Essay: Bevacizimab, Cetuximab and Panitumumab

This literature review examines the literature and clinical trials assessing the safety, efficacy, and effect on overall survival and progression free survival of the three “MABS”. Bevacizimab, Cetuximab and Panitumumab are three monoclonal antibodies used in the treatment of colorectal cancer and other cancers. The three have been proven to significantly improve overall survival of patients with colorectal cancer, especially the wild type KRAS exon 2 type of metastatic colorectal cancer. The three MABs are more effective when used in combination with chemotherapy drugs like fluorouracil, leucovorain, oxaliplatin or irinotecan.
INTRODUCTION
The colon and rectum {colorectal} cancers come about when abnormal cells grow in the colon or rectum to polyps. Over time the polyps can turn into cancer. Metastatic cancer occurs when the cancer spreads to other parts of the body, like the liver, lungs, bones or other organs.
Colorectal cancer {CRC} is the third most common cancer in man and second most common in women and accounts for 9,4% of all cancers worldwide.It is also the fourth most common cause of cancer related deaths {Ferlay et al 2008}. The prognosis for patients with resectable tumours depends on disease stage with those with distant metastasis having a 12% survival rate. Over 20% of CRC patients have metastasis by the time of diagnosis, and 80% with localized disease who demonstrate complete macroscopic clearance of the tumour by surgery, 50% will relapse due to presence of micro-metastasis {Koido et al 2013}.
The prognosis for patients with advanced metastatic disease remains poor due to recurrence, distant metastasis and resistance to chemotherapy. Therefore other methods of treatment are required. Immunotherapy becomes a candidate due to its proven success with other cancers. More research needs to be done and is being done. Classically combinations of various forms treatment have proven effective with other types of cancer and CRC is no exception. Immunotherapy is a type of treatment that uses certain parts of a person’s immune system to fight diseases like cancer.
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There are two types of immunotherapy namely active and passive. Active immunotherapy in patients with colorectal cancer involves treating with products that stimulate their own system. Their own antibodies are made to recognize an abnormal component in the cancer cells and then selectively kill them.
Passive immunotherapy involves treating patients with CRC or other cancers with products manufactured in the laboratory to mimic the body’s antibodies. These man-made antibodies target particular components on the colorectal cancer cells to deliver cell killing chemicals or radiation to the tumour leaving out the health cells. This is referred to as Targeted Therapy.
Monoclonal antibodies are a classic type of antibody, laboratory created to find and destroy a specific target, the colorectal cancer cells or other specific cancer. This brings a specific targeted action against the tumour and has fewer side effects compared to chemotherapy. Specific examples of monoclonal antibody treatment for colorectal cancer, which are the subject of this project include; Bevacizumab {Avastin}, Cetuximab {Erbitux} and Panitumumab {Vectibix}.
BACKGROUND
Monoclonal antibodies are a classic type of antibody, laboratory created to find and destroy a specific target. Specific examples of monoclonal treatments for colorectal cancer include the three mabs namely: Bevacizumab, Cetuximab and Panitumumab.
Bevacizumab {Avastin}, a monoclonal antibody that prevents tumours from growing the blood network that brings the nutrients for the cancer cell’s survival. It stops the action of vascular endothelial growth factor {VEGF}, a substance released by tumours to stimulate the formation of new blood cells, which slows its growth or even lead to death.
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Bevacizumab is FDA approved to be used alone or with other drugs for the treatment of colorectal cancer and other types of cancer. It is an angiogenesis inhibitor ie slowing down the growth of new blood vessels by inhibiting vascular endothelial growth factor [Los et al 2007]. This drug was approved by the FDA in 2004 for use in metastatic colorectal cancer combined with standard chemotherapy treatment as first line and with 5-fluorouracil based therapy for second line treatment. It is usually administered intravenously every 14 days.
Cetuximab [Erbitux], a monoclonal antibody that slows down cancer growth by targeting the epidermal growth factor receptor [EGFR] which is a protein found on the surface of 60-80% of colon cancer cells. Colorectal cancer cells have receptors [EGFR] where the epidermal growth factor attaches to. This triggers the cell to grow and divide into more cells. Cetuximab functions by attaching to the epidermal growth factor receptors, thereby blocking the EGF protein from reaching the cancer cells, stopping them from growing. It is administered intravenously and must be given first when used with other drugs.
Panitumumab [Vectibix], is another monoclonal antibody which targets the [EGFR] and less likely to cause an allergic reaction. [www.fightcolonrectalcancer.org/researchtreatment/immunotherapy-colon-cancer-part1/. Panitumumab is indicated for the treatment of patients with wild type KRAS [exon 2 in condons 12 or 13] metastatic colorectal cancer. It is fully human monoclonal antibody specific to the epidermal growth factor. It is also called a signal transduction inhibitor which binds to epidermal growth factor receptors. Panitumumab is administered intravenously.
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OBJECTIVES
The primary objective of this literature review is to evaluate whether the three mabs ie the monoclonal antibodies, bevacizumab, cetuximab and panitumumab, used for the treatment of metastatic colorectal cancer are effective, safe and cost effective. Do they increase overall and progression free survival?.
