A phase 2 BIOmarker driven trial with Nivolumab and Ipilimumab or VEGFR tKi in naïve metastatic Kidney cancer: the BIONIKK trial

Abstract

Background: Nine targeted agents have been approved for metastatic clear cell renal cell carcinoma (mccRCC) in the last 10 years, including VEGFR-tyrosine kinase inhibi- tors (TKI), mTOR inhibitors and checkpoint inhibitor (CI). Combination ofCI nivo- lumab and ipilimumab is currently compared to sunitinib in a randomised phase III trial in first-line setting. While treatment opportunities ofmccRCC are moving rapidly biomarker to select patients to receive TKI or CI are still lacking. Based on transcrip- tomic analysis, we have defined four distinct molecular groups (ccrcc1 to 4) in patients with mccRCC treated with sunitinib. These groups were mainly characterized by dis- tinct responses to suntinib as well as distinct immune cell compositions and inhibitory receptor expressions. Trial design: The proofofconcept study BIONIKK is a French multicentric rando- mised phase II designed to assess the use ofmolecular 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 ofeach 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 lat- ter include protein and gene expression analyses oftumor microenvironment (TME) from formalin-fixed and paraffin-embedded tumor samples. In addition, phenotype and functional status ofperipheral blood lymphocytes will be analysed with flow cytometry before and during treatment. A Bayesian model was used to avoid independ- ent analyses ofthe effect ofdrugs using hierarchical borrowing. Bionikk is not designed to be conclusive on the superiority ofany treatment but will generate important hypotheses on putative biomarkers to select patients to receive TKI, CI alone or in com- bination. From this point ofview, Bionikk is the first biomarker-driven trial in first line metastatic ccRCC. Clinical