Panitumumab for Treatment of Metastatic Colorectal Cancer
Panitumumab for Treatment of Metastatic Colorectal Cancer
Background: Panitumumab is a fully human monoclonal IgG2 antibody targeting the epidermal growth factor receptor (EGFR).
Aim: To review the efficacy of panitumumab in the treatment of metastatic colorectal cancer (mCRC).
Methods: Available literature identified from PubMed and conference websites was reviewed.
Results: In phase 2-3 studies, panitumumab monotherapy achieved objective response rates (ORRs) of 8-13% in relapsed/refractory EGFR-expressing mCRC. In a randomized phase 3 study (463 patients), panitumumab almost halved the risk of disease progression/death vs. a control group receiving only best supportive care (hazard ratio 0.54; 95% CI: 0.44-0.66; P < 0.0001). Objective response was achieved in 22/231 (10%) patients randomized to panitumumab - and also in 20/176 (11%) patients assigned to the control group who received panitumumab in a separate crossover protocol after disease progression. Response was confined to patients with tumours harbouring wild-type KRAS (ORR ≈20%). Panitumumab is also being evaluated in earlier lines of treatment. Panitumumab monotherapy is generally well tolerated; the most common toxicities are skin toxicity (≈90%) and diarrhoea (<30%). Development of anti-panitumumab antibodies (0.3% by ELISA) and grade 3-4 infusion reactions (<1%) are rare.
Conclusion: Panitumumab is an effective monotherapy option for patients with relapsed/refractory EGFR-expressing mCRC harbouring wild-type KRAS.
Chemotherapy options for metastatic colorectal cancer (mCRC) have expanded over the past decades to include the newer agents irinotecan and oxaliplatin. Incorporation of these agents into regimens containing the traditional agents 5-fluorouracil and leucovorin for first- or second-line treatment has extended median survival to over 20 months. Despite new chemotherapy regimens and improvements in screening and diagnosis, the 5-year survival rate for patients with mCRC remains dismally low at 5%, with limited options for patients who are refractory to, or relapse after, standard chemotherapy.
Intense research efforts over recent years have led to the development of several therapies specifically targeted at key molecular processes involved in tumour promotion and growth. Bevacizumab, a humanized monoclonal antibody (mAb) directed at soluble vascular endothelial growth factor (VEGF), a key factor in tumour angiogenesis, has further improved survival outcomes when added to first-line or subsequent chemotherapy for mCRC. The epidermal growth factor receptor (EGFR) has also emerged as an attractive target in cancer treatment, as its activation stimulates key processes involved in tumour growth and progression, including proliferation, angiogenesis and invasion/metastasis. EGFR, which is encoded by the proto-oncogene c-erb-B, is a member of the HER/erbB family of cytoplasmic tyrosine kinases that includes HER1 (EGFR/erbB1), HER2 (neu, erbB2), HER3 (erbB3) and HER4 (erbB4). EGFR can be activated by receptor overexpression and by ligand-dependent and ligand-independent mechanisms. Ligand binding to the receptor [by EGF or other ligands such as transforming growth factor alpha (TGF-α)] induces a conformational change that allows receptor dimerization and subsequent autophosphorylation of several tyrosine residues that function as docking sites for multiple signal transducers and adaptor molecules. This initiates an intracellular mitogenic signalling cascade via several pathways, including the RAS/RAF/mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt and phopholipase C pathways. Overexpression of EGFR has been noted in a range of solid tumour types, including CRC and has been linked to worsened outcome.
Monoclonal antibodies directed at the extracellular domain of the EGFR and small molecule inhibitors of the tyrosine kinase (TKIs) of the receptor have been evaluated in the treatment of solid tumours, including CRC, non-small-cell lung cancer and squamous cell carcinoma of the head and neck. TKIs directed against the EGFR appear to have poor activity in mCRC, but the anti-EGFR mAb cetuximab has shown efficacy, in combination with chemotherapy and also as monotherapy. Cetuximab is a chimeric/human antibody containing approximately 30% murine sequences. Development of human anti-murine antibodies has the potential to impair efficacy, as well as eliciting allergic responses/infusion reactions. Despite using prophylactic antihistamines, severe infusion reactions (bronchospasm, urticaria, hypotension and occasionally, cardiac arrest) are still a problem. Such reactions are reported to occur in approximately 3% of cetuximab recipients and in rare cases (<0.1%) are fatal. A recent report suggests that the incidence may be much higher in some geographical regions: 22% of patients treated at centres in Tennessee and North Carolina experienced grade 3-4 infusion reactions after receiving cetuximab. Subsequent investigation found that most hypersensitivity reactions to cetuximab were associated with pre-existing specific IgE antibodies against an oligosaccharide (galactose-α-1,3-galactose) component of the cetuximab molecule.
Panitumumab (ABX-EGF; Vectibix, Amgen, Thousand Oaks, CA, USA) is a 100% human IgG2 anti-EGFR mAb developed using XenoMouse (Abgenix, Fremont, CA, USA) technology. Panitumumab was approved for monotherapy of relapsed/refractory mCRC by the US Food and Drug Administration in September 2006 and conditionally approved (in patients with tumours harbouring wild-type KRAS) by the European Medicines Agency (EMEA) in December 2007. This review focuses on the efficacy and tolerability of panitumumab in the treatment of mCRC. Literature was identified from PubMed using the search terms 'panitumumab' and 'ABX-EGF'. All peer-reviewed primary publications on panitumumab were included. Similar articles on other EGFR inhibitors were also included to provide a context. Abstracts from conference websites were also included if they contained relevant data not available in fully published articles.