The secondary objective is to ascertain how these drugs have been accepted by the users.
METHODOLOGY
The literature and clinical trials selected for this review were randomly selected from three main databases. These were PubMed, Google scholar and the Internet. Background information on the modus operandi of the three drugs was important and is included.
Clinical trials where each drug was tested for efficacy, safety and overall survival were chosen. More trials where the drugs were combined with other chemotherapy drugs were also reviewed to get a clearer picture of when they were more effective. The ASPECCT and PEAK trials were the largest trials that looked at these immunotherapy drugs.
Four ongoing clinical trials were also evaluated, the study design, purpose, the intervention model and type of endpoints were compared.
The statistical results from the studies reviewed were used as they were presented and my observations, conclusions, views and recommendations are based on those results.
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CHOICE OF PATIENTS
In all the trials the patients had metastatic colorectal cancer confirmed radiologically and histologically. In some trials patients were confirmed to have the wild type KRAS {exon2 in condons 12 or 13} metastatic CRC. The patients ranged from 18 to 75 years of age.
All patients had to have baseline laboratory readings at initiation as listed below:
Haematology: Platelet Count 100 by 10/9/L
Prothrombin time and aPTT <1.5 by ULN
Absolute Neutrophil Count >1000
Haemoglobin >9,0g/dl
Renal Function: <2.0 by ULN
Creatinine Clearance >50 millilitres per minute
Liver Function: AST/ALT = 2.5 by ULN or <5.0 by ULN in liver
Metastasis
Total Bilirubin <2.0 by ULN
HIV Negative
Negative pregnancy test
Fertile patients had to use effective contraception during and one month after the study.
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DOSAGE OF BEVACIZUMAB, CETUXIMAB OR PANITUMUMAB
The initial dose was 400 mg of cetuximab per square metre of body surface area administered intravenously. This is followed up by weekly infusion of 250 mg of cetuximab per square meter of body surface area. For bevacizumab it was 5 mg/kg once every week and 6mg/kg for panitumumab once every week. The dosages were changed in some of the trials.
The tumour response evaluation was done every 8 weeks and patients observed for 30days after study.
RESULTS
572 patients with CRC {from December 2003 to August 2005} expressing EGFR immunohistochemically detectable underwent randomization with the primary end point of overall survival {Jonker et al 2007}. 287 patients were infused with bevacizumab weekly and best supportive care provided to285 patients.
Overall hazard ratio for death survival 0.77 {0.64-0.92} 95% CI
Progression free survival 0.68% {0.57-0.80} 95% CI
Median Overall Survival 6.1 months Test group
Median Overall Survival 4.6 months control group
Partial response 8.0% versus 0 {p<0.001}
Disease Stability 31.4% versus 10.9 {p<0.001
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RESULTS FOR THE CETUXIMAB MONOTHERAPY AND CETUXIMAB PLUS IRINOTECAN IN IRINOTECAN REFRACTORY METASTATIC COLORECTAL CANCER.
CetuximabCetuximab + Irinotecan
Rate of Response 10.8% 22.9%
Time to Tumour Progression 1.5 months 4.1 months
Median Survival Time 6.9 months 8.6 months
Toxic Effects + ++
RESULTS FOR THE FOLFIRI PLUS CETUXIMAB VERSUS FOLFIRI PLUS BEVACIZUMAB AS FIRSTLINE TREATMENT FOR PATIENTS WITH METASTATIC COLORECTAL CANCER [FIRE-3]: A RANDOMIZED, OPEN LABEL, PHASE 3 TRIAL [HEINEMANN ET AL 2014]
Folfiri +Cetuximab Folfiri + Bevacizumab
Objective Response 62.0% {56.2-67.5} 58% {52.1-63.7}
Median Progression Free Survival 10.0 months {8.8-10.8} 10.3 months {9.8-11.3}
Median Overall Survival 28.7 months {24.0-36.6} 25.0months{22-28}
Haematoxicity 25% 21%
Skin Reactions 26% 2%
Diarrhoea 11% 14%
7.
RESULTS FOR PANITUMUMAB VERSUS CETUXIMAB IN PATIENTS WITH CHEMOTHERAPY-REFRACTORY WILD TYPE KRAS EXON2 METASTATIC COLORECTAL CANCER {ASPECCT}: A RANDOMIZED, MULTICENTRE, OPEN-LABEL, NON INFERIORITY PHASE 3 STUDY {PRICE 14 APRIL 2014}.
Panitumumab Cetuximab
Median Overall Survival 10.4 months 10.0months
Skin Toxicity 13 % 10%
Hypomagnesaemia 7% 3%
3-4 Infusion Reactions <0.5% 2%
STUDY OF PANITUMUMAB PLUS MODIFIED FLUOROURACIL, LEUCOVORIN AND OXALIPLATIN[Mfolfox 6] IN PATIENTS WITH PREVIOUSLY UNTREATED, UNRESECTABLE WILD TYPE KRAS EXONMETASTATIC COLORECTAL CANCER {Swartzberg et al 2014].
