4.1.1 Cetuximab

Cetuximab (Erbitux2), a high-affinity recombinant Immunoglobulin G1 (IgG1), inhibits ligand binding and promotes EGFR interiorization and downregulation.⁴⁰ Various mechanisms are considered to cause the anti-cancer action of Cetuximab, involving the direct blockage of EGFR tyrosine kinase, restricting cell cycle, raising the quantity and activity of the cell death-inducing molecule, such as Bcl-2 and Bax, and increasing radiotherapy and chemotherapy anti-cancer effects.⁴¹ Besides, clinical trials proved that cetuximab inhibits invasion, angiogenesis, and metastasis.⁴²

The overactivation and high expression of EGFR in almost all HNSCC cases (over 90%) have been reported.^{43, 44} Consequently, elevated EGFR promotes oncogenesis and plays an independent poor prognostic role in HNSCC.^{44, 45} Furthermore, EGFR blockage makes tumor cells susceptible to radiation; on the other hand, radiotherapy promotes the expression of EGFR.^45-47 Therefore, EGFR-blocking would be a good choice to improve the outcome of patients in comparison to radiotherapy alone. Previous studies showed that combining cetuximab and radiotherapy restricts HNSCC more efficiently and decreases mortality and adverse effects.⁴⁵

Controversial findings on cetuximab efficiency and toxicity have been reported.^{48, 49} Recently, in a novel study, Fushimi et al. demonstrated that even though the combination of cetuximab and paclitaxel increased median progression-free survival (PFS) and overall survival (OS) in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/MHNSCC), this regime led to some adverse effects, such as rash-acneiform, anemia, and neutropenia.⁵⁰ Therefore, more reliable studies with larger sample sizes are required to ensure the efficiency of treating SCC patients with cetuximab.

In a non-randomized, phase II clinical trial by Sacco et al., 33 patients with R/MHNSCC were treated with Pembrolizumab and Cetuximab regimens. The patients were at least 18 years old with no previous history of immunotherapy. Given to median follow-up duration = 7.3 months (3.9–10.9), overall response rate was 45% (95% CI, 28%–62%).the most common adverse effect was oral mucositis, and no death occurred.⁵¹

In another phase II randomized clinical trial, Lonardi et al. evaluated the efficacy of Avelumab alone (arm 1, n = 30) in comparison to a dual combination of Cetuximab with Avelumab (arm 2, n = 30) in patients with aSCAC (advanced metastatic squamous cell anal carcinoma). Overall response rate were 10% (95% CI, 2.1%–26.5%) versus 17% (95% CI, 5.6%–34.7%), respectively. Disease control rate were 50% (95% CI, 31.3%–68.7%) versus 57% (95% CI, 37%–74.5%). At a median follow-up of 26.7 months (IQR 26.5%–26.9%), median PFS were 2 months (95% CI, 1.8–4 months) versus 3.9 months (95% CI, 2.1–5.6). median OS were 13.9 months (95% CI, 7.7–19.4) versus 7.8 (95% CI, 6.2–11.2). The results emphasized the promising role of dual therapy of EGFR and PD-L1 inhibitors in the future.⁵²

4.1.2 Zalutumumab

Machiels et al. showed that treating SCC with zalutumumab, a fully human IgG1 Mab against EGFR, inhibits tumor progression without any signs of adverse effects like rashes.⁵³ following these results, another study showed that zalutumumab's safety and efficiency in controlling R/MHNSCC are acceptable.⁵⁴ Data from Phase I and II trials proved this novel Mab as a safe and promising treatment for SCC; also, recent Phase III studies support previous findings.⁵⁵

4.1.3 Panitumumab

Panitumumab, a recombinant human IgG2 Mab to EGFR, showed successful results in restricting R/MHNSCC without significant adverse effects.⁵⁶ However, despite initial positive results, several studies demonstrated that panitumumab could not be a reliable therapy.^57-59 Eventually, evaluating panitumumab safety and efficacy in recent studies, Necchi et al. showed that treating SCC with this Mab would show good curative effects on cancer.⁶⁰ In conclusion, due to deep controversies in combining Panitumumab with other treatment options, we have a long way to approve its value in restricting HNSCC.

