Rybrevant
amivantamab
Species
Monkey
Longest study
13 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“The cynomolgus monkey was selected as the only pharmacologically relevant species for the nonclinical pharmacokinetic (PK) and toxicology assessments of amivantamab based on a comparison of sequence homology, cross-species comparisons of relative target-binding affinities, and functional activity in cell-based assays.”
Why that species
Similar binding to human and cyno EGFR/MET ECD, no rat binding; ~10-fold lower pEGFR inhibition in cyno cells
“Amivantamab bound to the ECD of human and cynomolgus monkey EGFR and MET with similar EC50 values (Table 3), but not to the ECD of rat EGFR or MET (data not included in review).”
Surrogate molecule
No surrogate; clinical molecule in monkey (comparator data from lazertinib and zalutumumab used for repro WoE)
“The cynomolgus monkey is considered the pharmacologically relevant species for the toxicology program of amivantamab (see Section 0, Safety Pharmacology).”
Species: general tox
Cynomolgus monkey only (pivotal 13-week GLP IV study)
“Janssen conducted a GLP-compliant 13-week toxicology study in cynomolgus monkeys.”
Species: DART
Not conducted; weight-of-evidence assessment instead
“Rather than conducting a dedicated embryofetal development study, Janssen provided a weight-of-evidence-based assessment of the potential for amivantamab to cause reproductive and embryofetal toxicity.”
Species: carcinogenicity
Not conducted (not necessary for advanced cancer)
“In addition, Janssen did not conduct dedicated studies to assess fertility or carcinogenicity as these studies are not necessary to support the development of a drug intended to treat patients with advanced cancer.”
Surrogate used in
No surrogate of amivantamab; repro assessment used comparator data (lazertinib rat EFD/fertility, zalutumumab monkey EFD)
“GLP-compliant study reports for both rat embryofetal development and fertility and early embryonic studies of lazertinib, a small molecule EGFR inhibitor; and an embryofetal development study in cynomolgus monkeys using zalutumumab, an anti-EGFR monoclonal antibody.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“Janssen conducted a GLP-compliant 13-week toxicology study in cynomolgus monkeys. Monkeys received intravenous amivantamab once weekly at doses of 0, 60, or 120 mg/kg.”
Pivotal GLP studies
Cynomolgus IV weekly: 4-week non-GLP tolerability, 6-week GLP (6-week recovery), 13-week GLP; 2-week SC local tolerance
“The repeat-dose toxicity of amivantamab in cynomolgus monkeys was evaluated in a 4-week tolerability non-GLP study, and 6-week toxicity with 6-week recovery and 13-week toxicity GLP studies.”
Route in tox
Intravenous (slow bolus, weekly); SC for local tolerance
“Route of administration: Intravenous; slow bolus injection”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (not appropriate for antibodies)
“Janssen did not conduct genetic toxicology studies as they are not appropriate for antibody therapies.”
Carcinogenicity
Not conducted (advanced cancer, ICH S9)
“In addition, Janssen did not conduct dedicated studies to assess fertility or carcinogenicity as these studies are not necessary to support the development of a drug intended to treat patients with advanced cancer.”
Reproductive & developmental
Not conducted; weight-of-evidence (EGFR/MET knockouts, lazertinib rat EFD, zalutumumab monkey EFD); embryofetal warning
“Rather than conducting a dedicated embryofetal development study, Janssen provided a weight-of-evidence-based assessment of the potential for amivantamab to cause reproductive and embryofetal toxicity.”
Safety pharmacology
Incorporated into 1-month, 6-week and 3-month monkey studies (CV, respiratory, observational CNS)
“Separate safety pharmacology studies were not conducted with amivantamab; however, the 1-month non-Good Laboratory Practice (GLP) tolerability study, and the 6-week and the 3-month toxicity GLP studies in cynomolgus monkeys incorporated cardiovascular and respiratory assessments as well as observational central nervous system (CNS) assessments (body temperature and clinical signs).”
Genotox: Ames
Not conducted (not appropriate for antibodies)
“Janssen did not conduct genetic toxicology studies as they are not appropriate for antibody therapies.”
Genotox: in vitro mammalian
Not conducted (not appropriate for antibodies)
“Janssen did not conduct genetic toxicology studies as they are not appropriate for antibody therapies.”
Genotox: in vivo
Not conducted (not appropriate for antibodies)
“Janssen did not conduct genetic toxicology studies as they are not appropriate for antibody therapies.”
Carcinogenicity model
Not conducted (not necessary for advanced cancer)
“In addition, Janssen did not conduct dedicated studies to assess fertility or carcinogenicity as these studies are not necessary to support the development of a drug intended to treat patients with advanced cancer.”
