NE Oncology Issue – September 2014

Senellart H, et al. ASCO 2014:TPS3666

Background

Cetuximab is a recombinant, chimeric, monoclonal antibody which binds specifically to the epidermal growth factor receptor (EGFR). Monotherapy with cetuximab improves overall survival (OS) and progression-free survival (PFS) in patients with wild type (wt) KRAS metastatic colorectal cancer (mCRC). When combined with the reversible EGFR inhibitor erlotinib, treatment with cetuximab yielded encouraging results in overall response rate (ORR) and PFS in chemo-refractory wtKRAS mCRC. The combination of cetuximab and the irreversible EGFR family tyrosine kinase inhibitor afatinib has been investigated in non-small cell lung cancer. The regimen was shown to be well-tolerated by patients who had acquired resistance to erlotinib or gefitinib. At ASCO 2014, Senellart and colleagues presented an overview of the rationale and design of UNICANCER GI (UCGI) 25, a phase II study in its early stages of enrollment that will investigate the combination of cetuximab and afatinib in patients with wtKRAS mCRC who have failed treatment with oxaliplatin and irinotecan.1

Study design

  • UCGI 25 is a multicentre, randomized, phase II study.
  • This trial plans to recruit 75 patients from 13 centres with wtKRAS mCRC who have failed after treatment with oxaliplatin and irinotecan.
    • As of May 31, 2014, 30 patients have been enrolled.
  • The inclusion period will last two years, and there will be a two-year follow-up period.
  • Eligibility criteria for this trial include:
    • mCRC with wt KRAS/NRAS status;
    • Eastern Cooperative Oncology Group (ECOG) status 0 or 1;
    • No disease progression with previous anti-EGFR targeted therapy;
    • Failure with a prior regimen containing irinotecan or oxaliplatin for metastatic disease;
    • Must have previously received a thymidylate synthase inhibitor (e.g., fluorouracil, capecitabine, raltitrexed, or fluorouracil-uracil) at any point for treatment of colorectal cancer (CRC).
  • Ineligibility criteria for this trial include:
    • Any mutation of KRAS and NRAS genes;
    • Prior severe reaction to a monoclonal antibody;
    • Disease progression with previous anti-EGFR targeted therapy.
  • Patients are randomized 2:1 to receive either afatinib plus cetuximab or cetuximab alone.
  • The dosages for each drug are:
    • Afatinib: 40 mg/day;
    • Cetuximab: 500 mg/m2 every 2 weeks;
    • Patients receive treatment until progression or occurrence of unacceptable adverse events (AEs).
  • Crossover is permitted in the group of patients treated with cetuximab alone. After disease progression, afatinib (40 mg/day) will be added to the treatment regimen.
  • Dose adjustments are permitted according to the occurrence of drug-related AEs.

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Key findings

  • The primary endpoint of this study is 6-month PFS rate, as measured by the percentage of patients without disease progression at 6 months with 95% CI.
  • Secondary endpoints of this trial are ORR, median PFS, OS, safety, tolerability, and quality of life.
    • PFS and OS will be estimated using the Kaplan-Meier method.
    • Survival estimates at one and two years will be calculated with their associated 95% CIs.
  • This trial will also aim to identify predictive factors for tumour response in an ancillary translational study.

Key conclusion

  • UCGI 25 is a multicentre, randomized, phase II trial designed to investigate the benefit of dual targeting of the EGFR protein using the combination of cetuximab and afatinib in patients with wtKRAS mCRC who are refractory to chemotherapy.

Reference: 1. Senellart H, Samalin E, Adenis A, et al. UCGI 25: A multicentric randomized phase II trial evaluating dual targeting of the epidermal growth
factor (EGFR) using the combination of cetuximab and afatinib versus cetuximab alone in patients (pts) with chemotherapy refractory wtRAS metastatic
colorectal cancer (mCRC). J Clin Oncol (ASCO Annual Meeting) 2014;32 (Suppl):abstr TPS3666.

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Canadian Perspectives

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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.

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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.

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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

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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.

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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

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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.

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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

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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.