Background: Panitumumab is a fully human monoclonal IgG2 antibody targeting the epidermal growth factor receptor (EGFR).
Aim: To review the efficacy of panitumumab in the treatment of metastatic colorectal cancer (mCRC).
Methods: Available literature identified from PubMed and conference websites was reviewed.
Results: In phase 2-3 studies, panitumumab monotherapy achieved objective response rates (ORRs) of 8-13% in relapsed/refractory EGFR-expressing mCRC. In a randomized phase 3 study (463 patients), panitumumab almost halved the risk of disease progression/death vs. a control group receiving only best supportive care (hazard ratio 0.54; 95% CI: 0.44-0.66; P < 0.0001). Objective response was achieved in 22/231 (10%) patients randomized to panitumumab - and also in 20/176 (11%) patients assigned to the control group who received panitumumab in a separate crossover protocol after disease progression. Response was confined to patients with tumours harbouring wild-type KRAS (ORR ≈20%). Panitumumab is also being evaluated in earlier lines of treatment. Panitumumab monotherapy is generally well tolerated; the most common toxicities are skin toxicity (≈90%) and diarrhoea (<30%). Development of anti-panitumumab antibodies (0.3% by ELISA) and grade 3-4 infusion reactions (<1%) are rare.
Conclusion: Panitumumab is an effective monotherapy option for patients with relapsed/refractory EGFR-expressing mCRC harbouring wild-type KRAS.
Chemotherapy options for metastatic colorectal cancer (mCRC) have expanded over the past decades to include the newer agents irinotecan and oxaliplatin. Incorporation of these agents into regimens containing the traditional agents 5-fluorouracil and leucovorin for first- or second-line treatment has extended median survival to over 20 months. Despite new chemotherapy regimens and improvements in screening and diagnosis, the 5-year survival rate for patients with mCRC remains dismally low at 5%, with limited options for patients who are refractory to, or relapse after, standard chemotherapy.
Intense research efforts over recent years have led to the development of several therapies specifically targeted at key molecular processes involved in tumour promotion and growth. Bevacizumab, a humanized monoclonal antibody (mAb) directed at soluble vascular endothelial growth factor (VEGF), a key factor in tumour angiogenesis, has further improved survival outcomes when added to first-line or subsequent chemotherapy for mCRC. The epidermal growth factor receptor (EGFR) has also emerged as an attractive target in cancer treatment, as its activation stimulates key processes involved in tumour growth and progression, including proliferation, angiogenesis and invasion/metastasis. EGFR, which is encoded by the proto-oncogene c-erb-B, is a member of the HER/erbB family of cytoplasmic tyrosine kinases that includes HER1 (EGFR/erbB1), HER2 (neu, erbB2), HER3 (erbB3) and HER4 (erbB4). EGFR can be activated by receptor overexpression and by ligand-dependent and ligand-independent mechanisms. Ligand binding to the receptor [by EGF or other ligands such as transforming growth factor alpha (TGF-α)] induces a conformational change that allows receptor dimerization and subsequent autophosphorylation of several tyrosine residues that function as docking sites for multiple signal transducers and adaptor molecules. This initiates an intracellular mitogenic signalling cascade via several pathways, including the RAS/RAF/mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt and phopholipase C pathways. Overexpression of EGFR has been noted in a range of solid tumour types, including CRC and has been linked to worsened outcome.
Monoclonal antibodies directed at the extracellular domain of the EGFR and small molecule inhibitors of the tyrosine kinase (TKIs) of the receptor have been evaluated in the treatment of solid tumours, including CRC, non-small-cell lung cancer and squamous cell carcinoma of the head and neck. TKIs directed against the EGFR appear to have poor activity in mCRC, but the anti-EGFR mAb cetuximab has shown efficacy, in combination with chemotherapy and also as monotherapy. Cetuximab is a chimeric/human antibody containing approximately 30% murine sequences. Development of human anti-murine antibodies has the potential to impair efficacy, as well as eliciting allergic responses/infusion reactions. Despite using prophylactic antihistamines, severe infusion reactions (bronchospasm, urticaria, hypotension and occasionally, cardiac arrest) are still a problem. Such reactions are reported to occur in approximately 3% of cetuximab recipients and in rare cases (<0.1%) are fatal. A recent report suggests that the incidence may be much higher in some geographical regions: 22% of patients treated at centres in Tennessee and North Carolina experienced grade 3-4 infusion reactions after receiving cetuximab. Subsequent investigation found that most hypersensitivity reactions to cetuximab were associated with pre-existing specific IgE antibodies against an oligosaccharide (galactose-α-1,3-galactose) component of the cetuximab molecule.
Panitumumab (ABX-EGF; Vectibix, Amgen, Thousand Oaks, CA, USA) is a 100% human IgG2 anti-EGFR mAb developed using XenoMouse (Abgenix, Fremont, CA, USA) technology. Panitumumab was approved for monotherapy of relapsed/refractory mCRC by the US Food and Drug Administration in September 2006 and conditionally approved (in patients with tumours harbouring wild-type KRAS) by the European Medicines Agency (EMEA) in December 2007. This review focuses on the efficacy and tolerability of panitumumab in the treatment of mCRC. Literature was identified from PubMed using the search terms 'panitumumab' and 'ABX-EGF'. All peer-reviewed primary publications on panitumumab were included. Similar articles on other EGFR inhibitors were also included to provide a context. Abstracts from conference websites were also included if they contained relevant data not available in fully published articles.