Machiels JPH, et al. ASCO 2016:6049


Targeted agents are often investigated in unselected end-stage cancer patients, which makes evaluation of their activity difficult and impairs translational research. At ASCO 2016, Machiels and colleagues conducted a “window” study where a targeted agent, the oral Erb family inhibitor afatinib, was given to patients with squamous cell carcinoma of the head and neck (SCCHN) between diagnosis and surgery, in order to resolve this issue.1

Study design

  • In this randomized, multicentre, early phase II window of opportunity trial, treatment-naïve patients with SCCHN were randomized 5:1 to receive:
    • Afatinib for 14 days before surgery; or
    • No treatment.
  • Main inclusion criteria were:
  • Patients with newly diagnosed histologically proven squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx; and
    • Patients selected for primary curative surgery.
    • Tumour biopsies, fludeoxyglucose positron emission tomography (FDG-PET), and magnetic resonance imaging (MRI) were performed at diagnosis and at surgery.
  • The primary endpoint was centrally reviewed metabolic FDG-PET/computed tomography (FDG-PET/CT) response, according to the European Organisation for Research and Treatment of Cancer (EORTC) guidelines.
    • The aim is to show a metabolic response rate >10% in the afatinib arm, with a power of 90% if true response rate was 30% and type 1 error was 10%.
  • Other endpoints included response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, dynamic contrast-enhanced MRI, diffusion weighted imaging MRI, and translational research.
  • No formal comparison was intended between arms; “no treatment” arm was intended to be used as a reference to interpret the results of translational research.

Study Design

Study Design

Key findings

  • A total of 30 patients were randomized in four institutions (n = 25 in the afatinib arm; n = 5 in the no-treatment arm).
    • Two patients and one patient were later found to be ineligible in the afatinib and no-treatment arms, respectively.
  • The median age was 58.3 years (range: 35.9–76.4) in the afatinib arm (n = 23) and 69.5 years (range: 55.9–77.5) in the no-treatment arm (n = 4).
  • In the afatinib arm, 19 and 4 patients had tumour located in the oral cavity and the oropharynx, respectively; in the no-treatment arm, all patients had tumour located in the oral cavity.
  • There were 34.8%, 21.7%, and 43.5% of patients in the afatinib arm with N0, N1, and N2 disease, respectively; in the no-treatment arm, there were 0%, 25.0%, and 75.0% of patients with N0, N1, and N2 disease, respectively.
  • In the afatinib arm:
    • One patient discontinued afatinib due to grade 3 renal failure and diarrhea, with delayed surgery by 24 days.
    • Of the 24 patients who completed the treatment, two patients had delayed surgery by two (due to organizational issues) and four days (due to grade 2 colitis), respectively.
  • In the no-treatment arm, one patient was lost to follow-up; one had delayed surgery due to a logistic reason independent from the patient; and one did not receive surgery due to progression.
  • Of the 23 eligible patients in the afatinib arm, 16 patients (69.6%) had a partial metabolic FDG-PET/CT response (PMR; 95% CI: 47.1–86.8; p <0.0001) and seven patients (30.4%) had stable disease. (Figure 1)
  • There was no complete metabolic FDG-PET/CT response or PMR in the no-treatment arm (n = 4).
  • In terms of RECIST response, five patients (21.7%) in the afatinib arm had a partial or complete response (95% CI: 7.5–43.7; p = 0.073) vs. 0% in the no-treatment arm. (Figure 1)
  • The adverse events (AEs) possibly related to afatinib before surgery are presented in Table 1.
  • Only the following AEs were reported (there were no grade 4 AEs related to afatinib):
    • Grade 1/2 AEs if they occurred in at least two patients; and
    • All grade 3 AEs.
  • No comorbidities associated with surgery were considered related to afatinib.

