Clinical studies -erbitux

By:eman abd el-raouf ahmed

Nada sabry

The content:

Definition

Mechanism of action

Case study

references

definitionErbitux is a targeted therapy. It is classified as a "monoclonal antibody" and "signal transduction inhibitor" by binding to epidermal growth factor receptors (EGFR).It is epidermal growth factor receptor (EGFR) inhibitor

used for the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer and head and neck cancer. Cetuximab is a chimeric (mouse/human) monoclonal antibody given by intravenous infusion that is distributed under the trade name Erbitux in the U.S. and Canada by the drug company Bristol-Myers Squibb and outside the U.S. and Canada by the drug company Merck KGaA. In Japan, Merck KGaA, Bristol-Myers Squibb and Eli Lilly have a co-distribution.

note

In July 2009, the FDA approved Erbitux for treatment of KRAS wild type colon cancer, since Cetuximab had little or no effect in colorectal tumors harboring a KRAS mutation (this also applied to the EGFR antibody panitumumab) This was the first genetic test to guide treatment of cancer. In July 2012, the FDA approved a real time PCR companion diagnostic test for KRAS, the therascreen KRAS test.

History

Ester Hurwitz, Michael Sela, and co-workers published observations in 1988. Yeda Research on behalf of the Weizmann Institute of Science in Israel, challengedthe Aventis-owned patent, licensed by Imclone, for the use of anti-Epidermal growth factor receptor antibodies in combination with chemotherapy, to slow the growth of certain tumors which was filed in 1989 by Rhone-Poulenc-Rorer. The court ruled that Yeda is sole owner of the patent in the U.S., while Yeda and Sanofi-Aventis co-own the patent's foreign counterparts.

Erbitux Precautions:

Before starting Erbitux treatment, make sure you tell your doctor about any other medications you are taking (including prescription, over-the-counter, vitamins, herbal remedies, etc.). Do not take aspirin, or products containing aspirin unless your doctor specifically permits this.

Do not receive any kind of immunization or vaccination without your doctor's approval while taking Erbitux.

Inform your health care professional if you are pregnant or may be pregnant prior to starting this treatment. Pregnancy category C (use in pregnancy only when benefit to the mother outweighs risk to the fetus).

For both men and women: Do not conceive a child (get pregnant) while taking Erbitux. Barrier methods of contraception, such as condoms, are recommended. Discuss

with your doctor when you may safely become pregnant or conceive a child after therapy.

Do not breast feed while taking Erbitux and for 60 days following the last dose

How Erbitux Is Given:

By intravenous (IV) infusion.

The amount of cetuxumab that you will receive depends on many factors, including your height and weight, your general health or other health problems, and the type of cancer or condition being treated. Your doctor will determine your dose and schedule.

Medical uses

Cetuximab is indicated for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, KRAS wild-type metastatic colorectal cancer (mCRC), in combination with chemotherapy, and as a single agent in patients who have failedoxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan. The positive opinion from the European regulatory agency, the Committee for Medicinal Products for Human Use (CHMP), was received for mCRC 1st line use in May 2008.

Cetuximab (Erbitux) is 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. The positive CHMP opinion for this indication was received in October 2008

A diagnostic immunohistochemistry assay (EGFR pharmDx) can be used to detect EGFR expression in the tumor material. Approximately 75% of patients with metastatic colorectal cancer have an EGFR-expressing tumor and are therefore considered eligible for treatment with cetuximab or panitumumab, according to FDA guidelines. Unfortunately, there is evidence that immunohistochemical EGFR receptor testing does not predict response to either cetuximab or panitumumab, so that this has been called a "misleading biomarker" that has nevertheless caused insurers and even health systems to deny payment for EGFR antibody treatment for patients who lack a positive tumor EGFR histochemical test.

1-Colorectal cancer

Cetuximab is indicated for the treatment of patients with EGFR expressing, KRAS wild-type metastatic colorectal cancer in combination with chemotherapy or as a single agent in patients who have failed in oxaliplatin- or irinotecan- base therapy and who are intolerant to irinotecan. While there remains some scientific controversy on this, assessment for EGFR expression is required for use in colorectal cancer, but not in head & neck cancer.

