Summary Basis of Decision for Erbitux
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Erbitux
Cetuximab, 2.0 mg/mL, Solution, Intravenous
ImClone Systems Inc.orporated
Submission control no: 088225
Date issued: 2007-01-11
Health Products and Food Branch
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), PrERBITUX*, Cetuximab, 2 mg/mL, solution, ImClone Systems Inc., N° de contrôle de la présentation 088225.
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02271249
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
*™ of ImClone Systems Incorporated
2 Notice of decision
On September 9, 2005, Health Canada issued a Notice of Compliance to ImClone Systems Inc. for the drug product Erbitux.
Erbitux contains the medicinal ingredient cetuximab, a recombinant, human/mouse chimeric IgG1 monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR), a protein expressed on the surface of certain tumour cells.
Erbitux in combination with a chemotherapy medicine, irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma (CRC) in patients who are refractory to other irinotecan-based chemotherapy regimens. Erbitux administered as a single agent, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are intolerant to irinotecan-based chemotherapy. When administered, Erbitux binds to the EGFR eliminating the ability of the tumour cell to receive the messages it needs for growth, progression and metastasis.
Priority review status was granted for Erbitux taking into consideration the severity of the disease that it treats, the lack of treatment for metastatic colorectal cancer and the clinical evidence of efficacy (based on the Health Canada's clinical evaluation).
Market authorization was based on quality (chemistry and manufacturing), preclinical, and clinical information submitted. The dosing regimen was based on a pivotal Phase II trial as well as several open-label, multi-centre Phase II studies, as a monotherapy and as a combination therapy. As a monotherapy, Erbitux showed an objective response-rate of 10.8% as compared to a rate of 22.9% when used as a combination therapy with irinotecan. Phase III trials are ongoing. The data submitted to date demonstrate that Erbitux can be administered safely when used under the conditions stated in the Product Monograph.
Erbitux (2 mg/mL, cetuximab) is presented as a liquid for intravenous injection. An initial dose of 400 mg/m2 is administered as a 120-minute infusion. Subsequent weekly doses of 250 mg/m2 are infused over 60 minutes. It is recommended that treatment be continued until progression of the underlying disease. Further dosing guidelines are available in the Product Monograph.
Erbitux is contraindicated in patients with known severe hypersensitivity to cetuximab. Detailed conditions for the use of Erbitux are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Erbitux is favourable for the treatment of EGFR-expressing metastatic colorectal carcinoma when used in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy regimens or as a single agent in patients who are intolerant to irinotecan-based chemotherapies.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
Description
Cetuximab, the medicinal ingredient of Erbitux, is a recombinant, human/mouse chimeric monoclonal antibody that binds specifically and with high affinity to the extracellular domain of the human epidermal growth factor receptor (EGFR). Cetuximab functions as a competitive antagonist that inhibits the binding of ligands to EGFR which results in the inhibition of growth and survival of tumour cells that express EGFR.
Manufacturing Process and Process Controls
Cetuximab is produced by recombinant DNA technology in a mouse myeloma derived cell line. The manufacture of cetuximab is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with the ICH guidelines. Results of these tests confirmed cell line identity and absence of adventitious agents/viral contaminants. Genetic characterization (restriction endonuclease mapping and copy number analysis) also demonstrated genetic stability of the master cell bank ranging from storage to production at the limit of in vitro cell age.
The manufacture of cetuximab comprises a series of steps which include cell culture, harvest, and purification. The purification is performed via a combination of chromatographic and viral inactivation/removal steps. The consistency of the manufacturing process is ensured through defined production procedures, critical quality tests, in-process limits and cetuximab certificate of analysis specifications. Microbial control is maintained throughout the manufacturing process by testing for bioburden as well as for bacterial endotoxins. In-process controls performed during manufacture were reviewed and are considered acceptable. The specifications for the raw materials used in manufacturing the drug substance are also considered satisfactory.
Characterisation
Detailed characterization studies were performed to provide assurance that cetuximab consistently exhibits the desired characteristic structure and biological activity. Results from process validation studies also indicate that the methods used during processing adequately control the levels of product and process-related impurities. The impurities that were reported and characterized were found to be within established limits.