4.1.4 Nimotuzumab

In 2013, Reddy et al. used nimotuzumab and humanized IgG1 antineoplastic Mab with CRT/RT as a viable therapeutic option in patients with HNSCC, and introduced this combination as a novel therapeutic choice.⁶¹ Moreover, in the last decade, further studies supported these results.^62-64 Consequently, Si et al. showed that using Nimotuzumab along with chemotherapy is a potential method and efficient therapy for skin cancers, even as a first-line treatment of SCC.⁶⁵ In addition, in some cases, Nimotuzumab showed a significant improvement in the OS rate in patients with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC).⁶⁶

A study was performed by Zhang et al., in which the effect of nimtuzumab in addition to chemo/radiotherapy for the treatment of unresectable esophageal SCC was investigated. The overall objective response rate was reported to be 92.6% and the patients were followed up for 35.1 months, during which the 1 year, 2 years and median overall survival rates were 61.1%, 35.2%, and 16 months, respectively. Also, 1-year, 2-year progression-free survival and median progression-free survival were evaluated as 42.6%, 16.7%, and 10 months, respectively.⁶⁷

4.1.5 Necitumumab

In a phase 3 randomized controlled trial by Thatcher et al., necitumumab, recombinant human IgG1 Mab binding to EGFR, has shown promising results in the treatment of stage IV squamous non-small-cell lung cancer patients. It improved the overall survival of these patients, accompanied by acceptable safety.⁶⁸ However, it was not consistent with another trial on this topic by Paz-Ares et al.⁶⁹

Nakao et al. reported severe hypomagnesemia in a 72-year-old man with Hashimoto's disease, old MI, disseminated nontuberculous mycobacteriosis, and lung SCC. He managed to survive for more than 3 years, but tumor progression was detected, after using Nivolumab as the fifth line of treatment. In the sixth line of treatment, cisplatin and gemcitabine combined with Necitumumab were used. On the eighth day of the second cycle, severe hypomagnesemia occurred, one of the documented adverse effects of monoclonal antibodies.⁷⁰

As a sixth-line treatment, a 72-year-old man with Hashimoto's disease and advanced lung squamous cell carcinoma was given cisplatin plus gemcitabine with necitumumab, which is a human monoclonal antibody that interacts with EGFR. Tumor decrease was detected, but on day 8 of the second cycle, asymptomatic grade 4 hypomagnesemia occurred. On day 40, he received magnesium replenishment, and his hypomagnesemia improved. However, tumor development was seen over the magnesium correction period. Although hypomagnesemia is a documented side effect of anti-EGFR antibody therapy, there have been no case reports of severe hypomagnesemia or its clinical course. Pembrolizumab monotherapy, carboplatin plus nab-paclitaxel, docetaxel plus ramucirumab, tegafur/gimeracil/oteracil (S-1) therapy, and nivolumab therapy were all used to treat him.

Even though he had attained long-term survival (>3 years), tumor growth was noticed shortly after starting nivolumab treatment. Nakao et al. opted to use cisplatin with gemcitabine in conjunction with necitumumab (every 3 weeks on days 1 and 8) therapy because his performance status was 1 at the end of nivolumab therapy as a fifth-line therapy, and he was in good overall condition. After one session of treatment, the tumor shrank significantly in comparison to the baseline partial response (2).

4.1.6 Pertuzumab

In clinical trials, the epidermal growth factor receptor (EGFR) inhibitor gefitinib (Iressa) showed anti-cancer effectiveness against malignancies such as non-small cell lung cancer and HNSCC. Factors that may predict response to gefitinib have been discovered through research on non-small cell lung cancer. The molecular markers that may predict response to gefitinib in HNSCC patients are poorly understood. Erjala et al. investigated putative connections between the gefitinib responsiveness and molecular markers of the EGFR/ErbB receptor family signaling pathway. Clonogenic survival experiments were used to establish the IC50 of gefitinib sensitivity. Western and real-time reverse transcription-PCR analyses of EGFR, ErbB2, ErbB3, and ErbB4 expression levels, as well as phosphorylation study of pEGFR, pErbB2, pErbB3, pAkt, and pErk, were used to characterize ErbB signaling. cDNA sequencing and real-time PCR were used to assess EGFR kinase domain sequences and EGFR gene copy numbers, respectively. Finally, the gefitinib response was compared to the anti-EGFR antibody cetuximab (Erbitux). They found that In HNSCC, EGFR amplification may predict gefitinib susceptibility. Other members of the EGFR/ErbB receptor family may have a role in gefitinib resistance. ErbB2 and ErbB3 may be prognostic markers and therapeutic targets in treating HNSCC with gefitinib in combination therapy. According to their findings, in HNSCC, EGFR amplification may predict sensitivity and increase ErbB2/ErbB3 signaling resistance to the EGFR TKI gefitinib.

