title: Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial.
abstract: BACKGROUND
  Previous trials have shown that anti-EGFR monoclonal antibodies can improve clinical outcomes of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SCCHN). We assessed the efficacy and safety of panitumumab combined with cisplatin and fluorouracil as first-line treatment for these patients.
  
  
  METHODS
  This open-label phase 3 randomised trial was done at 126 sites in 26 countries. Eligible patients were aged at least 18 years; had histologically or cytologically confirmed SCCHN; had distant metastatic or locoregionally recurrent disease, or both, that was deemed to be incurable by surgery or radiotherapy; had an Eastern Cooperative Oncology Group performance status of 1 or less; and had adequate haematological, renal, hepatic, and cardiac function. Patients were randomly assigned according to a computer-generated randomisation sequence (1:1; stratified by previous treatment, primary tumour site, and performance status) to one of two groups. Patients in both groups received up to six 3-week cycles of intravenous cisplatin (100 mg/m(2) on day 1 of each cycle) and fluorouracil (1000 mg/m(2) on days 1-4 of each cycle); those in the experimental group also received intravenous panitumumab (9 mg/kg on day 1 of each cycle). Patients in the experimental group could choose to continue maintenance panitumumab every 3 weeks. The primary endpoint was overall survival and was analysed by intention to treat. In a prospectively defined retrospective analysis, we assessed tumour human papillomavirus (HPV) status as a potential predictive biomarker of outcomes with a validated p16-INK4A (henceforth, p16) immunohistochemical assay. Patients and investigators were aware of group assignment; study statisticians were masked until primary analysis; and the central laboratory assessing p16 status was masked to identification of patients and treatment. This trial is registered with ClinicalTrials.gov, number NCT00460265.
  
  
  RESULTS
  Between May 15, 2007, and March 10, 2009, we randomly assigned 657 patients: 327 to the panitumumab group and 330 to the control group. Median overall survival was 11·1 months (95% CI 9·8-12·2) in the panitumumab group and 9·0 months (8·1-11·2) in the control group (hazard ratio [HR] 0·873, 95% CI 0·729-1·046; p=0·1403). Median progression-free survival was 5·8 months (95% CI 5·6-6·6) in the panitumumab group and 4·6 months (4·1-5·4) in the control group (HR 0·780, 95% CI 0·659-0·922; p=0·0036). Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group: skin or eye toxicity (62 [19%] of 325 included in safety analyses vs six [2%] of 325), diarrhoea (15 [5%] vs four [1%]), hypomagnesaemia (40 [12%] vs 12 [4%]), hypokalaemia (33 [10%] vs 23 [7%]), and dehydration (16 [5%] vs seven [2%]). Treatment-related deaths occurred in 14 patients (4%) in the panitumumab group and eight (2%) in the control group. Five (2%) of the fatal adverse events in the panitumumab group were attributed to the experimental agent. We had appropriate samples to assess p16 status for 443 (67%) patients, of whom 99 (22%) were p16 positive. Median overall survival in patients with p16-negative tumours was longer in the panitumumab group than in the control group (11·7 months [95% CI 9·7-13·7] vs 8·6 months [6·9-11·1]; HR 0·73 [95% CI 0·58-0·93]; p=0·0115), but this difference was not shown for p16-positive patients (11·0 months [7·3-12·9] vs 12·6 months [7·7-17·4]; 1·00 [0·62-1·61]; p=0·998). In the control group, p16-positive patients had numerically, but not statistically, longer overall survival than did p16-negative patients (HR 0·70 [95% CI 0·47-1·04]).
  
  
  CONCLUSIONS
  Although the addition of panitumumab to chemotherapy did not improve overall survival in an unselected population of patients with recurrent or metastatic SCCHN, it improved progression-free survival and had an acceptable toxicity profile. p16 status could be a prognostic and predictive marker in patients treated with panitumumab and chemotherapy. Prospective assessment will be necessary to validate our biomarker findings.
  
  
  BACKGROUND
  Amgen Inc.
authors.affiliation: Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium. jan.b.vermorken@uza.be
authors.forename: Jan B
authors.initials: JB
authors.lastname: Vermorken
authors.forename: Jan
authors.initials: J
authors.lastname: Stöhlmacher-Williams
authors.forename: Irina
authors.initials: I
authors.lastname: Davidenko
authors.forename: Lisa
authors.initials: L
authors.lastname: Licitra
authors.forename: Eric
authors.initials: E
authors.lastname: Winquist
authors.forename: Cristian
authors.initials: C
authors.lastname: Villanueva
authors.forename: Paolo
authors.initials: P
authors.lastname: Foa
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rottey
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Skladowski
authors.forename: Makoto
authors.initials: M
authors.lastname: Tahara
authors.forename: Vasant R
authors.initials: VR
authors.lastname: Pai
authors.forename: Sandrine
authors.initials: S
authors.lastname: Faivre
authors.forename: Cesar R
authors.initials: CR
authors.lastname: Blajman
authors.forename: Arlene A
authors.initials: AA
authors.lastname: Forastiere
authors.forename: Brian N
authors.initials: BN
authors.lastname: Stein
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Oliner
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Pan
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Bach
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001208:Asia; D014408:Biomarkers, Tumor / Q000032:analysis; D001706:Biopsy; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary / Q000821:virology; D002945:Cisplatin / Q000008:administration & dosage; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis; D018572:Disease-Free Survival; D005060:Europe; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006258:Head and Neck Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D009656:North America; D000077544:Panitumumab; D027383:Papillomaviridae / Q000302:isolation & purification; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012189:Retrospective Studies; D013020:South America; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D000077544:Panitumumab; D002945:Cisplatin; D005472:Fluorouracil