Abstract
The standard treatment of metastatic colorectal cancer (mCRC) is combination of 5‐ fluorouracil/folinic acid with irinotecan or oxaliplatin‐based chemotherapy. Epidermal growth factor receptor (EGFR) is overexpressed in 70%–80% of colorectal cancers (CRC). EGFR overexpression is known to be involved in carcinogenic processes, such as cell proliferation, apoptosis, angiogenesis and metastasis. Monoclonal antibodies targeting EGFR have shown antitumor activity and improved the efficacy of chemotherapy. Cetuximab is a chimeric immunoglobulin (Ig) G1 anti‐EGFR monoclonal antibody (MoAb). Several clinical studies have shown cetuximab, either as a single agent or in combination with irinotecan, having promising efficacy in patients with metastatic CRC. Cetuximab with 5‐fluorouracil/LV (leucovorin) plus irinotecan or oxaliplatin‐based chemotherapy has shown higher response rate and longer time to progression as first‐line treatment of mCRC. Currently, there are no data showing that addition of cetuximab would prolong overall survival in randomized studies. Panitumumab, a fully human IgG2 monoclonal antibody, has also shown antitumor activity against EGFR‐expressing mCRC with less allergic reaction. Anti‐EGFR MoAbs are well tolerated and have limited overlapping toxicities in combination with other cytotoxic drugs. The most common side effect of anti‐EGFR MoAb is an acneform skin rash, which is a surrogate marker of efficacy of treatment with MoAbs. In this review, we will discuss the use of anti‐EGFR MoAbs in the treatment of mCRC, with focus on cetuximab and panitumumab.
| Abbreviations | ||
| mCRC | = | metastatic colorectal cancer |
| MoAb | = | monoclonal antibody |
| ADCC | = | antibody‐dependent cell‐mediated cytotoxicity |
Introduction
Colorectal cancer (CRC) represents the second most lethal malignancy in the United States. In 2006, an estimated 148,610 new cases will be diagnosed, and 55,170 deaths will occur Citation1. The treatment of advanced colorectal cancer has recently evolved especially in the last 5 years. 5‐Fluorouracil (5‐FU) has been used for the treatment of metastatic colorectal cancer for over 40 years. With the addition of other chemotherapeutic drugs such as irinotecan and oxaliplatin, the median survival of patients with advanced colorectal cancer has almost doubled from 12 months to 21 months Citation2–4. Although traditional chemotherapy has improved the clinical outcome in metastatic colorectal cancer (mCRC), limitations of chemotherapeutics remain. Advanced colorectal cancer is still a deadly disease with 5‐year survival rate less than 10% Citation1, Citation5. Recently, targeted therapies that block cancer pathways and molecules involved in tumor growth, proliferation and angiogenesis have shown efficacy in the treatment of advanced colorectal cancer. One of the most promising targets for colorectal cancer therapy is the epidermal growth factor receptor (EGFR). EGFR is a 170‐kDa transmembrane phosphoglycoprotein which is overexpressed in 70%–80% of colorectal cancer patients Citation6. EGFR overexpression has been associated with tumor aggressiveness and poor prognosis Citation7–9. The primary therapeutic EGFR targeting involved two main‐class monoclonal antibodies that directly inhibit EGFR ligand/receptor binding: small molecular tyrosine kinase inhibitors which block EGFR tyrosine kinase autophosphorylation Citation10. The goal of this review is to provide an update of the most recent data of anti‐EGFR monoclonal antibodies in the treatment of metastatic CRC, including cetuximab and panitumumab.
Cetuximab background
Cetuximab is a human‐mouse chimeric immunoglobulin (Ig) G1 monoclonal antibody that binds to the extracellular domain of EGFR with a higher affinity than its natural ligands. Upon binding, cetuximab can competitively inhibit the binding of EGFR natural ligands, such as EGF and transforming growth factor‐α (TGF‐α), preventing receptor dimerization, phosphorylation and downstream processes. As a result, the binding of cetuximab inhibits cell proliferation and angiogenesis, induces apoptosis of cancer cells and prevents cancer cell metastasis Citation11. As a chimeric IgG1 monoclonal antibody, cetuximab may also exert its antitumor effect through antibody‐dependent cell‐mediated cytotoxicity (ADCC) Citation12, Citation13. In vivo studies have shown that cetuximab produces synergy with several cytotoxic agents, including irinotecan Citation14. Cetuximab can also reverse tumor resistance to chemotherapy and enhance the effects of radiation therapy Citation15, Citation16. Currently, it is the only anti‐EGFR monoclonal antibody that is approved for the treatment of EGFR‐expressing metastatic CRC in patients refractory or intolerant to irinotecan‐based chemotherapy.