In HNSCC, the majority of targeted treatments have focused on inhibiting EGFR. Combining EGFR inhibitors with medications that target other members of the ErbB family, such as pertuzumab, may provide further benefit to HNSCC targeted therapy. The findings suggest that analyzing ErbB receptor signaling characteristics may provide predictive information and that simultaneous targeting of EGFR and other ErbB family members may reduce HNSCC cell proliferation (Table 1).

4.2.1 Trastuzumab

HER2 is a tyrosine-kinase protein.⁷² HER2 plays a remarkable role in tumorigenesis. Its overexpression has been reported in many cancers, such as head and neck cancers.⁷³ Moreover, HER2 promotes cancer cell development and causes tumor cells’ resistance to radiotherapy and chemotherapy that leads to poor prognosis and disease progression.⁷⁴ Therefore, inhibiting HER2 activity through the administration of trastuzumab, a highly purified recombinant DNA-derived IgG1 kappa Mab binding specifically to the extracellular domain of HER2 receptor, would provide a new promising approach to cancer therapy.⁷² To date, extensive studies have been designed to evaluate the efficiency of numerous combinations of trastuzumab with other treatments. Immunocytochemistry analysis demonstrated that trastuzumab restricts HER2 overexpression and stops cancer development in patients with ESCC.⁷⁵ Supporting previous results, Yamazaki et al. showed that this combination has significant antitumor effects on all four-cell lines of SCC.⁷⁴

Therefore, using gefitinib and trastuzumab together would be a valuable and promising approach in HNSCC.

4.3.1 Cixutumumab

Cixutumumab is a fully human Mab targeting IGF-1R, which is involved in cancer development. Few studies on the efficiency of cixutumumab monotherapy and its combination with other methods demonstrated that this regimen shows no reliable restrictive effect on R/M HNSCC.^{77, 78}

4.4.1 Onartuzumab

Onartuzumab is a humanized and monovalent Mab that targets MET receptors and inhibits the signaling of hepatocyte growth factor (HGF).⁸¹ In a phase II study, Hirsch et al. could not approve onartuzumab as a promising treatment for patients with advanced squamous cell non-small-cell lung cancer since the study showed no reliable anti-tumor activities with various adverse effects such as pulmonary embolism and neutropenia.⁸² However, further studies are required to examine the efficacy of onartuzumab in a clinical setting.

4.4.2 Ficlatuzumab

Ficlatuzumab is a potent humanized IgG1 Mab that binds the hepatocyte growth factor (HGF inhibitor), preventing the activation of the c-Met pathway. It restricts HNSCC by restraining the proliferation and relocation of cancer cells and suppressing activation; therefore, based on this theory, Kumar et al. evaluated the impact of this novel Mab and concluded that ficlatuzumab viably mitigates stromal impacts on HNSCC progression.⁸³ Another study showed that ficlatuzumab, in combination with cetuximab has an appropriate safety profile and demonstrates promising cytotoxic effects in a refractory population of HNSCC patients.^{84, 85} In conclusion, targeting C-Met by ficlatuzumab seems a potentially promising method to manage SCC, according to recent studies.

4.5.1 Bevacizumab

Bevacizumab, a humanized IgG1 Mab, functions as an anti-VEGF recombinant Mab with the affinity to bind all VEGF-A isoforms.¹⁷ The primary mechanism of bevacizumab activity includes binding to VEGF-A and preventing it from joining VEGFR1 and VEGFR2.^{17, 19} Bevacizumab has proven beneficial therapeutic properties in the treatment of different cancers, including recurrent cervical,⁸⁷ colorectal,⁸⁸ renal-cell,⁸⁹ breast.⁹⁰ VEGF expression correlates to tumor invasion, venous and lymphatic invasion, lymph node metastasis, and tumor stage in ESCC. Therefore, it may be involved in the progression of esophageal carcinoma via its angiogenesis and lymphangiogenesis effects.⁸⁶ Adding a particular regimen of bevacizumab to chemotherapy and radiation results in a 95% positive response with relatively equal toxicity to other modalities, which confirmed the efficacy of adding bevacizumab and erlotinib to standard first-line treatment.⁹¹

Besides, A middle-eastern study proved bevacizumab as a promising treatment for HNSCC due to its negative effects on VEGF secretion.⁹²

