NE Oncology Issue – June 2007

Background

The epidermal growth factor receptor (EGFR) belongs to the human epidermal growth factor receptor (HER) family, a group of four known transmembrane receptors. Aberrant cell signalling, mediated through EGFR, plays a pivotal role in tumorigenesis and disease progression. Monoclonal antibodies such as cetuximab and panitumumab prevent the binding of the epidermal growth factor and TGF-alpha to the EGFR, and bring about inhibition of cell proliferation.1 Common side effects of anti-EGFR therapy include skin toxicities such as acneiform dermatitis, pruritis, erythema, rash, and dry skin. Interestingly, there is some evidence to suggest that the appearance of skin rash may be useful as a surrogate marker of EGFR efficacy. Ongoing studies in patients receiving anti-EGFR therapy are attempting to elucidate characteristics of target rashes that may correlate with a better anti-EGFR response.

The CRYSTAL trial was initiated by Van Cutsem, et al. to investigate the addition of cetuximab to FOLFIRI as a first-line treatment of EGFR-expressing metastatic colorectal cancer.2 The correlation of severity of skin toxicity with PFS was one of the secondary endpoints in this study.

Study design

  • Enrolled from 32 countries, patients (n = 1,217) had histologically confirmed unresectable mCRC, and EGFR expression in primary tumour or metastasis as detected by IHC.
  • Tumours had to be ≥1 bidimensionally measurable lesion.
  • Patients had not previously undergone chemotherapy for metastatic disease; adjuvant therapy was allowed if stopped at least six months before randomization (no irinotecan).
  • Patients had to have ECOG PS ≤2 at study entry and were randomized 1:1 to receive either:
    • Group A: cetuximab plus FOLFIRI
      • QW: cetuximab: 400 mg/m2 initial dose, then 250 mg/m2/week
      • Q2W: irinotecan 180 mg/m2, folinic acid 400 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2,400 mg/m2 over 46 hours or
    • Group B: FOLFIRI alone
      • Q2W: irinotecan 180 mg/m2, folinic acid 400 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2,400 mg/m2 over 46 hours
  • Patient population was as follows: total randomized patients n = 1,217; population evaluated for safety n = 1,202; and intent to treat population n = 1,198.
  • Primary endpoint was progression-free survival.
  • Secondary endpoints were OS, overall response rate (ORR), disease control rate (DCR), QoL (EORTC QLQ C30), and safety.

Key findings

  • PFS was found to be significantly prolonged with addition of cetuximab to FOLFIRI. Subgroup analysis of PFS:
    • Pronounced PFS benefit was seen in patients with metastases only to liver.
    • In other subgroups, there was a trend toward more favourable PFS with cetuximab plus FOLFIRI, except for patients with ECOG PS 2 at baseline.
    • There was a significantly longer median PFS for Group A versus Group B (8.9 months and 8 months, respectively, stratified log-rank p value 0.0479) as shown in Table 1, and a significant increase in response rate with cetuximab (46.9% versus 38.7%, p = 0.0038) (Figure 1).
    • Significant improvement in overall response rate was seen with addition of cetuximab to FOLFIRI.
    • Significantly more patients underwent surgery with curative intent (p = 0.0034) and had successful resection in the cetuximab arm (Figures 2 and 3).

Safety

  • Treatment was generally well tolerated; neutropenia, diarrhea, and skin reactions were the most common grade 3 or 4 adverse events (Table 2).
  • As expected, there were more grade 3 skin reactions associated with cetuximab versus control. There was also a slightly higher incidence of diarrhea.
  • All other adverse events, including neutropenia, were comparable between groups.
  • Better PFS outcomes associated with severity of skin reaction were seen in cetuximab-treated patients. Median PFS was 11.3 months for grade 3 skin reactions; 9.4 months for grade 2 skin reactions; 5.4 months for grade 0 or 1 skin reactions.

Key conclusions

  • There was a significant increase in response rate and PFS in the cetuximab plus FOLFIRI arm.
  • The relative risk of progression was reduced by approximately 15% in the cetuximab plus FOLFIRI group.
  • Treatment-related side effects of cetuximab plus FOLFIRI were as expected, with a moderate occurrence of diarrhea and significantly more frequent skin reactions as compared to FOLFIRI alone.

References: 1. McKarney L. Advances in the treatment of metastatic colorectal cancer. New Evidence in Oncology 2006;5:14–19. 2. Van Cutsem E, Nowacki M, Lang I. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): the CRYSTAL trial. Program and abstracts of the 43rd American Society of Clinical Oncology Annual Meeting; June 1–5, 2007; Chicago, Illinois; Abstract 4000.

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Contributors

dr-hirsh
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.

dr-cripps
Christine Cripps, MD, FRCPC
Medical Oncologist, Director,
Continuing Medical Education,
Ottawa Hospital Regional Cancer Centre
Dr. Christine Cripps is a medical oncologist and director of the Continuing Medical Education Department at the Ottawa Hospital Regional Cancer Centre. She also holds a position of Associate Professor, Medicine at the University of Ottawa. A keen teacher, Dr. Cripps’ main areas of interest include gastrointestinal cancer and head and neck cancer. She also enjoys cycling, skiing, and sailing when time permits.

dr-chia
Stephen K. L. Chia, MD, FRCPC
Assistant Professor of Medicine Department of Medicine
University of British Columbia
British Columbia Cancer Agency
Dr. Chia is a staff oncologist with the British Columbia Cancer Agency (BCCA), Vancouver, Canada. He also serves as physician coordinator for both the breast cancer and head and neck cancer clinical trials at the BCCA – Vancouver Cancer Centre. He is an active researcher in phase I-III trials in breast cancer, head and neck cancer and investigational new drugs. He is currently carrying out studies in breast cancer with grant funded research from the National Cancer Institute of Canada, Canadian Breast Cancer Alliance and Canadian Breast Cancer Foundation – British Columbia/Yukon Chapter. Dr. Chia is an active member of the British Columbia Breast Tumor Group, Breast Cancer Systemic Policy Group and Head and Neck Tumor Group.

dr-chang
José Chang, MD, FRCPC
Head of Medical Oncology, RS
McLaughlin Durham Regional Cancer Centre, Oshawa
Dr. José Chang is the principal investigator and site representative for the National Cancer Institute of Canada Clinical Trials Group, and is an examiner for the Medical Council of Canada. His research interests lie in the areas of breast cancer, melanoma, lymphoma, and quality of life during chemotherapy. Dr Chang has presented at major oncology meetings of the American Society of Clinical Oncology, San Antonio Breast Cancer Symposia, and European Breast Cancer Conference. A member of the editorial board of the journal Current Oncology, Dr. Chang has published in journals such as the Journal of Clinical Oncology, European Journal of Cancer, and Canadian Medical Association Journal.