A phase II trial of sunitinib and gemcitabine in sarcomatoid and/or poor-risk patients with metastatic renal cell carcinoma.

Abstract

408 Background: Sarcomatoid renal cell carcinoma (sRCC) is associated with aggressive biology and poor prognosis. Poor-risk RCC, as defined by established risk factors, demonstrates similar aggressive behavior. Though vascular endothelial growth factor (VEGF) therapy is the standard initial therapy for RCC, insufficient data exist in sRCC and efficacy is limited in poor-risk disease. The objective of this study was to investigate the efficacy of anti-angiogenic therapy and cytotoxic chemotherapy in clinically aggressive RCC. Methods: We conducted a phase II single arm trial at 3 institutions of sunitinib (37.5 mg PO daily, 2-weeks on, 1-week off) and gemcitabine (1,000 mg/m2 IV day 1 and 8 of every 21-day cycle) in patients (pts) with sarcomatoid or poor-risk RCC (NCT00556049). The primary endpoint was objective response rate (ORR) defined by RECIST. Secondary endpoints included overall survival (OS), safety, and biomarker correlatives. Results: Overall, 39 pts had sRCC and 33 had poor-risk RCC. Of the 32 sRCC pts with evaluable disease, the ORR was 26% (n=10) and stable disease rate (SDR) was 38% (n=15). Of the 31 evaluable poor-risk RCC pts, ORR was 24% (n=8) and SDR was 39% (n=13). OS for pts with sRCC was 10 months (95% CI 6, 24) and 15 months (95% CI 9, 29) for pts with poor-risk RCC. The most common ≥ grade 3 treatment-related adverse events included neutropenia (n=20), anemia (n=10), and fatigue (n=7). Of the 27 sRCC pts with tissue for central review, increased sarcomatoid histology (>10%) correlated with an improved clinical benefit rate (CBR, ORR + SDR) compared to pts with ≤10% sarcomatoid histology (CBR 100% for >10% versus 55% for ≤10% sarcomatoid, p=0.04), suggesting that sRCC was sensitive to combination therapy. Pts with clear-cell histology were more likely to experience an OR compared to those without clear-cell histology (32% versus 16%, p=0.23). Of 11 pts with tumor DNA sequencing data, no actionable gene mutations were identified. Conclusions: Our results suggest that VEGF targeted therapy and cytotoxic chemotherapy are an active combination in pts with rapidly progressive RCC. The combination may be more efficacious than either therapy alone and this is under further investigation (NCT01164228). Clinical trial information: NCT00556049.