54 Primary Progressive Disease and Outcomes with First-Line Nivolumab Plus Ipilimumab in Metastatic Renal Cell Carcinoma: A Real-World IMDC Analysis

Abstract

Abstract Background Nivolumab plus ipilimumab (NIVO+IPI) combination therapy is a first-line standard in metastatic renal cell carcinoma (mRCC). Despite durable responses in some patients, over 20% develop primary progressive disease (PPD) at first restaging imaging. In this study, we evaluated clinical factors associated with PPD and subsequent outcomes. Methods This retrospective real-world study analyzed patients with mRCC who received first-line NIVO+IPI, within the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Response to treatment was assessed by physician evaluation according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Multivariable logistic regression was used to identify factors associated with PPD. Among patients with PPD, Cox proportional hazards models were used for overall survival (OS) and time to next line therapy or death (TNTD), and Fine–Gray competing risks models for mortality without next-line therapy (MWNT). Results 1,601 patients with mRCC treated with first-line NIVO+IPI were included, of whom 487 (30.4%) experienced PP. In multivariable logistic regression analysis, liver metastases (odds ratio 1.67, 95%CI 1.24-2.26), Karnofsky performance status (KPS) <80% (1.54 (1.12-2.12)), low hemoglobin (1.35 (1.04-1.74)), and elevated neutrophils (1.50 (1.09-2.06)) were independently associated with higher odds of PPD, while prior nephrectomy was associated with lower odds (0.69 (0.54-0.88)). Among patients with PPD, the median time to end of first-line therapy (TEFL) was 2.1 months. The median TNTD was 3.6 months, and the median OS was 13.9 months. At 6 months, the cumulative incidence of initiating next-line therapy was 59%, while 16% died without receiving subsequent therapy. In multivariable analyses among patients with PPD, liver metastases, treatment initiation within 1 year of diagnosis, poor performance status, and elevated neutrophils were associated with shorter TNTD and worse OS, while low KPS, elevated neutrophils, and low hemoglobin were associated with increased MWNT, and prior nephrectomy remained protective (Table 1). Conclusions Primary progressive disease to first-line NIVO+IPI occurs in around 30% of patients with mRCC and is associated with poor clinical outcomes. This real-world analysis identified baseline factors at time of initiation of treatment reflecting aggressive disease biology. These findings emphasize the importance of early risk stratification to identify patients unlikely to benefit from NIVO+IPI, who may benefit from an alternative first-line approach or an early change in treatment.54 Table 1 Multivariable regression for predicting Time to Next Line Therapy or Death (TNTD), Mortality without Next-Line Therapy (MWNT), and Overall Survival (OS) among patients with primary PD Hazard Ratio (95% CI) P-value A. Time to Next Line Therapy or Death (TNTD) (N = 395) A Presence of liver metastasis 1.84(1.44-2.37) <.001 Diagnosis to therapy interval < 1-year 1.62(1.26-2.08) <.001 KPS < 80 1.49(1.16-1.91) 0.002 High neutrophils 1.69(1.32-2.18) <.001 B. Mortality without Next-Line Therapy (MWNT) (N = 402) B Nephrectomy 0.63(0.39-1.00) 0.050 KPS < 80 3.15(2.02-4.92) <.001 High neutrophils 1.84(1.17-2.91) 0.009 Hb < LLN 1.74(1.01-3.00) 0.047 C. Overall Survival (OS) (N = 395) A Presence of liver metastasis 1.36(1.03-1.80) 0.028 Diagnosis to therapy interval < 1-year 1.75(1.30-2.36) <.001 KPS < 80 1.88(1.43-2.46) <.001 Hb < LLN 1.52(1.17-1.98) 0.002 High neutrophils 1.76(1.32-2.33) <.001 Abbreviations: KPS = Karnofsky Performance Status; Hb = Hemoglobin, LLN = lower limit of normalA Using Cox regressionB Using Fine-Gray competing risks regression, with initiating next line as a competing risk