Key messages
Monoclonal antibodies have shown promising efficacy in the treatment of metastatic colorectal cancer.
Targeted therapies in combination with chemotherapy are tolerable; less toxicity.
Molecular markers are needed to identify patients who could best benefit from monoclonal antibodies therapy.
Cetuximab in metastatic colorectal cancer patients who are refractory or intolerant to irinotecan‐based chemotherapy
Data from several clinical phase II studies have shown that cetuximab, both in combination with irinotecan‐based chemotherapy and as a single agent, has promising efficacy in EGFR‐expressing metastatic CRC patients (Table ).
Table I. Phase II studies of cetuximab in combination with irinotecan or as single agent in the treatment of metastatic colorectal cancer.
A pilot phase II study performed by Saltz et al. Citation17 that enrolled 121 patients with EGFR‐expressing metastatic CRC, refractory to fluorouracil and irinotecan, found a 17% response rate to weekly cetuximab and irinotecan. Patients received cetuximab (loading dose of cetuximab was 400 mg/m2 followed by a weekly dose of 250 mg/m2) while the dosage and schedule of irinotecan remained unchanged. Out of 121 patients, 21 (17%) showed partial response, and the median overall survival was 7.6 months. To determine the independent activity of cetuximab, a subsequent study was performed with a similar patient population (57 patients) using single‐agent cetuximab therapy; 9.5% of the patients showed partial response, and 37% had a minor response or stable disease. The median overall survival was 6.4 months and median time to progression was 1.4 months.
These findings were subsequently confirmed by a European randomized phase II trial (the BOND study), which included 329 patients with EGFR‐expressing metastatic CRC, refractory to irinotecan‐based chemotherapy Citation5. Patients were randomized using a 1:2 ratio; 111 patients received single‐agent therapy (loading dose of cetuximab was initial infusion of 400 mg/m2 followed by a weekly dose of 250 mg/m2); 218 patients received combination therapy (cetuximab dose and schedule was the same as single‐agent arm; irinotecan dose and schedule was the same as they previously failed). As shown in Table , combined therapy with cetuximab/irinotecan produced significantly greater efficacy than the single‐agent therapy with a higher objective response rate (23% versus 11%) and a prolonged median time to tumor progression (4.1 months versus 1.5 months).
A recent phase II nonrandomized study by Lenz et al. Citation18 also showed promising efficacy of single‐agent cetuximab treatment in patients with EGFR‐expressing metastatic CRC who had failed at least two prior chemotherapies includes fluorouracil, irinotecan and oxaliplatin. Of the total 346 patients enrolled in this study, 40 (12%) patients had partial response and the median survival time was 6.7 months.
Finally, a randomized phase III trial by Abubakr et al. Citation19 compared safety data of irinotecan with or without cetuximab in 800 second‐line metastatic, EGFR‐expressing mCRC patients who had failed first‐line oxaliplatin in combination with a fluoropyrimidine. They showed that the combination of cetuximab and irinotecan is well tolerated and there are no increased characteristic toxicities of cetuximab and irinotecan.
Cetuximab as first‐line treatment in metastatic colorectal caner
Numerous studies conducted in recent years have shown cetuximab in combination with irinotecan‐ or oxaliplatin‐based chemotherapy as first‐line treatment is tolerable and has a high response rate (Table ).
Table II. Phase I/II studies of cetuximab in combination with irinotecan/5‐FU/FA or oxaliplatin/5‐FU/FA in the first‐line treatment of mCRC.
Cetuximab with irinotecan‐based chemotherapy as first‐line treatment
A study performed by Folprecht et al. Citation20 showed that cetuximab, in combination with irinotecan, infusional 5‐FU, and LV, in the first‐line therapy of patients with EGFR‐expressing metastatic CRC has a confirmed objective response rate of 67% in 21 evaluable patients. Twenty‐nine percent of patients had stable disease, and median time to progression was 9.9 months. A phase II trial by Rougier et al. Citation21 evaluated the safety and efficacy of cetuximab in combination with FOLFIRI regimen as first‐line treatment in 40 EGFR‐expressing mCRC patients; 46% of patients had partial response, and total disease control rate was 87% (partial response+stable disease).
