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”
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.”
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)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“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).”