In addition, a combination of bevacizumab with cisplatin and radiation therapy improved the 2-year OS and PFS with a few adverse events, such as a significant increase in myelosuppression and leukopenia.⁹³

In a phase II study, adding bevacizumab to pemetrexed in patients with HNSCC enhanced median OS to 11.3 months and treatment rate to 30%; however, toxic outcomes of bevacizumab application included significant bleeding in 15%, neutropenia in 10%, and infection in 12.5% of the patients and one death due to sepsis.⁹⁴ On the other hand, a phase I study on 10 patients with stage 4 HNSCC that received bevacizumab before chemoradiation, confirmed encouraging efficacy via tumor imaging with the most minor adverse effects.⁹⁵ Therefore, Bevacizumab has been proven efficacious in treating HNSCC owing to a high percentage of OS with acceptable toxicity observed in different studies.^{91, 93-95}

Twelve patients with Vulvar Squamous Cell Cancer (VSCC) were recommended targeted therapy and received one or more of bevacizumab, erlotinib, or pembrolizumab. The duration of therapy was 7 months. 10–15 mg/kg of bevacizumab was given intravenously every 3 weeks. The outcomes were CR: 22.2%, SD: 33%, and also TRAEs were seen in 75% of patients.⁹⁶

4.6.1 MEHD7945A (Duligotuzumab)

Duligotuzumab is a human IgG1 dual HER3/EGFR binding Mab for overcoming drug resistance due to the extensive crosstalk between ErbB/HER receptors. It has also been reported that membranous HER3 expression is significantly related to poor prognosis in HNSCC patients. Thereby, it may be used as a potential target for immunotherapy.⁹⁷ De Pauw et al. investigated the efficiency of Duligotuzumab with and without cisplatin in cetuximab-sensitive and resistant HNSCC cell lines; ultimately, the results proved this regimen as a practical option in the treatment of cetuximab-resistant HNSCC patients.⁹⁸ On the other hand, a randomized phase II study showed that Duligotuzumab has low efficiency in the R/MHNSCC treatment outcomes.⁹⁹ Putting an endpoint to controversies, recent studies on this dual antibody demonstrated that Duligotuzumab has positive effects on ionizing radiation.¹⁰⁰

4.6.2 DT-IgG

For higher efficiency in cancer therapy, scientists aimed to design antibodies that can simultaneously affect more than one receptor.¹⁰¹ One of these antibodies is DT-IgG, a fully humanized dual target antibody to EGFR and VEGF that restricts key growth factors.¹⁰² Supporting previous studies, in vivo and in vitro studies demonstrated that DT-IgG suppresses cancer cell growth and has significant antiangiogenic effects by targeting EGFR and VEGF.¹⁰¹ Therefore, these results suggest that DT-IgG is a helpful medication with enhanced clinical benefits in cancer therapy.

4.7.1 Bivatuzumab

Bivatuzumab mertansine (BIWI 1) is a new CD44v6-targeting humanized Mab with the toxin mertansine.¹⁰⁵ CD44v6 antigen is expressed in HNSCC and the normal squamous epithelium.¹⁰⁶ BIWI 1 has a potent antimicrotubular agent attached to a Mab against CD44v6.¹⁰⁶ Reichmann et al.'s study on adult patients with R/MHNSCC, treated with BIWI 1 intravenously, confirmed that by CD44v6 expressing tumors, bivatuzumab has direct mertansine activity (Table 3).¹⁰⁶

5.1.1 Nivolumab

PD-1, a cytotoxic T-cell response inhibitor molecule, contributes to skin cancer development.¹⁰⁹ It is often highly expressed in CSCC.^{110, 111} Antibodies targeting CTLA-4 and PD-1 display clinical effectiveness in metastatic melanoma and Merkel cell carcinoma.^112-114 Nivolumab, a fully human IgG4 Mab to inhibit PD-1, hinders the pathway, which prohibits activated T cells from cancer-fighting, consequently helping the immune system eliminate the tumor.¹¹⁵ Since HNSCC recurrence and metastasis are allowed by immune avoidance, T-cell suppression by PD-1 blockage represents potential clinical efficacy against these tumors.¹¹⁶ Expression of PD-L1 is enhanced in ESCC, which may sensitize the tumor to eradication by immune checkpoint inhibitors.¹¹⁷

