Erbitux
cetuximab
Species
MonkeyRat
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey (pivotal); supporting 4-week rat study
“The pivotal repeat-dose toxicity study is a 39 week study in Cynomolgus monkeys (study 070-087). A 4-week study in Sprague-Dawley rats was also conducted (study 54167).”
Why that species
Cynomolgus monkey considered appropriate; adverse reactions similar to those in humans
“The Cynomolgus monkey was considered an appropriate species for safety testing of cetuximab. The similarity of adverse reactions seen in monkeys and humans supports this notion.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkey
“A comprehensive 39-week repeat-dose toxicology study in the Cynomolgus monkey was conducted.”
Species: general tox
Cynomolgus monkey (39-week pivotal); supporting 4-week Sprague-Dawley rat study
“The pivotal repeat-dose toxicity study is a 39 week study in Cynomolgus monkeys (study 070-087). A 4-week study in Sprague-Dawley rats was also conducted (study 54167).”
Species: DART
Cynomolgus monkey (embryo-fetal development, organogenesis dosing)
“Pregnant cynomolgus monkeys were administered cetuximab intravenously once weekly during the period of organogenesis (gestation day [GD] 20-48) at dose levels 0.4 to 4 times the recommended dose of ERBITUX based on body surface area (BSA).”
Species: carcinogenicity
Not conducted
“No carcinogenicity studies were performed.”
Surrogate used in
No surrogate used; clinical antibody tested in cynomolgus monkey
“A comprehensive 39-week repeat-dose toxicology study in the Cynomolgus monkey was conducted.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“The pivotal repeat-dose toxicity study is a 39 week study in Cynomolgus monkeys (study 070-087).”
Pivotal GLP studies
39-week IV cynomolgus study: 12/38/120 mg/kg initial dose, then weekly 7.5/24/75 mg/kg
“The initial doses and subsequent weekly doses were 12 and 7.5 mg/kg for the low dose group, 38 and 24 mg/kg for the intermediate dose group, and 120 and 75 5 mg/kg for the high dose group.”
Route in tox
Intravenous infusion
“Toxicokinetics after repeated infusions of cetuximab to Cynomolgus monkeys, (0, 12, 38 and 120 mg/kg at week 1, subsequent weekly doses 0, 7.5, 24 and 75 mg/kg).”
Skipped studiesopen answer page →
Genotoxicity
Conducted (partial): Ames test and rat micronucleus test negative
“the applicant decided to perform a partial genotoxicity study using in vitro and in vivo assays in terms of an AMES test and a rat micronucleus test. No genotoxic potential of Cetuximab was observed.”
Carcinogenicity
Not conducted; not required given life-expectancy in the intended advanced cancer indication
“Based on the life-expectancy in the intended therapeutic indication, no long-term carcinogenisity studies are required80.”
Reproductive & developmental
Monkey embryo-fetal study: embryolethality and abortions, no fetal malformations
“While no fetal malformations occurred in offspring, there was an increased incidence of embryolethality and abortions at doses approximately 1 to 4 times the recommended dose of ERBITUX based on BSA.”
Safety pharmacology
Single-dose monkey CV/respiratory study plus endpoints in 39-week study: no cardiovascular or respiratory effects
“In conclusion, there were no indications of an effect of cetuximab on the cardiovascular and respiratory system.”
Genotox: Ames
Negative (Salmonella and E. coli, with and without S9)
“In vitro genotoxicity investigations using Salmonella typhimurium and Escherichia coli as test systems with and without addition of liver S9 mix as external metabolising system yielded no indications of a mutagenic potential of Cetuximab.”
Genotox: in vitro mammalian
Not conducted (partial battery: Ames and rat micronucleus only)
“the applicant decided to perform a partial genotoxicity study using in vitro and in vivo assays in terms of an AMES test and a rat micronucleus test.”
Genotox: in vivo
Rat micronucleus test negative (limited value: no cetuximab immunoreactivity with rat tissues)
“Furthermore, in an in vivo cytogenetic assay performed as a micronucleus test in male Wistar rats, cetuximab was not genotoxic. The results of the micronucleus test are considered of limited value due to the lack of immunoreactivity of Cetuximab with tissues from rats”
Carcinogenicity model
Not conducted; standard carcinogenicity studies considered inappropriate for biotechnology-derived products
“No standard carcinogenicity studies were performed with cetuximab as these are generally considered inappropriate for biotechnology-derived products79.”
