Nivolumab is a fully human immunoglobulin (Ig) G4 antibody that selectively inhibits the programmed death 1 (PD-1) immune checkpoint molecule, and has recently been launched for the treatment of renal cell cancer (RCC) in Japan. Based on its promising anti-tumor efficacy and manageable safety profile demonstrated in the phase III Checkmate 025 trial, nivolumab therapy is rapidly being introduced in metastatic RCC clinical practice. The phase Ia study of atezolizumab, which is a humanized anti-PD-ligand 1 (PD-L1) monoclonal IgG1 antibody, also demonstrated excellent treatment results. The identification of biomarkers to predict the response and side-effects of checkpoint inhibitor therapy is thus urgently needed. In this review, we introduce the current candidate biomarkers of immune checkpoint inhibitor therapy. Based on the mechanism of efficacy, the number of neoantigens and expression of major histocompatibility complex molecules are strong candidate biomarkers. Despite the various interference factors, PD-L1 expression can be considered a potential biomarker. In terms of clinical factors, serum clinical factors and severity of adverse events are examined. Although further implementation in prospective studies is necessary, if validated, these biomarkers can be utilized to measure therapeutic response and design treatment strategies for metastatic RCC.

Renal cell cancer (RCC) is one of the most frequent primary sites for metastatic pancreatic tumors although metastatic tumors are rare among pancreatic malignant tumors. The purpose of this study is to disclose the characterization and treatment outcomes of pancreatic metastases from RCC. Of 262 patients with metastatic RCC treated at our hospital between 1999 and 2013, the data of 20 (7.6%) who simultaneously developed or subsequently acquired pancreatic metastases were retrospectively reviewed and statistically analyzed. The median follow-up period from RCC diagnosis and pancreatic metastases was 13.4 years (inter-quartile range: IQR, 7.8–15.5 years) and 3.8 years (IQR, 2.1–5.5 years), respectively. Median duration from diagnosis of RCC to pancreatic metastasis was 7.8 years (IQR, 4.2–12.7 years). During this observation period, the estimated median overall survival (OS) time from the diagnosis of RCC to death or from pancreatic metastasis to death was not reached. The probability of patients surviving after pancreatic metastasis at 1, 3, and 5 years was 100, 87.7, and 78.9%, respectively. The estimated OS period from the diagnosis of metastases to death of the patients with pancreatic metastasis was significantly longer than that of the patients with non-pancreatic metastasis (median OS 2.7 years) (P < 0.0001). Surgical management for pancreatic metastasis was performed in 15 patients (75%). When the median follow-up period for these surgeries was 3.5 years (IQR, 1.9–5.2 years), the estimated median recurrence-free survival was 1.8 years. For the patients with multiple metastatic sites, molecularly targeted therapies were given to six (30%) patients. When the median follow-up period was 4.1 years (IQR, 3.0–4.4 years), no disease progression was observed. The pancreas is frequently the only metastatic site and metastasis typically occurs a long time after nephrectomy. The OS period of these patients is long and both surgical and medical treatment resulted in good outcomes.

Objectives: In the present study, we explored the real-world efficacy of the immuno-oncology checkpoint inhibitor nivolumab and the tyrosine kinase inhibitor cabozantinib in the second-line setting. Methods: Using the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) dataset, a retrospective analysis of patients with metastatic renal cell carcinoma (MRCC) treated with nivolumab or cabozantinib in the second line after prior therapy targeted to the vascular endothelial growth factor receptor (VEGFR) was performed. Baseline characteristics and imdc risk factors were collected. Overall survival (OS) and time to treatment failure (TTF) were calculated using Kaplan–Meier curves. Overall response rates (ORRS) were determined for each therapy. Multivariable Cox regression analysis was performed to determine survival differences between cabozantinib and nivolumab treatment. Results: The analysis included 225 patients treated with nivolumab and 53 treated with cabozantinib. No significant difference in median OS was observed: 22.10 months [95% confidence interval (CI): 17.18 months to not reached] with nivolumab and 23.70 months (95% CI: 15.52 months to not reached) with cabozantinib (p = 0.61). The TTF was also similar at 6.90 months (95% CI: 4.60 months to 9.20 months) with nivolumab and 7.39 months (95% CI: 5.52 months to 12.85 months) with cabozantinib (p = 0.20). The adjusted hazard ratio (HR) for nivolumab compared with cabozantinib was 1.30 (95% CI: 0.73 to 2.3), p = 0.38. When adjusted by IMDC criteria and age, the HR was 1.32 (95% CI: 0.74 to 2.38), p = 0.35. Conclusions: Real-world IMDC data indicate comparable OS and TTF for nivolumab and cabozantinib. Both agents are reasonable therapeutic options for patients progressing after initial first-line VEGFR-targeted therapy.