Nivolumab is a human IgG4 Mab that blocks the interaction between the PD-1 receptor and PD-L1 and PD-L2 via binding to the PD-1 receptor, leading to inhibition of T cell cytokine production and proliferation. A phase III study compared the effect of nivolumab and chemotherapy on unresectable recurrent or advanced ESCC. It demonstrated that nivolumab significantly improved the OS and had an acceptable safety profile.¹¹⁷ As an outcome of this result, the positive effects of nivolumab on OS in patients with R/MHNSCC have been proved earlier.¹¹⁸ In addition, a study on a patient with CSCC showed that complete remission was achieved within 6 months of immunotherapy with cetuximab and nivolumab.¹¹⁹ In the case of cost-effectiveness, studies have argued that although nivolumab increases OS, it is not a cost-effective option for treating R/MHNSCC.^{120, 121}

In a study conducted by Yamakawa et al., 143 patients were treated with nivolumab. 27.3% of patients showed overall response and the disease was controlled in 46.2% of them. The overall survival of the patients was 11.2 months and the progression-free survival rate was 2.7 months.¹²²

Matsubara et al. conducted a study to predict the efficacy of Nivolumab on esophageal SCC by combined positive score (CPS) and tumor proportion score (TPS). The mean progression-free survival (3.2, 2.5, and 1.5 months) and objective response rate (30%, 25%, and 0%) of patients with CPS ≥10, 1–10, and <1 had a downward trend, respectively.¹²³

5.1.2 Pembrolizumab

In multiple tumor forms, pembrolizumab, a highly selective humanized IgG4 Mab to PD-1 receptor, has demonstrated robust antitumor effects and a tolerable safety profile and is currently validated for one or even more progressive tumors treatment in more than 60 countries worldwide.¹²⁴ Several studies show that pembrolizumab provides better outcomes for patients with CSCC by targeting PD-1.¹²⁵ Moreover, a recent study supported this theory and showed the important survival advantages of pembrolizumab compared to usual treatments.¹²⁶ Shah et al. proved that pembrolizumab could be a promising and safe treatment for patients with metastatic ESCC.¹²⁷ Further studies on the monotherapy of pembrolizumab (or combined with cetuximab and chemotherapy) showed that this Mab has an acceptable efficiency and safety profile.¹²⁸ Therefore, pembrolizumab would make the first-line therapy for PD-L1-positive chronic or metastatic HNSCC with the least concerns in the future.

Phase Ib KEYNOTE-012 research showed that treating R/MHNSCC cases with particular pembrolizumab regimens (10 mg/kg every 2 weeks or 200 mg every 3 weeks) shows the highest survival rate and safety.¹²⁴ Also, the fixed dosage of pembrolizumab has been well accepted, yielding a better clinical objective response rate (ORR) with evidence of reliable reactions, which further supports this treatment.¹²⁹ Therefore, using pembrolizumab in patients with PD-L1-positive chronic or metastatic HNSCC can provide better outcomes in the future.¹³⁰ The last reports of this cohort demonstrated that 200 mg every 3 weeks of pembrolizumab had the best acceptance between cases and resulted in successful outcomes.¹³¹ In conclusion, various studies have to date, lightened many aspects of pembrolizumab efficiency, safety, and regimen and introduced this treatment as a promising option for treating patients with SCC.

Ferrarotto et al. evaluated the effects of pembrolizumab in 19 patients with advanced, refractory CSCC. The patients had a long-term follow-up of 44.1 months. The results indicated pembrolizumab to be effective and safe in this population; However, two patients (10%) experienced remarkable treatment-associated side effects.¹³²

One research paper evaluated 628 Asian patients with advanced or metastatic ESCC to compare the therapeutic effects of pembrolizumab with chemotherapy. There were 314 patients in each treatment group. The Pembrolizumab group demonstrated survival advantages over patients who were treated with chemotherapy. Additionally, Fewer treatment-related complications emerged in the pembrolizumab-treated patients, which confirmed the safety superiority of pembrolizumab over chemotherapy.¹³³

In another study, a regimen including pembrolizumab and cetuximab was administered to 33 patients with metastatic or recurrent HNSCC. This combination resulted in promising clinical advantages with a 6-month ORR of 45%, which exceeded the previously published ORR of monotherapy with each antibody. Of note, 15% of the patients experienced severe adverse effects. The most common grade 3 or higher side effect was oral mucositis in 9% of the patients. Five patients stopped the treatment due to side effects.⁵¹

One phase II study included 159 patients with locally advanced or metastatic/recurrent CSCC from 59 centers. Every 3 weeks, the patients have treated with pembrolizumab 200 mg intravenously, repeated for the utmost 35 cycles. The immediate, potent anti-tumor effects of pembrolizumab and its manageable toxicity, portrayed pembrolizumab as a promising treatment option in these patients.¹³⁴