Figure 1. Response rates in afatinib and no-treatment arms

Figure 1. Response rates in afatinib and no-treatment arms

Table 1. Adverse events possibly related to afatinib before surgery (n = 25)

Table 1. Adverse events possibly related to afatinib before surgery (n = 25)

Key conclusions

  • The two-week afatinib therapy induced a high rate of FDG-PET and RECIST response in newly diagnosed patients with SCCHN.
  • Afatinib can be safely administered before surgery in a majority of patients.
  • Complex multinational window of opportunity studies are feasible.
  • Adherence to protocol procedures is challenging and is crucial for future multinational window studies.
  • Translation research to evaluate predictive biomarkers is in progress.

Reference: 1. Machiels JPH, Menis J, Lia M, et al. Activity of afatinib administered in a window pre-operative study in squamous cell carcinoma of the head and neck (SCCHN): EORTC-90111. J Clin Oncol (ASCO Annual Meeting) 2016;34(Suppl):abstr 6049.

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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.

Graeme Fraser, MD, MSc, FRCPC
Dr. Graeme Fraser graduated from the University of Western Ontario (UWO) and completed post-graduate training in Internal Medicine and Hematology at UWO and McMaster University, respectively. His training in malignant hematology was supported by a National Cancer Institute of Canada–Terry Fox Foundation Clinical Research Fellowship. Dr. Fraser is a hematologist at the Juravinski Cancer Centre/Hamilton Health Sciences in Hamilton, Ontario, and he is an Associate Professor in the Department of Oncology. His research interests include the care of adolescent and young adult cancer patients, clinical trials in chronic lymphocytic leukemia, lymphoma, and myeloma, and practice guideline development as a member of the Cancer Care Ontario Program in Evidence-Based Care.

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 Canada (LC) since 2002 and is now Director of Research Fellowships for LC. Her research interests include the lymphoid cancers with particular focus on 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.

Investigator Commentaries

Alessandra Tedeschi, MD
Dr. Alessandra Tedeschi obtained her medical degree from the University of Bologna, Italy and subsequently trained in hemato-oncology at the University of Ancona, Italy. She completed two research stages on lymphoproliferative disorders in the Department of Hematology at the Niguarda Hospital in Milan, Italy. Dr. Tedeschi has been a consultant in Hematology at the Niguarda Cancer Center, Niguarda Hospital in Milan, Italy since 1999. Her clinical work focuses on the treatment of patients with indolent lymphoproliferative disorders and her research interests include the study of chronic lymphocytic leukemia (CLL) and Waldenström’s macroglobulinemia. Dr. Tedeschi is a principal and co-investigator on many national and international trials in CLL. She has published over 60 peer-reviewed research articles.

Veronique Leblond, MD
Dr. Veronique Leblond is a Professor and Head of the Department of Hematology at Pitié–Salpêtrière Hospital, Paris, France. She is the chair of the French Innovative Leukemia Group (FILO), focusing on acute leukemia, chronic lymphocytic leukemia (CLL), and Waldenström’s macroglobulinemia (WM), which includes more than 90 centres in France and Belgium. Dr. Leblond is responsible for a rare tumour network (K-VIROGREF) dedicated to the management of transplant recipients with virus-induced tumours, funded by the French National Cancer Institute (INCA) in 2012, and she is the head of GRECHY (Groupe de Recherche Clinique Hémopathie Lymphoïde) at the Pierre and Marie Curie University in Paris, France. She is also a member of the French Society of Hematology and the American Society of Hematology. Dr. Leblond was the principal investigator of several biological and clinical trials in WM and CLL. She received the Robert Kyle award in 2008 and the Waldenström award in 2012. Dr. Leblond is connected to several very active patient associations and charities including Laurette Fugain, SiLLC (Soutien et Information à la Leucémie Lymphoïde Chronique et la Maladie de Waldenström), International WM Foundation, and Waldenström France. She is an author of over 280 research articles, books, and book chapters.

