NE Oncology Issue – September 2014

Le Tourneau C et al. ASCO 2014:TPS6105


Several trials have investigated the therapeutic potential of targeting epidermal growth factor receptor (EGFR) in patients with head and neck squamous cell carcinoma (HNSCC). However, identification of predictive biomarkers in order to assess efficacy of therapy has been a challenge. Correlation of potential predictive and pharmacodynamic biomarkers with treatment outcome was reported in a trial in which expression analysis of sequential biopsies from patients with recurrent/metastatic HNSCC who were treated with erlotinib was performed.1 At ASCO 2014, Le Tourneau and colleagues presented an overview of the rationale and design of PREDICTOR, a phase II study in its early stages of enrollment whose goal is to identify potential predictive biomarkers of afatinib therapy in patients with untreated nonmetastatic HNSCC.2

Study design

  • PREDICTOR is a multicentre, randomized, phase II study.
  • Inclusion criteria for this trial include:
    • Age > 18 years;
    • Histologically or cytologically confirmed HNSCC of the oral cavity, paranasal sinus and nasal cavity, oropharynx, larynx or hypopharynx, previously untreated, amenable to curative treatment with surgery;
    • T2-4N0-2 tumours (except T2N0 endolaryngeal tumours);
    • Absence of metastases determined by positron emission tomography computerized tomography (PET CT) scan;
    • Planned date of surgery allowing the patient to receive between 14 and 28 days of afatinib treatment;
    • Eastern Cooperative Oncology Group (ECOG) performance status ≤2;
    • Adequate hematological, liver, renal, and cardiac function.
  • Exclusion criteria for this trial include:
    • Primary site of head and neck carcinoma in nasopharynx, or skin;
    • Patients receiving other anticancer medication or other anticancer nondrug therapies;
    • Patients with uncontrolled infection;
    • Patients with other concurrent severe and/or uncontrolled medical disease;
    • Clinically relevant cardiovascular abnormalities;
    • Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom or National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTC-AE) grade >1 diarrhea of any etiology;
    • Known pre-existing interstitial lung disease.
  • The trial plans to recruit 60 patients with untreated nonmetastatic HNSCC.
  • Patients will be randomized 2:1, with 40 patients in the treatment group and 20 patients in the control arm.
    • In the treatment group, afatinib will be administered orally at 40 mg/day on a continuous schedule for 14 to 28 days, depending on the date of surgery. Surgery will be performed within a week of the end of treatment, if possible.
    • In the control arm, no preoperative treatment will be administered.
  • Randomization will be stratified on the site of primary tumour (oropharynx vs. non-oropharynx).
  • Dose adjustments will be permitted according to the occurrence of drug-related adverse events (reduction to 30 mg/day).


Key findings

  • The primary objective of this study is to identify predictive and pharmacodynamic biomarkers of afatinib biological and clinical activity in patients with untreated nonmetastatic HNSCC by exploring the correlation between potential biomarkers at baseline (at biopsy, prior to afatinib treatment) and at surgery (following afatinib treatment).
    • An initial tumour biopsy will be collected during diagnostic pan-endoscopy and a tumour specimen will be collected during surgery.
    • Specimens will be analyzed by the following methods for the markers as listed:
      • Immunohistochemistry: expression of EGFRvIII, HER2, Ki67, BCL-2, ERCC1, TP53, and PTEN;
      • High throughput protein analysis using the reverse phase protein array platform: EGFR, phosphorylated- (p-) EGFR, HER2, p-HER2, HER3, p-HER3, HER4, p-HER4, ERK, p-ERK, MEK, p-MEK, STAT3, p-STAT3, AKT, p-AKT;
      • Fluorescence in-situ hybridization (FISH): EGFR, HER2, CCND1 gene copy number;
      • Polymerase chain reaction (PCR) sequencing: EGFR, HER2, PI3KCA mutations;
      • Quantitative reverse transcriptase PCR (RT-PCR): EGFR, EGFRvIII, HER2, HER3, HER4, and c-MET;
      • PCR: human papilloma virus (HPV) expression.
  • Secondary endpoints of this trial are:
    • To identify potential pharmacodynamic biomarkers of efficacy, where efficacy is defined as tumour size reduction between baseline and surgery (end of treatment);
    • To evaluate the efficacy of afatinib in the preoperative setting in untreated nonmetastatic HNSCC;
    • To assess safety and tolerability of afatinib, using criteria defined in the NCI CTC-AE version 4.0;
    • To assess pathological response to afatinib, as measured by presence or absence of invasive tumour in the surgical specimen and in the lymph nodes at the time of surgery;
    • To assess metabolic response to afatinib as measured by fluorodeoxyglucose positron emission tomography (FDG-PET) according to Positron Emission Tomography Response Criteria in Solid Tumours (PERCIST) criteria.
  • As of April 2014:
    • 13 centres have been opened to enrollment;
    • 41 patients have been randomized by 6 sites. (Figures 1, 2)

