Antibodies Targeting the Epidermal Growth Factor Receptor
The agents listed above are presented in alphabetical order and are the current FDA-approved antibody agents currently used in the treatment of various cancers. In the following section, we will review these agents in greater detail. Note, because all monoclonal antibodies are administered intravenously, the dosing is more complex than with the TKIs and dosing of some these agents is beyond the scope of this review, although we will review dosing of the more common and widely used agents such as trastuzumab and bevacizumab.
On Feb 12th, 2004, the US Food and Drug Administration (FDA) approved a chimeric monoclonal antibody against the epidermal growth factor receptor (EGFR) called Cetuximab (Erbitux, C225) for the second-line treatment of refractory colon cancer. As we discussed in the section on tyrosine kinase inhibitors (TKIs), EGFRs are receptors that span the cell membrane with ends protruding into both the outside and the inside of the cell. The part of the receptor that is found on the outside of the cell is called the extracellular domain and the end inside the cell is called the intracellular domain. Cetuximab binds to the EGFR and thereby interferes with the normal physiologic binding and cellular signaling pathways are interrupted. Put in a different way, by binding to the EGFR, Cetuximab does not allow the natural protein to bind to the receptor and to transmit its signals for growth, cell division, and differentiation.
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide with approximately one half million deaths per year. In 2009, there were 106,000 new cases of CRC with nearly 50,000 deaths in the United States alone. Combination chemotherapy with fluorouracil/leucovorin, irinotecan, oxaliplatin, and bevacizumab has increased survival rates of patients with metastatic colorectal cancer although eventual relapse is almost universal. Cetuximab is indicated for the treatment of patients with EGFR-expressing, KRAS wild-type (more on what this means below) metastatic colorectal cancer (mCRC), in combination with chemotherapy, and as a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy regimens and who are intolerant to irinotecan.
Before continuing, it would be prudent to briefly review biomarkers (a substance found in blood or tissue that is a sign of a disease). In mCRC, biomarkers, including K-ras, indicate probable response to cetuximab (Erbitux). K-ras is a protein that is activated when bound to GTP (another cellular energy molecule similar to the previously discussed ATP). GTP can then convert to a molecule known as GDP, which turns off K-ras. However, if K-ras is mutated, it can remain constantly active and no longer relies on EGFR to work, and therefore may be less likely to be affected by a therapy that blocks EGFR (i.e., cetuximab). Researchers refer to unmutated K-ras as "wild type,Ã" and feel that this wild type may be more responsive to cetuximab. Approximately 60% of patients with colorectal cancer have K-ras wild-type tumors and data have shown that these patients are significantly more likely to benefit from treatment with cetuximab (with or without chemotherapy). Interestingly, although approximately three quarters of all colorectal cancers are EGFR-positive by immunohistochemistry (IHC), there is no correlation between the presence and intensity of IHC staining and clinical response, first reported in 2005 in the Journal of Clinical Oncology.
The CRYSTAL trial was a large, randomized, phase III trial investigating the use of a chemotherapy regimen known as FOLFIRI versus FOLFIRI plus cetuximab as first-line treatment (initial treatment) in patients with EGFR-expressing advanced colorectal cancers. The data was published in April 2009 in the New England Journal of Medicine (first reported on at the ASCO 2007 meeting, OncoLink review of K-ras status in this trial presented at ASCO 2008 and reviewed here). In this study, patients received FOLFIRI with our without cetuximab. FOLFIRI is a chemotherapy regimen consisting of irinotecan in combinationwith two other drugs, 5-fluorouracil and leucovorin. This trial revealed statistically significant but modest improvements in the median progression-free survival (PFS) and overall survival (OS). Of equal importance in this publication is the subgroup analysis based on K-ras mutation status. Outcomes for patients with wild-type K-ras improved with the addition of cetuximab: median survival was 9.9 months for patients receiving cetuximab/FOLFIRI versus 8.7 months for patients receiving FOLFIRI alone. Outcomes for patients with mutant K-ras were not affected by the addition of cetuximab, demonstrating the importance of establishing K-ras mutation status prior to cetuximab therapy for CRC patients.
Other trials have also explored the utility of cetuximab in combined therapy: the BOND trial published in the New England Journal of Medicine in July 2004, compared irinotecan/cetuximab versus cetuximab alone in 329 patients with irinotecan-refractory mCRC. In that trial, combined therapy was associated with a significantly better response. The EPIC trial was a larger trial (1298 patients) published in 2008 and randomly assigned oxaliplatin-refractory patients to irinotecan with or without cetuximab. PFS was higher with combined therapy, although median survival was not significantly different, although the effect may have been diminished due to high crossover (nearly 50% of the patients receiving irinotecan alone subsequently received cetuximab after their disease progressed).
