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Cetuximab (Erbitux)

A chimeric monoclonal antibody of the G1 subclass with a high affinity and specificity to EGFR.

Trade name Erbitux.

An epidermal growth factor receptor (EGFR) inhibitor used for the treatment of metastatic colorectal cancer and head and neck cancer.

A chimeric (mouse/human) monoclonal antibody given by intravenous infusion.

Has a half-life of 114 hrs.

For treatment of KRAS wild type colon cancer.

Has lttle or no effect in colorectal tumors harboring a KRAS or NRAS mutation.

Indicated for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, KRAS wild-type metastatic colorectal cancer in combination with chemotherapy, and as a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy.

Has a greater benefit in patients with metastatic colon cancer treated with combination chemotherapy and left sided-cancers of the colon.

It’s benefit remains limited to patients  with left sided tumors.

Indicated for the treatment of patients with squamous cell carcinoma of the head and neck in combination with platinum-based chemotherapy for the 1st line treatment of recurrent and/or metastatic disease and in combination with radiation therapy for locally advanced disease.

A diagnostic immunohistochemistry assay can be used to detect EGFR expression in the tumor.

Approximately 75% of patients with metastatic colorectal cancer have an EGFR-expressing tumor and are therefore considered eligible for treatment.

Immunohistochemical EGFR receptor testing does not predict response to cetuximab.

Two large clinical trials of cetuximab, OPUS and CRYSTAL have provided evidence that cetuximab significantly improves the odds of a response to treatment in colorectal cancer and in one study, reduced the risk of disease progression.

Use does not significantly affect overall survival (OS) rates in mCRC patients with KRAS wild-type tumors.

Fails to benefit patients with early stages of colorectal cancer with no improvement in survival rates.

Adding this agent increases the side effects of chemotherapy.

Adding cetuximab to a three-drug chemotherapy regimen for first-line treatment of metastatic colorectal cancer does not improve response rate, progression-free survival or overall survival (ESMO).

In a Phase III study (COIN) of cetuximab in combination with capecitabine and oxaliplatin versus chemotherapy alone in first-line mCRC: did not meet its primary endpoint of overall survival in K-ras wild type patients (17 months vs. 17.9 months.

Approved for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck or as a single agent in patients who have had prior platinum-based therapy.

The EXTREME trial is a Phase III trial has demonstrated a survival benefit in 1st-line recurrent and/or metastatic disease by the addition of cetuximab to standard chemotherapy was almost three months.

In the above study the addition of cetuximab prolonged the median progression-free survival time from 3.3 to 5.6 months, and increased median overall survival from 7.4 to 10.1 months.

Resistance to cetuximab is likely to be mediated via signalling through the HER2/neu protein.

One of the more serious side effects is acne-like rash.

Infusion reactions include fevers, chills, rigors, urticaria, pruritis, rash, hypotension, nausea, vomiting, headache, bronchospasm, dyspnea, wheezing, angioedema, dizziness, anaphylaxis, cardiac arrest, and less commonly pulmonary and cardiac toxicity.

Pretreatment with diphenhydramine 30-60 min. before administration is standard of care.

Growth factors bind to cell surface receptors on the cell, and the receptors signal cells to divide.

Mutated receptors can signal cells to divide even without growth factor, causing the cells to divide uncontrollably.

Cetuximab binds to such receptors and turns off growth signals.

The EGFR sends a signal down a pathway that includes another protein KRAS.

If EGFR is mutated in some cancers, the KRAS protein may either be “wild type” or mutated.

If mutated, KRAS sends a signal to divide uncontrollably, even if EGFR has been blocked by cetuximab.

Cetuximab binds to EGFR and turns off the uncontrolled growth in cancers with EGFR mutations.

If the KRAS protein in mutated, cetuximab has been found not to work.

Mutated KRAS gene downstream sends a growth signal (the KRAS protein) and this mutated gene now does not respond to the EGFR receptor.

Before cetuximab is used, the standard of care is that the KRAS gene in the cancer cells is tested for mutation: if KRAS is normal (wild type), cetuximab may be beneficial, but if KRAS is mutated, indications are that cetuximab will not be beneficial.

The KRAS gene encodes a small G protein on the EGFR pathway.

Cetuximab and other EGFR inhibitors only work on tumors that are not mutated.

If the KRAS mutations are absent in the colorectal cancer cells, then the patient may be considered for treatment with Erbitux.

The detection of KRAS gene mutations identify patients that are unlikely to respond to treatment with targeted EGFR inhibitors, including cetuximab and panitumumab.

Genetic testing to confirm the absence of KRAS mutations is clinically routine before the start of treatment with EGFR inhibitors.

mCRC patients with wild-type KRAS tumors have been shown to benefit from a response rate of over 60% and a decreased risk for progression of over 40% when treated with Erbitux as 1st-line therapy.

Around 65% of mCRC patients have the KRAS wild-type gene.

