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Table 1. Checkpoint inhibitors in HNSCC
Immunotherapeutic Target Select ongoing trials
Pembrolizumab (Pembro) PD-1 NCT03546582 (KEYSTROKE) - SBRT +/- Pembro in recurrent or secondary primary HNSCC
NCT02641093 - Pembro + adjuvant RT or CRT (cisplatin) after surgery in HNSCC
NCT02296684 - Neoadjuvant Pembro + SOC (surgery or RT) in high risk HNSCC
NCT03765918 - Pembro before surgery and Pembro +/- Cisplatin and RT post-operatively in stage III-IV
LA HNSCC
Nivolumab (Nivo) PD-1 NCT03521570 - IMRT + Nivo for recurrent or second primary HNSCC after prior RT (resectable or eligible
for curative re-irradiation)
NCT03576417 - SOC (C/RT) +/- Nivo in HNSCC
NCT03247712 - Nivo + RT prior to surgical resection of HNSCC
Atezolizumab PD-L1 NCT03452137 - Atezolizumab or placebo as adjuvant therapy after definitive local therapy in high-risk LA
HNSCC
NCT03708224 - Effect of neoadjuvant Atezolizumab prior to surgical resection in HNSCC
NCT03818061 - Atezolizumab + Bevacizumab in recurrent/metastatic previously treated HNSCC
Durvalumab PD-L1 NCT03212469 - Durvalumab + RT or Durvalumab + Tremelimumab and SBRT in metastatic HNSCC (also
includes lung and esophageal tumors)
NCT02997332 (MEDINDUCTION) - Durvalumab + Docetaxel, Cisplatin and 5-FU for LA HNSCC
NCT03635164 - Radiotherapy + Durvalumab before surgical resection for HPV negative HNSCC
Avelumab PD-L1 NCT03498378 - Avelumab, Cetuximab, and Palbociclib in recurrent/metastatic HNSCC
NCT02999087 - Avelumab-cetuximab-radiotherapy vs. SOCs in LA HNSCC
NCT03260023 - TG4001 and avelumab in patients with HPV-16 positive recurrent or metastatic
malignancies (including OPSCC)
Ipilimumab CTLA-4 NCT02812524 - Intratumoral injections of ipilimumab prior to surgical resection in HNSCC
NCT03799445 - Ipilimumab, nivolumab, and RT for HPV positive OPSCC
Tremelimumab CTLA-4 NCT03522584 - Tremelimumab + Durvalumab + hypofractionated RT in recurrent/metastatic HNSCC
NCT03212469 - Durvalumab + RT or Durvalumab + Tremelimumab and SBRT in metastatic HNSCC (also
includes lung and esophageal tumors)
NCT02551159 (KESTREL) - MEDI 4736 +/- Tremelimumab vs. SOC in recurrent/metastatic HNSCC
(active, not recruiting)
Relatlimab Lag-3 NCT04080804 - Nivolumab +/- Relatlimab or Ipilimumab in head and neck cancer

HNSCC: head and neck squamous cell carcinoma; OPSCC: oropharynx squamous cell carcinoma; RT: radiation therapy; CRT:
chemoradiation therapy; LA: locally advanced; SBRT: stereotactic body radiation therapy; SOC: standard of care; HPV: human
papillomavirus

is evaluating Durvalumab with and without Tremelimumab in patients with R/M disease who have not
received previous treatment for recurrent disease. A summary of select ongoing clinical trials investigating
these therapies in addition to other checkpoint inhibitors is shown in Table 1.

DEVELOPMENT OF NOVEL IMMUNOTHERAPEUTICS
Despite these encouraging results and updated treatment guidelines, it should be noted that overall
response rates to these immunotherapies remains low for HNSCC and ongoing clinical trials are evaluating
novel immunotherapeutic strategies [Table 2].

Oncolytic viruses provide potential for direct tumor cell lysis with further activation of an immune
specific response. One of the most promising trials involving oncolytic vaccines in HNSCC to date
evaluates the use of pembrolizumab in combination with Talimogene laherparepvec in patients with R/M
disease. Final study results are pending, however initial updates suggest at least partial response in some
patients (NCT02626000). Additional oncolytic viruses are also under early phase studies (NCT00625456,
NCT03740256, NCT01584284).

Vaccinations represent a promising novel therapeutic strategy for various malignancies including
HNSCC. Vaccines currently under investigation in HNSCC target patient specific TA (NCT03633110,
NCT03548467), or TAs that are expressed in the majority of HNSCC such as mutant p53 (NCT02432963,
NCT02955290, NCT02544880, NCT03946358). Additional vaccines are designed to enhance a general
immune response such as those using the fowlpox-TRICOM vaccine (NCT00021424). For patients with
HPV-mediated disease, the potential for vaccines targeting HPV specific peptides has gained enthusiasm