Head and Neck Cancer
Switching gears, cetuximab was subsequently approved by the FDA in March 2006 for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based chemotherapy for head and neck cancers. Before exploring the implications of this FDA indication, we should briefly review head and neck malignancies, which account for about 5-7% of all new cancer cases in the US, occurring more than twice as often in men as in women. Notably, the prevalence of these cancers is highest amongst populations with high tobacco and alcohol use. The broad category of head and neck cancers can be further subdivided according to the primary tumor site, reflecting the complex anatomy of the head and neck region. These sites include the nasal cavity and paranasal sinuses, nasopharynx, oral cavity, oropharynx, salivary glands, larynx and the neck itself. As we have seen in prior sections, the histology of the cancer (i.e., the microscopic characteristics) is of critical importance in guiding therapy. In head and neck cancers, the most common histology is squamous cell carcinoma. Commonly, treatment of these cancers employs platinum-based chemotherapeutic agents (e.g., cisplatin or carboplatin). Head and neck malignancies are known to highly overexpress EGFR and this has been shown to confer a worse prognosis.
There are two landmark trials that we will review in the context of the use of cetuximab for head and neck squamous cell carcinoma, both of which were published in the New England Journal of Medicine. The Bonner trial was published in 2006, and randomized 424 patients with advanced head and neckcancers (lymph node spread) to high-dose radiotherapyor high-dose radiotherapy plus weekly cetuximab. This trial demonstrated improved local control of the primary disease site and improved overall survival. In a separate group of patients, those with platinum-resistant recurrentor metastatic squamous-cell carcinoma of the head and neck were evaluated and published on in the EXTREME trial in September 2008 in the New England Journal of Medicine. This trial randomly assigned patients with untreated recurrent or metastatic squamous cell carcinoma of the head and neck to receive cisplatin or carboplatin plus 5-fluorouracil or the same chemotherapy plus cetuximab. Adding cetuximab to platinum-based chemotherapy with fluorouracil significantly prolonged the median progression-free and overall survival rates. These results helped facilitate the approval of cetuximab by the European Commission in November 2008 for the treatment of first-line recurrent and/or metastatic SCCHN.
Non-Small Cell Lung Cancer
Before moving onto other agents, we should briefly discuss some investigations into the use of cetuximab in non-small cell lung cancer (NSCLC). It should be noted that as of March 2010, there is no FDA approval of this agent for use in NSCLC patients. In the section on the small molecule TKIs targeting EGFR (gefitinib and erlotinib), we saw improved survival in appropriately selected patients. Cetuximab is therefore an ideal agent to study in the context of NSCLC. A couple of trials here are worth mentioning. The FLEX trial (reviewed on OncoLink here following initial presentation at ASCO 2008) was a phase III trial published in May 2009 in The Lancet and looked at 1442 patients with EGFR-expressing tumors in stage IIIB (with pleural effusion) or metastatic NSCLC, and found that patients given chemotherapy plus cetuximab survived longer than those in the chemotherapy-alone group (median survival 11.3 months versus 10.1 months. Although a cost effective analysis of targeted agents is beyond the scope of this review, subsequent editorials have estimated the monetary cost of this 1.2 month increase to be approximately $62,000.
The issue has been more recently confounded by the final results of the BMS099 study, which were published in the Journal of Clinical Oncology in January of 2010. This trial was a phase III study that enrolled chemotherapy-naivepatients with stage IIIB (pleural effusion) or metastatic NSCLC. Patients were randomized to receive docetaxel/carboplatin with or without cetuximab. The primary end point was progression-free survival and it was a negative study, meaning that neither progression free or overall survival were meaningfully prolonged with the addition of cetuximab. It should be noted that while cetuximab has not received formal FDA approval for the treatment of patients with NSCLC, it is now recommended by the National Comprehensive Cancer Network (NCCN) in combination with vinorelbine plus cisplatin as a treatment option for patients with advanced or recurrent NSCLC who meet certain eligibility criteria (reasonably good performance status, EGFR expression, and no prior chemotherapy or targeted treatments).