Cetuximab with oxaliplatin‐based chemotherapy as first‐line treatment
An international phase II trial conducted by Diaz‐Rubio et al. Citation22 evaluated cetuximab in combination with FOLFOX4 regimen. The efficacy data on 42 patients yielded an overall confirmed response rate of 72%, comprising 4 (9%) complete responses (CR) and 27 (63%) partial responses (PR). There were also 10 (23%) patients with stable disease, yielding a disease control rate of 95%. A similar study performed by Seufferlein et al. Citation23 evaluated cetuximab in combination with 5‐fluorouracil (5‐FU)/folinic acid (FA) plus weekly oxaliplatin (L‐OHP) (FUFOX) as the first‐line treatment of patients with mCRC expressing EGFR. Fifty‐four percent patients had confirmed remission, including one complete response, among 41 patients at the recommended dose. Finally, a randomized phase II trial by Borner et al. Citation24 evaluated cetuximab in combination with capecitabine plus oxaliplatin (XELOX) regimen in first‐line treatment of metastatic colorectal cancer; 53% percent patients had partial response out of 67 accessible patients.
Phase III trials in the first‐line treatment of metastatic colorectal cancer are under way. In the CALGB 80405 study, patients with untreated metastatic colorectal cancer are randomized to receive cetuximab alone, bevacizumab alone or the combination of cetuximab and bevacizumab. Another trial is planning to compare addition of cetuximab to 5‐FU/LV/CPT‐11 with 5‐FU/LU/CPT‐11 alone. The results of these trials are eagerly awaited.
Cetuximab in combination with other molecular targeted therapies in the treatment of mCRC
With Food and Drug Administration (FDA) approval of bevacizumab in first‐line and second‐line treatment of mCRC, there is increasing clinical interest to combine different biological agents in the treatment of mCRC. A phase II (BOND II) study compared the combination of cetuximab and bevacizumab with or without irinotecan in irinotecan‐refractory mCRC patients. The addition of bevacizumab to the cetuximab/irinotecan combination resulted in a higher response rate (37% versus 23%) and median time to progression (7.9 months versus 4.1 months) than the cetuximab/irinotecan combination as seen in the BOND study Citation25. In vitro studies also suggest that the combination of anti‐EGFR monoclonal antibodies and tyrosine kinase inhibitors have enhanced antitumor activity Citation26.
Toxicity
Results from clinical trials investigating the efficacy of cetuximab in patients with metastatic CRC have demonstrated that this MoAb is well tolerated either as a single agent or in combination with standard chemotherapy. The most common side effect of cetuximab treatment is skin toxicity as acneiform rash or maculopapular rash that usually appears during the first 2–3 weeks of therapy and may resolve spontaneously during treatment Citation27. Acneiform rash has been observed in 90% of the patients receiving single‐agent cetuximab treatment and in 88% of the patients receiving combined therapy with irinotecan. Another common side effect of cetuximab is infusion reactions. The incidence of severe infusion reaction is estimated to be 3%, but these reactions are rarely fatal Citation28. Other uncommon side effects include interstitial lung disease and hypomagnesemia. Even though skin toxicity is most common in cetuximab treatment, it should not be a reason to discontinue cetuximab treatment.
Surrogate and predictive markers of clinical outcome
With FDA approval of cetuximab for use in mCRC, identifying molecular markers that can select patients who are likely to benefit from treatment of cetuximab is crucial for clinical practice to avoid chemotherapy toxicity and reduce treatment cost. Both phase II trials by Cunningham et al. and Saltz et al. failed to show a significant correlation between EGFR staining intensity and patients' response to treatment with either a cetuximab/irinotecan combination or with cetuximab alone. Furthermore, Lenz et al. Citation29 described a partial response in two out of nine mCRC patients who failed both irinotecan and oxaliplatin with undetectable EGFR protein expression levels. Chung et al. Citation30 evaluated 16 chemotherapy‐refractory, EGFR‐negative colorectal cancer patients who received cetuximab in a non‐study setting, with 4 out of 16 patients showing major objective response. Immunohistochemistry (IHC) is a semiquantitative and subjective method; it is affected by many factors and limited by the variability in the IHC methodology in different clinical trial centers. Using this technique to select patients most likely to respond to cetuximab is thus questionable.