Control of Drug Substance
Validation reports are considered satisfactory for all analytical procedures used for in-process and release testing of cetuximab. The drug substance specifications, and analytical methods used for quality control of cetuximab are considered acceptable.
Stability
Based upon the real-time and accelerated stability data submitted, the proposed shelf-life, storage, and shipping conditions for cetuximab are supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Erbitux, 100 mg/vial, is a sterile, clear, and colourless liquid for intravenous (IV) administration that may contain a small amount of easily visible, white, amorphous cetuximab particulates. Each single-use, ready-to-use vial contains 100 mg of cetuximab as a 2.0 mg/mL preservative-free solution in phosphate buffered saline (sodium chloride, sodium phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate, and water for injection). In addition, sodium hydroxide solution and hydrochloric acid solution are used for pH adjustment. All excipients used in the manufacture of Erbitux are acceptable for use in drugs according to the Food and Drug Regulations.
Erbitux is packaged in 50 mL nominal volume Type I Flint glass moulded vials. The vials are stoppered with Teflon-coated grey plug stoppers, sealed with aluminum/polypropylene flip seals, and packaged in a carton.
The aforementioned particulates have been shown to be product-related and do not affect the quality of the product. However, Erbitux must be administered with the use of a low protein binding 0.22-micron in-line filter and should not be administered as an IV push or bolus. Removal of these particulates following filtration does not cause a measurable decrease in protein concentration.
Pharmaceutical Development
During the pharmaceutical development of Erbitux, no changes were made to the formulation. Furthermore, there were no differences between the manufacturing process used to prepare the clinical and commercial Erbitux drug product. Changes were made, however, to the cetuximab drug substance manufacturing process during development. Data pertaining to the physicochemical characteristics and biological activity demonstrated biocomparability between development and commercial batches.
Manufacturing Process and Process Controls
The Erbitux manufacturing process consists of adjusting cetuximab formulated bulk concentration and filling into vials using proper aseptic process techniques, and conventional pharmaceutical equipment and facilities.
The manufacturing facility is a cGMP (current Good Manufacturing Practices) compliant, multi-product facility. All manufacturing equipment, in-process manufacturing steps and detailed operating parameters are adequately described in the submitted documentation and are found acceptable.
Control of Drug Product
Erbitux is tested to verify its appearance, identity, purity, sterility, and potency, as well as the formulation-relevant parameters: protein content, pH, and osmolality. Validation reports were satisfactorily submitted for all analytical procedures used for in-process and release testing of the drug product, and to justify the specification of the drug product. Analytical testing results from final batch analyses were reviewed and considered to be acceptable according to the specifications of the drug product.
Stability
Based on the real-time and accelerated stability data submitted, the proposed shelf-life of 36 months at 2-8°C for Erbitux is considered acceptable.
3.1.3 Facilities and Equipment
An On-Site Evaluation (OSE) of facilities involved in the manufacture and testing of cetuximab has been successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada. The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured. All facilities are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
Pre-harvest culture fluid from each lot is tested to ensure freedom of adventitious microorganisms (bioburden, mycoplasma, and viruses). Steps from the purification process designed to remove and inactivate viruses are adequately validated.
Raw materials of animal and recombinant origin used in the manufacturing process have been adequately tested to ensure freedom of adventitious agents. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Summary and Conclusion
The Chemistry and Manufacturing information submitted for Erbitux has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
The use of cetuximab as an anti-cancer therapy is based on its interaction with EGFR, a commonly expressed transmembrane glycoprotein of the tyrosine kinase growth factor receptor family. EGFR is expressed in many normal human tissues. Data support that its activation and signalling play a role in the pathogenesis of human cancer and it has been recognized as a proto-oncogene. Cetuximab is an antibody that antagonizes the activation of EGFR resulting in the inhibition of cell proliferation and other cellular functions.