Cetuximab and Side Effects
One of the main side effects of therapy with cetuximab parallels anti-EGFR therapies with small molecule TKIs: namely, the incidence of an acne-like rash. This rash rarely leads to dose reductions or termination of therapy. It is generally reversible after treatment is finished and is also likely associated with a good response to therapy as seen with gefitinib and erlotinib. Because cetuximab is a chimeric antibody, severe infusion reactions are also possible, including but not limited to: fevers, chills, hives, itchiness, rash, low blood pressure, nausea or vomiting, headache, shortness of breath, wheezing, swelling of the face, dizziness, severe allergic reactions, and cardiac arrest. Therefore, pretreatment with diphenhydramine (Benadryl) 30-60 minutes before administration is a standard of care. Other common side effects include increased sensitivity to light, low blood levels of magnesium, and less commonly, lung and heart toxicity.
Here are the following current FDA approved indications for cetuximab:
- Locally or regionally advanced squamous cell carcinoma of the head and neck in combination with radiation therapy.
- Recurrent or metastatic squamous cell carcinoma of the head and neck progressing after platinum-based therapy.
- As a single agent, EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens or in patients who are intolerant to irinotecan-based regimens.
- In combination with irinotecan, EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy.
Panitumumab (Vectibix, ABX-EGF) was first approved in September 2006 for patients with EGFR-expressing metastatic colorectal cancer (mCRC) with disease progression. Although both cetuximab and panitumumab target EGFR, the two antibodies differ in their isotype and, therefore, may have slightly different clinical effects. Cetuximab is an IgG2 antibody and panitumumab is an IgG1 antibody. Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate their effects via antibody-dependent cellular cytotoxicity (ADCC) that we discussed in the introduction to antibody therapies.
Panitumumab is produced by immunization of transgenic mice (mice whose DNA have been modified to express some human genes) that are able to produce human immunoglobulin light and heavy chains. After immunization of these animals, a specific clone of B cells that produced an antibody against EGFR was selected and immortalized (grown indefinitely) in Chinese hamster ovary (CHO) cells, which were then used for the full-scale manufacture of the 100% human antibody. Because panitumumab is a completely humanized antibody (as opposed to the chimeric nature of cetuximab or humanized nature of bevacizumab), it is expected to result in less immunogenic reactions both during infusions and following treatment.
In phase II studies, panitumumab monotherapy used for the treatmentof chemorefractory colorectal cancer was active and well tolerated and, in May 2007, a phase III trial was published the Journal of Clinical Oncology. The studyÃ•s findings were initially reported at the American Association of Cancer Research Annual Meeting (AACR) in 2006 (OncoLink review can be found here). In this trial, 463 patients with some EGFR overexpression were randomized to panitumumab versus best supportive care (BSC) if they had radiological documentation of disease progression within the past 6 months. Panitumumab was found to significantly prolong PFS although the magnitude was small. There was no improvement in overall survival (OS).
A subsequent analysis of the data was published in April 2008 in the same journal in order to examine the influence of K-ras status on the results, in light of the importance of this gene found in colon cancer trials with cetuximab. As we briefly discussed before, K-ras is a protein that if mutated, can remain constantly active, rendering EGFR overexpression alone less important. Researchers refer to unmutated K-ras as "wild type (WT)Ã"; approximately 60% of patients with colorectal cancer have K-ras wild-type tumors. Not surprisingly, the efficacy of panitumumab was limited to patients with K-ras WT tumors. Median PFS in the WT K-ras group was 5 weeks longer in the group receiving panitumumab. In July 2009, the FDA updated the labels of both panitumumab and cetuximab to include information about mutation status since only WT patients benefit.
Panitumumab and Side Effects
As expected, as compared to cetuximab, infusion reactions are less common with panitumumab and occur in less than 1% of treated patients. Furthermore, unlike cetuximab, no pre-infusional diphenhydramine is required. Adverse effects that were significantly more frequent with panitumumab include skin toxicity (redness, acne-like rash, itching, or exfoliation), diarrhea and nausea, abdominal pain, fatigue. Uncommonly, low magnesium has also been reported, as has the development of interstitial lung disease (pulmonary fibrosis).
Here is the current FDA approved indication for panitumumab:
- Single agent for the treatment of metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy regimens. Note: approval is based on progression- free survival; no data demonstrate an improvement in disease-related symptoms or increased survival with panitumumab. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for panitumumab in patients whose tumors had KRAS mutations in codon 12 or 13. Use of panitumumab is not recommended for the treatment of colorectal cancer with these mutations.