Lazcluze
lazertinib
Species
RatDog
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“The Applicant evaluated the safety of lazertinib using Sprague-Dawley rats and Beagle dogs in GLP-compliant oral repeat-dose toxicology studies of up to 13-weeks duration.”
Why that species
PK and metabolic profiles comparable to human; no human-specific metabolites
“Overall, the PK profile in rats and dogs appears to be well described, and comparisons with human PK data supported the rat and dog as relevant non-clinical species for testing toxicity.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 13-week dog study, one high dose (8 mg/kg; approximately 2 times the clinical AUC at the 240 mg human dose) male dog was euthanized on Day 70”
Species: general tox
Sprague-Dawley rat and Beagle dog (oral, up to 13 weeks)
“The Applicant evaluated the safety of lazertinib using Sprague-Dawley rats and Beagle dogs in GLP-compliant oral repeat-dose toxicology studies of up to 13-weeks duration.”
Species: DART
Rat and rabbit (embryo-fetal development); rat fertility study also conducted
“The Applicant conducted GLP-compliant embryo-fetal development studies in Sprague-Dawley rats and New Zealand White rabbits.”
Species: carcinogenicity
Not conducted (advanced cancer indication)
“The Applicant did not conduct carcinogenicity studies to support the currently proposed indication (NSCLC), and these studies are not needed to support a marketing application for a drug intended to treat patients with advanced cancer.”
Surrogate used in
No surrogate used; lazertinib itself tested in rats and dogs
“The Applicant evaluated the safety of lazertinib using Sprague-Dawley rats and Beagle dogs in GLP-compliant oral repeat-dose toxicology studies of up to 13-weeks duration.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog)
“The Applicant evaluated the safety of lazertinib using Sprague-Dawley rats and Beagle dogs in GLP-compliant oral repeat-dose toxicology studies of up to 13-weeks duration.”
Pivotal GLP studies
4-week and 13-week oral studies in rats and dogs
“The toxicological profile of lazertinib was assessed in pivotal repeat-dose oral 4-week and 13-week toxicity studies in SD rats and Beagle dogs.”
Route in tox
Oral
“The toxicological profile of lazertinib was assessed in pivotal repeat-dose oral 4-week and 13-week toxicity studies in SD rats and Beagle dogs.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration (CHL cells) and rat bone marrow micronucleus assays
“Lazertinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in either the in vitro chromosome aberration assay in Chinese hamster lung cells or the in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity
Not conducted (advanced cancer indication)
“The Applicant did not conduct carcinogenicity studies to support the currently proposed indication (NSCLC), and these studies are not needed to support a marketing application for a drug intended to treat patients with advanced cancer.”
Reproductive & developmental
Rat and rabbit EFD; rabbit vertebral and skull malformations at 45 mg/kg
“There was an increase in the incidence of skeletal malformations in the vertebra and skull (fused maxillary process/zygomatic arch), and unossified hyoid skull (skeletal variation) at 45 mg/kg compared to controls.”
Safety pharmacology
hERG IC50 5.3 µM, ~883-fold above unbound clinical Cmax
“The unbound Cmax of lazertinib at the recommended human dose of 240 mg calculated by the FDA nonclinical team is ~6 nM, thus the 5.3 μM IC50 for hERG channel inhibition corresponds to an ~883-fold multiple.”
Genotox: Ames
Negative
“Lazertinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in either the in vitro chromosome aberration assay in Chinese hamster lung cells or the in vivo bone marrow micronucleus assay in rats.”
Genotox: in vitro mammalian
Chromosome aberration assay (Chinese hamster lung cells): negative
“Lazertinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in either the in vitro chromosome aberration assay in Chinese hamster lung cells or the in vivo bone marrow micronucleus assay in rats.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Lazertinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in either the in vitro chromosome aberration assay in Chinese hamster lung cells or the in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity model
Not conducted (not needed for advanced cancer)
“The Applicant did not conduct carcinogenicity studies to support the currently proposed indication (NSCLC), and these studies are not needed to support a marketing application for a drug intended to treat patients with advanced cancer.”
