Early Progressive Disease During Nivolumab Plus Ipilimumab Therapy Predicts Poor Survival in Japanese Patients with Advanced Renal Cell Carcinoma: A Single-Center 12-Week Landmark Study

Background: It is clinically important to identify early progressive disease (PD) during nivolumab plus ipilimumab therapy for advanced renal cell carcinoma (RCC). However, the predictors of early PD are unclarified. We evaluated the prognostic impact and baseline predictors of early PD. Materials and Methods: We retrospectively reviewed consecutive patients with advanced RCC who received nivolumab plus ipilimumab at Kyushu Cancer Center between September 2018 and January 2026. Tumor response was assessed using the RECIST version 1.1 guidelines. Early PD was defined as PD within 12 weeks from treatment initiation or PD at the first radiologic assessment. Overall survival (OS) was evaluated at the 12-week landmark. Cox regression was used to identify prognostic factors for landmark OS, and logistic regression was used to explore predictors of early PD. Results: The 12-week landmark cohort comprised 38 patients (early PD, n=14; non-early PD, n=24). Landmark OS was significantly shorter in the early PD group than in the non-early PD group (median, 12.9 vs. 66.1 months; log-rank P< 0.001). In multivariable Cox regression, early PD (hazard ratio 3.67; 95% confidence interval 1.28– 10.59; P=0.016) and International Metastatic RCC Database Consortium (IMDC) poor risk (hazard ratio 3.16; 95% confidence interval 1.24– 8.07; P=0.016) were independently associated with worse OS. In exploratory multivariable logistic regression, non-clear cell histology was significantly associated with early PD (odds ratio 9.01; 95% confidence interval 1.45– 56.20; P=0.019). Conclusion: Early PD during nivolumab plus ipilimumab identifies a high-risk population with markedly inferior survival. Non-clear cell histology was significantly associated with early PD in exploratory multivariable analysis and may help guide individualized first-line treatment selection and patient counseling in advanced RCC. Plain Language Summary: Some patients with advanced kidney cancer treated with nivolumab plus ipilimumab experience rapid tumor growth soon after starting therapy, and these patients often have poor outcomes. We examined whether early disease worsening predicts survival and which baseline factors are linked to early worsening. We reviewed 40 patients treated at a single cancer center and performed a 12-week landmark analysis of 38 patients who were followed up for more than 12 weeks. Patients with early disease worsening had markedly shorter survival than those without early worsening. We also found that the non-clear cell tumor type was strongly associated with early worsening. These findings may help clinicians identify patients who are unlikely to benefit from nivolumab plus ipilimumab and may support informed discussions with patients when selecting first-line treatment options. Keywords: advanced renal cell carcinoma, nivolumab, ipilimumab, early progressive disease, landmark analysis, non-clear cell histology, overall survival, IMDC risk classification