Carcinogenicity timing
Not required given life-expectancy in the advanced cancer indication
“Based on the life-expectancy in the intended therapeutic indication, no long-term carcinogenisity studies are required80.”
hERG / QT
No hERG assay; no ECG, heart rate or blood pressure effects in 39-week monkey study
“Electrocardiography, determination of heart rate and blood pressure (pre-dose, week 4, 13, 26 and 39, 1 h after infusion) revealed no findings related to treatment with cetuximab.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Erbitux don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oncology monoclonal antibodies (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Skin primary target organ with dose-dependent effects at all doses; severe skin reactions and 5 deaths at high dose (EMA assessment report, p. 11)
NOAEL / key findings
Skin primary target organ with dose-dependent effects at all doses; severe skin reactions and 5 deaths at high dose
“Clinical and necropsy findings indicated that the skin was the primary target organ, with dose-dependent effects observed at all dose levels. Severe skin reactions and 5 intercurrent deaths were observed in the high dose group.”
Risksopen answer page →
Immune & cytokine safety
Anti-drug antibodies in 3/22 monkeys (13.6%), affecting serum concentration in one
“Antibody responses were observed in 3/22 (13.6%) Cynomolgus monkeys. An effect on cetuximab serum concentrations was observed for one of these animals only.”
Biodistribution & persistence
Saturable clearance at higher doses; distribution mainly within plasma volume
“Clearance decreased and terminal half-life increased with increasing dose, indicating a saturated clearance at higher doses. Distribution volume indicated that cetuximab is mainly located in the plasma volume.”
Modality-specific risk
EGFR-mediated maturation defect of the epidermis (skin toxicity)
“Pathogenetically the skin lesions were considered to be related to a Cetuximab induced maturation defect of the epidermis.”
Anti-drug antibodies: animals
Antibodies in 3/22 monkeys (13.6%); effect on serum cetuximab in one animal
“Antibody responses were observed in 3/22 (13.6%) Cynomolgus monkeys. An effect on cetuximab serum concentrations was observed for one of these animals only.”
Anti-drug antibodies: patients
Binding anti-cetuximab antibodies <5% of 105 evaluable patients (ELISA)
“The incidence of anti-cetuximab binding antibodies in 105 patients (from studies I4E-MC-JXBA, I4E-MC-JXBB, and I4E-MC-JXBD) with at least one post-baseline blood sample (≥4 weeks post first ERBITUX administration) was <5%.”
Label warnings
Boxed warning: INFUSION REACTIONS and CARDIOPULMONARY ARREST
- Infusion Reactions
- Cardiopulmonary Arrest
- Pulmonary Toxicity
- Dermatologic Toxicity
- Risks Associated with Use in Combination with Radiation and Cisplatin
- Hypomagnesemia and Accompanying Electrolyte Abnormalities
- Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with Ras-Mutant mCRC
- Embryo-Fetal Toxicity
Hypersensitivity & infusion reactionsCardiovascularPulmonary toxicitySkin reactionsMetabolic & endocrineSecondary malignancyEmbryo-fetal toxicity
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Erbitux don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oncology monoclonal antibodies (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Skin primary target organ with dose-dependent effects at all doses; severe skin reactions and 5 deaths at high dose (EMA assessment report, p. 11)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey study with treatment-free recovery period
“In the 39-week repeat-dose toxicity study in Cynomolgus monkeys, examination of individual sexual cycle length from week 25 onwards, including the treatment-free period, revealed an impairment of menstrual cyclicity in Cetuximab treated females such as increased incidences of irregular cyclicity or absence of cyclicity when compared to controls.”
Pivotal GLP studies
39-week IV cynomolgus study: 12/38/120 mg/kg initial dose, then weekly 7.5/24/75 mg/kg
“The initial doses and subsequent weekly doses were 12 and 7.5 mg/kg for the low dose group, 38 and 24 mg/kg for the intermediate dose group, and 120 and 75 5 mg/kg for the high dose group.”
DART package
Species: DART
Cynomolgus monkey (embryo-fetal development, organogenesis dosing)
“Pregnant cynomolgus monkeys were administered cetuximab intravenously once weekly during the period of organogenesis (gestation day [GD] 20-48) at dose levels 0.4 to 4 times the recommended dose of ERBITUX based on body surface area (BSA).”
Reproductive & developmental
Monkey embryo-fetal study: embryolethality and abortions, no fetal malformations
“While no fetal malformations occurred in offspring, there was an increased incidence of embryolethality and abortions at doses approximately 1 to 4 times the recommended dose of ERBITUX based on BSA.”
PPND / ePPND: when
Not conducted: no reproductive and developmental toxicity studies performed
“No reproductive and developmental toxicity studies were performed.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No carcinogenicity studies were performed.”
Carcinogenicity model
Not conducted; standard carcinogenicity studies considered inappropriate for biotechnology-derived products
“No standard carcinogenicity studies were performed with cetuximab as these are generally considered inappropriate for biotechnology-derived products79.”
