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DOI: 10.1111/iju.14635 Since the medical significance of upfront CN was rejected by the CARMENA and SURTIME trials, the selection of this option for the initial treatment of aRCC has been challenging. Thus, there is a need for data regarding the efficacy of ICIs without prior nephrectomy. We reviewed data of 16 aRCC patients receiving nivolumab plus ipilimumab as first-line therapy without prior nephrectomy at three affiliated institutions (institutional review board number: 2020–0009). We assessed tumor response across primary kidney lesions and metastatic lesions, as well as survival and ORRs. Over half of patients were men aged >65 years, pathologically diagnosed with clear-cell RCC (Table S1). Five (31%) and 11 (69%) patients were classified as the International Metastatic Renal Cell Carcinoma Database Consortium intermediateand poor-risk groups, respectively. During the median follow-up period of 8.14 months (IQR 6.89–11.2), eight (50%) and four (25%) patients had disease progression and died, respectively. The median progression-free survival was 8.32 months (95% CI 2.50– not reached; Fig. S1a), and the 6-month overall survival rate was 86.7% (Fig. S1b). The incidence of immune-related adverse events was 56% (n = 9; Table S2). Tumor response was assessed in 15 patients with eligible radiographic data according to RECIST version 1.1. In all targeted lesions, the median bTS magnitude was 20.7% (IQR 54.1–19.8%) and ORR was 53% (Table S3; Fig. S2a). The median time between treatment initiation and bTS diagnosis was 3.19 months (IQR 2.27–6.58). In primary lesions, the median bTS magnitude was 30.7% (IQR 42.9–2.99%) and eight (53%) patients experienced >30% tumor shrinkage (Table S3; Fig. S2b). In metastatic lesions, the median bTS magnitude was 41.5% (IQR 84.4–39.5%), and one (7%) and seven patients (47%) had 100% and >30% tumor shrinkage, respectively (Table S3; Fig. S2c). Tumor response between primary and metastatic lesions was generally parallel, but only one patient (patient 6) showed a mixed response (Fig. 1). Also, the magnitude of tumor response ranged more widely in metastatic lesions than in primary lesions. Furthermore, the response in all targeted lesions was more affected by response in metastatic lesions than in primary lesions (Fig. 1; Table S3). For example, the BORs of patients 3 and 4 were PD, owing to the considerable tumor growth in metastatic lesions despite controlled primary lesions. The present retrospective study showed the favorable survival and high ORRs, together with frequent tumor shrinkage for both primary and metastatic lesions in nivolumab plus ipilimumab without prior nephrectomy for aRCC. Notably, 53% of patients showed >30% shrinkage in primary lesions, and all patients had >30% shrinkage in metastatic lesions. A post-hoc analysis of the CheckMate214 trial showed that 35% of the patients without nephrectomy achieved >30% tumor shrinkage in primary lesions. Therefore, the rate we calculated was unexpectedly higher, even though the present cohort comprised real-world patients. These data suggest that frontline therapy with nivolumab plus ipilimumab increases the number of treatment options, including deferred CN and metastasectomy. Nevertheless, we require additional data on the efficacy and safety of deferred CN after ICIs and metastasectomy in the ICI era. The lack of tumor response (i.e. PD as the BOR) was caused by the absence of effect in metastatic lesions than in primary lesions (Fig. 1; Table S3). Importantly, the rate of PD as the BOR (33%) was higher than the general population rate. This pattern might be explained by many poor-risk patients with a high burden of risk factors (including high rate of synchronous metastasis) in the present cohort. Additionally, the focus on metastatic, as well as primary, lesions was different from the approach used in the CheckMate214 trial. The present study had several limitations. First, the retrospective nature of the study (consisting of a small sample size with short follow-up duration) inevitably induces biases. Second, the heterogeneous histopathological type might affect the data of the tumor response. Third, we could not evaluate the possibility of pseudoprogression, because the tumor response was assessed according to RECIST version 1.1. In summary, the present preliminary data contribute to the evidence of efficacy in terms of tumor response in primary and metastatic lesions of aRCC patients in frontline nivolumab plus ipilimumab therapy without prior nephrectomy.