Effect of improved systemic therapy on patient survival in metastatic non‐clear‐cell renal cell carcinoma

Abstract

DOI: 10.1111/iju.14523 Non-clear-cell RCC accounts for up to 25% of all kidney cancers. The survival rate of patients with metastatic non-clear-cell RCC has been reported to be worse than that of patients with metastatic clear-cell RCC. Pivotal clinical trials have demonstrated the efficacy of mTTs or ICIs against metastatic clear-cell RCC, which has led to upgrading of systemic therapy strategies for such disease. However, there is still a paucity of information on how these improved therapies affect survival in patients with metastatic non-clear-cell RCC. In the present study, therefore, we aimed to investigate the relationship between different time periods of initiation of systemic therapy strategies and the associated survival rates in such populations. We retrospectively analyzed 38 patients with metastatic non-clear-cell RCC treated with systemic therapy between January 2008 and December 2018 at two Japanese institutions. In all 38 patients, OS after the initiation of first-line therapy was 15.4 months (95% CI 12.4– 23.8; Fig. S1). The objective response rate was 13% (n = 5; Table S1). The patients were divided into two groups based on the date of initiation of therapy; patients in whom therapy was initiated in the period 2008–2011 and those in whom therapy was initiated in 2012–2018 were categorized into an early (n = 12) and a late therapy initiation period group (n = 26), respectively. There was no significant difference in patient characteristics between the periods (all P > 0.05), except for lymph node metastasis status (P = 0.0336; Table S2). OS was significantly longer among the patients in the late therapy initiation period group than among those in the early group (P = 0.0009; Fig. 1a). Multivariate analysis showed further that systemic therapy initiation period was an independent factor for OS (P = 0.0067), together with the International Metastatic Renal Cell Carcinoma Database Consortium risk (P = 0.0198) and liver metastasis status (P = 0.0452; Table S3). The number of lines of therapy showed an increasing trend according to systemic therapy initiation period, and nivolumab was administered only in the late period (Table S4). Subsequent therapy and nivolumab administration appeared to improve OS (Fig. S2a: P = 0.0048; and Fig. S2b: P = 0.133, respectively). On comparing OS between the entire metastatic non-clear-cell RCC population and the metastatic clear-cell RCC population (n = 182), OS was significantly shorter in the metastatic non-clearcell RCC population (P = 0.0001; Fig. S1); this was consistent with the results of a previous study conducted in the mTT setting. In the early therapy initiation period group, OS was significantly shorter in the metastatic non-clear-cell RCC population than in the metastatic clearcell RCC population (P < 0.0001; Fig. 1b), whereas the difference was statistically insignificant in the late therapy initiation period group (P = 0.104; Fig. 1c). This analysis demonstrates that advancements in systemic therapy in the last decade have positively influenced survival in patients with metastatic non-clear-cell RCC. OS in metastatic non-clear-cell RCC patients was closer to that in metastatic clear-cell RCC patients according to these periods, indicating an improvement in the survival of metastatic non-clear-cell RCC patients. Studies have shown that the median OS in metastatic non-clear-cell RCC patients receiving first-line therapy with TKIs or mammalian target of rapamycin inhibitors ranged from 11.6 to 31.5 months, and our results were consistent with those data. Recently, the efficacy of ICIs in metastatic non-clear-cell RCC patients has been reported. Indeed, our data also showed a tendency for improved survival due to nivolumab therapy, compared to that with mTTs (Fig. S2b). Additionally, an increase in the number of lines of therapy was associated with prolonged OS (Fig. S2a), in line with a previous study conducted in the mTT setting. Collectively, these factors might contribute to the improvement in survival during successive periods of systemic therapy. Although the reasons for inferior outcomes in metastatic non-clear-cell RCC patients remain unclear, it could be attributed to different molecular alterations underlying its pathogenesis. In clear-cell RCC, von Hippel-Lindau inactivation and subsequent hypoxia-inducible factor accumulation upregulate the expression of genes encoding pathogenic factors such as vascular endothelial growth factor or platelet-derived growth factor which are targets for