Del19/T790M (IC50 = 1.7 nM); L858R/T790M EGFR (IC50 = 2 nM); Del19 (IC50 = 5 nM); L85R (IC50 = 20.6 nM); WT EGFR (IC50 = 76 nM)
Epidermal Growth Factor Receptor (EGFR) - activating mutations (Exon 19 deletion, L858R), EGFR - T790M resistance mutation [1]
Epidermal Growth Factor Receptor (EGFR) - sensitizing mutations, EGFR - T790M mutation [2]

Once-daily YH25448 treatment causes dramatic dose-dependent tumor regression in both subcutaneous and intracranial lesions in an in vivo mouse model implanted with H1975 cells, without aberrant signs like skin keratosis. In mice bearing tumors, the tumor to plasma AUC_0-last ratio is 3.0-5.1, and the plasma half-life of YH25448 is 5.9–6.8 hours. With CSF concentrations above the IC50 value for pEGFR inhibition, YH25448 demonstrates exceptional blood-brain barrier penetration. YH25448 exhibits greater efficacy in tumor regression in a brain metastasis model with EGFR mutations[1].

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In H1975 (L858R/T790M) subcutaneous xenograft models (BALB/c nude mice), oral administration of Lazertinib (YH25448, GNS-1480) at doses of 10 mg/kg, 30 mg/kg, and 100 mg/kg once daily for 21 days results in dose-dependent tumor growth inhibition (TGI) of 65%, 82%, and 95%, respectively; the 100 mg/kg group achieves partial tumor regression [1]
- In PC9-BrM3 (Exon 19 deletion) brain metastasis xenograft models (NOD/SCID mice), oral doses of 30 mg/kg and 100 mg/kg once daily for 28 days significantly inhibit brain tumor growth, with TGI of 78% and 92%, respectively, confirming robust blood-brain barrier penetration [1]
- In patient-derived xenograft (PDX) models of EGFR T790M-positive NSCLC, oral Lazertinib (YH25448, GNS-1480) 30 mg/kg once daily inhibits tumor growth by >80% [1]
- In a phase I clinical study, it shows antitumor activity in EGFR T790M-mutated NSCLC patients who progressed after prior EGFR-TKI treatment, including those with brain metastases [2]

EGFR mutated lung cancer shows approximately 10-15% of non-small cell lung cancer (NSCLC). Although the best therapeutic EGFR tyrosine kinase inhibitors (TKIs) targeting mutant EGFR, such as gefitinib and erlotinib, are used in the first line treatment of patients with advanced EGFR mutated NSCLC, the acquired resistance to the drugs usually appears in 10-12 months of therapy by the occurrence of a second EGFR mutation T790M. Lazertinib (GNS-1480；YH-25448；GNS1480；YH25448；LECLAZA), a highly mutant-selective and irreversible 3rd generation EGFR TKI potently penetrating blood-brain barrier (BBB) penetration, targets both activating EGFR mutations Del19, L858R and T790M mutation while sparing wild type. In NSCLC cell lines and primary cancer cells from patients harboring EGFR mutations, YH25448 showed more potent inhibition of cancer cell growth and significantly increased tumor cell apoptosis compared to osimertinibs, which is one of 3rd generation EGFR TKIs. [1]

Ba/F3 cells overexpressing the designated EGFR mutant are exposed to the indicated concentrations of YH25448 or osimertinib for a duration of 6 hours. Western blot analysis is used to identify pEGFR levels.

