Table 1.

Clinical phase III trials for the treatment of HNSCC patients with ICI.

Treatment Setting	Trial	Description	Objective	Results
ICI–chemo	KEYNOTE 048 (NCT02358031)	Pembrolizumab monotherapy vs. pembrolizumab + platinum-based CT + 5-FU vs. cetuximab + platinum-based CT + 5-FU	Pembrolizumab as a first-line treatment of R/M HNSCC.	OS over SOC was improved with pembrolizumab alone in populations with PD-L1 CPS ≥ 20 (p = 0.0007) and CPS ≥ 1 (p = 0.0086). Pembrolizumab + CT significantly improved OS in the total population (p = 0.0034) [52].
Dual checkpoint blockade	CheckMate 651 (NCT02741570)	Nivolumab + ipilimumab vs. SOC (EXTREME study regimen) as first-line treatment in patients with R/M HNSCC	Combination nivolumab + ipilimumab has shown significant promise in patients with NSCLC, advanced melanoma, and advanced RCC.	Trial failed end point. OS for dual immune checkpoint blockade 13.9 months vs. 13.5 months for the EXTREME group. Higher OS for double immune blockade when CPS > 20 (17.6 months), but also n.s., ORR 34%, and DOR 32.6 months. No single nivolumab arm for comparison [53].
Dual checkpoint blockade	CheckMate 714 (NCT02823574)	Nivolumab + ipilimumab vs. nivolumab + ipilimumab placebo in R/M HNSCC	R/M HNSCC ORR, DOR, TTR.	Study aim failed: OS for nivolumab plus ipilimumab 10.0 months vs. 12.0 for nivolumab plus placebo. ORR: 13.2 for nivolumab plus ipilimumab vs. 18.3 for nivolumab plus placebo.
Dual checkpoint blockade	KESTREL (NCT02551159)	Durvalumab + tremelimumab vs. durvalumab monotherapy vs. SOC CT in treatment-naive R/M HNSCC patients	First-line treatment for R/M HNSCC targeting both PD-L1 and CTLA-4 pathways has potential for synergistic anti-tumor effects.	Results ongoing [54].
Dual checkpoint blockade	EAGLE (NCT02369874)	Durvalumab monotherapy vs. durvalumab + tremelimumab vs. SOC in R/M HNSCC with progress on platinum therapy	Second-line treatment for R/M HNSCC targeting both PD-1 and CTLA-4 pathways may induce synergistic anti-tumor effects.	Did not meet primary endpoint of improved OS [55,56].
Single ICI adjuvant	WO40242 (NCT03452137)	Atezolizumab vs. placebo for high-risk stage IV HPV- or stage III HPV+ HNSCC after definitive local therapy	To evaluate the efficacy and safety of atezolizumab as an adjuvant therapy.	Primary outcomes include independently assessed event-free survival (IRF assessed EFS) and OS.
ICI–chemo- radiation	GORTEC 2017– 01 (REACH) (NCT02999087)	Avelumab + cetuximab and RT vs. SOC in LA HNSCC	The expansion of GORTEC 2015–01, based on the hypothesis of a synergistic benefit when avelumab is combined with cetuximab + RT.	This study demonstrated an acceptable safety profile and was approved for continuation by the Data and Safety Oversight Committee [57].
ICI–radiation	JAVELIN (NCT02952586)	Avelumab + SOC CRT vs. SOC CRT in LA HNSCC patients	The combination of avelumab and CRT may synergistically activate multiple immune-mediated mechanisms and improve long-term disease control [58].	Currently recruiting.
ICI–radiation	KEYNOTE-412 (NCT03040999)	Pembrolizumab or placebo + CRT in LA HNSCC patients	CRT exhibits immunomodulatory effects; preclinical data indicate efficacy may be improved with the addition of pembrolizumab [59].	Adult patients with newly diagnosed, pathologically proven, untreated LA-HNSCC are being recruited [59].
ICI–radiation	(NCT03349710)	Nivolumab monotherapy vs. nivolumab + cisplatin in combination with RT in cisplatin ineligibility or eligibility will be assessed in LA HNSCC patients	To evaluate whether nivolumab in combination with RT is more efficient compared to cetuximab in combination with RT.	Recruitment completed. n = 74. AE, SAE evaluation.
Dual checkpoint blockade, ICI–radiation, adjuvant–neoadjuvant	IMSTAR-HN NCT03700905	Multicenter randomized controlled study of nivolumab alone or in combination with ipilimumab as an immunotherapy vs. standard follow-up in surgical resectable HNSCC after adjuvant therapy	The combination of anti-PD-1 and anti-CTLA-4 as maintenance therapy may improve DFS due to the anti-tumor effect of immunotherapy by enhancing the cross-presentation of tumor antigens. Primary: DFS at 3 years.	Active, not recruiting, 276 participants estimated.
ICI–chemo, ICI–radiation	NCT01810913	Docetaxel–cetuximab or the addition of an immunotherapy drug, atezolizumab, to the usual chemotherapy and radiation therapy in high-risk HNSCC	DFS, OS.	Active, recruiting, 613 patients estimated.
ICI–radiation	NCT03258554	Radiation therapy with durvalumab or cetuximab in treating patients with locoregionally advanced head and neck cancer who cannot take cisplatin	It is not clear whether radiation therapy with durvalumab is more effective than usual radiation therapy with cetuximab in treating patients with head and neck cancer (DLT, PFS, OS).	Recruitment suspended.
ICI–AB–chemo	NCT05063552	An evaluation of the application of the investigational drugs atezolizumab and/or bevacizumab with or without standard chemotherapy in the second-line treatment of advanced head and neck cancer	To investigate the progression-free survival (PFS) of patients receiving chemotherapy plus cetuximab, chemotherapy plus bevacizumab, and atezolizumab plus bevacizumab (phase II). To assess the overall survival (OS) of patients treated with chemotherapy plus cetuximab versus the superior arm from the phase II portion of the protocol (phase III).	Recruiting.
ICI–AB	NCT04199104	A trial of pembrolizumab with or without lenvatinib (E7080/MK-7902) as a first-line treatment (1 L) in a programmed cell death ligand 1 (PD-L1)-selected population with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M HNSCC). (LEAP-010) (MK-7902-010) (LEAP-10)	ORR, PFS, OS.	Recruiting.

ICI: immune checkpoint inhibitor, AB: antibody, ORR: objective response rate, DOR: duration of response, SOC: standard of care, OS: overall survival, DFS: disease-free survival, PFS: progression-free survival.