In an attempt to profile the biomarker aspects of pembrolizumab therapy, Haddad et al. investigated the correlations between certain biomarkers and clinical outcomes of pembrolizumab therapy in 192 patients with metastatic/recurrent HNSCC. Among the quantified biomarkers, tumor mutational burden (TMB), PD-L1, and 18-gene T-cell-inflamed gene expression seemed to have the potential as predictive biomarkers of patients’ response to pembrolizumab.¹³⁵

However, combining the treatment of pembrolizumab with Acalabrutinib failed to increase the efficacy of pembrolizumab monotherapy. The related toxicity of this combination was another obstacle that seemed to hinder the feasibility of this treatment.¹³⁶

Cohen et al. applied pembrolizumab with intralesional SD-101 in a population of recurrent/metastatic HNSCC patients. The treatment combination prompted the objective response, especially in patients who were human papillomavirus positive. The results could be due to enhanced inflammation and activity of effector immune cells inside the tumor.¹³⁷

In a recent phase II study, the combined therapy of pembrolizumab with afatinib was tested. Additionally, a biomarker quantification was also performed. Twenty-nine patients with recurrent or metastatic HNSCC whose disease was refractory post platinum therapy were included. The conclusion suggested that afatinib may enhance pembrolizumab efficacy with improved ORR. Also, antigen presentation and cytotoxicity induced by natural killer cells (NK cells), indicated upregulation in the tumor tissue. Nonetheless, treatment toxicity of grade ≥3 was reported in 37.9% of the cases, which can be an issue of concern in applying this combination.¹³⁸

A study performed by Tao et al., to compare the effect of pembrolizumab and cetuximab in the treatment of locally advanced SCC of the head and neck. Seventy five percent of patients had metastases. There was no significant difference between the locoregional control rate (p = .91), progression-free survival (p = .47), and overall survival (p = .49) of the two groups. But the toxicity in pembrolizumab treatment was lower than cetuximab.¹³⁹

5.1.3 Durvalumab

Durvalumab is a human IgG1 kappa Mab blocking PD-L1 on malignant cells from binding to PD-1 and CD80 on T cells, subsequently allowing higher T cell activation and anti-cancer activity.^{140, 141} The first studies on anti-PD-L1 agents showed that Durvalumab significantly improves OS and PFS in R/MHNSCC cases with a few acceptable adverse effects.¹⁴² Despite appropriate outcomes of applying durvalumab for HNSCC cases in the phase I/II study, Segal et al. reported several adverse events, such as fatigue, diarrhea, and nausea; therefore, much attention has been attracted to controlling the adverse effects of this treatment.¹⁴³ On the other hand, parallel studies have shown that combining Durvalumab with tremelimumab could ameliorate outcomes even in cases with <25% PD-L1 expression.¹⁴⁴ In another study, Ferris et al. demonstrated that this combination has a higher response rate and survival, with no significant difference in OS.¹⁸

Taken together, due to the high survival of patients using durvalumab, it is a novel promising treatment for HNSCC not only in patients with high PD-L1 profiles but also in patients with low PD-L1 manifestations.^{142, 144}

In patients with esophageal squamous cell carcinoma, Park et al. looked at the efficacy of adjuvant durvalumab after neoadjuvant concurrent chemoradiotherapy (CCRT) (ESCC). In patients with ESCC, they were unable to show that adjuvant durvalumab enhanced survival following neoadjuvant CCRT. However, post-CCRT PD-L1 expression may predict survival in patients who get adjuvant durvalumab following neoadjuvant CCRT, although it needs to be shown. The use of adjuvant durvalumab was generally safe in this research, with events equivalent to those seen in prior durvalumab monotherapy studies. Only three individuals had to stop taking the study medicine permanently due to side effects, most of which were minor. In conclusion, the current placebo-controlled, double-blind, randomized phase II study failed to fulfill the primary goal, likely due to the small sample size and the control arm's outperformance. They did, however, gain important information for future study design. First, after neoadjuvant CCRT and surgery, adjuvant durvalumab therapy appears to be safe. Second, patients who receive adjuvant PD-1/PD-L1 inhibitors may benefit from knowing their post-CCRT PD-L1 status. Third, because patients with ypCR have a favorable prognosis and are less likely to benefit from adjuvant durvalumab, future studies studying adjuvant immunotherapy should be cautious when enrolling this population. They are cautiously optimistic that the efficacy of adjuvant ICIs, such as durvalumab, in patients with esophageal cancer will be confirmed in larger investigations.