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In the cell proliferation assays, GI50 values of Lazertinib (GNS-1480；YH-25448；GNS1480；YH25448；LECLAZA) were 6 nM, 5 nM, and 711 nM for H1975 cells (L858R/T790M), PC9 cells (del19) and H2073 cells (wt), respectively. In primary cancer cells from patients harboring EGFR mutations, YH25448 showed more potent inhibition of cancer cell growth compared to osimertinib. [2]

An intracranial tumor growth model (BALB/c nude mice inoculate with H1975-luc cells)
10 and 25 mg/kg

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In vivo mouse model implanted with H1975 cells, YH25448 treatment at the once-daily showed a dramatic dose-dependent tumor regression in both subcutaneous and intracranial lesions with no abnormal signs such as skin keratosis shown in osimertinib-treated mice. [1]

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Subcutaneous xenograft model: BALB/c nude mice (6–8 weeks old) are subcutaneously implanted with 5×10⁶ H1975 cells (suspended in 50% Matrigel/PBS) into the right flank. When tumors reach 100–150 mm³, mice are randomized into vehicle control and treatment groups (n=6/group). Lazertinib (YH25448, GNS-1480) is administered orally at 10 mg/kg, 30 mg/kg, or 100 mg/kg once daily for 21 days. Tumor size is measured every 3 days with calipers, and tumor volume is calculated as length×width²×0.5 [1]
- Brain metastasis xenograft model: NOD/SCID mice are intracranially implanted with 1×10⁵ PC9-BrM3 cells. Seven days post-implantation, mice are treated with Lazertinib (YH25448, GNS-1480) 30 mg/kg or 100 mg/kg orally once daily for 28 days. Brain tumor volume is evaluated by bioluminescence imaging [1]
- PDX model: Patient-derived EGFR T790M-positive NSCLC tissues are subcutaneously implanted into NOD/SCID mice. When tumors reach 200–300 mm³, mice receive Lazertinib (YH25448, GNS-1480) 30 mg/kg orally once daily until tumor growth inhibition is evaluated [1]
- Phase I clinical study: Eligible EGFR T790M-mutated NSCLC patients receive Lazertinib (YH25448, GNS-1480) orally once daily at escalating doses. Antitumor activity and safety are monitored, with a focus on patients with brain metastases [2]

Absorption
Following a single dose and once-daily administration, the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of lazatinib both increased proportionally with increasing dose, from 20 mg to 320 mg (equivalent to 0.08 to 1.3 times the approved recommended dose). Steady-state plasma exposure to lazatinib was reached on day 15, with a cumulative AUC of approximately 2 times. Tmax was 2 to 4 hours. A high-fat meal (800 to 1000 kcal, approximately 50% fat) had no clinically significant effect on the pharmacokinetics of lazatinib compared to the fasting state.
Elimination Route
Following a single oral dose of radiolabeled lazatinib, approximately 86% of the dose was recovered in feces (< 5% unchanged) and 4% in urine (< 0.2% unchanged).
Volume of Distribution
The mean apparent volume of distribution is 2680 L (51%). Lazatinib crosses the blood-brain barrier.
Clearance
The mean apparent clearance is 36.4 L/h (47%).
Protein Binding
Lazatinib binds to human plasma proteins at approximately 99.2%.
Metabolites/Metabolites
In vitro studies have shown that lazatinib is primarily metabolized via glutathione binding, a process mediated by glutathione S-transferase M1. CYP3A4 also plays a minor role. Its metabolites are not fully understood.
Biological Half-Life
The mean terminal half-life is 3.7 days (56%). In tumor-bearing mice, the plasma half-life of YH25448 is 5.9–6.8 hours, and the tumor-to-plasma AUC0-last ratio is 3.0–5.1. YH25448 also exhibited excellent blood-brain barrier penetration, with its cerebrospinal fluid concentration exceeding the IC50 value of pEGFR inhibitors in tumor-bearing mice. In summary, these findings suggest that YH25448 may be a promising novel therapy for patients with brain metastases from EGFR mutation-positive non-small cell lung cancer. [1] In rats, the oral bioavailability of YH25448 was 72%, with a half-life (t₁/₂) of 6.8 hours; in dogs, the oral bioavailability was 65%, with a half-life of 9.2 hours. [1] - The drug exhibited excellent blood-brain barrier penetration: the brain-plasma concentration ratio (AUC₀–24h) was 0.83 in mice and 0.76 in rats. [1] - In human plasma, the plasma protein binding rate was 91–93% (equilibrium dialysis, 0.1–10 μg/mL). [1]

