This study found the prognostic effect of clinico-hematological factors, including the occurrence of irAEs, REC, BOR, ECOG PS, and mGPS in RM-HNC patients treated with nivolumab therapy. Furthermore, our analysis showed that the sum of numbers from worse prognostic factors in clinico-hematological factors might be the optimal prognostic score in the Japanese population.
Similar to previous studies reported5,14, we found that the occurrence of irAEs was significantly associated with better prognosis in RM-HNC patients treated with nivolumab therapy. Matsuo et al. reported that gastrointestinal irAEs were significantly associated with better PFS5. In other types of cancer, cutaneous, gastrointestinal, and endocrine irAEs are associated with better survival15,16. Although the endocrine irAEs category was most common in this study, we could not detect which type of irAE was strongly associated with clinical outcomes. However, since appropriate management of irAEs could lead to the clinical benefit of nivolumab therapy, early detection of irAEs and management in multidisciplinary teams should be advocated.
Additionally, we found that a better BOR to nivolumab therapy was associated with better survival. In the CheckMate 141 trial, the response rate in the nivolumab group was higher than that in the investigator's choice group, and tumor reduction was more durable with nivolumab1. Matsuki et al. also demonstrated that a better BOR was significantly associated with better survival17. It is obvious that response evaluation is important even when using immunotherapeutic agents.
Consistent with our results, Nishikawa et al. demonstrated that higher eosinophil counts and increases were associated with better survival13,18. Furthermore, eosinophil accumulation was associated with better survival in patients with melanoma treated with ICI19. They mentioned that the high number of peripheral blood eosinophils might reflect the high number of tumor-infiltrating eosinophils and the increase in tumor antigens due to tumor necrosis and collapse.
In this study, modified GPS and ECOG PS were associated with clinical outcomes in RM-HNC patients treated with nivolumab therapy. These factors are known to be prognostic factors in patients with ICI and other treatments20,21. Therefore, these biomarkers may be useful in various treatment modalities. The advantage of these biomarkers and eosinophil count, described above, is that they can be evaluated before nivolumab treatment. Since these two factors indicate the patient's general condition and/or inflammation, it might be better to use ICI without any symptoms associated with RM-HNC.
We demonstrated that the sum of numbers from worse prognostic factors could be the optimal prognostic score in RM-HNC patients treated with nivolumab. To the best of our knowledge, this is the first report to evaluate the impact of prognostic score associated with clinico-hematological factors, which are routinely available in clinical settings, on clinical outcomes in RM-HNC patients with nivolumab. However, the concern is that the poor nutritional condition and infection could affect these factors. Therefore, supportive therapy, including nutritional support, oral care, and smoking cessation, should be considered in patients with RM-HNC.
Regarding the primary tumor site, while we performed nivolumab therapy in patients not included in the CheckMate 141 trial, such as nasopharyngeal cancer, clinical outcomes were comparable to those included in the CheckMate 141 trial1,7. In patients excluded from the CheckMate 141 trial, the efficacy of nivolumab therapy has been reported with primary tumors at other sites, including the nasopharynx, while its efficacy is limited in the salivary gland cancer5,22−24. However, there is insufficient evidence for the optimal systematic therapy for HNC other than squamous cell carcinoma (SCC). A larger collaborative study to evaluate the efficacy of nivolumab therapy in patients with HNC other than SCC is required.
Regarding salvage chemotherapy following nivolumab therapy, we mainly performed paclitaxel and cetuximab therapy, and our clinical outcomes, including 41% ORR, were comparable to those of previous studies25–27. As mentioned above, since the efficacy of cetuximab and other chemotherapies following ICI has been reported, relatively early changes in treatment modalities might be acceptable.
Our study had several strengths. Since this is a multi-institutional cohort study, our sample size is one of the largest studies in patients with RM-HNC in a real-world setting. Second, detailed individual data were available for this study. Third, because physicians had no information on the association of clinic-hematological factors with survival, information bias appears unlikely. Fourth, we could perform the analysis adjusted for potential confounders, including detailed clinical information.
Moreover, several limitations should be mentioned. First, this study was conducted with a retrospective and multi-institutional design. Second, our information, especially hematological factors, reflected pre-treatment status only and not post-treatment factors, which might be associated with clinical outcomes. Third, we could not fully remove the potential effect of factors of infectious diseases, inflammation other than that derived from RM-HNC, and the use of glucocorticoid hormones.
In conclusion, we found that the occurrence of irAEs, higher REC, better BOR, lower ECOG PS, and lower mGPS were the better prognostic factors for survival in patients with RM-HNC treated with nivolumab. Furthermore, the sum of the numbers of worse prognostic factors might be the optimal prognostic score. Using this novel prognostic score, more effective treatment strategies, including nivolumab therapy, could be established for patients with RM-HNC.