title: Randomized Phase II Study of Duligotuzumab (MEHD7945A) vs. Cetuximab in Squamous Cell Carcinoma of the Head and Neck (MEHGAN Study).
abstract: BACKGROUND
  Duligotuzumab, a novel dual-action humanized IgG1 antibody that blocks ligand binding to epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3), inhibits signaling from all ligand-dependent HER dimers, and can elicit antibody-dependent cell-mediated cytotoxicity. High tumor-expression of neuregulin 1 (NRG1), a ligand to HER3, may enhance sensitivity to duligotuzumab.
  
  
  METHODS
  This multicenter, open-label, randomized phase II study (MEHGAN) evaluated drug efficacy in patients with recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) progressive on/after chemotherapy and among patients with NRG1-high tumors. Patients received duligotuzumab (1100 mg IV, q2w) or cetuximab (400 mg/m2load, 250 mg/m2IV, q1w) until progression or intolerable toxicity. Tumor samples were assayed for biomarkers [NRG1, ERBB3, and human papillomavirus (HPV) status].
  
  
  RESULTS
  Patients (N= 121) were randomized (duligotuzumab:cetuximab; 59:62), median age 62 years; ECOG 0-2. Both arms (duligotuzumab vs. cetuximab, respectively) showed comparable progression-free survival [4.2 vs. 4.0 months; HR: 1.23 (90% confidence interval (CI): 0.89-1.70)], overall survival [7.2 vs. 8.7 months; HR 1.15 (90% CI: 0.81-1.63)], and objective response rate (12 vs. 14.5%), with no difference between patients withNRG1-high tumors orERBB3-low tumors. Responses in both arms were confined to HPV-negative patients. Grade ≥3 adverse events (AEs) (duligotuzumab vs. cetuximab, respectively) included infections (22 vs. 11.5%) and GI disorders (17 vs. 7%), contributing to higher rates of serious AEs (41 vs. 29.5%). Metabolic disorders were less frequent with duligotuzumab (10 vs. 16%); any grade rash-related events were less with duligotuzumab (49 vs. 67%).
  
  
  CONCLUSIONS
  While several lines of preclinical evidence had supported the premise that the blockade of HER3 in addition to that of EGFR may improve outcomes for patients with R/M SCCHN overall or specifically in those patients whose tumors express high levels ofNRG1, this study provided definitive clinical evidence refuting this hypothesis. Duligotuzumab did not improve patient outcomes in comparison to cetuximab despite frequent expression ofNRG1. These data indicate that inhibition of EGFR alone is sufficient to block EGFR-HER3 signaling, suggesting that HER2 plays a minimal role in this disease. Extensive biomarker analyses further show that HPV-negative SCCHN but not HPV-positive SCCHN are most likely to respond to EGFR blockage by cetuximab or duligotuzumab.
authors.affiliation: Centre Léon Bérard, Université de Lyon , Lyon , France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Fayette
authors.affiliation: Massachusetts General Hospital , Boston, MA , USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Wirth
authors.affiliation: Oncomed SRL , Timisoara , Romania.
authors.forename: Cristina
authors.initials: C
authors.lastname: Oprean
authors.affiliation: Medisprof SRL , Cluj-Napoca , Romania.
authors.forename: Anghel
authors.initials: A
authors.lastname: Udrea
authors.affiliation: University of Colorado Cancer Center , Aurora, CO , USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.affiliation: Peter MacCallum Cancer Centre, University of Melbourne , Melbourne, VIC , Australia.
authors.forename: Danny
authors.initials: D
authors.lastname: Rischin
authors.affiliation: Royal Marsden NHS Trust, The Institute of Cancer Research London , Sutton , UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Nutting
authors.affiliation: University of Wisconsin Hospital and Clinics , Madison, WI , USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Harari
authors.affiliation: Jász-Nagykun-Szolnok Megyei Hetényi Géza Kórház , Szolnok , Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Csoszi
authors.affiliation: Institutul Oncologic Prof. Dr. Ion Chiricuta Cluj-Napoca , Cluj-Napoca , Romania.
authors.forename: Dana
authors.initials: D
authors.lastname: Cernea
authors.affiliation: Medical University of South Carolina , Charleston, SC , USA.
authors.forename: Paul
authors.initials: P
authors.lastname: O'Brien
authors.affiliation: Genentech , South San Francisco, CA , USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Hanley
authors.affiliation: Genentech , South San Francisco, CA , USA.
authors.forename: Amy V
authors.initials: AV
authors.lastname: Kapp
authors.affiliation: Genentech , South San Francisco, CA , USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Anderson
authors.affiliation: Genentech , South San Francisco, CA , USA.
authors.forename: Elicia
authors.initials: E
authors.lastname: Penuel
authors.affiliation: Genentech , South San Francisco, CA , USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: McCall
authors.affiliation: Genentech , South San Francisco, CA , USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pirzkall
authors.affiliation: Antwerp University Hospital , Edegem , Belgium.
authors.forename: Jan B
authors.initials: JB
authors.lastname: Vermorken
keywords: EGFR; HER3; HPV; MEHD7945A; NRG1; SCCHN; cetuximab; duligotuzumab