PMID- 27843803
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220413
IS  - 2234-943X (Print)
IS  - 2234-943X (Electronic)
IS  - 2234-943X (Linking)
VI  - 6
DP  - 2016
TI  - Randomized Phase II Study of Duligotuzumab (MEHD7945A) vs. Cetuximab in Squamous 
      Cell Carcinoma of the Head and Neck (MEHGAN Study).
PG  - 232
LID - 232
AB  - 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/m(2) load, 
      250 mg/m(2) IV, 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 with NRG1-high tumors or ERBB3-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%). CONCLUSION: 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 of NRG1, this study provided 
      definitive clinical evidence refuting this hypothesis. Duligotuzumab did not 
      improve patient outcomes in comparison to cetuximab despite frequent expression 
      of NRG1. 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.
FAU - Fayette, Jerome
AU  - Fayette J
AD  - Centre Leon Berard, Universite de Lyon , Lyon , France.
FAU - Wirth, Lori
AU  - Wirth L
AD  - Massachusetts General Hospital , Boston, MA , USA.
FAU - Oprean, Cristina
AU  - Oprean C
AD  - Oncomed SRL , Timisoara , Romania.
FAU - Udrea, Anghel
AU  - Udrea A
AD  - Medisprof SRL , Cluj-Napoca , Romania.
FAU - Jimeno, Antonio
AU  - Jimeno A
AD  - University of Colorado Cancer Center , Aurora, CO , USA.
FAU - Rischin, Danny
AU  - Rischin D
AD  - Peter MacCallum Cancer Centre, University of Melbourne , Melbourne, VIC , 
      Australia.
FAU - Nutting, Christopher
AU  - Nutting C
AD  - Royal Marsden NHS Trust, The Institute of Cancer Research London , Sutton , UK.
FAU - Harari, Paul M
AU  - Harari PM
AD  - University of Wisconsin Hospital and Clinics , Madison, WI , USA.
FAU - Csoszi, Tibor
AU  - Csoszi T
AD  - Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz , Szolnok , Hungary.
FAU - Cernea, Dana
AU  - Cernea D
AD  - Institutul Oncologic Prof. Dr. Ion Chiricuta Cluj-Napoca , Cluj-Napoca , Romania.
FAU - O'Brien, Paul
AU  - O'Brien P
AD  - Medical University of South Carolina , Charleston, SC , USA.
FAU - Hanley, William D
AU  - Hanley WD
AD  - Genentech , South San Francisco, CA , USA.
FAU - Kapp, Amy V
AU  - Kapp AV
AD  - Genentech , South San Francisco, CA , USA.
FAU - Anderson, Maria
AU  - Anderson M
AD  - Genentech , South San Francisco, CA , USA.
FAU - Penuel, Elicia
AU  - Penuel E
AD  - Genentech , South San Francisco, CA , USA.
FAU - McCall, Bruce
AU  - McCall B
AD  - Genentech , South San Francisco, CA , USA.
FAU - Pirzkall, Andrea
AU  - Pirzkall A
AD  - Genentech , South San Francisco, CA , USA.
FAU - Vermorken, Jan B
AU  - Vermorken JB
AD  - Antwerp University Hospital , Edegem , Belgium.
LA  - eng
PT  - Journal Article
DEP - 20161031
PL  - Switzerland
TA  - Front Oncol
JT  - Frontiers in oncology
JID - 101568867
CIN - Front Oncol. 2017 Mar 13;7:31. PMID: 28348975
PMC - PMC5086582
OTO - NOTNLM
OT  - EGFR
OT  - HER3
OT  - HPV
OT  - MEHD7945A
OT  - NRG1
OT  - SCCHN
OT  - cetuximab
OT  - duligotuzumab
EDAT- 2016/11/16 06:00
MHDA- 2016/11/16 06:01
PMCR- 2016/01/01
CRDT- 2016/11/16 06:00
PHST- 2016/08/29 00:00 [received]
PHST- 2016/10/14 00:00 [accepted]
PHST- 2016/11/16 06:00 [entrez]
PHST- 2016/11/16 06:00 [pubmed]
PHST- 2016/11/16 06:01 [medline]
PHST- 2016/01/01 00:00 [pmc-release]
AID - 10.3389/fonc.2016.00232 [doi]
PST - epublish
SO  - Front Oncol. 2016 Oct 31;6:232. doi: 10.3389/fonc.2016.00232. eCollection 2016.