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Heft Neal et al. J Cancer Metastasis Treat 2019;5:76 I http://dx.doi.org/10.20517/2394-4722.2019.32 Page 5 of 11

Cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), was designed
as a targeted therapy. However, recent studies have suggested that it may be tumoricidal via immune
[63]
modulation . Accumulating evidence suggests that cetuximab increases antibody dependent cellular
cytotoxicity (ADCC) of NKs [63-65] . As Tregs inhibit NK mediated ADCC, through a TGF-β dependent
pathway, it is postulated Cetuximab’s mechanism of action may be through reduction or inhibition of Tregs.
A recent study demonstrated a decrease in the number of Treg in peripheral blood samples in HNSCC
patients treated with Cetuximab. This observed decrease in Treg population also correlated with improved
[63]
overall survival in this cohort . Additional mechanisms of cetuximab have also been suggested, including
increased crosstalk between dendritic cells and NK cells with further activation of the adaptive immune
[68]
response, specifically targeting EGFR expressing cells [66,67] and activation of the complement system .
More recent studies have also indicated that cetuximab may increase CTLA-4 and PD-1/PD-L1 expression
and suggest a need for combination therapies [64,69] .

Both Pembrolizumab and Nivolumab which target PD-1 have proven to have clinical benefit in patients
with progressive disease after platinum based therapy [7,70] . Initial approval for these drugs occurred
in 2016 after the published results from multiple clinical trials were released. The phase III clinical
trial, CHECKMATE-141, evaluated nivolumab vs. standard of care (SOC) chemotherapy in patients
with platinum refractory R/M HNSCC. The overall response rate (ORR) for the nivolumab group
was 13.3% compared to 5.5% in the SOC arm. Furthermore, nivolumab demonstrated an improved
survival [7.5 months vs. 5.1 months (HR = 0.7, 97.7%CI: 0.51-0.96)] which was the 1st time a 2nd line
[7]
agent demonstrated survival benefit . Similar results were seen in the KEYNOTE 040 trial, comparing
Pembrolizumab to SOC in patients with R/M HNSCC who had failed platinum therapy. In this trial there
was an ORR of 14.6% in the pembrolizumab group compared to 10.1% in the SOC group and a median
[70]
OS of 8.4 months vs. 6.9 months (95%CI: 0.65-0.98) . Both studies had secondary endpoints evaluating
survival outcomes stratified by PD-L1 status and revealed a greater benefit in patients with positive PD-
L1 expression although not statistically significant. These results supported the use of nivolumab or
pembrolizumab as a standard of care treatment for patients with platinum refractor R/M HNSCC.

Until recently, there has been no data supporting use of PD-1 inhibitors as a first line treatment option
for R/M HNSCC. The results of the KEYNOTE 048 trial were presented at the 2019 American Society of
[71]
Clinical Oncology meeting . This study evaluated the use of pembrolizumab alone, pembrolizumab with
platinum and fluorouracil, vs. the EXTREME regimen in patients with R/M HNSCC. Results revealed an
improvement in OS in all patients treated with pembrolizumab with a PD-L1 combined positive score ≥ 1%
[9]
by the 22C3 assay .

While there are no mature data evaluating the effect of anti-PD-L1 therapeutics, such as Atezolizumab
or Durvalumab, ongoing phase I and II trials have demonstrated excellent safety profiles with promising
[72]
responses. A phase I trial published by Colevas et al. in 2018 enrolled 32 patients with advanced
unresectable or incurable HNSCC who underwent treatment with Atezolizumab. The overall response rate
in this cohort was 22% with a median progression free survival of 2.6 months and median overall survival
of 6 months. Responses were found to be independent of PD-L1 expression level or HPV status. While 66%
of patients experienced treatment related adverse events, only 4 patients (13%) had grade 3 or 4 toxicity.
Given these results, a phase III randomized control trial is currently underway investigating the use of
Atezolizumab in HNSCC (NCT03452137). Durvalumab has also been evaluated in Phase I/II trials in
[73]
HNSCC. A study by Segal et al. published in 2019 examined 62 patients with unresectable and previously
treated HNSCC treated with Durvalumab and found an ORR of 6.5% with a median overall survival of 8.4
months. Unfortunately, the results of the phase III EAGLE trial evaluating Durvalumab as single modality
therapy in patients with progressive disease after platinum therapy was did not reveal any survival benefit
[74]
alone or in combination with CTLA-4 inhibitor, Tremelimumab . An ongoing trial (NCT02551159)