivariate analysis NLR > 5 before chemotherapy and the presence of bone metastases were associated with reduced OS. The authors consider an NLR <5 as a prognostic biomarker of survival in NSCLC that benefits from Pembrolizumab immunotherapy in the second line [30].

NLR dynamics in the first 21 days after the start of immunotherapy was evaluated on a group of 509 patients with advanced cancers. And in this case, the value of 5 for NLR was identified as significant for predicting OS. The moderate decrease of NLR in the first weeks after the initiation of immunotherapy was associated with the longest OS (median of 27.8 months). Rapid variations, whether they were decreases or increases in NLr, were associated with shorter OS (median of 11.4 months). The non-linear change in NLR and the correlation with survival is reported for the first time by this study. An early decrease in NLR in the first 6 weeks of treatment is associated with a good prognosis in the case of patients with metastatic renal cancer treated with immunotherapy. At the same time, a relative change by ≥25% from baseline NLR value is associated with reduced ORR and OS in the same study [31,32].

NLR dynamics in the first 21 days after the start of immunotherapy was evaluated on a group of 509 patients with advanced cancers. And in this case, the value of 5 for NLR was identified as significant for predicting OS. The moderate decrease of NLR in the first weeks after the initiation of immunotherapy was associated with the longest OS (median of 27.8 months). Rapid variations, whether they were decreases or increases in NLR, were associated with shorter OS (median of 11.4 months). The non-linear change in NLR and the correlation with survival is reported for the first time by this study. An early decrease in NLR in the first 6 weeks of treatment is associated with a good prognosis in the case of patients with metastatic renal cancer treated with immunotherapy. At the same time, a relative change of ≥25% from baseline NLR value is associated with reduced ORR and OS in the same study [33]. Even if the ATTRACTION-2 study demonstrated the significant benefit in the survival of patients with advanced gastric cancer, the different responses in subgroups of patients justified the interest in identifying biomarkers correlated with treatment response. A multivariate analysis demonstrated in a study that included 98 cases of advanced gastric cancer treated with Nivolumab (3 mg/kg or 240 mg/body every two weeks) that, Eastern Cooperative Oncology Group (ECOG) index of 0 or 1, Pretreatment NLR > 3 and an NLR difference ≧ 2 evaluated in the first 60 days of treatment are variables correlated with treatment response, the median follow-up period in the study being 4.9 months. Delta variatiaon of NLR in the first 2 months after the initiation of immunotherapy is considered a possible predictive biomarker for treatment with Nivolumab. A NLR value of 2.5 was considered suggestive by Yamada et al. to separate subgroups of patients according to prognosis for cases of gastric and gastroesophageal junction treated with Nivolumab in monotherapy [34,35]. The potential biomarker value of NLR, but also of the delta NLR variation during immunotherapy for different types of cancer is summarized in Table 3 [Table 3], [27,28,29,30,31,32,33,34,35].

4.3. Immunotherapy and HNC beyond HNSCC (focus on other histological types and second primary malignancy)

Certain histological subtypes or primary sites of HNC were not included in the CheckMate-141 trial. The study by Ueda et al. included 97 cases with these subtypes in order to evaluate the benefit of Nivolumab. Among these categories we mention nasopharyngeal squamous carcinoma and other adenoid cystic carcinoma. If for nasopharyngeal cancer the results of the study agree with those of the NCI-9742 trial, the benefit of Nivolumab being comparable to historical data, in the case of rare head and neck adenoid cystic and neuroendocrine tumors only 1 out of 14 cases was associated with a favorable response, the indication to administer immunotherapy in this case being considered premature by the authors. However, in undifferentiated tumors, Nivolumab was associated with benefit [36].

Patil et al. evaluated the benefit of a low dose of immunotherapy added to triple metronomic chemotherapy (TMC), based on data that support the OS benefit provided by metronomic chemotherapy. The phase III superiority study included relapsed or newly diagnosed patients with palliative treatment indication Eastern Cooperative Oncology Group performance status of 0-1. The TMC regimen included oral Methotrexate 9 mg/m2 once a week, Celecoxib 200 mg twice a day and Erlotinib 150 mg once a day, 20 mg Nivolumab being added every 3 weeks in the study arm. Having OS as an objective at 1 year, the results of the trial highlighted a benefit of the TMC + immunotherapy regimen (TMC-I), the median OS being 6.7 months and 10.1 months in the TMC arm and TMC-I, respectively. It should be noted that the rate of AEs is higher by 3.9% in the TMC arm. The study is proposed as paving the way for a new standard for cases with palliative indication that do not benefit from standard dose immunotherapy for various reasons [37].

SPM can be associated with radiotherapy treatment of HNC. SPM is considered an invasive cancer at a non-contiguous site diagnosed at least 6 months after the completion of radiotherapy. Analyzing the incidence of PMS in the head and neck region, Ng et al. identified a risk of 9% analyzing a group of 1512 patients, the majority of oropharyngeal cancer cases. Growth rates of 4, 10, and 25% were associated with time intervals of 5, 10, and 15 years at completion of treatment, with an estimated 5-year overall survival of 44%. Smoking is considered a risk factor not only of HNC, but also of PMS in the head and neck region. However, in the case of hypopharyngeal cancer, it is considered that SPM does not decrease OS. This observation is associated by Guo with the unfavorable prognosis of this subtype of HNC or with a shorter follow-up period of these cases. Intensity modulated radiotherapy (IMRT) is recommended as a technique for re-irradiation, taking into account the limits imposed by possible treatment related toxicities and the need to reduce the dose to organs at risk (OARs). The risk of PMS is considered proportional to the radiation dose, oral cancer and thyroid cancer are among the subtypes of PMS mentioned in the neck and neck region. If radiotherapy is associated with an increased risk of PMS, the new data report a reduction of this risk in cases treated with ICI for the first cancer. In the case of nasopharyngeal cancer, the use of intensity-modulated irradiation techniques is associated with a significantly lower risk of PMS compared to conventional radiotherapy. An irradiation dose >60 Gy is considered necessary to achieve tumor control, grade ≥3 late toxicity being estimated at 23.8%. If radiotherapy is associated with an increased risk of PMS, the new data report a reduction of this risk in cases treated with ICI for the first cancer [38,39,40].