Sunitinib is an orally‐administered, multitargeted tyrosine kinase inhibitor. The main targets are vascular endothelial growth factor receptor (VEGFR)‐1, VEGFR‐2, VEGFR‐3, platelet‐derived growth factor receptor (PDGFR)‐α, and PDGFR‐β. Among therapeutic targeting agents, it is the best available in the USA for patients with metastatic renal cell cancer (RCC). Well‐constructed clinical trials have led to the worldwide approval of various agents for RCC. However, in clinical practice, it remains difficult to determine the best treatment strategy with these agents. Therefore, the identification of biomarkers to predict response and side‐effects and to select optimal dosages is urgently needed. Potential mechanisms of action and resistance need to be understood in order to make accurate predictions. This article briefly reviews candidate biomarkers of sunitinib therapy in terms of clinical variables, genetic factors, and circulating proteins and endothelial cells. Although further validation and implementation is necessary, if validated, biomarkers will help measure the therapeutic response in individual patients and establish treatment strategies for metastatic RCC. (Cancer Sci, 102: 1949–1957)

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? A randomized prospective phase III clinical trial for systemic treatment‐naïve metastatic renal cell cancer (RCC) patients demonstrated the superiority of sunitinib over interferon with an acceptable safety profile. However, a commonly asked question is whether patients with RCC in clinical trials are representative of those with this disease being seen in ordinary clinical practice. To our knowledge, this is the first report of sunitinib for the Japanese patients with metastatic RCC in ordinary clinical practice. The estimated median PFS and OS in this study were 9.3 and 32.2 months, respectively. The application of the MSKCC model distinctly separated OS curves ( P < 0.001), suggesting that MSKCC prognostic factors might be still valid to predict survival in metastatic RCC in the era of molecular targeted therapy. OBJECTIVES: To report the treatment efficacy and safety profile of sunitinib for patients with metastatic renal cell carcinoma (RCC) in ordinary clinical practice. In addition, to investigate the prognostic clinicopathological factors in these patients. PATIENTS AND METHODS: The present study consisted of native Japanese patients with metastatic RCC, comprising 29 pretreated and 34 systemic treatment‐naïve patients. Univariate and multivariate analyses were performed by the log‐rank test and the Cox proportional hazards model, respectively. RESULTS: Estimated median progression‐free survival and overall survival (OS) were 9.3 months (95% confidence interval, CI, 5.0–13.7) and 32.2 months (95% CI, 24.4–40.0), respectively. Among the patients pretreated before sunitinib, two patients were treated with initialized systemic therapy with sorafenib and the remaining 27 were initialized with interferon‐α. The OS from the initial systemic therapy of the patients in pretreated groups was 79.6 months (95% CI, 14.6–144.5). The application of the Memorial Sloan‐Kettering Cancer Center model distinctly separated the OS curves ( P < 0.001). The most common grade 3 adverse events were fatigue (53%), thrombocytopaenia (48%), hand‐foot syndrome (16%), anaemia (20%), hypertension (10%) and leucopaenia (9%), although these events were manageable and reversible. CONCLUSIONS: Sunitinib has a favourable efficacy/safety profile for Japanese metastatic RCC patients in clinical practice. The estimated median OS was >2 years with acceptable tolerability. The median OS from the initial systemic therapy of the pretreated patients was >6 years. Memorial Sloan‐Kettering Cancer Center prognostic factors still appear to be valid for predicting survival in metastatic RCC in the era of molecular targeted therapy.