The non-clinical pharmacological investigation involved in vitro antitumour activity studies with human tumour cell lines, in vivo antitumour activity studies using human tumour xenograft models in immunodeficient mice, studies of combination therapy using cytotoxic drugs or radiotherapy, and studies of the mechanism of action of cetuximab.
The development program for non-clinical safety testing was based on investigations of the immunoreactivity of cetuximab with EGFR in various tissues of different species. It was found that cetuximab binds to EGFR in a variety of Cynomolgus monkey (CM) tissues in a pattern similar to that seen in human tissues. As a result, the CM was considered to represent a relevant model for non-clinical safety studies.
The majority of the studies utilized a placebo-or comparator-controlled, parallel-group design, using cells or animals treated identically, with the exception of treatment with either cetuximab or the control substance.
3.2.1 Pharmacodynamics
Comparative tissue binding (immunoreactivity) studies of cetuximab were carried out with tissues from various species including mice, rats, dogs, goats, CMs and normal human tissues. It was noted that although there was no reactivity in CM tissues in one study, two other studies of increased sensitivity demonstrated immunoreactivity in CM tissues. Cetuximab was also found to react with EGFR in a variety of normal human tissues. More importantly, cetuximab bound with high affinity and in a similar fashion to EGFR-positive human cancer cell lines. Several studies demonstrated cell cycle arrest with its use.
The binding of cetuximab to EGFR has three direct antitumour consequences:
- Receptor binding of the natural ligands (EGF and TGF-α) is blocked.
- Internalization of EGFR is induced, possibly leading to receptor downregulation and therefore, a decreased amount of available receptors on the cell surface.
- A cytotoxic immune effector is targeted towards EGFR-expressing tumour cells via its fragment crystalline (Fc) portion.
Cetuximab may also trigger tumour-directed antibody-dependent cellular cytotoxicity (ADCC). The data from these studies support the antagonizing action of cetuximab in preventing the activation of EGFR resulting in inhibition of cell proliferation and other cellular functions. The blockade of EGFR signalling by cetuximab caused tumour cell death in non-clinical models.
Furthermore, studies have demonstrated that tumour growth may be suppressed through the inhibition of angiogenesis resulting from direct and indirect effects of cetuximab. In addition, the complex process leading to metastasis has been shown to be blocked by cetuximab through different mechanisms in a dose-dependent manner. Generally, tumour growth inhibition was under 50% with the use of cetuximab in vitro. The in vivo efficacy of cetuximab was enhanced compared to that in vitro. Superior antitumour activity of cetuximab in vivo may be explained by its simultaneous inhibitory effect on angiogenesis as well as by other mechanisms not existing in vitro.
Concomitant treatment with cetuximab and irinotecan chemotherapy was more efficacious in many experiments in comparison to cetuximab or irinotecan used alone. This was particularly true in irinotecan-refractory tumours. Although the fundamental mechanisms responsible for the documented synergistic effects have still not been fully elucidated, EGFR blockade should enhance tumour cell death under conditions of cellular stress such as those experienced through damage induced by chemotherapy and radiation. In addition, studies have demonstrated that cetuximab can augment the anti-tumour activity of several anti-cancer agents.
No other studies were performed to analyze possible drug interactions of cetuximab other than that with chemotherapeutic drugs. Although cetuximab was the object of many studies, many unknown factors remain concerning its mechanisms of action and its interaction mechanisms with other anti-tumour agents, particularly irinotecan.
3.2.2 Pharmacokinetics
All pharmacokinetic (PK) studies were conducted in the CM. Studies included one single-dose study and a toxicokinetic evaluation of a repeat-dose study. Additional supportive PK data include serum concentrations from a single-dose safety pharmacology study. All studies used intravenous (IV) infusion administration of cetuximab. The formulations used were isotonic, phosphate buffered solutions for infusion.
Absorption, Distribution, Metabolism and Excretion
As cetuximab was only given intravenously, no study on absorption was performed. Data did show that administered doses in CM were not proportional to resulting circulating levels of cetuximab. Concentration increased at a faster rate than dose, with Cmax generally occurring at the end of the infusion as is expected for a short IV infusion. Clearance decreased in a non-linear fashion as doses increased. There was a risk of accumulation of cetuximab in the blood. The volume of distribution (Vd) suggested that cetuximab was predominantly present in the intravascular space.