Carcinogenicity timing
Not required (advanced cancer)
“In addition, Janssen did not conduct dedicated studies to assess fertility or carcinogenicity as these studies are not necessary to support the development of a drug intended to treat patients with advanced cancer.”
hERG / QT
No hERG assay; no cardiovascular, CNS or respiratory findings in monkeys up to 120 mg/kg/week
“There were no cardiovascular, observational CNS, or respiratory findings associated with intravenous (IV) administration of amivantamab up to 120 mg/kg/week in cynomolgus monkeys.”
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 Rybrevant 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 multispecifics
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: NOAEL 120 mg/kg/wk (highest dose; >=5.3x human AUC); minimal liver, kidney, stomach findings (FDA multi-discipline review, p. 57)
NOAEL / key findings
NOAEL 120 mg/kg/wk (highest dose; >=5.3x human AUC); minimal liver, kidney, stomach findings
“The no-observed-adverse-effect level (NOAEL) in the toxicology studies was 120 mg/kg/week (highest tested dose) for the 6-week and 3-month toxicity GLP studies.”
Risksopen answer page →
Immune & cytokine safety
Low CRS risk in human blood cytokine release assay; ADA in 17/67 monkeys; no immunotoxicity
“In an in vitro assay using human blood, the cytokine release profile for amivantamab was similar to that of the negative control, indicating a low risk for cytokine release syndrome.”
Biodistribution & persistence
No distribution/metabolism/excretion studies (IgG mAb); nonlinear TMDD PK below 20 mg/kg/week
“Conventional distribution, metabolism, and excretion studies were not conducted for amivantamab since it is a immunoglobulin G (IgG)-based monoclonal antibody (mAb) with a molecular weight of approximately 148,000 Daltons (kD).”
Modality-specific risk
On-target EGFR/MET epithelial toxicity under-tested: only ~5x margin and lower cyno potency; embryofetal risk
“However, the exposure margin at the highest dose was only about 5-fold the clinical AUC indicating that the high dose levels were not set at an appropriate level.”
Anti-drug antibodies: animals
17 of 67 monkeys ADA-positive; 5 of these showed faster concentration decrease
“Among the 67 cynomolgus monkeys dosed with amivantamab in the IV single-dose, 1-month, 6-week, and 3-month studies, 17 tested positive for the presence of anti-drug antibodies (ADA). Five of the 17 ADA-positive animals exhibited a faster concentration decrease compared with other animals in the same dose group.”
Anti-drug antibodies: patients
Treatment-emergent ADA in 0.2% (4/1,862) of patients
“4 of the 1,862 (0.2%) patients who received RYBREVANT as a single agent or in combination developed a treatment-emergent anti-amivantamab-vmjw antibodies.”
Label warnings
- Infusion-Related Reactions
- Interstitial Lung Disease/Pneumonitis
- Venous Thromboembolic (VTE) Events with Concomitant Use of RYBREVANT and Lazertinib
- Dermatologic Adverse Reactions
- Ocular Toxicity
- Embryo-Fetal Toxicity
Hypersensitivity & infusion reactionsImmune-mediated reactionsPulmonary toxicityThrombosis & embolismSkin reactionsOcular toxicityEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
US and ex-US (Australia, Canada, China, France, Japan, Korea, Spain, Taiwan, UK): first-in-human dose escalation/expansion in advanced NSCLC
“Ongoing Australia, Canada, China, France, Japan, Republic of Korea, Spain, Taiwan, UK, US 53 Phase 1 First-in-human, openlabel, 2- part, dose escalation and dose expansion, multicenter study Men and women ≥18 years of age with histologically or cytologically confirmed advanced NSCLC”
Repeat-dose tox before first-in-human
6-week GLP cynomolgus monkey IV study (0, 20, 60, 120 mg/kg/week) reviewed with the original IND
“Dr. Stephanie Aungst reviewed the 6-week GLP-compliant repeat dose toxicology study in cynomolgus monkeys dosed with JNJ-61186372 at 0, 20, 60, and 120 mg/kg/week at the time of original IND submission;”
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Rybrevant 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 multispecifics
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: NOAEL 120 mg/kg/wk (highest dose; >=5.3x human AUC); minimal liver, kidney, stomach findings (FDA multi-discipline review, p. 57)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week GLP cynomolgus monkey IV study, weekly 60 or 120 mg/kg
“Janssen conducted a GLP-compliant 13-week toxicology study in cynomolgus monkeys. Monkeys received intravenous amivantamab once weekly at doses of 0, 60, or 120 mg/kg.”
Pivotal GLP studies
Cynomolgus IV weekly: 4-week non-GLP tolerability, 6-week GLP (6-week recovery), 13-week GLP; 2-week SC local tolerance
“The repeat-dose toxicity of amivantamab in cynomolgus monkeys was evaluated in a 4-week tolerability non-GLP study, and 6-week toxicity with 6-week recovery and 13-week toxicity GLP studies.”
