NE Oncology Issue – November 2007
Panitumumab is the first fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFR), and the latest monoclonal antibody to be approved by the U.S. Food and Drug Administration for previously treated, advanced colorectal cancer. The EGF receptor has been extensively studied in many tumours and has been reported to be overexpressed in approximately 80% of colorectal cancers.1 The prognostic value of EGFR expression in colorectal cancer is still under investigation. Tumour biomarkers such as KRAS mutations have been shown to predict the response to another EGFR monoclonal antibody, cetuximab, in patients with colorectal cancer.2,3 KRAS mutations are among the most common genetic alterations in cancer, and they are activating mutations yielding proteins with reduced guanosine triphosphatase (GTPase) activity,4 causing EGFR signalling to continue despite therapy with EGFR inhibitors. In a recent phase II study, the presence of KRAS mutations was significantly associated with a lower survival rate and shorter time to disease progression compared with tumours carrying wild-type KRAS alleles, whereas high EGFR gene copy number and wild-type KRAS were associated with a better outcome.3 Assessment of biomarkers such as EGFR copy number and KRAS mutational status may facilitate the identification of patients most and least likely to respond to EGFR inhibitors. Presented at ECCO 14 were the results of a retrospective analysis of the KRAS mutational status of patients enrolled in single arm, phase II trials of panitumumab monotherapy for advanced colorectal cancer,4,5 as well as a randomized phase III trial comparing panitumumab to best supportive care (BSC).6
- Archived tumour samples, collected during primary resections in three separate single-arm, phase II trials of panitumumab monotherapy for advanced colo-rectal cancer, were analyzed for KRAS mutations by DNA sequencing.
- The presence of KRAS mutations was correlated with a less favourable clinical outcome, including response rate and progression-free survival, compared to patients carrying wild-type KRAS. (Table 1 and Figure 1).
Phase III panitumumab study6
- This recently reported study7 assigned 463 patients with previously-treated metastatic colorectal cancer to treatment with either panitumumab (6 mg/kg every two weeks) plus best supportive care or best supportive care alone.
- The primary objective of the current analysis was to determine if the effect of panitumumab on KRAS progression-free survival was greater in patients with wild-type KRAS genes than those carrying KRAS mutations.
- Patient baseline characteristics are shown in Table 2.
- Tumour sample DNA was analyzed for seven somatic mutations in KRAS codons 12 and 13 using real-time polymerase chain reaction (PCR); 243 wild-type samples and 184 samples with KRAS mutations were identified.
- Panitumumab efficacy appeared to be confined to the subgroup of KRAS wild-type. (Figures 2A and 2B).
- Panitumumab also significantly improved PFS in the wild-type KRAS group, irrespective of age, prior therapy, performance status, extent of disease, or EGFR gene copy number (Figure 3).
- Tumour response was also significantly better in the wild-type KRAS group receiving panitumumab as determined by the central laboratory (Table 3) and investigator assessment.
- Combined analysis of patients in the panitumumab group and those who crossed over to panitumumab revealed a longer overall survival in patients without KRAS mutations than in those with KRAS mutations (HR 0.67; 95% CI, 0.55–0.82).
- The investigators suggested that an assessment of KRAS status should be considered as a way of identifying those patients who are most likely to respond to panitumumab.
References: 1. Spano JP, Lagorce C, Atlan D et al. Impact of EGFR expression on colorectal cancer patient prognosis and survival. Ann Oncol 2005;16:102–108. 2. Khambata-Ford S, Garrett CR, Meropol NJ, et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 2007;25:3230–3237. 3. Finocchiaro G, Cappuzzo F, Jänne PA, et al. EGFR, HER2 and KRAS as predictive factors for cetuximab sensitivity in colorectal cancer. J Clin Oncol 2007;25(18S);402. 4. Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer 2003;3:459–465. 5. Freeman D, Juan T, Meropol NJ, et al. Association of somatic KRAS gene mutations and clinical outcome in patients with metastatic colorectal cancer receiving panitumumab monotherapy. Proceedings of ECCO 14 — The European Cancer Conference; September 23–27, 2007; Barcelona, Spain; Abstract 3014. 6. Amado RG, Wolf M, Freeman D, et al. Analysis of KRAS mutations in patients with metastatic colorectal cancer receiving panitumumab monotherapy. Proceedings of ECCO 14 — The European Cancer Conference; September 23–27, 2007; Barcelona, Spain; Abstract 0007. 7. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007;25:1658–1664.
