50Clinical characteristics, determinants and subsequent therapy of primary refractory metastatic renal cell carcinoma (mRCC): an international metastatic database consortium (IMDC) study

Abstract Background Immune checkpoint inhibitor (ICI)-based regimens, represent the current standard of care for first line (1 L) metastatic renal cell carcinoma (mRCC). A subset of patients (pts) experience progressive disease (PD) on first restaging and are considered “primary refractory.” Herein, we characterize this patient population and examine practice patterns and outcomes of subsequent second line (2 L) therapy. Methods Data from pts with mRCC treated with 1 L ICI-based regimens with available data on their best response to 1 L were collected from the IMDC. Pts were categorized as primary refractory (PD as best response) and non-primary refractory (stable disease or partial/complete response as best response). Logistic regression was used to identify independent factors associated with primary refractory mRCC. Overall survival (OS) and time to treatment failure (TTF) were calculated from initiation of 2 L therapy; their distributions were estimated by the Kaplan Meier methodology. Results In total, 2001 pts were included in this study, of which 1301 (65%) were treated with dual ICI combination, and 701 (35%) with ICI + VEGF combination. Of 2001 pts, 494 (24%) had PD as best response. Primary refractory and non-primary refractory groups did not differ by age or gender. The primary refractory group had a higher rate of pts treated with dual ICI combination (76 vs. 62%), higher rate of pts with poor IMDC risk group (39 vs. 25%), more pts with non-clear cell RCC (16 vs. 10%; all P < .001). The primary refractory group had lower KPS (median: 80 vs. 90), higher percentage of anemia (61% vs. 47%), neutrophilia (19% vs. 12%), and thrombocytosis (23 vs 16%; all P < .001). The primary refractory group had more liver (24 vs. 15%; P < .001), bone (39 vs 31%; P = .001) and lymph nodes metastasis (52 vs. 46%; P = .03) at the start of the 1 L treatment. On multivariate analysis, factors that were independently associated with primary refractory RCC were anemia (Odds Ratio (OR)=1.32, 95% confidence interval (CI) 1.01-1.74, P = .04), KPS <80% (OR = 1.92, CI 1.38-2.66, P < .001), neutrophilia (OR = 1.5, 95% CI 1.03-2.17, P = .03), non-clear cell histology (OR = 1.55, 95% CI 1.07-2.26, P = .02), and the presence of liver metastasis (OR = 2.03, 95% CI 1.5-2.75, P < .001). Dual-ICI combination was associated with a 1.8-fold increase of primary refractory mRCC (OR = 1.86, 95% CI: 1.39–2.49, P < .001). 356 (72%) pts with primary refractory mRCC went on to receive subsequent 2 L therapy. The most common regimens in the 2 L setting included: cabozantinib (n = 137; 38%); sunitinib (n = 115; 32%), and pazopanib (n = 37; 10%). 22% of patients had IMDC poor risk at initiation of 2 L. Median follow-up from 2 L initiation was 18.8 months. Median OS was 14.5 months, and the median TTF was 5.5 months for the whole cohort. The outcomes of patients with primary refractory mRCC receiving 2 L therapies are summarized in Table. Conclusions In this large multicenter cohort of pts with mRCC, the presence of liver metastasis, the receipt of dual ICI combination therapy, and a KPS < 80 are independent risk factors for primary refractory disease. Cabozantinib is the most frequently used regimen as 2 L therapy in this patient population and demonstrates favorable clinical outcomes. Biomarker evaluation is needed to explore the mechanism of primary resistance and novel therapeutic strategies for this group.