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Page 6 of 10 Farlow et al. J Cancer Metastasis Treat 2019;5:18 I http://dx.doi.org/10.20517/2394-4722.2018.100
[22]
In a later study, Wolf et al. utilized subcutaneous injections of IRX-2, a biologic composed of a mixture
of purified cytokines, along with cyclophosphamide, indomethacin, and zinc in a cohort of 27 patients with
HNSCC. There were no significant adverse events related to treatment noted. Of 23 evaluable subjects, 4
had an objective decrease in tumor size, although this did not constitute a true partial response by RECIST
criteria. Increased lymphocytic infiltration into tumors was associated with increased response and overall
survival [22,23] .

[24]
More recently, Uppaluri et al. presented preliminary results from an ongoing single-armed trial of
advanced HPV negative HNSCC subjects who received neoadjuvant pembrolizumab (an anti-PD-1 antibody)
that was continued post-operatively. No serious drug-related adverse events were reported. Significantly
decreased high-risk pathologic features, pathologic treatment response, and clinical-to-pathologic
downstaging was observed among the 21 subjects. Baseline high tumor expression of the programmed
[25]
cell death protein ligand (PD-L1) was correlated with pathologic treatment effect. Ferris et al. presented
interim results of a window trial of nivolumab (another anti-PD-1 antibody) for HNSCC. In half of the 23
evaluable subjects, tumor dimensions were reduced after treatment. As part of another ongoing neoadjuvant
[26]
trial, Colevas et al. are administering anti-PD-1 antibody prior to planned curative surgery or radiation
in HNSCC. They presented results from a single subject where their novel nuclear medicine imaging test
correlated with tissue markers of immunologic activity.

A novel antibody MEDI6469, an OX40 (CD134) agonist, was also studied in a window of opportunity setting
[27]
by Bell et al. . No significant adverse events were reported, and immunologic response was detected in 4 of
17 subjects. There was a significant difference between responders and non-responders in genes associated
with major histocompatibility complex (MHC I)-mediated antigen processing.

[28]
Shayan et al. combined motolimod, a small molecule agonist of the toll-like receptor 8, along with
cetuximab in 14 patients planned for curative surgery. One subject withdrew from the study due to an
unspecified cetuximab toxicity. Study results showed that the expected increase in suppressive co-signaling
molecule expression induced by cetuximab monotherapy was counteracted by the addition of motolimod,
resulting in increased circulating EGFR-specific T cells and greater tumor infiltration of leukocytes.

OTHER WINDOW TRIALS
While not a classic targeted therapy or immunotherapy, metformin, an anti-hyperglycemic, has been shown
[29]
to be associated with improved outcomes in HNSCC . It is postulated that metformin’s metabolic effects
[30]
through inhibition of mitochondrial oxidative phosphorylation may be proapoptotic in HNSCC. Curry et al.
executed a single-armed window trial of metformin among 39 subjects with HNSCC of the oral cavity or
larynx, each who took between 9-24 days of the drug without significant side effects. Markers of increased
apoptosis and altered stromal metabolism were identified in the 33 evaluable subjects.

The results of several additional targeted therapy and immunotherapy trials have yet to be published. Those
listed in ClinicalTrials.gov are briefly reviewed in Table 3.

CONSIDERATIONS IN DESIGNING FUTURE WINDOW TRIALS
Window trials offer the opportunity to study the safety, mechanism, and efficacy of novel agents in
treatment-naïve HNSCC. The studies outlined here have demonstrated the overall safety of each agent
studied, with limited numbers of treatment-related adverse events and no clear post-operative complications
attributable to the investigational drug. They have also confirmed the intended knockdown of upregulated
pathways in HNSCC with targeted therapies and have shed light on the immunomodulatory mechanisms
behind newer immunotherapies. Promising preliminary data reveal clinical, radiologic, and pathologic
responses in some treated subjects along with possible biomarkers predictive of sensitivity or resistance to