Ronald Louis Burkes, MD, FRCPC
Professor of Medicine, University of Toronto
Medical oncologist, Mount Sinai Hospital/Princess Margaret Hospital/ University Health Network in Toronto
Dr. Burkes was the program director for the medical oncology training program at the University of Toronto from 1996 to 2005 and director of the Clinical Teaching Unit at Princess Margaret Hospital (PMH) from 1999 to 2005. He has won numerous teaching awards including departmental and university-wide awards, the Anderson Award in Program Development and the Hasselback Award for Teaching Excellence at PMH. He has presented at many local, provincial, national, and international meetings.
His research interests include lung and GI malignancies, and he has numerous publications including 57 peer-reviewed, 107 non–peer-reviewed and two book chapters.
Susan F. Dent, BSc., MD, FRCPC
Associate Professor of Medicine, University of Ottawa
Medical oncologist, Ottawa Hospital Cancer Center
Dr. Dent obtained her MD at McMaster University and completed her postgraduate training in internal medicine and medical oncology at the University of Ottawa. Her areas of interest include breast cancer, new drug development, and research ethics. She has a number of peer-reviewed publications and has regularly contributed to non–peer-reviewed Canadian oncology journals. She is a member of the Cancer Care Ontario Breast Disease Site Group Guidelines Committee, the vice chair for the Ontario Cancer Research Ethics Board and a member of the National Cancer Institute of Canada Auditing and Monitoring Committee.
Glenwood Dillon Goss, M.B., B.Ch., FCP(SA), FRCPC
Head of Medical Oncology, Ottawa Hospital Regional Cancer Centre
Director of the lung cancer program, Ottawa Hospital Regional Cancer Centre
Professor of Medicine, University of Ottawa
Dr. Goss graduated from the University of Witwatersrand, Johannesburg, South Africa and completed his post-graduate training at the Royal Marsden Hospital in London, England. He is a member of the National Cancer Institute of Canada Investigational New Drug Executive Committee and Lung Site Executive Committee. His principal areas of research relate to lung cancer and investigation of new drugs. Dr. Goss was a founding member of the Canadian Association of Medical Oncologists (1987) and has served as president.
Vera Hirsh, MD, FRCPC
Chief of the Hematology-Oncology Service, Santa Cabrini Hospital
Associate Professor, Medicine and Oncology, McGill University
Associate Physician, Oncology Service, at the Royal Victoria, Montreal General, and Montreal Chest Hospitals
With a current practice in both hematology and oncology, Dr. Vera Hirsh is an associate professor of medicine and oncology at McGill University. Her research at the Quebec Pulmonary Unit focuses on the treatment of lung cancer, and she continues to chair ongoing international chemotherapy trials. Dr. Hirsh chaired the Quebec Lung Cancer Committee to establish guidelines for the treatment of lung cancer. In addition, she has published abstracts, articles, and book chapters. Dr. Hirsh is a member of advisory boards for many pharmaceutical companies and the Medical Oncology Standing Committee of RTOG.
Jean Maroun, MD, FRCPC, FRCP (London)
Medical oncologist, Ottawa Hospital Regional Cancer Centre
Professor of Medicine, University of Ottawa
Dr. Maroun chairs the Ontario Provincial Gastrointestinal Practice Guidelines Committee. His principal interest lies in clinical research into new drug development and new combinations in the treatment of colorectal cancer. Dr. Maroun has long experience in the management of GI malignancies and his clinical and basic research focus is on thymidylate synthase inhibitors. He is a past president of the Canadian Oncology Societies and the Canadian Association of Medical Oncologists. Dr. Maroun has published extensively in peer-reviewed journals and is involved provincially and nationally in numerous academic and research committees.