On the other hand, multiple clinical trials evaluate durvalumab, a programmed cell death ligand-1 (PD-L1)-blocking monoclonal antibody, for treating HNSCC. Arends et al. looked at circulating proteins at the start of the study to see if there were any relevant biomarkers and to figure out what pathways were linked to durvalumab's clinical outcomes. For 158 durvalumab-treated HNSCC patients in the phase II HAWK and CONDOR trials as a discovery dataset and 209 durvalumab-treated HNSCC patients in the phase III EAGLE study as a validation dataset, 66 serum proteins were evaluated using multiplex immunoassays before therapy. Higher baseline concentrations of interleukin-6 (IL-6), C-reactive protein, S100 calcium-binding protein A12, and angiopoietin-2 (ANGPT2) were associated with shorter overall survival (OS) after durvalumab treatment (p.05), in comparison higher concentrations of osteocalcin were associated with longer OS after durvalumab treatment (p.05). After correcting for baseline clinical variables, all five proteins remained strongly linked with OS, with consistent results across clinical efficacy endpoints based on univariate correlation analysis. The EAGLE trial's validation dataset validated the independent associations of IL-6 and osteocalcin with OS and preserved directional patterns for the other biomarkers discovered in the discovery dataset. Their findings show that immunosuppressive proteins play a key role in HNSCC resistance to durvalumab treatment. There was a positive link between osteocalcin and clinical outcomes, which needs further examination. In conclusion, in durvalumab-treated patients with HNSCC, circulating IL-6 and osteocalcin concentrations at baseline have been demonstrated to be independently linked with clinical outcomes, with trends of additional effects for ANGPT2 in three clinical studies. In clinical trials of ICI monotherapy and combination therapy, measurement of these biomarkers before and after treatment should be the priority.^{145, 146}

5.1.4 Avelumab

Avelumab is a fully human IgG1 lambda Mab against PD-L1 that has shown a ADCC activity.¹⁴⁷ In a study by Elbers et al., a combination of avelumab with cetuximab-RT showed in patients with advanced-stage HNSCC. In this study, it has been shown that avelumab plus cetuximab-RT is a possible therapy for patients who are not suitable for cisplatin treatment and also have advanced-stage HNSCC.¹⁴⁸

Guigay et al. examined the effect of avelumab, an anti-programmed death ligand 1 antibody, in metastatic or refractory head and neck squamous cell carcinoma (R/M SCCHN). Patients were aged ≥18 years and had previously received platinum-based chemotherapy. Within 6 months of treatment, some were ineligible for platinum-based chemotherapy, and some had refractory SCCHN. A dosage of 10 mg/kg every 2 weeks of avelumab was given to patients. The efficacy and safety of avelumab were reported and had a low rate of grade ≥3 TRAEs in R/M SCCHN and heavily pretreated patients.¹⁴⁹

5.1.5 Cemiplimab

Cemiplimab, a high-affinity IgG4 Mab, blocks the PD-1/PD-L1 pathway.¹⁵⁰ The treatment of CSCC with cemiplimab is more efficacious compared to platinum-based chemotherapy in terms of OS.¹⁵¹ Gross et al. proved that treating stage III/IV (M0) CSCC-HN cases with two doses of cemiplimab 350 mg, every 3 weeks before surgery shows no grade 3 or 4 adverse events. They also reported 55% pathologic complete response and 15% other major pathologic response (NPR, ≤10% viable tumor). Therefore, these results suggest cemiplimab as a potential neoadjuvant therapy.¹⁵²

Migden et al. reported a response of 50% in a phase 1 study of cemiplimab for expansion cohorts of patients with locally advanced or metastatic CSCC with 26 patients and 47% in a pivotal phase 2 study of cemiplimab for a cohort of patients with metastatic disease with 59 patients.¹⁵³

In a study made by Rischin et al.,¹⁵⁴ patients with advanced cutaneous squamous cell carcinoma: metastatic (mCSCC) and locally advanced (CSCC) were evaluated. Patients were derived into three groups, group 1 (mCSCC) and 2 (CSCC) received 3 mg/kg of cemiplimab every 2 weeks, and group 3 received 350 mg every 3 weeks. ORR per ICR was 46.1%, and the median duration of follow-up was 15.7 months. CR rates were 20.3%, 12.8%, and 16.1% for groups 1, 2, and 3. OS estimated by Kaplan–Meier was 73.3%, but the median OS was unavailable. Finally, Grade ≥3 TRAEs were seen in 17.1% of patients.