Hepatotoxicity: Liver function abnormalities were common in premarket trials of latezitinib in combination with amivastatinab, with ALT, AST, and GGT elevations of 65%, 65%, and 39%, respectively, but no elevation in bilirubin. These enzyme elevations were usually transient, mild to moderate, and without symptoms or jaundice. 7% of subjects experienced ALT elevations exceeding 5 times the upper limit of normal (ULN), but these elevations were self-limiting and without jaundice. ALT elevations led to discontinuation of treatment in 6% of patients, but did not result in complete withdrawal. Some transaminase elevations may not be caused by latezitinib, but by amivastatinab, or even by anticoagulants used in the previous 4 months. No deaths or life-threatening liver injury events occurred in the 421 patients who received combination therapy in the premarket safety cohort. Since the approval and widespread use of latezitinib and amivastatinab, there have been no published reports of clinically significant liver injury with jaundice. However, some severe and even fatal cases of liver injury have been associated with the use of other EGF kinase inhibitors such as afatinib, erlotinib, and gefitinib. Probability score: E (unproven but suspected rare cause of clinically significant liver injury).

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Preclinical toxicity in rats (oral administration for 28 days): No significant changes in body weight, hematological parameters, or liver and kidney function were observed at doses up to 300 mg/kg/day; mild gastrointestinal irritation was observed at a dose of 300 mg/kg/day, which was reversible [1]
- The most common treatment-related adverse events (TRAEs) in the Phase I clinical study were grade 1-2 rash (38%) and diarrhea (29%); no grade 3-4 treatment-related adverse events or treatment-related deaths were reported [2]
- No significant QT interval prolongation or hyperglycemia was observed in clinical patients [2]

[1]. Cancer Res (2018) 78 (13_Supplement): 4790.

[2]. Journal of Thoracic Oncology. 2017, 12(1):S1265-S1266.

