Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor‐risk metastatic renal cell carcinoma

Abstract

BACKGROUND: Sarcomatoid renal cell carcinoma (RCC) is associated with an aggressive biology and a poor prognosis. Poorrisk RCC is defined by clinical prognostic factors and demonstrates similarly aggressive behavior. No standard treatment exists for patients with sarcomatoid RCC, and treatment options for patients with poor-risk disease are of limited benefit. The objective of this study was to investigate the efficacy of antiangiogenic therapy in combination with cytotoxic chemotherapy in clinically aggressive RCC. METHODS: This was a phase 2, single-arm trial of sunitinib and gemcitabine in patients with sarcomatoid or poor-risk RCC. The primary endpoint was the objective response rate (ORR). Secondary endpoints included the time to progression (TTP), overall survival (OS), safety, and biomarker correlatives. RESULTS: Overall, 39 patients had sarcomatoid RCC, and 33 had poor-risk RCC. The ORR was 26% for patients with sarcomatoid RCC and 24% for patients with poor-risk RCC. The median TTP and OS for patients with sarcomatoid RCC were 5 and 10 months, respectively. For patients with poor-risk disease, the median TTP and OS were 5.5 and 15 months, respectively. Patients whose tumors had >10% sarcomatoid histology had a higher clinical benefit rate (ORR plus stable disease) than those with 10% sarcomatoid histology (P 5.04). The most common grade 3 or higher treatment-related adverse events included neutropenia (n 5 20), anemia (n 5 10), and fatigue (n 5 7). CONCLUSIONS: These results suggest that antiangiogenic therapy and cytotoxic chemotherapy are an active and well-tolerated combination for patients with aggressive RCC. The combination may be more efficacious than either therapy alone and is currently under further investigation. Cancer 2015;121:3435-43. V C 2015 American Cancer Society.KEYWORDS: chemotherapy, poor risk, renal cell carcinoma, sarcomatoid, vascular endothelial growth factor (VEGF), targeted. INTRODUCTIONRenal cell carcinoma (RCC) consists of a biologically heterogeneous group of tumors with distinct histopathologic and clinical features. Sarcomatoid RCC, a morphologic feature that can be identified across all RCC histologies, is characterized by the occurrence of spindle-shaped mesenchymal cells. The presence of sarcomatoid features has been reported in up to 29% of collecting duct carcinomas, in 9% to 11% of clear cell, chromophobe, and unclassified RCCs, and less frequently in papillary RCC (3%).1 Regardless of the underlying histology, sarcomatoid differentiation is associated with a more aggressive disease phenotype. 2,3 In most series, patients with metastatic sarcomatoid RCC had an estimated overall survival (OS) of 6 to 10 months.

Kidney Cancer, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology

“…[186][187][188][189][190][191] The potential role of sunitinib in combination gemcitabine has been investigated in a phase II trial of RCC with sarcomatoid features. 192 Results show that the combination is well tolerated and active, especially in patients with rapidly progressing disease. 192 Ongoing trials are studying sunitinib in combination with gemcitabine compared with sunitinib alone in patients with sarcomatoid features (ClinicalTrials.…”

“…192 Results show that the combination is well tolerated and active, especially in patients with rapidly progressing disease. 192 Ongoing trials are studying sunitinib in combination with gemcitabine compared with sunitinib alone in patients with sarcomatoid features (ClinicalTrials. gov identifier: NCT01164228).…”

Renal cancer subtypes: Should we be lumping or splitting for therapeutic decision making?

“…Relatively less is known about these rare kidney cancer subtypes. Collecting duct carcinomas were recognized as a distinct clinical diagnosis in the 1980s and are characterized by a tubulopapillary pattern and desmoplastic stroma; in some cases, they are difficult to distinguish histologically from urothelial carcinomas. However, biologically, they may be very different from urothelial carcinomas, because the 2 cancers contain very different patterns of chromosomal gain and loss .…”

Medical treatment of renal cancer: new horizons

“…Michaelson et al (2015) reported a phase 2 study of the combination of gemcitabine with sunitinib in patients poor-risk features, including patients with sarcomatoid histology the combination was tolerated and showed some activity and is currently being evaluated in a randomised study (Clinicaltrials.gov, NCT01164228).…”