Key conclusions

  • PREDICTOR is a multicentre, randomized, phase II trial designed to identify potential predictive and pharmacodynamic biomarkers of afatinib activity in patients with untreated nonmetastatic HNSCC. The main characteristics of this study are:
    • The pre-operative setting in untreated patients: advantage of having specimens collected before treatment (biopsy) and after surgery (surgical specimen); and
    • Randomization versus no treatment: the only way to be able to draw robust conclusions regarding the potential predictive and pharmacodynamics value of the biomarkers under evaluation.

References: 1. Agulnik M, da Cunha Santos G, Hedley D, et al. Predictive and pharmacodynamic biomarker studies in tumor and skin tissue samples of patients with recurrent or metastatic squamous cell carcinoma of the head and neck treated with erlotinib. J Clin Oncol 2007;25:2184–90. 2. Le Tourneau C, Delord J-P, Dolivet G, et al. PREDICTOR: Randomized phase II study of pre-operative afatinib in untreated non-metastatic head and neck squamous cell carcinoma patients (HNSCC) aiming at identifying predictive and pharmacodynamic biomarkers of efficacy. J Clin Oncol (ASCO Annual Meeting) 2014;32(Suppl):abstr TPS6105.

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Canadian Perspectives


Carolyn Owen, MD

Dr. Carolyn Owen completed postgraduate training in internal medicine and hematology at the University of Ottawa and the University of British Columbia, respectively, followed by a research fellowship in molecular genetics at Barts and the London School of Medicine and Dentistry in London, UK. Her research focused on familial myelodysplasia and acute myeloid leukemia. She is currently an Assistant Professor at the Foothills Medical Centre & Tom Baker Cancer Centre, and her clinical interests are low-grade lymphoma and chronic lymphocytic leukemia. She is also the local principal investigator in Calgary for several clinical trials in these areas.


David Macdonald, MD, FRCPC

Dr. David Macdonald is a hematologist at the QEII Health Sciences Centre in Halifax, Nova Scotia, and Assistant Professor in the Division of Hematology at Dalhousie University’s Faculty of Medicine. Dr. Macdonald chairs the Hematology Cancer Site Team for Cancer Care Nova Scotia. His interests are in hematologic malignancies and, in particular, lymphoproliferative disorders. He has done a Clinical Trials Fellowship with the National Cancer Institute of Canada – Clinical Trials Groups and is actively engaged in clinical trials research. Dr. Macdonald has also completed a clinical fellowship in the lymphoma group at the British Columbia Cancer Agency in Vancouver, and he maintains a clinical research program in lymphoma.


Jeffrey Rothenstein, MD, FRCPC

Dr. Jeffrey Rothenstein is a medical oncologist at the R.S. McLaughlin Durham Regional Cancer Centre in Oshawa and an Adjunct Assistant Professor in the Department of Oncology at Queen’s University in Kingston, Ontario. He completed his internal medicine and medical oncology training at the University of Toronto. Dr. Rothenstein’s main clinical focus is on the management of thoracic and gastrointestinal malignancies. He is the lung cancer site group leader at the R.S. McLaughlin Durham Regional Cancer Center.