Many clinical trials have been conducted to investigate the efficacy of cetuximab (Erbitux) in metastatic colorectal cancer (mCRC) and there is increasing evidence to support the use of biomarkers, such as KRAS, to predict tumor response to anti-EGFR therapies. Two large clinical trials of cetuximab, OPUS and CRYSTAL, have recently been published, and have provided further evidence that cetuximab significantly improves the odds of a response to treatment and in one study, reduced the risk of disease progression. However, cetuximab did not significantly affect overall survival (OS) rates in mCRC patients with KRAS wild-type tumors.

A study in June 2010 found that Erbitux failed to benefit patients with less advanced (non-metastasized) stages of colorectal cancer with no improvement in survival rates. Adding Erbitux instead increased the side effects of chemotherapy. Several recent studies showed:Adding the targeted drug 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, researchers reported at the 35th Congress of the European Society for Medical Oncology (ESMO) in Milan, ItalyA second 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; HR 1.038; 95% CI 0.90 - 1.20; p=0.68).

2- Head and neck cancer

Cetuximab was 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 therapy

Mechanism of action

When growth factors bind to their receptors on the surface of the cell, the receptors give a signal

that causes cells to divide. Some cancers are caused by mutated receptors that give a signal

to divide even without growth factor. That causes the cells to divide uncontrollably.

Cetuximab binds to such receptors and turns off that signal.

The EGFR sends a signal down a pathway ( MAPK) that includes another protein, KRAS (also spelled K-ras). In some cancers, the EGFR is mutated, and is present to a larger or smaller degree. In these 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 (although in practice, studies have shown that the effect of cetuximab does not actually depend on the amount of EGFR receptor protein found on the cancer cells). However, if the KRAS protein is mutated, cetuximab has been found not to work, because the mutated KRAS gene downstream is causing the problem by continuously sending a growth signal (the KRAS protein) and this mutated gene now does not respond to the EGFR receptor.

Therefore, 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 might work. But if KRAS is mutated, indications are that cetuximab (and also panitumumab) will not work, because the mutated

KRAS gene continuously sends a KRAS protein signal to divide, even when cetuximab has turned the earlier EGFR signal off.

KRAS testing

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.

KRAS mutational analysis is commercially available from a number of laboratories.

In July 2009, the US Food and Drug Administration (FDA) updated the labels of two anti-EGFR monoclonal antibody drugs (panitumumab (Vectibix) and cetuximab (Erbitux)) indicated for treatment of metastatic colorectal cancer to include information about KRAS mutations. In 2012, the FDA also cleared a genetic test designed to detect the presence of seven mutations in the KRAS gene in colorectal cancer cells. This test is used to screen patients with metastatic colorectal cancer for treatment with Erbitux. If the test result indicates that the KRAS mutations are absent in the colorectal cancer cells, then the patient may be considered for treatment with Erbitux.

Erbitux Side Effects:

Important things to remember about the side effects of cetuxumabinclude:

Most people do not experience all of the side effects listed.

Side effects are often predictable in terms of their onset and duration.

Side effects are almost always reversible and will go away after treatment is complete.

There are many options to help minimize or prevent side effects.

There is no relationship between the presence or severity of side effects and the effectiveness of Erbitux.

The following side effects are common (occurring in greater than 30%) for patients taking Erbitux: Rash (acne-like)

Generalized weakness, malaise

Fever

Low magnesium level (see blood test abnormalities)

Case study-erbitux

Immunohistochemical analysis of the primary tumor specimen showed an intense and diffuse staining for EGFR. Cytogenetic fluorescence in situ hybridization (FISH) analysis for the EGFR gene was negative for gene amplification but demonstrated polysomy of the chromosome 7p12 (CEP7) with an average of five copies (range 3–7) of chromosome 7 per cell. Analysis of EGFR activating mutations was not performed. The patient was then treated with cetuximab (Erbitux®, Merck KGaA, Darmstadt, Germany), administered iv at a loading dose of 400 mg/m2 over 2 hours and then at 250 mg/m2 weekly in combination with cisplatin (100 mg/m2) every 21 days as described by Herbst et al. After the second cycle, a minor response was documented clinically and by CT-PET, along with the onset of a WHO grade 2 classic anti-EGFR-dependent acneiform rash; the patient continued treatment with four complete cycles of cisplatin and 11 doses of cetuximab. He also experienced WHO grade 1 paresthesias of the extremities and mild renal function impairment. Both these side effects were attributed to cisplatin

