Renal cell carcinoma (RCC) is resistant to chemotherapy and radiotherapy, and cytokines are effective in only a limited subset of patients. There is no effective treatment for patients whose disease does not respond to cytokine therapy, or initially responds but then progresses. Understanding the angiogenesis resulting from downregulation of the von Hippel-Lindau (VHL) gene through mutation or silencing, which occurs in the vast majority of clear-cell RCC, has led to the development of a new generation of targeted therapies, including sunitinib.OBJECTIVE
To confirm the antitumor efficacy of single-agent sunitinib in patients with metastatic, cytokine-refractory clear-cell RCC.DESIGN
Between February and November 2004, this open-label, single-arm multicenter study enrolled adult patients with measurable clear-cell RCC with metastases who had undergone nephrectomy and experienced failure of one cytokine therapy (interleukin-2, interferon-α, or the combination). Patients with brain metastases, significant cardiac events, poor performance status or inadequate renal, hepatic, hematologic or cardiac function were excluded.INTERVENTION
Patients self-administered sunitinib orally at 50 mg per day initially in 6-week cycles, each comprising 4 consecutive weeks followed by 2 weeks off treatment, until disease progressed, unacceptable toxicity ensued or consent was withdrawn.OUTCOME MEASURES
The primary endpoint was objective response rate; secondary endpoints were response duration, progression-free survival (PFS), overall survival and safety. Clinical response was assessed by both the treating physicians and independent radiologists, using the Response Evaluation Criteria in Solid Tumors.RESULTS
Among the 105 evaluable patients (median age 56 years), toxic effects were primarily of grade 2 severity, most prominently fatigue, diarrhea and other gastrointestinal complaints, stomatitis, hypertension, pancytopenia, hand-foot syndrome and hair color changes; some of the adverse effects were grade 3/4 at lower incidences. Grade 4 laboratory abnormalities were rare and included neutropenia, anemia, and elevated lipase. On independent third-party analysis, 34% (95% CI 25-44%) of patients had overall response and 29% had stable disease. These results were similar to those of the investigator analysis, which showed 44% (95% CI 34-53%) had overall response and 22% had stable disease. The authors estimated 10 months for median duration of response, although this parameter is not yet determined by third-party analysis. Median PFS was 8.3 months (95% CI 7.8-14.5 months) by third-party assessment, or 8.1 months (95% CI 5.5-10.4 months) by investigator assessment. Median overall survival time had not been reached, but 6-month survival rate was 79% (95% CI 70-86%).CONCLUSION
Sunitinib is effective in second-line therapy for patients with metastatic clear-cell RCC refractory to cytokine treatment and has acceptable side effects.