Patients with KRAS wild-type tumors demonstrated significantly increased response rates and disease free survival when treated with cetuximab and standard chemotherapy (OPUS AND CRYSTAL) in metastatic renal cancer, compared to patients receiving chemotherapy alone.

Has five time greater affinity for EGFR than natural ligands and inhibits ligand induced activation of the EGFR.

Stimulates EGFR internalization which essentially removes the receptor from cell surface for interaction with ligands.

Induces apoptosis and suppression of tumor cell growth and has antiangiogenic activity as well.

Immunoglobulin G1 monoclonal antibody that binds to EGFR extracellular domain and blocks ligand binding.

Can mediate antibody dependent cellular cytotoxicity against certain tumor types.

Response to therapy is independent of EGFR staining, and this criteria is no longer used for EGFR directed therapy.

It is he KRAS mutation status that is the most important predictor for the lack of benefit from anti-EGFR therapy.

Acne like rash among the most common side effects.

Rash seen in up to 86% of patients.

Infusion reactions up to 10% of patients.

14% have conjunctivitis and an occasional patient can have blepharitis.

Alpha-gal is present in the drug.

BOND-1 trial randomized 329 patients with progression after irinotecan-based treatment to cetuximab and irinotecan and cetuximab alone: response rate in combination therapy was 22% versus 10.8%, median time to progression was 4.1 months versus one 0.5 months with no difference in median survival:cetuximab restored sensitivity to treatment with irinotecan.

CAIRO2 trial conducted in the Netherlands evaluated 775 untreated patients with metastatic colorectal cancer randomly treated with capecitabine, oxaliplatin and bevacizumab (COB) vs. COB plus cetuximab with survival as the end-point and KRAS mutation also evaluated: addition of cetuximab to COB decreases progression free survival from 10.7 months in the COB group to 9.4 months in the COB-C group, overall survival and response rates did not differ.

CAIRO2 trial the addition of cetuximab to the COB regimen resulted in a significantly shorter progression free survival, particularly in patients with mutated KRAS tumors, but the addition of cetuximab did not improve outcome in the wild type KRAS tumors either.

The addition of cetuximab to FOLFIRI chemotherapy as first-line therapy in metastatic colon cancer improves survival in patients with KRAS wild type disease (Van Cutsem et al).

 

A long-term analysis of the New EPOC clinical trial led investigators to assert that cetuximab therapy should not be used in patients with resectable colorectal liver metastasis (Bridgewater, JA).

 

 

The median follow-up time was 66.7 months, and the median PFS was 22.2 months in the chemotherapy arm versus 15.5 months in the chemotherapy plus cetuximab arm: The median OS was 81.0 months versus 55.4 months, respectively.

 

 

Patients in the cetuximab plus chemotherapy arm had increased rates of skin rash (16%), thromboembolic eventsyy I (8%), and oral mucositis (10%) compared with those in the chemotherapy-only arm.

 

 

The addition of cetuximab to chemotherapy improves the overall survival in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival.

The addition of cetuximab in patients with KRAS wild type disease to chemotherapy resulted in significant improvements in overall survival with the median survival 23.5 versus 20 months, progression free survival median 9.9 versus 8.4 months and response rates of 57.3% versus 39.7% compared with FOLFIRI alone, confirming KRAS as a powerful biomarker predictor for cetuximab efficacy. (Van Cutsem E et al).

Among patients with advanced, refractory, colorectal cancer, the therapeutic benefit of cetuximab, is limited to those who have cancer that has unmutated copies of the KRAS gene (Karapetis).

In patients with locally advanced head and neck cancer the addition of cetuximab to chemoradiation in a cooperative group trial showed no increased survival benefit with a 2 year progression free survival of 63.4% with cetuximab versus 64.3% with cisplatin-based chemoradiation alone (KK Ang et al).

Other studies have shown the combination of cetuximab and radiation is superior to radiation alone in patients with stage III/IV oropharyngeal, hypopharyngeal, or laryngeal squamous cell cancer of the head and neck with clinically and statistically improvement improved duration of local regional control 24.4 verses 14.9 weeks and overall survival (BonnerJA et al).

In a single arm trial evaluating the efficacy of cetuximab in 103 patients with recurrent metastatic squamous cell carcinoma of the head and neck following progression on platinum-based therapy had an objective response rate of 13% with the median duration of approximately four months(Vermoken JB et al).

In a phase III trial cetuximab in recurrent metastatic head and neck cancer had a 2.7 month increased overall survival with the addition cetuximab to cis-platinum os carboplatinum plus 5-FU.

A clinical trial of patients with human papillomavirus (HPV)-positive oropharyngeal cancer demonstrated worse overall survival with cetuximab plus radiation therapy than with cisplatin plus radiation, the current standard treatment (NCI).

Adding cetuximab to chemoradiotherapy for localized esophageal cancer is associated with the shorter median survival compared with no cetuximab, 22.1 months versus 25.4 months.

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