Publication: 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
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Date
2021-03-10
Authors
Sastre, J.
García-Alfonso, P.
Viéitez, J. M.
Cano, M. T.
Rivera, F.
Reina-Zoilo, J. J.
Salud-Salvia, A.
Quintero, G.
Robles-Díaz, L
Safont, M. J.
Advisors
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Publisher
Elsevier Ltd on behalf of European Society for Medical Oncology
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Abstract
Background: 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.
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MeSH Terms
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Drug Therapy::Antineoplastic Protocols::Antineoplastic Combined Chemotherapy Protocols
Medical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Alkaloids::Camptothecin
Medical 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-Kinases
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical 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-raf
Medical Subject Headings::Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms
Medical Subject Headings::Diseases::Neoplasms::Neoplastic Processes::Neoplasm Metastasis::Neoplastic Cells, Circulating
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Coenzymes::Tetrahydrofolates::Formyltetrahydrofolates::Leucovorin
Medical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Asthenia
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Confidence Intervals
Medical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Pyrimidines::Pyrimidinones::Uracil::Fluorouracil
Medical Subject Headings::Diseases::Hemic and Lymphatic Diseases::Hematologic Diseases::Leukocyte Disorders::Leukopenia::Agranulocytosis::Neutropenia
Medical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Signs and Symptoms, Digestive::Diarrhea
Medical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Alkaloids::Camptothecin
Medical 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-Kinases
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical 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-raf
Medical Subject Headings::Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms
Medical Subject Headings::Diseases::Neoplasms::Neoplastic Processes::Neoplasm Metastasis::Neoplastic Cells, Circulating
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Coenzymes::Tetrahydrofolates::Formyltetrahydrofolates::Leucovorin
Medical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Asthenia
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Confidence Intervals
Medical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Pyrimidines::Pyrimidinones::Uracil::Fluorouracil
Medical Subject Headings::Diseases::Hemic and Lymphatic Diseases::Hematologic Diseases::Leukocyte Disorders::Leukopenia::Agranulocytosis::Neutropenia
Medical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Signs and Symptoms, Digestive::Diarrhea
DeCS Terms
CIE Terms
Keywords
BRAF, Colorectal cancer, PIK3CA, RAS, Targeted therapy, Neoplasias colorrectales, Terapia dirigida, Neoplastic cells circulating, Células neoplásicas circulantes
Citation
Sastre 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):100062