PK parameters obtained from the CM after a single-dose of the lowest dose (7.5 mg/kg) correspond to the PK parameters obtained in humans after a single dose of the initial dose (400 mg/m2). Similar correlations were found for the toxicokinetic values (Cmax, AUClast) obtained during steady state conditions. Cmax values at the lowest dose level in CM were approximately equal to twice those obtained in humans under the standard treatment regimen of a 400 mg/m2 initial dose, followed by 250 mg/m2 weekly (400/250 mg/m2). AUC last values from CM at the lowest dose level corresponded to those obtained in humans under the standard treatment regimen.
No studies were conducted to evaluate metabolism or excretion.
Drug Interactions
Immunogenic reactions in CM occurred in one study. Only one of the monkeys that experienced an immunogenic reaction showed a reduction in serum concentration of cetuximab after administration of the drug.
No influence of anti-cetuximab antibodies on cetuximab PK was observed in other animals. In addition, no gender-dependent differences were observed for the PK parameters.
3.2.3 Toxicology
Acute and Sub-Acute Studies
Acute and sub-acute studies were conducted in mice and rats. The no observed effect level (NOEL) determined from these studies was in the range of 282 to 300 mg/kg in the acute studies and well over 40 mg/kg in the sub-acute studies. In all systems, doses ranging from 0 to 300 mg/kg IV did not show meaningful toxicity.
Chronic Studies
Chronic studies were conducted in monkeys with the human therapeutic dose in mind (12 to 120 mg/kg). This resulted in exposure approximately 1 to 2 times the systemic therapeutic dose at the lowest doses and up to 21 times the human dose at the highest doses. Toxicity comparable with what was expected was found. Kinetic studies resulted in steady-state circulating levels by week 4, with no accumulation over the period of the study (39 weeks).
Single-dose Toxicity
In four single-dose IV toxicity studies (two in mice and two in rats) some animals were found dead after the third day of blood collection. The deaths were attributed to stress during blood collection and were not considered to be treatment related. A dose level of 200 mg/kg was found to be the highest no observed adverse effect level (NOAEL) in rats.
Repeat-dose Toxicity
One pivotal study on repeat-dose toxicity of chronic duration was performed in CM. Based on the data from this study, the toxicological profile of cetuximab was characterized by alterations of epithelial tissues, predominantly of the skin, which led to infection, severe morbidity and death in some animals in the high-dose group. High dose decedents had haematological alterations. Their deaths were considered to be related to septicaemia secondary to ulcerative dermatitis, and were therefore indirectly related to treatment with cetuximab. Cetuximab was tolerated in the low- and intermediate-dose groups, however, due to the presence of pharmacologically-mediated skin alterations at all dose levels, a NOAEL could not be determined.
In rats, it was concluded that cetuximab is immunogenic and induces humoral immune responses as early as 7 days following initial administration. The humoral response appears to be inversely related to the dose.
Immunogenicity
Within the pivotal study, investigations on immunogenicity revealed induction of anti-cetuximab antibodies. Of the 22 animals in the study, 3 were considered to display an antibody-response against cetuximab. The incidence of immunogenicity was 13.6% in CM and the presence of anti-cetuximab antibody resulted in decreased serum concentration and increased clearance in one animal.
Genotoxicity and Carcinogenicity
Cetuximab showed no genotoxic potential in the in vitro and in vivo assays performed. No studies on carcinogenicity were performed.
Reproductive and Developmental Toxicity
No reproductive and developmental toxicity studies were performed.
Local Tolerance
The results of the study (reddening of the ear and slight dilation of veins) suggest possible local reactions when using these drugs in humans.
Experimental results concluded that potential process-related impurities were removed to acceptably low levels. Excipients included in the manufacture of Erbitux are of pharmacopoeial grade, therefore, toxicity testing of excipients and impurities was not conducted.