DART package
Species: DART
Not conducted; weight-of-evidence assessment instead
“Rather than conducting a dedicated embryofetal development study, Janssen provided a weight-of-evidence-based assessment of the potential for amivantamab to cause reproductive and embryofetal toxicity.”
Reproductive & developmental
Not conducted; weight-of-evidence (EGFR/MET knockouts, lazertinib rat EFD, zalutumumab monkey EFD); embryofetal warning
“Rather than conducting a dedicated embryofetal development study, Janssen provided a weight-of-evidence-based assessment of the potential for amivantamab to cause reproductive and embryofetal toxicity.”
PPND / ePPND: when
Not conducted: fertility and pre-/postnatal development studies not necessary for the BLA in this indication
“fertility and early embryonic development and prenatal and postnatal development studies are not necessary for the submission of a BLA for the proposed indication.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not necessary for advanced cancer)
“In addition, Janssen did not conduct dedicated studies to assess fertility or carcinogenicity as these studies are not necessary to support the development of a drug intended to treat patients with advanced cancer.”
Carcinogenicity model
Not conducted (not necessary for advanced cancer)
“In addition, Janssen did not conduct dedicated studies to assess fertility or carcinogenicity as these studies are not necessary to support the development of a drug intended to treat patients with advanced cancer.”
Carcinogenicity timing
Not required (advanced cancer)
“In addition, Janssen did not conduct dedicated studies to assess fertility or carcinogenicity as these studies are not necessary to support the development of a drug intended to treat patients with advanced cancer.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey AUC at 120 mg/kg 5x human AUC at the 1050 mg clinical dose
“Exposures achieved in monkeys at the 120 mg/kg dose level were 5x1 times higher than the AUC in patients (102954 µg*h/mL) at the once weekly dose for 4 weeks, then every 2 weeks clinical dose of 1050 mg.”
NOAEL / key findings
NOAEL 120 mg/kg/wk (highest dose; >=5.3x human AUC); minimal liver, kidney, stomach findings
“The no-observed-adverse-effect level (NOAEL) in the toxicology studies was 120 mg/kg/week (highest tested dose) for the 6-week and 3-month toxicity GLP studies.”
Efficacy evidenceopen answer page →
Efficacy evidence
Patient-derived tumor xenografts with EGFR exon 20 insertion mutations in mice
“In mice bearing patient derived tumors with exon 20 insertion mutations, administration of intraperitoneal (i.p.) amivantamab twice weekly resulted in significant tumor growth inhibition and complete responses in several animals, as did cetuximab and osimertinib.”
Why that model
Human cell xenografts used; amivantamab does not interact with murine c-Met or EGFR
“For the pharmacology efficacy studies, mouse models with human cell xenografts were used, and Amivantamab did not exhibit any interaction with murine c-Met or EGFR in cross-reactivity studies while beneficial properties against human c-Met or EGFR have been shown, which is satisfactory.”
Reviewer's view of the efficacy data
EMA: human-xenograft mouse efficacy models satisfactory given no murine cross-reactivity
“For the pharmacology efficacy studies, mouse models with human cell xenografts were used, and Amivantamab did not exhibit any interaction with murine c-Met or EGFR in cross-reactivity studies while beneficial properties against human c-Met or EGFR have been shown, which is satisfactory.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No embryo-fetal development study; weight-of-evidence assessment of reproductive and embryo-fetal risk instead
Why: Risks to human development can be communicated from existing scientific information without further animal studies · Weight of evidence
“Rather than conducting a dedicated embryofetal development study, Janssen provided a weight-of-evidence-based assessment of the potential for amivantamab to cause reproductive and embryofetal toxicity.”
“Taken together, the view that the risks of amivantamab to human development can be communicated appropriately to patients and prescribers based on the existing scientific information without conducting additional developmental animal studies is agreed.”
OtherCriticised but acceptedBeyond the letter
Highest dose in monkey repeat-dose studies not fully justified (dose volume above recommended maximum)
Why: EGFR and MET are well characterised targets and the indication is advanced cancer · Pharmacology or kinetics · Serious disease
“Taken together, the highest dose level employed in the repeat-dose toxicity studies is not considered fully justified but given that EFGR and MET are rather well characterised targets, and that amivantamab is indicated for treatment of patients with advanced cancer, no further studies are needed.”
Similar precedents
PortrazzaAntibodies · necitumumab · EGFRMonkey only · 26 wkVectibixAntibodies · panitumumab · EGFRMonkey only · 26 wkErbituxAntibodies · cetuximab · EGFRMonkey + rodent · 39 wkLazcluzeSmall molecules · lazertinib · EGFR (mutant-selective)Rodent + dog or minipig · 13 wkTabrectaSmall molecules · capmatinib · METMonkey + rodent · 13 wkTepmetkoSmall molecules · tepotinib · METRodent + dog or minipig · 39 wk