Nine targeted agents have been approved for metastatic clear cell renal cell carcinoma (mccRCC) in the last 10 years, including VEGFR-tyrosine kinase inhibitors (TKI), mTOR inhibitors and checkpoint inhibitor (CI). Combination of CI nivolumab and ipilimumab is currently compared to sunitinib in a randomised phase III trial in first-line setting. While treatment opportunities of mccRCC are moving rapidly biomarker to select patients to receive TKI or CI are still lacking. Based on transcriptomic analysis, we have defined four distinct molecular groups (ccrcc1 to 4) in patients with mccRCC treated with sunitinib. These groups were mainly characterized by distinct responses to suntinib as well as distinct immune cell compositions and inhibitory receptor expressions.
The proof of concept study BIONIKK is a French multicentric randomised phase II designed to assess the use of molecular groups to select treatment in first-line mccRCC. Molecular group is determined on frozen tumor sample within 2 weeks. Treatment is then allocated between TKI and nivolumab plus ipilimumab for ccrcc2 and 3 and between nivolumab alone and nivolumab plus ipilimumab for ccrcc1 and 4. Main objective is to assess efficacy of each treatment arm according to molecular group. Primary endpoint is overall response rate using RECIST 1.1. Main secondary endpoints include PFS, OS and their relationship to exploratory biomarkers. These latter include protein and gene expression analyses of tumor microenvironment (TME) from formalin-fixed and paraffin-embedded tumor samples. In addition, phenotype and functional status of peripheral blood lymphocytes will be analysed with flow cytometry before and during treatment. A Bayesian model was used to avoid independent analyses of the effect of drugs using hierarchical borrowing. Bionikk is not designed to be conclusive on the superiority of any treatment but will generate important hypotheses on putative biomarkers to select patients to receive TKI, CI alone or in combination. From this point of view, Bionikk is the first biomarker-driven trial in first line metastatic ccRCC.
Clinical trial identification
NCT02960906 First received: August 18, 2016
Legal entity responsible for the study
Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie
Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie and Bristol-Myers Squibb
S. Oudard: Honorarium fees from Astellas, Pfizer, Sanofi, Janssen, Bristol-Myers Squibb. Y-A. Vano: Honorarium fees from Bristol-Myers Squibb, Pfizer, Novartis, Astellas, Sanofi, Janssen, Roche. All other authors have declared no conflicts of interest.