3.2.4 Summary and Conclusion
The non-clinical data provides support for the antitumour activity and the mechanisms of action of Erbitux, in addition to its use as a monotherapy or combination therapy.
The toxicological and PK data are considered to be sufficient to support positive conclusions about the PKs and safety of Erbitux.
3.3 Clinical basis for decision
3.3.1 Human Pharmacology
In the human studies, the doses of 250-400mg/m2 were determined largely and empirically based on levels of tolerability. The recommended dose is 400 mg/m2 for an initial infusion, followed by weekly infusions of 250 mg/m2. A dose modification guideline is provided with this regimen based on the appearance of an acneiform rash, a common, and at times, very severe side-effect with EGFR receptor antagonists.
3.3.2 Pharmacodynamics
Two pharmacodynamic (PD) studies were conducted. The first study involved the immunohistochemical analysis of tumour tissue from 12 patients. Resulting data indicated levels of saturation of the tumour EGFR by cetuximab as being between 10-95% depending on the dose.
A second PD study was conducted to characterize the effects of single doses of Erbitux (50-500 mg/m2) on expression and saturation of EGFR and other downstream signalling pathways in normal skin and tumour tissue from cancer patients. The skin biopsies were often inconclusive, however, EGFR analysis in skin biopsy samples demonstrated a decrease in EGFR protein levels across the 250-500 mg/m2 dose range. Maximal decreases occurred at doses of 400 mg/m2, whereas at doses below 250 mg/m2, slight increases in EGFR protein levels were noted.
3.3.3 Pharmacokinetics
The PK information is based on serum concentration data obtained from 19 trials comprised of a total of 906 patients with various tumour types. Of the 19 trials, 10 were escalation studies in which concentration data was obtained from a total of 175 patients receiving doses ranging from 5-500 mg/m2. The remaining 9 were target dose trials.
These were conducted with 731 patients receiving the target dose (initial dose of 400 mg/m2 followed by weekly doses of 250 mg/m2). The indication for 4 of the 9 target studies was metastatic colorectal cancer (CRC).
Derived PK parameters were examined following single and multiple doses in 12 of the studies. In the 7 additional studies, serum cetuximab peak and trough concentrations were determined.
Erbitux administered as monotherapy or in combination with concomitant chemotherapy (particularly with irinotecan) or radiotherapy exhibits non-linear PK. This was demonstrated as the area under the concentration time curve (AUC) increased in a greater than dose proportional manner as the dose increased from 20 to 400 mg/m2. Additionally, Erbitux clearance (CL) decreased from 0.08 to 0.02 L/h/m2 as the dose increased from 20 to 200 mg/m2 and appeared to plateau at doses above 200 mg/m2. Based on these results, it was determined that doses above 200 mg/m2 will maintain therapeutic levels for longer periods of time.
A comparison of the derived PK parameters from the non-compartmental analysis and the retrospective pooled population PK analysis was performed. A concentration-dependent decrease in CL was observed in the population PK analysis, similar to that observed in the non-compartmental analysis.
The volume of distribution (Vd) appeared to be independent of dose and approximated the vascular space. Following a 2 hour infusion of 400 mg/m2 of Erbitux, the maximum mean serum concentration (Cmax) was 184 μg/mL and the mean half-life was 97 hours. A 1 hour infusion of 250 mg/m2 produced a mean Cmax of 140 μg/mL. Serum Erbitux concentrations reached maximum levels at the end of infusion.
Following the target dose-regimen, Erbitux concentrations reached steady-state levels by the third weekly infusion with mean peak and trough concentrations across studies ranging from 168 to 235 μg/mL and 41 to 85 μg/mL respectively. The mean half-life was 114 hours. Increases in Erbitux half-life and exposure were approximately dose proportional. At the recommended weekly dose, the median half-life for Erbitux was 64 hours.
When administered in patients with metastatic CRC at the recommended dose, Erbitux in combination with irinotecan exhibited mean trough levels ranging from 46 to 66 μg/mL over the course of therapy. As a monotherapy, similar serum concentrations of Erbitux were obtained.