Carcinogenicity timing
Not required for advanced cancer indication (NSCLC)
“The Applicant did not conduct carcinogenicity studies to support the currently proposed indication (NSCLC), and these studies are not needed to support a marketing application for a drug intended to treat patients with advanced cancer.”
hERG / QT
hERG IC50 5.3 µM, ~883-fold the unbound Cmax (~6 nM) at 240 mg
“The unbound Cmax of lazertinib at the recommended human dose of 240 mg calculated by the FDA nonclinical team is ~6 nM, thus the 5.3 μM IC50 for hERG channel inhibition corresponds to an ~883-fold multiple.”
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 Lazcluze 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 small molecules (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, eye, GI, liver, kidney, heart, esophagus, lung, reproductive organs and bone marrow (FDA multi-discipline review, p. 41)
NOAEL / key findings
Skin, eye, GI, liver, kidney, heart, esophagus, lung, reproductive organs and bone marrow
“Consistent with its mechanism of action as an EGFR inhibitor, lazertinib induced skin/eyelid, ocular, and gastrointestinal (GI) toxicity in rats and/or dogs. Additional target organs in animals included the liver, kidney, heart, esophagus, lung, reproductive organs, and bone marrow.”
Risksopen answer page →
Immune & cytokine safety
Skin sensitizer in mouse local lymph node assay
“Lazertinib was classified as a skin sensitizer in a local lymph node assay in mice, but did not meet the requirement for inducing serious eye damage in a bovine corneal opacity and permeability (BCOP) test.”
Biodistribution & persistence
Melanin binding in uveal tract and pigmented skin
“Distribution of 14C-lazertinib-derived radioactivity in the uveal tract and pigmented skin indicated melanin binding.”
Modality-specific risk
Severe cardiac toxicity in dogs at high dose
“Although not readily observed in patients, lazertinib induced severe cardiac toxicity in the 4-week toxicology study in two male dogs at the high dose level (20 mg/kg; approximately 4.8 times the clinical AUC at the 240 mg human dose).”
Anti-drug antibodies: animals
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.
Anti-drug antibodies: patients
No immunogenicity studies conducted for lazertinib
“No immunogenicity studies have been conducted for lazertinib.”
Label warnings
- Venous Thromboembolic Events
- Interstitial Lung Disease (ILD)/Pneumonitis
- Dermatologic Adverse Reactions
- Hepatotoxicity
- Ocular Toxicity
- Embryo-Fetal Toxicity
Thrombosis & embolismImmune-mediated reactionsPulmonary toxicitySkin reactionsHepatotoxicityOcular toxicityEmbryo-fetal toxicity
US prescribing information, 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 Lazcluze 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 small molecules (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, eye, GI, liver, kidney, heart, esophagus, lung, reproductive organs and bone marrow (FDA multi-discipline review, p. 41)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week dog and rat (oral) with 8-week recovery
“Histologic findings in the kidney of other high dose dogs in the 13-week study included slight tubule degeneration/regeneration and marked infarct, which were not present after an 8-week recovery period.”
Pivotal GLP studies
4-week and 13-week oral studies in rats and dogs
“The toxicological profile of lazertinib was assessed in pivotal repeat-dose oral 4-week and 13-week toxicity studies in SD rats and Beagle dogs.”
DART package
Species: DART
Rat and rabbit (embryo-fetal development); rat fertility study also conducted
“The Applicant conducted GLP-compliant embryo-fetal development studies in Sprague-Dawley rats and New Zealand White rabbits.”
Reproductive & developmental
Rat and rabbit EFD; rabbit vertebral and skull malformations at 45 mg/kg
“There was an increase in the incidence of skeletal malformations in the vertebra and skull (fused maxillary process/zygomatic arch), and unossified hyoid skull (skeletal variation) at 45 mg/kg compared to controls.”