Carcinogenicity timing
Not required given life-expectancy in the advanced cancer indication
“Based on the life-expectancy in the intended therapeutic indication, no long-term carcinogenisity studies are required80.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: lowest monkey dose (12 then 7.5 mg/kg weekly) equals the human therapeutic dose
“The dosage was based on the human therapeutic starting dose of 400 mg/m2 and subsequent weekly doses of 250 mg/m2 , which translates to 12 and 7.5 mg/kg for a human ofbody surface area of 1.8 m2”
NOAEL / key findings
Skin primary target organ with dose-dependent effects at all doses; severe skin reactions and 5 deaths at high dose
“Clinical and necropsy findings indicated that the skin was the primary target organ, with dose-dependent effects observed at all dose levels. Severe skin reactions and 5 intercurrent deaths were observed in the high dose group.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human tumour xenografts (GEO colon, renal, A431) in immunodeficient mice treated with cetuximab
“In immuno-deficient mice, GEO (human colon cancer) cell tumour growth was markedly reduced by cetuximab 1 mg twice weekly for 3-5 weeks and even more by a combination of cetuximab and VEGF antisense.”
Why that model
EGFR-expressing human tumour xenografts used; EGFR-negative xenografts unresponsive, linking activity to EGFR blockade
“These cells do not express EGFR and the result supports the hypothesis that the antitumour effect of cetuximab is linked to blockade of EGFR.”
Reviewer's view of the efficacy data
EMA: sufficient knowledge, largely from published in vitro literature; batch characteristics of test material not described
“Although batch characteristics for the cetuximab substance used are not described, overall, there is sufficient knowledge from in vitro studies published in the literature that cetuximab binds to the EGFR and to some degree inhibits the signals required for cell growth and expression of angiogenetic factors.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
No reproductive and developmental toxicity studies; menstrual cyclicity evaluated within the 39-week monkey study
Why: Reproduction toxicity studies not required for anticancer agents; only possible finding was impaired menstrual cyclicity · Within the guideline · Weight of evidence
“Reproductive and developmental toxicity No reproductive and developmental toxicity studies were performed.”
“Based on the repeated dose toxicity study, there are no serious concerns regarding reproductive toxicity as the only alteration possibly related to treatment with cetuximab was an impairment of menstrual cyclicity. Studies of toxicity to reproduction are not required for anticancer agents, since it is assumed that reproductive occurrences are generally expected 81.”
Safety marginVerdict not stated
No exposure margin in the 39-week monkey study: low dose (12 then 7.5 mg/kg) equals the human therapeutic dose
“The dosage was based on the human therapeutic starting dose of 400 mg/m2 and subsequent weekly doses of 250 mg/m2 , which translates to 12 and 7.5 mg/kg for a human ofbody surface area of 1.8 m2 and 60 kg body weight.”
SpeciesCriticised but acceptedBeyond the letter
Cynomolgus monkey used without data on cetuximab binding affinity to monkey versus human EGFR
Why: Similarity of adverse reactions in monkeys and humans supports the species · Human data
“However, information about the binding affinity of cetuximab to monkey EGFR relative to human EGFR is lacking, and this makes the evaluation of the toxicology findings difficult.”
“The Cynomolgus monkey was considered an appropriate species for safety testing of cetuximab. The similarity of adverse reactions seen in monkeys and humans supports this notion.”
OtherAccepted with a conditionBeyond the letter
No nonclinical toxicity studies of co-administration with irinotecan
Why: Commitment to submit clinical combination data from ongoing and planned studies · Human data
“No toxicological studies have investigated the the co-administration of cetuximab and irinotecan. The applicant has committed to submit further clinical data on the combination of cetuximab and irinotecan generated in the ongoing/planned phase III studies.”
“Thus, the lack of non-clinical invistigations on the toxicity of co-administration with irinotecan has been adequately justified by the applicant.”
Safety pharmacologyAcceptedBeyond the letter
No specific CNS safety pharmacology studies
Why: Nature of the product, specific receptor targeting and toxicology findings · Low-risk modality · Weight of evidence
“The applicant has submitted a justification for not conducting specific studies on the effects of cetuximab on the CNS. Taking into consideration the nature of the product, the specific receptor targeting, and the findings from the toxicology studies, the justification provided by the applicant is acceptable.”
Similar precedents
PortrazzaAntibodies · necitumumab · EGFRMonkey only · 26 wkVectibixAntibodies · panitumumab · EGFRMonkey only · 26 wkLazcluzeSmall molecules · lazertinib · EGFR (mutant-selective)Rodent + dog or minipig · 13 wkRybrevantMultispecifics · amivantamab · EGFR x METMonkey only · 13 wkCampathAntibodies · alemtuzumab · CD52Monkey + rodent · 4 wkTecentriqAntibodies · atezolizumab · PD-L1Monkey + rodent · 26 wk