3.3.4 Clinical Efficacy
Pivotal Trial
The efficacy of Erbitux is based on one pivotal trial and two supportive trials. The pivotal trial was an open, randomized, multi-centre, Phase II study that took place in 56 centres throughout Europe. It examined the use of Erbitux alone or in combination with irinotecan in patients with metastatic colorectal adenocarcinoma. In order to be included in the trial, patients had to express EGFR as well as have documented disease progression after at least 6 weeks of treatment with a defined irinotecan containing therapy.
Patients were randomized 2:1 to cetuximab in combination with the same dose of irinotecan to which they became refractory (arm A, 218 patients) or to cetuximab as a monotherapy (arm B, 111 patients). The duration of treatment persisted until progression of the disease or the presence of unacceptable side effects occurred.
The primary objective of the study was to determine the objective confirmed response rate of the combination of cetuximab plus irinotecan and of cetuximab as a single agent in patients with metastatic CRC whose response to an irinotecan-containing regimen is disease progression. A variety of secondary objectives were also assessed.
The efficacy of the product as a monotherapy showed an objective response-rate of 10.8% in patients with metastatic CRC who had progression of their disease following an irinotecan-containing regimen. In comparison, as a combination therapy added to an existing irinotecan containing regimen an objective response rate of 22.9% was obtained. These findings appear to be confirmed in populations that failed other prior combination regimens where objective response rates varied but were of the order of 24% for combination therapy and of the order of 12% for monotherapy.
Time to progression was a median of 5.9 months in the combination arms and 4.2 months in the single therapy arms.
Non-Pivotal Trials
Two supportive studies were considered as non-pivotal trials. The primary and secondary objectives were similar to those for the pivotal trial. Both trials were Phase II, multi-centre and open label.
The first study concluded that the combination of cetuximab and irinotecan was a safe and active regimen for patients with EGFR-positive, irinotecan-refractory, advanced CRC. In the refractory patient population with few or no therapeutic options, this combination resulted in a 13% response rate and offered 53% of the patients a chance of durable tumour control. The second study concluded similar results citing a 14.3% response in the irinotecan refractory patient population and an 8.8% response rate in all treated patients. Both studies violated protocol, however, these violations did not confound the determination of the response rate. Each of the studies confirmed that cetuximab alone or in combination with irinotecan can induce responses in the refractory CRC population. Phase III trials are ongoing.
3.3.5 Clinical Safety
One-hundred percent of the patients in the pivotal trial experienced an adverse event (AE). Eighty percent of these were grade 3 or 4 in nature. The most commonly reported AEs in order of frequency were asthenia, diarrhea, nausea, abdominal pain and acne. Based on the data from this trial, the AE profile of the combination of irinotecan and cetuximab is the aggregate of the AE profile of each individual agent. There was no evidence that the addition of either agent exacerbated the AE profile of the other agent, nor was there any evidence of frequently occurring new AEs. The most common AEs associated with irinotecan were less frequent than in other trials with irinotecan in CRC. Similar results were observed in the non-pivotal studies.
More than 1123 cancer patients were treated with cetuximab during its clinical development including 633 patients with advanced CRC. The most serious adverse reactions associated with cetuximab were infusion reactions (occasionally severe, there is a report of a death in an ongoing study), dermatologic toxicity, interstitial lung disease, fever, sepsis, kidney failure and pulmonary embolus. In general, patients were able to tolerate the AEs caused by cetuximab. In the indicated population (patients with metastatic CRC), there appeared to be a higher likelihood of AEs in patients who received cetuximab concomitantly with irinotecan relative to cetuximab monotherapy. Acneiform-rash skin toxicity was the most common AE associated with cetuximab. In most patients there was improvement in severe skin reactions with dose reduction or cessation of cetuximab, however, even in those patients with improvement, complete resolution of toxicity did not occur prior to death or discontinuation from study.
Even in the presence of antihistamine prophylaxis, infusion reactions occurred (19% in patients with cetuximab and irinotecan and 25% in patients who received cetuximab alone). Treatment of patients with a test dose of cetuximab was found to not be predictive of occurrence of severe infusion reaction.