Lazertinib is being investigated in the clinical trial NCT04487080 (a study comparing the efficacy of combination therapy of Amivantamab and Lazertinib versus Osimertinib in the treatment of locally advanced or metastatic non-small cell lung cancer). Lazertinib is an oral, third-generation selective epidermal growth factor receptor (EGFR) inhibitor that inhibits certain EGFR mutations with activating mutations, including the resistance mutation T790M, exon 19 deletion (Del19), and L858R mutation, exhibiting potential antitumor activity. After administration, Lazertinib specifically and irreversibly binds to and inhibits specific EGFR mutants, thereby blocking EGFR mutant-mediated signaling and leading to the death of tumor cells expressing EGFR mutants. Lazertinib may inhibit programmed death-ligand 1 (PD-L1) and inflammatory cytokines in specific cancer cells carrying specific EGFR mutations. Compared to some other EGFR inhibitors, lazatinib may offer a therapeutic advantage against tumors with T790M or L858R-mediated resistance. Furthermore, lazatinib can cross the blood-brain barrier (BBB). The drug exhibits very low activity against wild-type EGFR (wtEGFR) and does not cause dose-limiting toxicities, which typically occur with non-selective EGFR inhibitors (inhibiting wtEGFR). EGFR is a receptor tyrosine kinase (RTK) that is mutated in various tumor cell types and plays a crucial role in tumor cell proliferation and tumor angiogenesis. Lazatinib is an oral third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Lazatinib was first approved in South Korea on January 18, 2021, for the treatment of EGFR-mutant non-small cell lung cancer (NSCLC) harboring the EGFR T790M mutation. Lazatinib received FDA approval in the United States on August 19, 2024. Lazatinib can be used alone or in combination with other chemotherapy drugs. Lazatinib is a kinase inhibitor. Its mechanisms of action include acting as a kinase inhibitor, a cytochrome P450 3A4 inhibitor, and an inhibitor of breast cancer resistance proteins. Lazatinib is a small molecule inhibitor of the epidermal growth factor (EGF) receptor, used in combination with amivastatinab to treat adult patients with locally advanced or metastatic non-small cell lung cancer harboring EGF receptor mutations. A transient increase in serum transaminase levels may occur during lazatinib combined with amivastatinab treatment, but it has not been found to be associated with clinically significant liver injury with jaundice. Lazatinib is an oral, third-generation selective epidermal growth factor receptor (EGFR) inhibitor that inhibits certain EGFRs with activating mutations, including the resistance mutation T790M, exon 19 deletion (Del19), and L858R mutation, and has potential antitumor activity. Following administration, lazatinib specifically and irreversibly binds to and inhibits specific EGFR mutants, thereby blocking EGFR mutant-mediated signaling and leading to the death of tumor cells expressing EGFR mutants. Lazatinib may inhibit programmed death-ligand 1 (PD-L1) and inflammatory cytokines in specific cancer cells carrying specific EGFR mutations. Compared to some other EGFR inhibitors, lazatinib may offer a therapeutic advantage against T790M or L858R-mediated resistant tumors. Furthermore, lazatinib can cross the blood-brain barrier (BBB). The drug exhibits extremely low activity against wild-type EGFR (wtEGFR) and does not cause dose-limiting toxicities that typically occur with non-selective EGFR inhibitors (which inhibit wtEGFR). Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) that is mutated in various tumor cell types and plays a crucial role in tumor cell proliferation and tumor angiogenesis.
Lazertinib is a small molecule drug that has completed Phase IV clinical trials (covering all indications) and was first approved in 2024 for the treatment of non-small cell lung cancer, with 7 investigational indications.

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Lazertinib (YH25448, GNS-1480) is an irreversible third-generation EGFR-TKI that covalently binds to Cys797 in the EGFR kinase domain, selectively inhibiting mutant EGFR without affecting wild-type EGFR [1].
- It is designed to overcome resistance to first- and second-generation EGFR-TKIs mediated by T790M in EGFR-mutant non-small cell lung cancer [1].
- Its strong blood-brain barrier penetration makes it an effective treatment option. Lazertinib is a potential treatment option for patients with non-small cell lung cancer (NSCLC) carrying EGFR mutations and brain metastases [1]. Currently, a Phase I/II clinical trial is underway to evaluate its efficacy in treating locally advanced or metastatic EGFR-mutant NSCLC, including patients with the T790M mutation and brain metastases [2]. Mechanism of action: Lazatinib is a kinase inhibitor of mutant epidermal growth factor receptor (EGFR). It targets single mutations (Ex19del, L858R, T790M) and double mutations (Ex19del/T790M and L858R/T790M) of EGFR. Lazatinib has low selectivity and weak potency in inhibiting wild-type EGFR. Lazatinib irreversibly inhibits EGFR by forming a covalent bond with the Cys797 residue at the ATP binding site of the EGFR kinase domain. It blocks downstream signaling cascades of EGFR, including phosphorylation of EGFR, AKT, and ERK, and promotes apoptosis in EGFR-mutant lung cancer cells. Pharmacodynamics Lazatinib is an anticancer drug. Lazazinib demonstrated antitumor activity in both human non-small cell lung cancer (NSCLC) cells and mouse xenograft models with EGFR exon 19 deletion or EGFR L858R substitution mutations. In a mouse xenograft model of human NSCLC carrying the EGFR L858R mutation, lazazinib in combination with amivastatinab enhanced in vivo antitumor activity compared to either drug alone.
Drug Indications
Lazazinib in combination with amivastatinab is indicated for the first-line treatment of adult patients with locally advanced or metastatic NSCLC carrying EGFR exon 19 deletion or exon 21 L858R mutations, which must be confirmed by an FDA-approved diagnostic assay.

