The role of targeted agents in the management of metastatic in colorectal cancer

Eric Van Cutsem, MD, PhD

Digestive Oncology Unit, University Hospital Gasthuisberg, 3000 Leuven, Belgium

The management of patients with metastatic colorectal cancer (CRC) has changed dramatically over the last years, with increasing chances of prolonged survival. The median survival of patients with unresectable metastatic disease approaches now 24 months. The development of new cytotoxic and targeted agents, as well as the multidisciplinary management of patients with resectable and initially non-resectable metastases contribute to the progress. The development of the cytotoxic agents irinotecan, oxaliplatin and capecitabine and of the biological agents bevacizumab, cetuximab and panitumumab has clearly increased the therapeutic options for patients with metastatic colorectal cancer. Several other new agents are far advanced in development in colorectal cancer.
There is a strong preclinical and clinical rationale for the use of Vascular Endothelial Growth Factor (VEGF) inhibitors in colorectal cancer. The anti-VEGF monoclonal antibody, bevacizumab, increases the activity of a variety of active cytotoxic regimens in metastatic CRC. It has been shown to increase the activity of a variety of active cytotoxic regimens in the fi rst line treatment of metastatic CRC: 5-fl uorouracil (5-FU)/leucovorin, capecitabine, irinotecan- and oxaliplatin-based regimens. Bevacizumab also increases the activity of FOLFOX (5-FU/LV/oxaliplatin) in second-line treatment.
Aflibercept (VEGF trap) is engineered soluble receptor made from extracellular domains of VEGFR1 and VEGFR1 and binds to all isoforms of VEGF and to placental growth factor. Aflibercept is under active investigation in phase 3 in combination with standard cytotoxic combinations in metastatic CRC. Several small molecule VEGFR tyrosine kinase (e.g. cediranib, sunitinib, axitinib) are actually in phase 3 development in combination with standard combination cytotoxic regimens in metastatic CRC.
The activity of the anti-epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab has been shown initially in chemotherapy refractory metastatic CRC. The combination of cetuximab with irinotecan is more active in this setting than cetuximab alone. The activity of anti-EGFR antibodies is confi ned to patients with a KRAS wild type tumour. Recent data showed also an increased activity of cetuximab and panitumumab in combination with chemotherapy in less advanced stages of metastatic CRC. The activity of the anti-EGFR antibodies is confi ned to patients with a KRAS wild type tumour and it is known that ± 60 % of colorectal cancers are KRAS wild type tumours.
Many open questions and challenges remain in relation to the use of the anti-VEGF and anti-EGFR antibodies in metastatic CRC. Answers are needed to optimize the outcome for patients and the more optimal use of the resources. A crucial challenge is to demonstrate which patients are more likely to respond to bevacizumab-containing regimens and to the anti-EGFR antibodies cetuximab and panitumumab. Validated predictive for angiogenesis inhibitors are not yet available. Amongst the markers under investigation are Single Nucleotide Polymorphisms (SNP’s). The data on KRAS as a predictor marker for resistance to anti-EGFR antibodies open new perspectives for the development of other predictive markers and also for the classifi cation of metastatic CRC according to KRAS status. Emerging markers are BRAF, PI3K and the ligands amphi- and epiregulin.
A second important challenge is the strategic question on the best combination, on the best sequence and on the most optimal use of the different cytotoxic agents in combination with the biologicals in CRC. Amongst other relevant clinical questions are questions on the optimal duration of bevacizumab, on the continuation of bevacizumab after progression, on the signifi cance of skin rash in patients treated with anti-EGFR antibodies and on the real impact of bevacizumab and cetuximab in the neoadjuvant preoperative treatment of liver metastases. An important challenge is the understanding of the mechanism why tumours that initially respond to a combination of cytotoxics and biologicals may become resistant to this combination.
In conclusion: the management of patients with advanced colorectal cancer has improved. The angiogenesis inhibitor, bevacizumab, as well as the EGFR-inhibitors have clearly increased the therapeutic armentarium of patients with metastatic colorectal cancer. The introduction of the new agents offer also prospects for an increased chance of a longer survival for patients with metastatic colorectal cancer. The major challenge is now to implement strategies in which patients can be selected, based on molecular characteristics and/or pharmacogenomic profi les so that the new drugs and the resources can be used optimally for our patients with metastatic colorectal cancer.

公益財団法人東京生化学研究会 CHAAO事業