Diarrhea and neutropenia in the clinical studies were most often due to concomitant chemotherapy. Addition of cetuximab did not appear to worsen AEs associated with chemotherapy, and concomitant chemotherapy treatment did not appear to impact cetuximab-associated AEs.
There did not appear to be an influence of gender, age or race on cetuximab-induced AEs. In any case, multiple AEs are normally seen in all patients with malignancies, some of which are attributable to disease and others to the therapy or its consequences. When administering Erbitux, pre-treatment with antihistamines is recommended, thereby decreasing the severity or even eliminating any serious immune-reaction related events with Erbitux.
The safety profile of Erbitux as a single agent is well defined and acceptable, typical of a monoclonal antibody, and is consistent across the studies.
3.3.6 Issues Outstanding
The clinical trials did not raise any major efficacy issues. Two matters of concern were allergic reactions and human anti-chimeric antibody (HACA) formation and the potential for these antibodies to reduce the long-term efficacy of Erbitux. In non-clinical studies, up to 13.9% of the CMs studied presented antibody formation. Incidence in human studies was significantly lower and the response rate did not seem to be affected. Even if a diminished response were to occur, considering the severity of the disease, its life-threatening nature, and the limited survival of patients, there is significant justification in allowing for antibody formation and a potential decreased response as a worthwhile risk, taking into consideration the alternatives.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Metastatic CRC is a major health problem. Even with the best currently available therapies, most patients will die as a result of the disease within 1-2 years of diagnosis. Erbitux used as a monotherapy or combination therapy with irinotecan has resulted in a significantly higher level of anti-tumour activity for treating irinotecan refractory EGFR-expressing metastatic CRC patients for whom no other alternate treatments are available. The mean survival, however, is not significantly prolonged. In general, patients were able to tolerate AEs. In the indicated population, there appeared to be a higher likelihood of AEs in patients that received concomitant therapy.
Even in the presence of antihistamine prophylaxis, infusion reactions occurred. Treatment of patients with a test dose of Erbitux was found not to be predictive of occurrence of severe infusion reactions. The hypersensitivity reaction is characteristic of the class of agents that include monoclonal antibodies and occurs at a similar frequency as with other currently approved monoclonal antibodies. In most patients, improvement in severe skin reactions occurred with dose reduction or cessation of Erbitux, however, even in those patients with improvement, complete resolution of toxicity did not occur prior to death or discontinuation from study.
Overall, the safety profile of Erbitux as a single agent and in combination with irinotecan was well defined and consistent across studies. There did not appear to be clinically relevant cardiac, hepatic, renal, or respiratory toxicities, and the laboratory safety profile was minimally affected by Erbitux. Of interest, Erbitux was not associated with the typical chemotherapy-induced complications such as myelosuppression and hair loss. More importantly, Erbitux could be given safely with irinotecan.
In conclusion, Erbitux used as a monotherapy or combination therapy with irinotecan has resulted in a significantly higher level of anti-tumour activity for treating irinotecan refractory EGFR-expressing metastatic CRC patients for whom no other alternate treatments are available. Considering the severity of the disease, the lack of available treatments, and the relatively manageable safety profile, the benefits of the monotherapy or combination therapy outweigh the risks.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Erbitux is favourable in the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to other irinotecan-based chemotherapy treatments. Erbitux administered as a single agent is also favourable for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are intolerant to irinotecan-based therapy. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Erbitux
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2003-09-29 |
| Request for priority status | |
| Filed | 2003-10-01 |
| Approval issued by BGTD | 2003-10-15 |
| Submission filed | 2003-11-24 |
| Screening | |
| Screening Acceptance Letter issued | 2003-12-24 |
| Review | |
| On-Site Evaluation | 2005-01-25 - 2005-01-28 |
| Clinical Evaluation complete | 2005-09-07 |
| Quality Evaluation complete | 2005-09-06 |
| Labelling Review complete | 2005-08-30 |
| NOC issued by Director General | 2005-09-09 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| ERBITUX | 02271249 | IMCLONE, LLC | CETUXIMAB 2 MG / ML |