Clinical and immunomodulatory effects of bevacizumab and low‐dose interleukin‐2 in patients with metastatic renal cell carcinoma: results from a phase II trial

Abstract

Study Type – Therapy (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? As single agents, both IL‐2 and bevacizumab have demonstrated clinical activity in advanced RCC. This study demonstrated the feasibility of the combination, its safety and unfortunately the lack of enhanced activity if one compares the combination with existing data of bevacizumab alone. OBJECTIVE Low‐dose interleukin‐2 (IL‐2) is a historical treatment for metastatic renal cell carcinoma (mRCC). Increased vascular endothelial growth factor (VEGF) levels inhibit dendritic cell (DC) differentiation and augment production of immunosuppressive regulatory T (Treg) cells. Bevacizumab is an antibody that binds to VEGF, has activity in mRCC and may augment the anti‐tumour immune effects of IL‐2. To determine the clinical and immunomodulatory effects of this combination, a prospective, phase II trial of bevacizumab plus low‐dose IL‐2 was conducted. PATIENTS AND METHODS Patients with untreated mRCC received bevacizumab (10 mg/kg i.v. every 2 weeks) and IL‐2 (125 000 units/kg/day subcutaneously from Monday to Friday for 6 consecutive weeks followed by a 2‐week rest period). Endpoints included progression‐free survival, Response Evaluation Criteria in Solid Tumors‐defined objective response rate, immunomodulatory effects and safety. RESULTS Between January 2005 and September 2007, twenty‐six patients with untreated mRCC were enrolled. The median progression‐free survival was 9.6 months (95% CI, 4.1–16.9 months) The objective response rate was 15% and an additional 38% of patients had tumour burden reduction of <30%. Grade 3 constitutional adverse events (fatigue, fever/chills) and neutropenia were observed in 42% and 12% of patients, respectively. Peripheral blood CD1c + myeloid and CD303 + plasmacytoid DC increased during treatment as did IL‐8 levels and CD4 + CD25 + FoxP3 + Treg cells. No changes in T helper type 1/2‐associated cytokines were observed. CONCLUSION Bevacizumab plus low‐dose IL‐2 has modest clinical activity in mRCC. Toxicity was largely IL‐2 related without enhancement of bevacizumab‐related toxicity. Biological data indicate inhibition of VEGF levels and increase of immunosuppressive Treg cells without an effect on DC activation.