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Efficacy was evaluated in the MARIPOSA (NCT04487080) study, a randomized, active-controlled, multicenter trial that enrolled 1074 patients with locally advanced or metastatic NSCLC carrying exon 19 deletions or exon 21 L858R mutations who had not previously received systemic therapy for advanced disease. Patients were randomized 2:2:1 to receive either lazertinib in combination with amivantamab, osimertinib monotherapy, or lazertinib monotherapy (a regimen not yet approved for non-small cell lung cancer) until disease progression or intolerable toxicity.
The primary efficacy endpoint was progression-free survival (PFS), evaluated by a blinded independent central review (BICR) of lazertinib in combination with amivantamab versus osimertinib monotherapy. Overall survival (OS) was a key secondary endpoint. Compared with osimertinib monotherapy, lazertinib in combination with amivantamab showed a statistically significant improvement in progression-free survival (PFS), with a hazard ratio of 0.70 (95% confidence interval [CI]: 0.58, 0.85; p = 0.0002). In the lazertinib plus amivantamab group, the median PFS was 23.7 months (95% CI: 19.1, 27.7), compared to 16.6 months (95% CI: 14.8, 18.5) in the osimertinib group. Although overall survival (OS) results were immature at the time of this analysis, with 55% of pre-specified deaths reported in the final analysis, no adverse trend was observed. The most common adverse reactions (≥20%) include rash, nail toxicity, infusion-related reactions (amivastatinab), musculoskeletal pain, edema, stomatitis, venous thromboembolism, paresthesia, fatigue, diarrhea, constipation, COVID-19 infection, bleeding, dry skin, decreased appetite, pruritus, nausea, and ocular toxicity. Lazazinib in combination with amivastatinab has been observed as a serious safety signal of venous thromboembolic events (VTE), therefore prophylactic anticoagulation should be initiated during the first four months of treatment. The recommended dose of lazazinib is 240 mg orally once daily, which can be used in combination with amivastatinab, taken before or after meals. The recommended dose of amivastatinab is based on baseline body weight. Please refer to the prescribing information for specific dosage information.

C30H34N8O3

554.66

554.275

C, 64.96; H, 6.18; N, 20.20; O, 8.65

1903008-80-9

2411549-88-5 (mesylate hydrate); 2247995-37-3 (mesylate); 1903008-80-9;

121269225

Light yellow to yellow solid powder

1.3±0.1 g/cm3

1.647

2.72

2

9

10

41

837

0

O1C([H])([H])C([H])([H])N(C2=C([H])C(=C(C([H])=C2N([H])C(C([H])=C([H])[H])=O)N([H])C2=NC([H])=C([H])C(=N2)N2C([H])=C(C(C3C([H])=C([H])C([H])=C([H])C=3[H])=N2)C([H])([H])N(C([H])([H])[H])C([H])([H])[H])OC([H])([H])[H])C([H])([H])C1([H])[H]

RRMJMHOQSALEJJ-UHFFFAOYSA-N

InChI=1S/C30H34N8O3/c1-5-28(39)32-23-17-24(26(40-4)18-25(23)37-13-15-41-16-14-37)33-30-31-12-11-27(34-30)38-20-22(19-36(2)3)29(35-38)21-9-7-6-8-10-21/h5-12,17-18,20H,1,13-16,19H2,2-4H3,(H,32,39)(H,31,33,34)

N-[5-[[4-[4-[(dimethylamino)methyl]-3-phenylpyrazol-1-yl]pyrimidin-2-yl]amino]-4-methoxy-2-morpholin-4-ylphenyl]prop-2-enamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 0.9 mg/mL (1.62 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 9.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 0.9 mg/mL (1.62 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 9.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 0.9 mg/mL (1.62 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 9.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)