Combination of Bevacizumab plus low-doses Immunotherapy plus Chemotherapy (BIC regimen) in metastatic renal cell cancer: antitumor effects and variations of T-regulatory cells (Treg) during the treatment. A multicentre study of the Italian Oncology Group for Clinical Research (GOIRC)

Background: Bevacizumab (B) is effective in metastatic Renal Cell Cancer (mRCC) and has a synergistic effect with Chemotherapy (Ch) in many tumors. The activity of B plus immunotherapy (It) with interleukin- 2 (IL-2) and interferon-α (IFN-α) has not been studied. Our previous dose-finding study showed the feasibility of the combination B+It+Ch (BIC regimen) [JCO Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 15586]. Aim of this study is to explore the efficacy of BIC and to correlate its efficacy with the variations in circulating T regulatory lymphocytes (Treg). Methods: Patients (pts) with histological diagnosis of mRCC, previous nephrectomy, PS 0-1, adequate organ function, no untreated CNS metastases and 0-2 previous systemic regimens were treated with B (10 mg/kg days 1 and 15) plus Ch (Gemcitabine: 1,000 mg/m2 i.v. in 1 hour followed by 5-fluorouracil 600 mg/m2 iv bolus days 1 and 8 every 28) plus It (IL-2: 1 MUI/m2 bid sc days 8, 9, 15, 16 and 1 MUI/m2/die sc from day 10 to 12 and from 17 to 19; and IFN-α: 3 MUI sc on days 10, 12, 17, 19). This phase II study was conducted according to two stages Minimax Simon design. CT was repeated for a maximum of 6 cycles followed by maintenance with B and It until progressive disease (PD). In 30 pts, blood samples for Treg were evaluated on days: 1, 8, 15, 22, 29 of cycle 1 and at the disease progression (PD). Recist criteria and ITT analysis were applied. Results: 45 pts were included: male 66%; median age 59 years; 47% pre-treated; 18% PS ≥ 1; 43 pts were evaluable for response (2 too early) and we observed 33% partial response (PR), 31% stable disease (SD) and 31% PD for an overall disease control rate (DCR) of 64%. Median PR/SD duration was 7.3 months (mths). Median TTP was 8.2 mths (95% CI: 6.9-9.4). In 24 not pre-treated pts DCR was 79%. In MSKCC poor risk group (13%) we observed 33% PR and a DCR of 83% with a TTP of 8.7 mths. Treatment was well tolerated, grade 3-4 toxicity included neutropenia non-febrile 36%, febrile 2%, thrombocytopenia 27%, flu-like syndrome 19%, hypertension 7%. Data show overall increased percentage of Treg, identified by FACS analysis as CD4+/CD25high/FoxP3+ in PBMCs, after the first week of It (day 15) and a overall decrease after the treatment with B (day 22); but from day 15 to 22 in PR/SD pts Treg decrease, while PD pts Treg increase. Conclusions: BIC combination is effective in all subgroups of mRCC and is well tolerated. Variation in Treg during first cycle seems to be correlated with the response to treatment