In September 2006, during the treatment, the patient experienced recurrent convulsive seizures that required hospitalization. Neurologic examination was normal. An EEG showed a diffuse slowing of background activity. Rare and brief sequences of slow waves were recorded on the central regions, bilaterally. A brain CT-scan demonstrated the presence of at least five bilobar, parenchymal, metastatic lesions (Figure 2). Total-body CT-PET documented a partial response (PR > 50%) of all the evaluable extracranial metastatic lesions (Figure 1). Response was assessed according to the RECIST criteria for radiological CT imaging and to the 1999 EORTC recommendations for the use of [18F]fluorodeoxyglucose PET.

discussion

The epidermal growth factor receptor (EGFR) signalling pathway is involved in the physiological cell differentiation of secretory acinus and related ducts, the functional unit of salivary glands. Immunohistochemical studies demonstrated different degrees of EGFR expression in several salivary gland carcinomas, including MECs and adenoid cystic carcinomas (ACCs). In MECs, the percentage of membrane staining of EGFR is approximately 77% which is higher than in normal tissue.

EGFR overexpression is related to a poorer prognosis and a more aggressive behaviour of the disease but its overall prognostic value has not been completely established Thus, the development of anti-HER2 or anti-EGFR strategies in salivary gland carcinomas could represent a reasonable approach based on a biological rationale. In head and neck squamous cell carcinoma (HNSCC), the anti-EGFR monoclonal antibody cetuximab has been proven to prolong overall survival and to enhance response rates in recurrent/metastatic disease in combination with cisplatin or fluorouracil in combination with radiotherapy

Whether cetuximab can overcome platinum resistance in cisplatin-pretreated patients remains controversial Among predictive factors of response to anti-EGFR strategies in HNSCC, EGFR gene amplification status is predictive of sensitivity to the EGFR-tyrosine kinase inhibitor, gefitinibOn the other hand, no activating mutations in the EGFR gene are associated with response to anti-EGFR strategies.

To date, only a few, small clinical trials have investigated the antitumor activity of anti-EGFR targeted agents in the salivary gland neoplasms. In a phase II study of cetuximab monotherapyin 22 patients with recurrent/metastatic salivary gland carcinomas, including two MECs, 11 patients had stable disease, seven of which remained progression-free for over 6 months. None of these patients displayed EGFR amplification or chromosome 7 polysomy .In a recent phase II study of lapatinib, a dual inhibitor of EGFR and HER2, in recurrent/metastatic salivary gland carcinomas, including two MECs, Agulnik et al. demonstrated disease stabilization that lasted for more than 6 months in 36% of the patients; no objective responses were observed. None of the patients in the cohort with disease stabilization, however, were patients with MEC

In our report, the patient was pretreated with two lines of platinum-containing chemotherapy with no evidence of response; a response was only observed upon treatment with cisplatin along with cetuximab. We do not know whether the response was due to cetuximab alone or due to a synergistic effect with the restoration of cisplatin sensitivity. The chromosome 7 polysomy, documented in the patient, may account for increased protein expression at the membrane level and clinical response. However, a clear genotype/phenotype correlation cannot be established on the basis of only this data. Finally, a mixed pattern of central nervous system (CNS) progression and systemic response was concomitantly observed in our patient. Such an effect is often seen in metastatic breast cancer patients treated with trastuzumab who develop CNS metastases while responding at different metastatic sites. The creation of a CNS sanctuary for cancer cells results from the inability of trastuzumab to cross the blood-brain barrier due to its relatively high molecular weight; this mechanism presumably also applies to cetuximab in different neoplastic conditions, as our case demonstrates

Conclusion

In conclusion, this case report indicates cetuximab function in a recurrent and metastatic MEC of the salivary glands. EGFR expression is a prerequisite for cetuximab use but EGFR gene amplification, or

at least chromosome 7 polysomy, seems to be necessary for elicitation of biological activity. Our findings also emphasize the importance of CT-PET in monitoring neoplastic diseases during molecular targeted therapies. The inability of cetuximab to cross the blood-brain barrier and the consequent development of CNS metastases during treatment is a subject of concern that requires further study.

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