In the present study, we revealed that patients with RMHNC receiving pembrolizumab or nivolumab exhibited a PFS of 3.7 months, an OS of 6.8 months, and an ORR of 21% for patients with HNSCC in a real-world setting. Further, the median PFS was 4.3 months and the median OS was 11.8 months in patients with NPC. In clinical practice, we often encounter patients with RMHNC who do not meet the eligibility criteria for clinical trials, such as the KEYNOTE-040 and CheckMate-141 trials. Our study included patients with carcinoma of the nasal cavity/paranasal sinuses, nasopharynx, external auditory canal, and other rare sites; histology of non- SCC; and non-platinum-refractory carcinoma. Recently, a few retrospective studies were investigated to evaluate the efficacy of nivolumab in RMHNC. Hori et al.  reviewed 93 patients with RMHNC, including non-SCC and patients not exposed to platinum, and reported an ORR of 18% and a PFS of 4.3 months for all patients. In addition, 100 patients with RMHNC, including those with non-SCC and cancer of the nasopharynx, were analyzed by Okamoto , who reported an ORR, median PFS, and OS of 13.5%, 3.7 months, and 9.6 months, respectively, which were in line with the results of our study conducted in a real-world setting.
In HNC, approximately one-quarter of cases are related to human papillomavirus (HPV) infection, which is predominantly found in the oropharynx and oral cavity and is associated with favorable prognosis . However, it is still controversial as to whether HPV status should be considered for the use of immune checkpoint inhibitors. In KEYNOTE-012 , response rates were higher in patients with HPV-associated cancer compared with patients with non-HPV associated cancer, with ORR values of 24% (95% CI, 13–40%) and 16% (95% CI, 10–23%), respectively. In contrast, in the CheckMate-141 trial, patients received a consistent benefit from nivolumab, regardless of HPV status (HPV-negative patients, HR 0.59, 95% CI: 0.38–0.92; HPV-positive patients, HR 0.60, 95% CI: 0.37–0.97) . In our study, there was a trend toward favorable PFS or OS in HPV-associated disease than non-HPV-associated disease, but the trend was not significant. Therefore, HPV status should not limit the use of immune checkpoint inhibitors, as patients with both HPV-positive and HPV-negative RMHNC may experience survival benefit with the available PD-1 inhibitors.
Of note, this study demonstrated the importance of previous radiotherapy associated with a favorable clinical outcome for immune checkpoint inhibitors. Patients with a history of concurrent chemoradiotherapy or radiotherapy alone had a longer OS with immunotherapy. A possible explanation for this is that radiotherapy at the tumor site could enhance the presentation of tumor cell-derived antigens, giving rise to primed cytotoxic T cells and leading to local and systemic effects on both local and metastatic disease via the abscopal effect . Immunotherapy, such as blockade of the PD-1/PD-L1 signaling pathway, may provide an opportunity to boost the abscopal effect . Twyman-Saint Victor et al.  demonstrated that radiotherapy, in combination with inhibitors of cytotoxic T lymphocyte-associated antigen (CTLA4) and PD-L1, increased abscopal response rates in melanoma. Our results could provide indirect evidence of this effect in RMHNC.
The PD-1 inhibitors, nivolumab and pembrolizumab, each resulted in similar OS in Phase 3 trials: 7.5 months (95% CI 5.5–9.1) for nivolumab and 8.4 months (95% CI 6.4–9.4) for pembrolizumab, respectively [12, 13]. Interestingly, our study revealed that the two treatment groups of PD-1 inhibitors had a significant difference in OS (nivolumab vs. pembrolizumab, median OS, 6.8 months vs. 11.8 months, p = 0.017). This result should be interpreted with caution because of several confounding factors, such as imbalanced distribution of HNSCC and NPC and difference in patient population.
There were several limitations to this study. First, we divided patients with HNC into those with HNSCC and those with NPC and compared parameters between these groups, but the number of patients was too small to make reliable comparisons between the two groups. Second, we failed to define the interaction between the efficacy of immunotherapy and PD-L1 expression owing to limited sample size and insufficient tissue samples. Given that several patients with a PD-L1 CPS score of 1 or higher achieved a deep response, further studies are needed to solidify the importance of PD-L1 expression for the efficacy of immunotherapy in patients with RMHNC. Finally, the effects of immune checkpoint inhibitors may have been underestimated because this study included heavily treated patients with a maximum of four lines of prior palliative chemotherapy.