Rana R. McKay, MD
A fourth of patients with sarcomatoid or poor-risk metastatic renal-cell carcinoma (RCC) responded to treatment with the combination of sunitinib and gemcitabine, according to data reported at the Genitourinary Cancers Symposium in Orlando.
Ten of 39 patients with sarcomatoid RCC and eight of 33 with poor-risk disease had objective responses, including one complete response in the sarcomatoid group. About 40% of patients in each subtype had stable disease during treatment with the targeted-cytotoxic combination.
The median time to progression (TTP) was 5 to 6 months in both groups, and median overall survival was 10 months among patients with sarcomatoid RCC and 15 months in the high-risk group.
“Patients with sarcomatoid or poor-risk renal cell carcinoma have frequent objective responses with acceptable toxicity when treated with gemcitabine and sunitinib,” said Rana R. McKay, MD, an oncology fellow at Dana-Farber Cancer Institute in Boston. “A prospective randomized trial is underway to validate our findings. Patients with rapidly progressive disease may have fundamentally differing disease pathogenesis, and molecular studies are warranted to investigate disease drivers and potential therapeutic targets.”
Sarcomatoid RCC occurs across all RCC histologies and is associated with an aggressive phenotype. A subgroup of patients with nonsarcomatoid histology have similarly aggressive tumor biology and rapid disease progression.
Angiogenesis inhibitors that target vascular endothelial growth factor (VEGF) are standard first-line therapy for most patients with RCC. The addition of chemotherapy to VEGF inhibitors had proven active in patients with sarcomatoid or high-risk phenotypes of RCC, providing a rationale to evaluate sunitinib and gemcitabine in such patients.
McKay reported findings from a prospective, nonrandomized clinical trial limited to patients with histologically confirmed sarcomatoid RCC or nonsarcomatoid high-risk RCC (as defined by the presence of three or more previously identified clinical features). Eligible patients had received no more than one prior systemic therapy and had no prior exposure to sunitinib or gemcitabine.
All patients received intravenous gemcitabine 1,000 mg/m2 on days 1 and 8 of every 21-day cycle plus oral sunitinib 37.5 mg daily for 14 consecutive days, followed by 7 days off.
Patients underwent response/disease status assessment at baseline and then every 3 weeks, and the primary endpoint was overall response rate. Secondary endpoints included time to progression, overall survival, safety, and biomarker analysis.
Data analysis included 72 patients: 39 with sarcomatoid RCC and 33 with nonsarcomatoid high-risk RCC. The patients had a median age of about 60. Pathology was clear cell 24 of 39 patients with sarcomatoid RCC and 27 of 32 with high-risk RCC. Three fourths of the patients had lung metastases, and more than 60% had lymph-node involvement.
All but six patients in the sarcomatoid group had prior nephrectomy, as did 21 of 33 patients with nonsarcomatoid high-risk RCC. Few patients had undergone radiation therapy or received systemic agents for metastatic disease.
McKay reported that 26% of patients with sarcomatoid RCC achieved objective responses, including one patient who had a complete response. An additional 15 patients (38%) had stable disease. In the nonsarcomatoid high-risk group, 24% of patients had partial responses, and 39% (13 of 32) had stable disease.
The median TTP was 5 months in the sarcomatoid group and 5.5 months in the nonsarcomatoid group.
Grade 3 or higher treatment-related adverse events occurred in 39 of the 72 patients. The most frequent grade 3 adverse events were neutropenia (19 patients) and anemia (10). Grade 4 adverse events occurred infrequently (four of 72 patients).
Correlation of pathologic findings and clinical activity (N=21) showed that patients whose tumors had more than 10% sarcomatoid histology (N=10) were more likely to achieve stable disease or better as compared with patients whose tumors had lower concentrations of sarcomatoid histology (100% versus 54%, P
Investigators performed genomic profiling for 11 patients (eight sarcomatoid, three high risk) and found no mutations in oncogenic driver genes.
McKay R, Choueiri T K, Werner L. “A phase II trial of sunitinib and gemcitabine in sarcomatoid and/or poor-risk patients with metastatic renal cell carcinoma.” Presented at: 2015 Genitourinary Cancers Symposium; February 26-28, 2015; Orlando, FL. Abstract 408.
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