Author(s): M Del Prete aff1 , R Giampieri aff1 , L Faloppi aff1 , M Bianconi aff1 , A Bittoni aff1 , K Andrikou aff1 , S Cascinu [*] aff1
colorectal cancer; EGFR; panitumumab; RAS; review
Colorectal cancer is the second leading cause of cancer mortality in the Western world. Approximately 20-25% of patients present with metastatic disease at diagnosis and a further 20-35% will develop metastases during the course of their disease. Despite the improved outcomes for metastatic colorectal cancer (mCRC) patients in the last years, due to an increased surgical resections of liver metastases and new systemic therapeutic options, the prognosis for these patients remains poor, with a 5-year survival rate of approximately 10-20% [1,2 ].
In recent years, the identification of molecular pathways involved in tumor metastasis and progression has led to the development of innovative therapeutic options targeting different pathways, such as the VEGF and the EGF receptor (EGFR). The addition of targeted biological agents to chemotherapy has improved the median survival in mCRC to 24-28 months [ 3-6 ].
EGFR has been shown to play an important role in the development of CRC. Inhibition of this receptor has been proved to be one of the most promising strategies for the treatment of mCRC, leading to the approval of two monoclonal antibodies inhibiting EGFR signaling, after extensive preclinical and clinical studies: cetuximab and panitumumab.
Panitumumab is a fully human monoclonal antibody that binds to the extracellular domain of EGFR competing with endogenous ligand binding. Its role in the treatment algorithm of patients with mCRC continues to evolve and important questions remain unanswered, even if several clinical trials, as described in this paper, demonstrated the activity of panitumumab in mCRC. The efficacy of anti-EGFR antibodies in the treatment of chemorefractory patients with KRAS wild-type (WT) tumors is well established, supported by several clinical trials [7,8 ], whereas their use in combination with chemotherapy in earlier lines of treatment is a more complex issue [4,9 ]. Their optimal timing of use and chemotherapy backbone, their clinical differences and further predictive biomarkers and are currently under evaluation.
In the present review we analyze the use, efficacy and tolerability of panitumumab in mCRC, focusing on recently reported data and future perspectives.
Pharmacodynamics of panitumumab
Panitumumab is a fully human IgG2 monoclonal antibody that binds with high affinity to the extracellular domain of EGFR in both tumor and normal tissue cells. By competing with endogenous ligand binding, panitumumab inhibits receptor phosphorylation and activation of EGFR associated cell signaling [ 10 ].
EGFR, coded by a gene located in locus 7p11.2 of chromosome 7, is a transmembrane glycoprotein mediating signal transduction in carcinogenesis and disease progression. It is a 170 kDa receptor tyrosine kinase and a member of the human EGF receptor (HER) or ErbB family, a group of four transmembrane receptors that also includes HER-2/neu (ErbB2), HER-3 (ErbB3) and HER-4 (ErbB4). EGFR is the type 1 receptor of this family, also known as HER-1 (ErbB1), and is composed of an extracellular ligand-binding domain, a transmembrane segment and an...