Meanwhile, both the Cunningham et al. and the Saltz et al. trials did show a positive relationship between acne‐like skin rash and response and overall survival on cetuximab, suggesting that skin toxicity may be a surrogate marker to determine clinical outcome of cetuximab treatment.
Studies have explored the possibility of other predictors of cetuximab efficacy. A recent cohort study from Moroni el al. Citation31 found that EGFR gene copy number may predict patients' response to cetuximab and panitumumab. In another study, Lievre et al. Citation32 found that KRAS mutation was significantly associated with resistance to cetuximab. Our group has previously tested the gene expression levels and gene polymorphisms in the EGFR signaling pathway. Our preliminary data demonstrated that EGFR gene expression levels and CyclinD1 gene polymorphisms were significantly associated with cetuximab efficacy Citation33, Citation34. Cetuximab may also exert its antitumor effect through ADCC. As a chimeric IgG1 monoclonal antibody, the Fc region of cetuximab may engage Fc receptor‐bearing immune effector cells, e.g. natural killer (NK) cells, leading to tumor killing Citation13, Citation35. Indeed, our preliminary data have shown that two fragment C receptor polymorphisms (FCGR2A and FCGR3A) may be predictors of cetuximab efficacy Citation36.
Panitumumab
Panitumumab is a high‐affinity fully human IgG2 monoclonal antibody directed against EGFR Citation37. In vitro studies have demonstrated that panitumumab inhibits EGFR tyrosine phosphorylation and tumor cell activation, resulting in the inhibition of tumor cell proliferation Citation38. Several clinical trials in mCRC have recently shown that panitumumab is well tolerated and has demonstrated efficacy in mCRC patients who had failed multiple lines of standard chemotherapy.
In a phase II study, Malik et al. Citation39 assessed the efficacy of single‐agent panitumumab treatment in 148 patients with metastatic CRC refractory to 5‐FU and either CPT‐11 or oxaliplatin. Fifteen patients (10%) had confirmed partial response and 54 (36.5%) had stable disease. Median time to progression was 2.5 months and median overall survival time was 9.4 months. Hecht et al. Citation40 showed panitumumab also had similar antitumor activity in mCRC patients with both low and negative EGFR levels.
A phase III multicenter randomized controlled trial by Gibson et al. Citation41 evaluated panitumumab as third‐line monotherapy in metastatic colorectal cancer patients. Patients who received panitumumab every two weeks showed a 46% decrease in tumor progression rate versus those who received best supportive care alone.
Hecht et al. Citation42 evaluated panitumumab in combination with irinotecan‐fluorouracil‐leucovorin (IFL) or FOLFIRI as first‐line treatment of mCRC. The IFL regimen had 19 patients, and the FOLFIRI regimen had 24 patients. The objective response rate for IFL was 47%, and for FOLFIRI 33%. Total disease control rates were 73% and 82%, respectively. A nonregistrational phase IIIb study initiated in 2005 to evaluate panitumumab plus bevacizumab in first‐line colorectal cancer (PACCE) is under way.
Panitumumab is well tolerated either as monotherapy or in combination with other chemotherapy. The most common side effect in most mCRC patients treated with panitumumab was a reversible skin rash Citation43, as seen with cetuximab. The side effects of panitumumab were minimal since panitumumab is a fully human antibody instead of part mouse. The studies also suggested that skin rash may be a surrogate marker for panitumumab response, as was described for cetuximab Citation44.
Conclusion
This is a fast‐changing era for the treatment of advanced colorectal cancer. With FDA approval of cetuximab and bevacizumab in the treatment of mCRC, molecular targeted agents that inhibit major cancer pathways are becoming powerful tools in the treatment of mCRC. Cetuximab, as a chimeric anti‐EGFR MoAb, demonstrates promising efficacy in mCRC patients who failed prior chemotherapy or as first‐line treatment in combination with irinotecan‐ or oxaliplatin‐based chemotherapy. In addition, patients do not experience increasing toxicity with cetuximab. Panitumumab also shows good antitumor activity in mCRC patients in in vitro and in vivo studies. With so many choices of therapeutic agents and combinations in the treatment of mCRC, it is vital to identify molecular markers that can select patients who will best respond to these agents. More extensive pharmacogenetic studies are needed to maximize the benefit of treatment and minimize the potential toxicity.
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