Simon Rule, MD
Dr. Simon Rule is a Professor in Hematology at the Institute of Translational & Stratified Medicine, Plymouth University Peninsula Schools of Medicine & Dentistry, and a Hematologist at the Derriford Hospital in Plymouth, United Kingdom (UK). He has been a member of the National Cancer Research Network (NCRN) Lymphoma Committee since 2000 and serves as Chair of the NCRN Low Grade Lymphoma Clinical Studies Group. Dr. Rule’s clinical research interests are in non-Hodgkin lymphoma (NHL) and new drug development, with a specific interest in mantle cell lymphoma. Dr. Rule has been an author of over 70 publications in peer-reviewed journals. Over the last five years, Dr. Rule has been the Chief Investigator on 12 National studies and Principal Investigator on over 40 studies, mostly involving NHL. Within the UK, Dr. Rule runs all of the national clinical trials for mantle cell lymphoma.

Expert Commentary

Clemens-Martin Wendtner, MD
Dr. Clemens-Martin Wendtner is a Professor of Medicine and the Director of the Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine at the Klinikum Schwabing, Munich — an academic hospital of the University of Munich. He completed his MD at the University of Münster in 1993. Thereafter, he received postdoctoral training at the Max-Planck-Institute in Martinsried, Germany and at the National Institutes of Health (NIH) in Bethesda, U.S.A., until 1995. After a clinical fellowship at the University of Munich, he gained his German and U.S.A. licence (ECFMG) in Internal Medicine before specializing as a hematologist and oncologist at the same institution. Dr. Wendtner received his postdoctoral lecture qualification at the University of Munich in 2002, and since 2004, has been a full professor of Internal Medicine, Hematology, and Medical Oncology at the University of Cologne. Dr. Wendtner is a member of multiple national and international societies in the field of Medicine and has won several research awards, including first prize at the 6th International Symposium on Biological Therapy of Cancer in Munich, and a merit award from the American Society of Clinical Oncology. As a founding member of the German CLL Study Group (GCLLSG), he participates on the Steering Committee and is Secretary of the GCLLSG. He has been principal investigator for numerous phase I–III clinical studies, and his interests focus on the development of new therapies in the field of CLL.

Professor Tony Mok studied medicine at the University of Alberta and subsequently completed his fellowship training at the Princess Margaret Hospital in Toronto. After practising oncology and internal medicine for seven years in Toronto, he returned to Hong Kong in 1996 to pursue an academic career. Prof. Mok is a Li Shu Fan Medical Foundation Named Professor and Chairman of Clinical Oncology at The Chinese University of Hong Kong, Hong Kong. His main research interest focuses on biomarker and molecular targeted therapy in lung cancer. He co-founded the Lung Cancer Research Group, and has led a number of important multinational clinical trials, which include the IPASS (IRESSA Pan-Asia Study), a landmark study that established the role of first-line gefitinib in patients with EGFR mutation. Prof. Mok is the Past President of the International Association for the Study of Lung Cancer (IASLC), Past Chair of the American Society of Clinical Oncology (ASCO) International Affairs Committee, a member of the ASCO Publications Committee and Vice Secretary of the Chinese Society of Clinical Oncology (CSCO). Prof. Mok has contributed to over 200 articles in international peer-reviewed journals, including the New England Journal of Medicine, Science, Lancet, and Journal of Clinical Oncology, and contributed to multiple editorials and textbooks. He is an Editor on Thoracic Oncology for the Journal of Clinical Oncology. He has also authored eight books in Chinese and hosted three television series in Hong Kong.

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 BC 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.

Sandeep Sehdev, MD
Dr. Sandeep Sehdev is an Assistant Professor (adjunct) at McMaster University in Hamilton and a medical oncologist serving the William Osler Health System in Brampton and Etobicoke and the Headwaters Healthcare Centre in Orangeville. He graduated from medical school at the University of Ottawa and completed a residency in oncology at the University of Toronto and Princess Margaret Hospital. Dr. Sehdev is currently a general community oncologist and continuing health education lead for oncology with a special interest in advocacy, community oncology and patient education, and applications of technology in learning. He has been involved in multiple multicentre clinical trials.