title: Abituzumab combined with cetuximab plus irinotecan versus cetuximab plus irinotecan alone for patients with KRAS wild-type metastatic colorectal cancer: the randomised phase I/II POSEIDON trial.
abstract: BACKGROUND
  Integrins are involved in tumour progression and metastasis, and differentially expressed on colorectal cancer (CRC) cells. Abituzumab (EMD 525797), a humanised monoclonal antibody targeting integrin αν heterodimers, has demonstrated preclinical activity. This trial was designed to assess the tolerability of different doses of abituzumab in combination with cetuximab and irinotecan (phase I) and explore the efficacy and tolerability of the combination versus that of cetuximab and irinotecan in patients with metastatic CRC (mCRC) (phase II part).
  
  
  METHODS
  Eligible patients had KRAS (exon 2) wild-type mCRC and had received prior oxaliplatin-containing therapy. The trial comprised an initial safety run-in using abituzumab doses up to 1000 mg combined with a standard of care (SoC: cetuximab plus irinotecan) and a phase II part in which patients were randomised 1 : 1 : 1 to receive abituzumab 500 mg (arm A) or 1000 mg (arm B) every 2 weeks combined with SoC, or SoC alone (arm C). The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival (OS), response rate (RR) and tolerability. Associations between tumour integrin expression and outcomes were also assessed.
  
  
  RESULTS
  Phase I showed that abituzumab doses up to 1000 mg were well tolerated in combination with SoC. Seventy-three (arm A), 71 (arm B) and 72 (arm C) patients were randomised to the phase II part. Baseline characteristics were balanced. PFS was similar in the three arms: arm A versus SoC, hazard ratio (HR) 1.13 [95% confidence interval (CI) 0.78-1.64]; arm B versus SoC, HR 1.11 (95% CI 0.77-1.61). RRs were also similar. A trend toward improved OS was observed: arm A versus SoC, HR 0.83 (95% CI 0.54-1.28); arm B versus SoC, HR 0.80 (95% CI 0.52-1.25). Grade ≥3 treatment-emergent adverse events were observed in 72%, 78% and 67% of patients. High tumour integrin αvβ6 expression was associated with longer OS in arms A [HR 0.55 (0.30-1.00)] and B [HR 0.41 (0.21-0.81)] than in arm C.
  
  
  CONCLUSIONS
  The primary PFS end point was not met, although predefined exploratory biomarker analyses identified subgroups of patients in whom abituzumab may have benefit. The tolerability of abituzumab combined with cetuximab and irinotecan was acceptable. Further study is warranted. CLINICALTRIALS.GOV IDENTIFIER: NCT01008475.
authors.affiliation: Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Élez
authors.affiliation: Department of Comprehensive Cancer Care, Masarykuv Onkologicky Ustav, Brno, Czech Republic.
authors.forename: I
authors.initials: I
authors.lastname: Kocáková
authors.affiliation: Medical Clinic I, Prosper-Hospital, Recklinghausen.
authors.forename: T
authors.initials: T
authors.lastname: Höhler
authors.affiliation: Department of Hematology/Oncology, Cancer Center Heilbronn-Franken, Heilbronn.
authors.forename: U M
authors.initials: UM
authors.lastname: Martens
authors.affiliation: Department of Oncology/Hematology, University Hospital Hamburg, Hamburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Bokemeyer
authors.affiliation: Department of Digestive Oncology, University Hospital Gasthuisberg Leuven and KULeuven, Leuven, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Van Cutsem
authors.affiliation: Department of Oncology, Palacký University Medical School and Teaching Hospital, Olomouc.
authors.forename: B
authors.initials: B
authors.lastname: Melichar
authors.affiliation: Department of Oncology, Horovice, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Smakal
authors.affiliation: Department of Oncology, Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz-Rendelointezet, Szolnok, Hungary.
authors.forename: T
authors.initials: T
authors.lastname: Csőszi
authors.affiliation: GOU VPO St-Petersburg SMA, n/a Mechnikov Federal Agency of Healthcare, St Petersburg.
authors.forename: E
authors.initials: E
authors.lastname: Topuzov
authors.affiliation: City Clinical Oncology Dispensary, St Petersburg.
authors.forename: R
authors.initials: R
authors.lastname: Orlova
authors.affiliation: S.I. Russian Cancer Research Center, Moscow, Russia.
authors.forename: S
authors.initials: S
authors.lastname: Tjulandin
authors.affiliation: University Hospital Marques de Valdecilla, Santander, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Rivera
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Straub
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Bruns
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Quaratino
authors.affiliation: Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address: jtabernero@vhio.net.
authors.forename: J
authors.initials: J
authors.lastname: Tabernero
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / 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; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D039564:Integrin alphaV / Q000096:biosynthesis / Q000276:immunology; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D039564:Integrin alphaV; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C000592911:Abituzumab; D000077146:Irinotecan; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D002166:Camptothecin
keywords: abituzumab; biomarker; colorectal cancer; integrin; monoclonal antibody; phase I/II