In a phase I trial, Babiker et al. studied 15 patients who received combined therapy of cemiplimab, cyclophosphamide, radiation therapy (RT), and granulocyte-macrophage colony-stimulating factor1 (GM-CSF). Mostly seen TEAEs were fatigue, constipation, asthenia, dyspnea, maculopapular rash, and pneumonia. Only two patients faced grade ≥3 TEAE (pneumonia). The efficacy of this combination therapy was not above other PD-1 inhibitor monotherapies in R/M SCCHN.¹⁵⁵

Treatment with Cemiplimab-rwlc (CEMI) in metastatic or locally advanced CSCC has demonstrated its efficacy. Eighteen patients were evaluated in a study, and 3 mg/kg every 2 weeks or 350 mg every 3 weeks infusions of CEMI were given to the patients. Median follow-up was 8 months, ORR was 67%, CR was 33%, PR was 33%, and DCR was 72%. Thirty three percent of adverse events with grades 2, 3, and 5 were observed in six patients.¹⁵⁶

A study was conducted by Bailly-Caille et al. on advanced cutaneous SCC, in which the therapeutic effect of Cemiplimab alone and in combination with radiotherapy was investigated. In this study, the observed objective response rate was 47.6 in Cemiplimab consumption versus 41.6 in combined treatment. The simultaneous use of radiotherapy and Cemiplimab (3 months) caused a faster clinical-radiological response than the use of Cemiplimab alone (5.5 months).¹⁵⁷

In a study by Ríos-Viñuela et al., 13 patients with advanced cutaneous SCC were treated with Cemiplimab. 23% of patients showed complete response and 38% partial response to treatment. 80% of patients with partial response experienced disease progression during follow-up. 46% of patients showed mild side effects.¹⁵⁸

A phase 2 study was conducted by Gross et al. to investigate the effect of neoadjuvant therapy of cemiplimab in cutaneous SCC. 51% of patients showed a complete pathological response and 13% of them showed a major pathological response, that is, less than 10% of tumor cells remaining. Also, objective response was reported in 68% of patients.¹⁵⁹

5.2.1 Ipilimumab

The combination of chemotherapy as the first line therapy with ipilimumab, a human IgG1 kappa antibody to CTLA4, has not resulted in significant changes in survival¹⁶¹; therefore, attention was attracted to using this treatment combined with other agents as a second line therapy. For the first time in a study, a combination of ipilimumab with programmed death (PD)-1 inhibitor nivolumab, a known melanoma treatment approved by the FDA, had successful results in treating a patient with refractory HNSCC after 4 months; on the other hand, examining the level of PD ligand-1 is required until we can use this method as a proved treatment.¹⁶² A novel study, designed in 2020, showed the successful effects of this combination before the surgery in patients with oral cavity squamous cell carcinoma (OSCC).¹⁶³

Altogether, more studies are required to find new methods and to consider the side effects of ipilimumab, to prove safer approaches.

5.2.2 Tremelimumab

Tremelimumab is a fully human IgG2 Mab that targets cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and exhibits antitumoral effects by blocking the CTLA-4 pathway.¹⁶⁴

Phase II research investigated the efficiency of tremelimumab as monotherapy. There were about 244 patients in each group. One group received durvalumab as monotherapy (group 1), the second group received both tremelimumab and durvalumab as combined therapy, and the third group was standard of care (SoC). The results showed no marked differences in OS between durvalumab monotherapy or combined use of durvalumab and tremelimumab versus SoC. However, survival rates increased in 12–24 months, and response rates showed that durvalumab was a beneficial therapeutic agent.¹⁸ Ferris et al. conducted a study to investigate the effect of using Durvalumab with or without tremelimumab in patients with recurrent or metastatic head and neck SCC. The results showed that OS did not significantly differ in the case of durvalumab monotherapy or durvalumab plus tremelimumab combination therapy compared to SoC.¹⁸ A phase 2 study was also conducted on durvalumab (D), tremelimumab (T) monotherapy, and combined durvalumab and tremelimumab therapy (T + D). The study showed acceptable toxicity in pretreated, PD-L1 low/negative, and R/M HNSCC patients, and no side effects were observed.¹⁶⁵