## 3 Results  
### Anatomical Site Is Associated with OS in Immunotherapy-Treated R/M HNSCC Patients  
We queried our annotated HNSCC clinical database and identified 53 R/M patients treated with single-agent, anti-PD-1 therapy, nivolumab and/or pembrolizumab (Table 1). Twenty patients were treated in the single-line and 33 patients were treated in the second/third lines following some combination of surgical salvage, radiation, and/or chemotherapy. This cohort was primarily managed with nivolumab (71.2%; 37/52). One patient was treated with pembrolizumab, progressed, and then switched to nivolumab; this case was excluded from the nivolumab vs. pembrolizumab analyses. A majority of our R/M cohort presented with distant metastasis (79.2%; 42/53) and self-identified as current/former tobacco users (83%; 44/53). Our study population skewed toward orophvx (39.6%; 21/53), followed by oral cavity (28.3%; 15/53), larynx (18.9%; 10/53), and other anatomical sites (unknown primary and hypopharynx; 13.2%; 7/53).  
In our R/M HNSCC cohort, median overall survival (OS) after initiating immunotherapy was 6.3 months (Figure 1a). Nivolumab and pembrolizumab showed equivalent efficacy (log-rank, \(p\) = 0.9) and this observation was maintained even after adjusting for co-variates in a Cox regression model (Figure 1b). Anti-PD-1 immunotherapies were less active in R/M oral cavity SCC patients than in R/M oropharyngeal and laryngeal SCC patients; median OS was 2.9, 11.4, and 14.2 months post-immunotherapy treatment in oral cavity, oroph  
\begin{table}
\begin{tabular}{l c} \hline \hline
**Age, years (range)** & 63.4 (23–86) \\
**Gender** & 40\% (n=21) \\ Male & 28\% (n=15) \\ Female & 19\% (n=10) \\
**Smoking history** & 13\% (n=7) \\ Yes & 19\% (n=10) \\ No & 19\% (n=10) \\
**Anatomical Site** & 19\% (n=11) \\ Oropharynx & 19\% (n=10) \\ Other & 13\% (n=7) \\
**Definitive treatment** & 19\% (n=10) \\ Non-Surgical & 15\% (n=29) \\ Surgical & 14\% (n=24) \\
**Time to recurrence** (months after definitive treatment) & 7 (1–57) \\
**Recurrence** & 19\% (n=11) \\ Local/Regional & 21\% (n=11) \\ Distant & 19\% (n=42) \\
**Immunotherapy** & 19\% (n=15) \\ Pembrolizumab & 28\% (n=15) \\ Nivolumab & 19\% (n=37) \\ Both & 2\% (n=1) \\ \hline \hline \end{tabular}
\end{table}
Table 1: Clinicopathologic characteristics of R/M HNSCC patients treated with anti-PD-1 immunotherapy.  
ynx, and larynx SCC, respectively (Figure 1c). As shown in Figure 1d, R/M patients who were surgically managed in the initial treatment setting had inferior prognosis compared to non-surgically managed patients (log-rank, \(p\) = 0.001), which is likely due to the fact that a majority of the non-surgically managed patients had oropharynx SCC (Figure 1e; 55.2%; 16/29; \(\chi\)2, \(p\) < 0.001). Multivariate model, adjusting for smoking, anatomical site, recurrence pattern at presentation (locoregional vs. distant), and immunotherapy choice, revealed that anatomical site is an independent prognostic biomarker in this cohort; oropharyngeal (HR 0.28, 95% CI: 0.122 to 0.66; \(p\) = 0.003) and laryngeal (HR 0.22, 95% CI: 0.077 to 0.65; \(p\) = 0.006) SCC patients had superior prognosis compared to oral cavity SCC patients (Figure 1f).  
Figure 1: Anatomical site is associated with OS in immunotherapy-treated R/M HNSCC patients. (**a**) KM plot for the entire cohort. (**b**) KM plot based on anti-PD-1 immunotherapy choice. (**c**) KM plot based on anatomical site. (**d**) KM plot based on initial treatment approach. (**e**) Initial treatment approach based on anatomical site. (**f**) Multivariate model for the entire cohort presented as a forest plot. **\(p\) < 0.01.