PPND / ePPND: when
PPND not conducted: not needed for advanced NSCLC indication (ICH S9)
“Prenatal and postnatal development studies were not conducted or needed to support the use of lazertinib in the currently proposed indication (NSCLC) per ICH S9.”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer indication)
“The Applicant did not conduct carcinogenicity studies to support the currently proposed indication (NSCLC), and these studies are not needed to support a marketing application for a drug intended to treat patients with advanced cancer.”
Carcinogenicity model
Not conducted (not needed for advanced cancer)
“The Applicant did not conduct carcinogenicity studies to support the currently proposed indication (NSCLC), and these studies are not needed to support a marketing application for a drug intended to treat patients with advanced cancer.”
Carcinogenicity timing
Not required for advanced cancer indication (NSCLC)
“The Applicant did not conduct carcinogenicity studies to support the currently proposed indication (NSCLC), and these studies are not needed to support a marketing application for a drug intended to treat patients with advanced cancer.”
Safety marginopen answer page →
Safety margin at NOAEL
Low: NOAEL/LOAEL exposures at or below clinical exposure at the recommended dose
“In general, low exposure margins based on systemic exposure at NOAELs or LOAELs were observed in animal studies, and corresponded to clinical exposures at or below the recommended human dose of 240 mg/kg/day.”
NOAEL / key findings
Skin, eye, GI, liver, kidney, heart, esophagus, lung, reproductive organs and bone marrow
“Consistent with its mechanism of action as an EGFR inhibitor, lazertinib induced skin/eyelid, ocular, and gastrointestinal (GI) toxicity in rats and/or dogs. Additional target organs in animals included the liver, kidney, heart, esophagus, lung, reproductive organs, and bone marrow.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human NSCLC xenografts (EGFR del19, L858R/T790M) in nude mice, including intracranial model
“Further, oral administration of lazertinib inhibited both SC and intracranial tumor growth and extended survival in a dual implantation NSCLC EGFR L858R/T790M mutant xenograft model in nude mice, suggesting lazertinib may have activity against brain metastases.”
Why that model
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.
Reviewer's view of the efficacy data
EMA: in vivo and in vitro pharmacology support the indication, with significant tumor inhibition in EGFR-mutant xenografts
“Overall, in vivo primary pharmacology studies, in combination with the in vitro pharmacology studies, support the proposed indication for lazertinib and demonstrated significant tumor growth inhibition in EGFR mutant cell line xenograft models, specifically for EGFR cell lines harboring the Del19 and L858R/T790M mutations.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginAcceptedBeyond the letter
Low exposure margins: NOAEL or LOAEL exposures at or below clinical exposure at the recommended dose
Why: Expected for a TKI; animal target toxicities match the human toxicity profile known from other TKIs · Pharmacology or kinetics · Class precedent · Human data
“In general, low exposure margins based on systemic exposure at NOAELs or LOAELs were observed in animal studies, and corresponded to clinical exposures at or below the recommended human dose of 240 mg/kg/day.”
“This is expected due to the pharmacological mode of action of lazertinib as a TKI, and the different target toxicities observed in animals correlate with the toxicity profile observed in humans, which is also known from other TKIs.”
DARTVerdict not stated
Rat fertility and early embryonic development study conducted without toxicokinetics
“Treated males were mated with treated females at the same dose level; toxicokinetics were not conducted.”
Similar precedents
ErbituxAntibodies · cetuximab · EGFRMonkey + rodent · 39 wkPortrazzaAntibodies · necitumumab · EGFRMonkey only · 26 wkRybrevantMultispecifics · amivantamab · EGFR x METMonkey only · 13 wkVectibixAntibodies · panitumumab · EGFRMonkey only · 26 wkAyvakitSmall molecules · avapritinib · KIT/PDGFRARodent + dog or minipig · 39 wkBalversaSmall molecules · erdafitinib · FGFR1-4Rodent + dog or minipig · 13 wk