4.4. Radiotherapy and immunotherapy in HNC—an alliance with perspectives

The subject of a synergistic association between immunotherapy and radiotherapy already has both the support of fundamental and clinical research. If, in the case of higher doses per fraction, the release of tumor neoantigens is the main pathophysiological substrate associated with the augmentation of the immune response, in the case of irradiation with the standard fractionation regimen, the reprogramming of the tumor microenvironment (TME) and the conversion of a “cold” immune phenotype into a “imflamed” phenotype could be associated with increasing response rates to immunotherapy. It is well known that in HNC the abundance of tumor infiltrating lymphocytes (TIL) has been associated with a favorable prognosis. The tumor/stroma ratio seems to have an essential role in establishing the prognosis, this proportion being dependent on the anatomical location but also on the involvement of viral etiology. The presence of CD8+ T lymphocytes, although reduced in tumors not associated with HPV, is considered prognostic. The presence of regulatory T lymphocytes (Treg) has an immunosuppressive role, and an association of a reduced proportion of CD8+ with an abundance of Treg could induce immunosuppression and reduce the response rates to immunotherapy. The exception are high Foxp3 Tregs whose high expression associated with CD8 lymphocytes and PD-L1 levels was correlated with the favorable response to the combination of radiotherapy—chemotherapy with Cisplatin or to the combination of radiotherapy—biological therapy with Cetuxiumab. The presence of natural killer (NK) cells is also correlated with a favorable prognosis, but is reduced in HPV negative HNC. Tumor-associated macrophages (TAM) have been associated with progression, metastasis, and the risk of recurrence after treatment. M2 macrophages are generally associated with the evolution of the disease, while M1 type macrophages have an antitumor role. For this reason, TME reprogramming with the help of radiotherapy or chemotherapy with the promotion of M1 macrophages can be an effective strategy to induce tumor regression [41,42,43,44,45,46].

The synergistic effects of immunotherapy and radiotherapy in HNC were summarized by Wong et al. in 6 main conclusions. The effects of radiotherapy and immunotherapy are shown to be synergistic by preclinical data, there is a potential for exploitation of the immune landscape characteristic of HNC cancers induced by viruses including Epstein-Barr Virus (EBV) in nasopharyngeal cancer and Human Papilloma Virus (HPV) in oropharyngeal cancer. Currently, the association between immunotherapy and radiotherapy is intensively analyzed in clinical studies, but until now there is no consensus and conclusive clinical evidence to demonstrate additional benefits brought by irradiation to immunotherapy. The sequence, dose and optimal administration time of each treatment must be identified in order to obtain a maximum synergistic potential [47].

However, the dual immunosuppressive and immunostimulatory effect of irradiation, coexisting in a fragile balance, makes it necessary to evaluate in studies the optimal therapeutic sequence. Immunosuppression induced by concurrent radio-chemotherapy-immunotherapy, but also the immunosupresion asoociated with elective irradiation of lymph nodes could be the cause of failures in clinical trials such as JAVELIN Head and Neck 100 (NCT02952586). Even if it refers to another ICI, Pembrolizumab, a sequential combination is considered optimal in the case of delivering radio-chemotherapy and immunotherapy [48,49,50,51]. Until now, at least 9 phase III trials have evaluated or are evaluating different immunotherapy agents in different sequences and associations in HNC. However, it is worth mentioning CHECKMATE 577 and PACIFIC trials, both trials with favorable results include the therapeutic sequence in which immunotherapy is administered as maintenance after radiochemotherapy and radiochemotherapy plus surgery respectively in lung and esophagus cancers. The IMvoke 010 trial (NCT03452137) addresses the concept of Atezolizumab in maintenance after definitive treatment of any type of HNC with a high risk of recurrence [48,52]. Nivolumab in combination with immunotherapy in different sequences and regimes, even if it is induction settings, concurrent setting or adjuvant/maintenance treatment associated with definitive radiotherapy in standard fractionation, SBRT or re-irradiation is evaluated for a possible synergistic association in clinical trials [Table 4] [52,53,54,55,56,57,58,59,60,61,62].

5. Conclusions

The reported data must be interpreted within the limits generated by the small group of patients included, presenting an early experience of two academic center with Nivolumab immunotherapy in platinum-refractory HNC. It should be noted a median PFS during immunotherapy (including even adenoid cystic carcinoma) that exceeds the data from the literature, a possible explanation being the possible benefit of Nivolumab for cases with nadir NLR values <3.5 and the intensive chemotherapy and radiotherapy treatment delivered in most of the cases. The administration of radiotherapy and chemotherapy during the evolution of the disease could be a potentiation factor that augment the immune response by modulation of TME. To our knowledge, these are the first two cases of PMS in the head neck region treated with Nivolumab. The inaccessibility of a more conformal irradiation technique limits the irradiation with maximum doses and also the association of concurrent chemotherapy. The reported data support a possible benefit of the sequential administration of radiotherapy, immunotherapy and SPM. Higher positive dynamic of NLR could be associated with worst outcome during immunotherapy. All study observations including the role of infections and antibiotic treatment as well as the possible biomarker value of NLR variation during immunotherapy should be investigated in multicenter clinical trials to be validated.