Investigator Commentaries


Stephan Stilgenbauer, MD

Dr. Stephan Stilgenbauer is Associate Professor and Deputy Chairman at the Department of Internal Medicine III (Hematology, Oncology, Rheumatology and Infectious Diseases) at Ulm University, Germany. He received his medical training at Heidelberg Medical School and was trained in internal medicine and hematology-oncology at the Universities of Heidelberg and Ulm. He spent a postdoctoral fellowship at the German Cancer Research Center (DKFZ) in Heidelberg. His research focus is on the molecular pathogenesis of hematological malignancies and translation of this research into novel treatment strategies. Dr. Stilgenbauer has authored or co-authored numerous original articles, reviews, and book chapters in journals such as The New England Journal of Medicine, The Lancet, Nature Medicine, the Proceedings of the National Academy of Sciences of the United States of America, Journal of Clinical Oncology, Blood, Leukemia, Haematologica, among others.


C. Tom Kouroukis, MD

Dr. C. Tom Kouroukis graduated from the University of Toronto and completed training in Internal Medicine, Hematology and MSc (Health Research Methodology) training at McGill and McMaster Universities. He was awarded a National Cancer Institute of Canada Clinical Research Fellowship. He is a hematologist at the Juravinski Cancer Centre/Hamilton Health Science, Chair of the Hematology Disease Site Team, Head of the Division of Malignant Hematology, and Associate Professor in the Department of Oncology. He is Co-chair of the Hematology Cancer Disease Site Group of the Cancer Care Ontario Practice Guidelines Initiative and Chair of the Stem Cell Committee of Cancer Care Ontario. His research interests include the care of older patients with hematological cancers, the impact and evaluation of co-morbidity in older cancer patients, clinical trials, and practice guideline development.

Expert Commentaries

Laurie H. Sehn, MD, MPH
Dr. Laurie H. Sehn is a Clinical Assistant Professor at the BC Cancer Agency and the University of British Columbia in Vancouver. She has been a medical oncologist and clinical investigator with the Lymphoma Tumour Group since 1998. Dr. Sehn has served on the Board of Directors of Lymphoma Foundation Canada (LFC) since 2002 and is currently Director of Research Fellowships for the LFC. Dr. Sehn’s research interests include all of the lymphoid cancers, with particular interest in the biology and treatment of large-cell lymphoma, the application of new imaging techniques such as PET scanning to lymphoma management, and innovative new approaches to treatment.

Dietger Niederwieser, MD
Dr. Dietger Niederwieser is the Head of the Department of Hematology and Oncology at the University Hospital of Leipzig in Germany. He completed his medical degree and postgraduate training in internal medicine and hemato-oncology at the University of Innsbruck in Austria. His research interests include leukemia, myelodysplastic syndrome, renal cell carcinoma, Hodgkin lymphoma, allogeneic stem cell transplantation, and graft versus host disease and he is currently involved in a variety of clinical trials in these areas. Dr. Niederwieser is President of the Worldwide Network for Blood and Marrow Transplantation, past President of the European Group for Bone and Marrow Transplantation (EBMT), and a former Chair of the EBMT Chronic Leukemia Working Party. He is a member of several scientific societies, including the European Hematology Association, the American Society of Hematology, and the American Society of Clinical Oncology and he serves as an external reviewer for universities in Europe and the United States. Dr. Niederwieser is the author or co-author of numerous articles (<390) published in international peer-reviewed journals, such as The New England Journal of Medicine, Blood, the Journal of Clinical Oncology, the Journal of the American Medical Association, Nature Clinical Practice Oncology, Annals of Oncology, Leukemia, and Bone Marrow Transplantation.

Case Study


Barbara Melosky, MD, FRCP(C)

Dr. Barbara Melosky is a Clinical Associate Professor of Medicine at the University of British Columbia and a medical oncologist at the British Columbia Cancer Agency in Vancouver. She graduated from medical school at the University of Manitoba, and did a residency in internal medicine and an oncology fellowship at the University of British Columbia. Dr. Melosky is currently working in the fields of lung and gastrointestinal malignancies with a special interest in the side effects of targeted therapy. She sits on the Executive Committee for the Lung Disease Site NCIC Clinical Trials Group and is the annual Chair of the Canadian Lung Cancer Conference.