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Page 2 of 10 Quenelle et al. J Unexplored Med Data 2018;3:7 I http://dx.doi.org/10.20517/2572-8180.2018.02

tumors (LA-HNSCC); individual trials have shown benefit but large meta-analyses show no overall survival
benefit [1,3,4] . Cytotoxic therapy plays a large role in palliation in the recurrent and metastatic setting, where
options including multi-drug regimens may be toxic with modest benefit or single agent therapy with small
benefit . Overall survival for recurrent and metastatic head and neck squamous cell carcinoma (RM HNSCC)
[5-7]
remains generally poor at less than 1 year with current cytotoxic therapeutic options . The most commonly
[5-7]
used first line chemotherapeutic regimen of cisplatin or carboplatin/5-FU/Cetuximab (Eribitux®, Eli Lilly) had
a reported overall survival (OS) benefit of 10.1 months when the data was first published in 2008, and is the
only one to have a level 1 recommendation from the National Comprehensive Cancer Network (NCCN) .
[6,8]
Cetuximab as a single agent use in second line has a 13% response rate and 7.5 month OS .
[9]

In the last several years, a new class of systemic therapies have been developed that harness the body’s
immune responses in fighting tumors. Classified broadly as immunotherapy, this is a heterogeneous group of
therapies that target specific immune pathways to amplify the body’s natural tumor fighting abilities. Vaccine
therapies are also in development, and have been approved in other malignancies such as melanoma .
[10]
Another vaccine target is Epstein-Barr Virus (EBV) related malignancies, such as nasopharyngeal carcinoma.
These are under development with ongoing trials looking at efficacy and safety.

One of the most successful groups of therapies to emerge is a class of drugs that target the programmed
death-1/programmed death ligand-1 (PD-1 and PD-L1) pathway, as well as a co-regulatory pathway
mediated through cytotoxic T-lymphocyte-associated protein 4 (CTLA 4). This pathway has been named the
“checkpoint pathway” with agents acting on these proteins generally referred to as checkpoint inhibitors.
Ipilumumab (Yervoy®, Bristol-Myers Squibb) is the first US Food and Drug Administration (FDA) approved
CTLA-4 inhibitor which came to the market in 2011 for treatment of melanoma; the first PD-1 inhibitor,
pembrolizumab (Keytruda®, Merck) was approved for melanoma in September 2014, and nivolumab
(Opdivo®, Bristol-Myers Squibb) gained its first approval in December 2014, also in melanoma. Since then,
these agents have gained approval in multiple tumor types and multiple settings, including head and neck
squamous cell carcinoma.

This article will review the indications for checkpoint inhibitors in head and neck tumors, examining the
data and discussing adverse events and their management, as well as review data on upcoming therapies.

PEMBROLIZUMAB
Pembrolizumab (Keytruda®) is a monoclonal IgG4 isotype antibody that binds to the programmed death-1 (PD-1)
receptor on T-cells, preventing them from binding programmed death-ligand 1 (PD-L1) and programmed
death-ligand 2 (PD-L2) ligands expressed on tumor cells . The first study done with pembrolizumab in
[11]
recurrent or metastatic HNSCC is the phase I KEYNOTE 012, a multi-cohort trial looking at multiple tumor
types, including HNSCC. It was conducted as a two-part safety and efficacy trial, with the primary outcome
in both phases being safety and overall response rate (ORR). In the first phase (1a), 60 patients all with high
PD-L1 expression (> 1%) were enrolled; 23 were human papillomavirus (HPV) positive, 37 HPV negative.
Pembrolizumab was dosed at 10 mg/kg every 2 weeks. 17% of patients had grade 3 or 4 adverse events, and
the ORR was 18%, further broken down as 25% in HPV positive and 14% in HPV negative patients .
[12]

In the second phase expansion cohort (1b), 132 patients were enrolled, this time regardless of PD-L1
expression . Fifty-seven percent of these patients had received at least 2 prior lines of therapy. Primary
[13]
outcomes were again safety and ORR; secondary outcomes were evaluated in this portion of the trial and
included progression free survival (PFS), OS, and relationship of outcome to PD-L1 expression. In this
cohort, the dose of pembrolizumab was changed to 200 mg every 3 weeks. ORR was again 18% and grade 3
or 4 adverse events dropped to 9%. PFS was 2 months, and OS was 8 months. In HPV positive patients, the
ORR was 32%.