Panitumumab Bevacizumab
Progression Free Survival 0.87 0.67
Median Overall Survival 34.2 months 24.3 months
WT RAS subgroup of KRAS 41.3 months 28.9 months
And NON KRAS
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DISCUSSION
In the clinical trial by Jonker et al, it is very apparent that cetuximab improves overall and progression free survival. There is also preservation of quality of life measures in patients with CRC where other treatments would have failed. However the difference between the best supportive care group and cetuximab group is not great despite being statistically significant only 1.5 months.
When cetuximab is compared with itself in combination with irinotecan in normally irinotecan resistant metastatic CRC its effect is very significant. The negative aspect there is the presence of more toxic effects due to the irinotecan. The monoclonal antibody drugs are less toxic compared to chemotherapy drugs and cetuximab is no exception. When it is combined with irinotecan cetuximab seems to unmask whatever would have caused the resistance.
In the phase 3 clinical trials held in Germany and Austria, whose primary endpoint was objective response analysed by intention to treat, there was not much significant difference between the two groups .However the FOLFIRI plus Cetuximab group was associated with longer overallsurvival of a median of 3.7 months over FOLFIRI plus bevacozumab group. This might indicate that cetuximab would be a better first line regimen for patients with KRAS exon 2 wild type metastatic colorectal cancer.
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When one considers the other mab as I want to call these three monoclonal antibody drugs, panitumumab versus cetuximab in patients with wild type KRAS exon 2 metastatic CRC in the ASPECCT TRIAL done in several countries, panitumumab is non inferior to cetuximab. Both provide similar overall survival benefits. There are however very small but meanful differences in the rate of grade 3-4 infusion reactions.
In the PEAK study where both panitumumab and bevacizumab were given in combination with modified fluorouracil, leucovorin and oxaliplatin {Mfolfox}, progression free survival was similar. Overall survival was improved with panitumumab relative to bevacizumab when combined with Mfolfox 6 in patients wild type KRAS exon 2 tumours. Patients with WT KRAS tumours experienced more clinical benefit with anti-epidermal growth factor receptor therapy.
In the CAIRO 3 clinical trial maintenance treatment with capecitabine and bevacizumab was studied in Holland {Simkens April 2015}. The progression free survival was the same between the maintenance group and the observation group. The conclusion was that maintenance treatment with capecitabine and bevacizumab in patients metastatic CRC is effective and does not compromise quality of life.
There are fewer side effects with these three drugs when used on their own compared to the chemotherapy drugs but side effects are still experienced. The main side effects of bevacizumab are hypertension and an increased risk of bleeding which requires monitoring. Cetuximab causes mild effects on the liver, flu-like symptoms, tiredness and weakness, skin reactions, sore mouth and throat, loss of fertility and increased hair growth.
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Panitumumab causes hypomagnesaemia according to the ASPECCT clinical trial and Cheng {2009}. When administering panitumumab magnesium levels should be monitored from initiation to at least 8 weeks after stopping the administration of the drug.
The three drugs come at a price. Bevacizumab costs $42000 to $55000 per year and extends life by 4.7 months from 15.6 to 20.3 months {Mayer 2004}. In the UK the National Institute for Health and Clinical Excellence has taken a position against this drug due to the cost and somewhat minimal benefit. Here in the third world the use of these drugs is greatly curtailed because of the cost factor. Where individuals have run out of options of treatment and can afford them the uptake is but on a global scale there are limitations.
The design of the clinical studies was basically similar. The study type was interventional, allocation being randomization and masking was open label. The purpose of the studies was treatment and the primary endpoint being overall survival and progression free survival for the phase 3 clinical trials. The endpoint for the phase 2 trials was safety and efficacy. In all the trials the objectives were realized. The intervention models used were the parallel and the factorial assignment models.
CONCLUSION
There was a huge expectation when the three ‘’mabs’’ came aboard after the successes with melanoma, kidney and lung cancers. Bevacizumab, Cetuximab and Panitumumab {mabs} improve overall survival and progression free survival on their own and are more effective when used in combination with chemotherapy drugs like fluorouracil, leucovorin, capecitabine and oxaliplatin. The expectation is for long term cures with minimal side effects.
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Monoclonal antibodies being very specific were supposed to offer much more than what is on the table right now. While it is accepted that there are significant improved overall survival, the major increases we all wanted to see have not happened. More research and trials are being done to improve on the progress made so far. The knowledge gathered from the success of the three ‘’mabs’’ should facilitate the production of more potent monoclonal antibodies to treat metastatic colorectal cancer.
In the meantime the issue of cost of these drugs needs to be looked at, with pharmaceutical companies realizing that they can still make their money when more people have access. The uptake will be higher if the cost becomes affordable.
While more trials and research is going on it is recommended that more be expended in the prevention of colorectal cancer.Changes in our life styles are fundamental more so to those who have a genetic predisposition to colorectal cancer. Physical exercise, detoxification via drinking more clean water, eating foods with lots of fibre will go a long way in reducing the incidence of colorectal cancer.
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