Journal Article

Phase II study on first-line treatment of NIVolumab in combination with folfoxiri/bevacizumab in patients with Advanced COloRectal cancer RAS or BRAF mutated – NIVACOR trial (GOIRC-03-2018)

Nasti, Guglielmo, Maiello, Evaristo, Tonini, Giuseppe, Normanno, Nicola, Pinto, Carmine, Antonuzzo, Lorenzo, Iachetta, Francesco, Zaniboni, Alberto, Damato, Angela, Bergamo, Francesca, Bordonaro, Roberto, Berselli, Annalisa, Romagnani, Alessandra

2020

Overview

Background FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab has shown to be one of the therapeutic regimens in first line with the highest activity in patients (pts.) with metastatic colorectal cancer (mCRC) unselected for biomolecular alterations. Generally, tumors co-opt the programmed death-1/ligand 1 (PD-1/PD-L1) signaling pathway as one key mechanism to evade immune surveillance. As today, anti-PD-1 monoclonal antibodies are FDA approved only for DNA mismatch repair deficient/microsatellite instability-high (MMRd/MSI-H), which represent only about 5% among all mCRC. Nowadays, there are no data demonstrating anti PD-1 activity in proficient and stable disease (MMRp/MSS). A different target in mCRC is also the Vascular Endothelial Growth Factor A (VEGF-A), which acts on endothelial cells to stimulate angiogenesis. VEGF-A inhibition with bevacizumab has shown to increase the immune cell infiltration, providing a solid rationale for combining VEGF targeted agents with immune checkpoint inhibitors. Based on these evidences, we explore the combination of triplet chemotherapy (FOLFOXIRI) with bevacizumab and nivolumab in pts. with mCRC RAS/BRAF mutant regardless of microsatellite status. Methods/design This is a prospective, open-label, multicentric phase II trial where pts. with mCRC RAS/BRAF mutated, in first line will receive nivolumab in combination with FOLFOXIRI/bevacizumab every 2 weeks for 8 cycles followed by maintenance with bevacizumab plus nivolumab every 2 weeks. Bevacizumab will be administered intravenously at dose of 5 mg/kg every 2 weeks and nivolumab intravenously as a flat dose of 240 mg every 2 weeks. The primary endpoint is the overall response rate (ORR). This study hypothesis is that the treatment is able to improve the ORR from 66 to 80%. Secondary endpoints include OS, safety, time to progression, duration of response. Collateral translational studies evaluate the i) tumor mutational burden, and ii) genetic alterations by circulating free DNA (cfDNA) obtained from plasma samples. The trial is open to enrollment, 9 of planned 70 pts. have been enrolled. Trial registration NIVACOR is registered at ClinicalTrials.gov: NCT04072198 , August 28, 2019.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: 5-Fluorouracil / Adolescent / Adult / Aged / Angiogenesis / Antigens / Antineoplastic agents / Antineoplastic Agents, Immunological - administration & dosage / Antineoplastic Combined Chemotherapy Protocols - administration & dosage / Apoptosis / Bevacizumab / Bevacizumab - administration & dosage / Biomedical and Life Sciences / Biomedicine / Camptothecin - administration & dosage / Camptothecin - analogs & derivatives / Cancer metastasis / Cancer patients / Cancer Research / Cancer therapies / Care and treatment / Chemotherapy / Clinical trials / Clinical Trials, Phase II as Topic / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - genetics / Cytotoxicity / Deoxyribonucleic acid / DNA / DNA repair / Drug approval / Drug dosages / Endothelial cells / Endothelium / Female / First line therapy / Fluorouracil - administration & dosage / FOLFOXIRI Bevacizumab / Folinic acid / Health aspects / Health Promotion and Disease Prevention / Humans / Immune checkpoint inhibitors / Immunosurveillance / Immunotherapy / Irinotecan / Leucovorin - administration & dosage / Lymphocytes / Male / Medical and radiation oncology / Medicine/Public Health / Metastases / Metastasis / Metastatic colorectal Cancer / Microsatellite instability / Middle Aged / Mismatch repair / Monoclonal antibodies / Multicenter Studies as Topic / Mutation / Nivolumab / Nivolumab - administration & dosage / Oncology / Organoplatinum Compounds - administration & dosage / Oxaliplatin / Patients / PD-1 protein / PD-L1 protein / Progression-Free Survival / Prospective Studies / Proto-Oncogene Proteins B-raf - genetics / Proto-Oncogene Proteins p21(ras) - genetics / Signal transduction / Study Protocol / Surgical Oncology / Targeted cancer therapy / Tumors / Vascular endothelial growth factor / Vascular Endothelial Growth Factor A - antagonists & inhibitors / Young Adult