Sastre, J.García-Alfonso, P.Viéitez, J. M.Cano, M. T.Rivera, F.Reina-Zoilo, J. J.Salud-Salvia, A.Quintero, G.Robles-Díaz, LSafont, M. J.La Casta, A.Gil, S.Polo, E.Asensio-Martínez, E.García-Paredes, B.López, R. L.Guillot, M.Valladares-Ayerbes, M.Aranda, E.Díaz-Rubio, E.2022-08-182022-08-182021-03-10Sastre J, García-Alfonso P, Viéitez JM, Cano MT, Rivera F, Reina-Zoilo JJ, et al. Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD). Influence of BRAF and PIK3CA mutations on the efficacy of FOLFIRI plus bevacizumab or cetuximab as first-line therapy in patients with RAS wild-type metastatic colorectal carcinoma and <3 baseline circulating tumour cells: the randomised phase II VISNÚ-2 study. ESMO Open. 2021 Apr;6(2):100062http://hdl.handle.net/10668/3917Background: We explored the influence of BRAF and PIK3CA mutational status on the efficacy of bevacizumab or cetuximab plus 5-fluorouracil/leucovorin and irinotecan (FOLFIRI) as first-line therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC). Patients and methods: VISNÚ-2 was a multicentre, randomised, phase II study. Patients with RAS wild-type mCRC and <3 circulating tumour cells/7.5 ml blood were stratified by BRAF/PIK3CA status (wild-type versus mutated) and number of affected organs (1 versus >1), and allocated to bevacizumab (5 mg/kg every 2 weeks) or cetuximab (400 mg/m2 then 250 mg/m2 weekly) plus FOLFIRI [irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 (bolus) then 2400 mg/m2 (46-h continuous infusion) every 2 weeks]. The primary endpoint was progression-free survival (PFS). All analyses were exploratory. Results: Two hundred and forty patients with BRAF/PIK3CA wild-type (n = 196) or BRAF- and/or PIK3CA-mutated tumours (n = 44) were enrolled. Median PFS was 12.7 and 8.8 months in patients with BRAF/PIK3CA wild-type and BRAF/PIK3CA-mutated tumours, respectively [hazard ratio (HR) = 1.22; 95% confidence interval (CI) 0.80-1.85; P = 0.3602]. In the BRAF- and/or PIK3CA-mutated cohort, median PFS was 2.8, 8.8 and 15.0 months in patients with BRAF/PI3KCA-mutated (n = 8), BRAF-mutated/PI3KCA wild-type (n = 16) and BRAF wild-type/PI3KCA-mutated (n = 20) tumours, respectively (P = 0.0002). PFS was similar with bevacizumab plus FOLFIRI versus cetuximab plus FOLFIRI in BRAF/PIK3CA wild-type (HR = 0.99; 95% CI 0.67-1.45; P = 0.9486) and BRAF/PIK3CA-mutated tumours (HR = 1.11; 95% CI 0.53-2.35; P = 0.7820). The most common grade 3/4 treatment-related adverse events were neutropenia, diarrhoea and asthenia in both treatment groups. Conclusions: BRAF/PIK3CA status influences outcomes in patients with RAS wild-type mCRC but does not appear to assist with the selection of first-line targeted therapy.enAttribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/BRAFColorectal cancerPIK3CARASTargeted therapyNeoplasias colorrectalesTerapia dirigidaNeoplastic cells circulatingCélulas neoplásicas circulantesMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Drug Therapy::Antineoplastic Protocols::Antineoplastic Combined Chemotherapy ProtocolsMedical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Alkaloids::CamptothecinMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Phosphatidylinositol 3-Kinases::Phosphatidylinositol 3-Kinase::Class I Phosphatidylinositol 3-KinasesMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Serine-Threonine Kinases::MAP Kinase Kinase Kinases::raf Kinases::Proto-Oncogene Proteins B-rafMedical Subject Headings::Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal NeoplasmsMedical Subject Headings::Diseases::Neoplasms::Neoplastic Processes::Neoplasm Metastasis::Neoplastic Cells, CirculatingMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Coenzymes::Tetrahydrofolates::Formyltetrahydrofolates::LeucovorinMedical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::AstheniaMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Confidence IntervalsMedical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Pyrimidines::Pyrimidinones::Uracil::FluorouracilMedical Subject Headings::Diseases::Hemic and Lymphatic Diseases::Hematologic Diseases::Leukocyte Disorders::Leukopenia::Agranulocytosis::NeutropeniaMedical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Signs and Symptoms, Digestive::DiarrheaInfluence of BRAF and PIK3CA mutations on the efficacy of FOLFIRI plus bevacizumab or cetuximab as first-line therapy in patients with RAS wild-type metastatic colorectal carcinoma and <3 baseline circulating tumour cells: the randomised phase II VISNÚ-2 studyresearch article33711671open access10.1016/j.esmoop.2021.1000622059-7029PMC7970062