We previously demonstrated the therapeutic outcomes and safety profiles in Japanese patients with mRCC after TKI in real-world clinical practice . Although the efficacy of nivolumab therapy for mRCC is not in doubt, as shown in Fig. 1A-C, it is not effective in all patients. Therefore, it is important to identify the prognostic factors that predict the response of nivolumab to achieve a better stratification of patients with mRCC. In this study, we reported that PFS and OS in mRCC patients with high GNRI treated with nivolumab were significantly better than those with low GNRI. To the best of our knowledge, this is the first report to show the effectiveness of GNRI as a prognostic biomarker in nivolumab therapy for mRCC.
The association of the prognosis of patients with RCC with systemic inflammation was previously reported. When they investigated the impact of the risk group disagreement between the Memorial Sloan Kettering Cancer Center (MSKCC) and IMDC classifications on prognosis, it was determined that disagreement between both classifications may have a negative impact on prognosis in mRCC patients because of the inclusion of systematic inflammation markers . Another report also suggested that the combination of C-reative protein (CRP) value with the number of risk factors in the IMDC classification might achieve better stratification of prognosis in patients with IMDC intermediate risk treated with TKI . We previously reported that modified Glasgow Prognostic Score based on serum albumin as a nutritional status indicator and CRP was a significant prognostic biomarker in mRCC treated with nivolumab . Thus, nutritional status also plays a key role in predicting the prognosis of mRCC patients. Sarcopenia was also suggested to be a prognostic factor for patients with mRCC  and those receiving treatment by surgery  and TKI . The effective prevention and treatment of sarcopenia was reported to be achieved by improving diet and nutrition . Cancer-associated cachexia is characterized by severe loss of muscle mass with or without loss of fat  and is associated with increased morbidity and mortality, especially interleukin-6 levels correlating with weight loss in certain human cancers . Therefore, a simple nutritional screening tool that can act as a prognostic marker for mRCC patients treated with nivolumab is needed, because the association of the nutritional index with the prognosis of mRCC patients was suggested.
GNRI was reported to be a new simplified screening tool to assess the nutrition-related risk that has been shown to be associated with mortality in older adult patients as well as those with various diseases [8, 19, 20]. Recently, GNRI has been reported to be associated with the prognostic factor of undergoing nephrectomy  and being treated with targeted therapy . However, there have been no reports suggesting the association of GNRI with the prognosis of mRCC patients treated with nivolumab therapy, although the association of GNRI with prognosis in patients with non-small cell lung cancer treated with nivolumab therapy has been reported .
Some reports have suggested that patients with weight gain achieved better survival outcomes. PFS and OS as well as ORR were significantly better in overweight patients that had a BMI ≥ 25 with various cancers treated with anti-PD-1/programmed death-ligand 1 inhibitors . A higher BMI and weight gain during nivolumab therapy were good predictive markers of OS in mRCC patients receiving nivolumab therapy . The better survival outcomes in overweight patients are related to the white adipose tissue, which induces and/or coordinates host defenses, being a source of cytokines and chemokines . Adipose tissue modulates the helper T-cell (Th)1/Th2 balance, decreases the activation of regulatory T-cell through adiponectin, increases pro-inflammatory macrophages, activates T-cells with the binding between LIGHT-HVEM (herpesvirus entry mediator), and increases the inflammatory status through the CD40 pathway [27–29].
Some reports suggested that pre-treatment albumin level was also associated with prognosis in mRCC patients. Lower serum albumin has been reported to be related with poorer OS and PFS in mRCC patients treated with targeted therapy . Another report suggested that a lower albumin to alkaline phosphatase ratio was associated with worse OS and PFS in mRCC patients receiving nivolumab monotherapy . As one of the reasons for the association between albumin and prognosis in mRCC patients, the formation of neutrophil extracellular traps, which are released to the tumor microenvironment by cancer cells to recruit neutrophils and which play a key regulatory role in cancer aggressiveness, such as cancer invasion and distant metastases , was inhibited by serum albumin .
Therefore, GNRI was suggested to be the prognostic factor for mRCC patients treated with nivolumab therapy in our study. GNRI, which is a simple nutritional screening tool, combined with IMDC risk classification or substituted for KPS in IMDC risk classification, could provide improved stratification for the prognosis of mRCC patients receiving nivolumab therapy in real-world clinical practice.
We conducted this retrospective study to clarify the effectiveness of GNRI in nivolumab therapy. There are several limitations to our study. First, this was a small, retrospective study at a single institution. Additional large-scale and/or prospective studies are needed to clarify the effectiveness of GNRI in nivolumab therapy. Second, all cases were treated with nivolumab therapy as a second-line or later therapy, rather than as a first-line therapy. GNRI as a first-line targeted therapy was also shown to have a significant difference in OS for mRCC patients compared to the previous study . Therefore, these pre-treatment variables, which include body weight and albumin at baseline, may be influenced by the previous first-line therapy.
In conclusion, the present study demonstrated that GNRI was a significant prognostic biomarker in mRCC patients treated with nivolumab. This simple classification might be useful in clinical practice. Our preliminary findings from a retrospective, single-institutional cohort require future external validation.