title: FOLFOXIRI in combination with panitumumab as first-line treatment in quadruple wild-type (KRAS, NRAS, HRAS, BRAF) metastatic colorectal cancer patients: a phase II trial by the Gruppo Oncologico Nord Ovest (GONO).
abstract: BACKGROUND
  The FOLFOXIRI regimen developed by the Gruppo Oncologico Nord Ovest (GONO) demonstrated higher activity and efficacy compared with FOLFIRI in metastatic colorectal cancer (mCRC). Panitumumab is effective in some patients with KRAS codon 12-13 wild-type mCRC. KRAS codon 61, HRAS, NRAS, and BRAF V600E mutations might predict resistance to anti-epidermal growth factor receptor antibodies.
  
  
  METHODS
  We conducted a phase II study evaluating the combination of panitumumab (6 mg/kg on day 1) with a slightly modified GONO-FOLFOXIRI (irinotecan 150 mg/m², oxaliplatin 85 mg/m², and folinate 200 mg/m² on day 1, followed by fluorouracil 3000 mg/m² as a 48-h continuous infusion starting on day 1) repeated every 2 weeks as first-line treatment of wild-type KRAS, HRAS, NRAS (codon 12-13-61), and BRAF unresectable mCRC patients. Fluorouracil dose was reduced to 2400 mg/m² after two of the first three patients reported grade 3-4 diarrhoea (in one case with febrile neutropenia). Induction treatment was scheduled for a maximum of 12 cycles, followed by panitumumab ± fluorouracil/folinate maintenance until progression. Primary end point was overall response rate (ORR).
  
  
  RESULTS
  Eighty-seven patients were screened and 37 were enrolled. Thirty-three patients achieved an objective response (ORR: 89%; 95% CI 75% to 96%). Sixteen patients (43%) underwent secondary surgery of metastases, and R0 resection was achieved in 13 cases (35%). At a median follow-up of 17.7 months, median progression-free survival was 11.3 months (95% CI 9.7-12.9 months). After amendment, most common grade 3-4 adverse events reported during induction treatment were neutropenia (48%; febrile neutropenia: 5%), diarrhoea (35%), asthenia (27%), stomatitis (14%), and skin toxic effect (14%). One treatment-related death was registered.
  
  
  CONCLUSIONS
  Adding panitumumab to FOLFOXIRI is feasible decreasing the dose of fluorouracil and irinotecan to reduce the risk of diarrhoea. Activity and secondary resectability of metastases among Ras-BRAF wild-type patients are promising.
authors.affiliation: Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Fornaro
authors.forename: S
authors.initials: S
authors.lastname: Lonardi
authors.forename: G
authors.initials: G
authors.lastname: Masi
authors.forename: F
authors.initials: F
authors.lastname: Loupakis
authors.forename: F
authors.initials: F
authors.lastname: Bergamo
authors.forename: L
authors.initials: L
authors.lastname: Salvatore
authors.forename: C
authors.initials: C
authors.lastname: Cremolini
authors.forename: M
authors.initials: M
authors.lastname: Schirripa
authors.forename: C
authors.initials: C
authors.lastname: Vivaldi
authors.forename: G
authors.initials: G
authors.lastname: Aprile
authors.forename: A
authors.initials: A
authors.lastname: Zaniboni
authors.forename: S
authors.initials: S
authors.lastname: Bracarda
authors.forename: G
authors.initials: G
authors.lastname: Fontanini
authors.forename: E
authors.initials: E
authors.lastname: Sensi
authors.forename: C
authors.initials: C
authors.lastname: Lupi
authors.forename: M
authors.initials: M
authors.lastname: Morvillo
authors.forename: V
authors.initials: V
authors.lastname: Zagonel
authors.forename: A
authors.initials: A
authors.lastname: Falcone
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000601:surgery; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000276:immunology; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D002955:Leucovorin / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000627:therapeutic use; D000077544:Panitumumab; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; C117307:KRAS protein, human; D008565:Membrane Proteins; D009944:Organoplatinum Compounds; D011518:Proto-Oncogene Proteins; D000077544:Panitumumab; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: BRAF; FOLFOXIRI; Ras; metastatic colorectal cancer; panitumumab