SUMMARY

• LAZCLUZE (lazertinib) is an orally administered, third-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI).¹
• A majority of EGFR mutations observed in non-small cell lung cancer (NSCLC) tumors comprise Exon 19 deletions (Exon19del) and L858R point mutations in Exon 21; the less frequently occurring mutations include Exon 20 insertion (Exon20ins) mutations.^2,3
• Lazertinib demonstrated potent (>90%) inhibition of kinase activities of EGFR mutations (T790M, T790M/L858R, and L858R), with 50% inhibitory concentration (IC₅₀) values in the low nanomolar range (1.7-20.6 nmol/L) compared with wild-type (WT) EGFR (IC₅₀: 76 nmol/L) in vitro.⁴
• EGFR phosphorylation and downstream signaling pathways were inhibited by lazertinib in vitro and in vivo; in addition, lazertinib inhibited cancer cell proliferation and induced cellular apoptosis in EGFR-mutant NSCLC cell lines.⁴
• Lazertinib demonstrated tumor growth reduction in EGFR-mutant NSCLC in vivo patient-derived xenograft mouse models and exhibited a high degree of blood brain barrier (BBB) penetration with intracranial tumor suppression in a brain metastasis mouse model.⁴

BACKGROUND

The EGFR is a transmembrane protein receptor involved in normal cellular and pathological processes, including cell proliferation, survival, oncogenesis, and metastasis.⁵ EGFR mutations are common in NSCLC tumors, with a majority of these mutations comprising Exon19del and L858R point mutations in Exon 21.^2,3

The first-generation EGFR-TKIs, which bind reversibly to EGFR, and second-generation EGFR-TKIs, which bind irreversibly to EGFR, are used as targeted treatments in patients with NSCLC harboring sensitizing mutations of EGFR. These agents inhibit EGFR, reduce downstream signaling, and prevent intracellular phosphorylation, with further inhibition of signaling cascades. However, the development of secondary EGFR mutations, such as T790M ‘gatekeeper’ mutation in Exon 20, and activation of downstream signaling pathways, such as the mesenchymal-epithelial transition (MET) oncogene amplification, has led to resistance towards these agents after 8 to 12 months of treatment.^5,6 The T790M mutation is reported to occur in approximately 60% of acquired resistance cases after treatment with first- and second-generation EGFR TKIs.⁴ Second-generation EGFRTKIs have shown lower selectivity for Exon19del/T790M or L858R/T790M EGFR mutants than for WT EGFR. Thirdgeneration EGFR-TKIs bind irreversibly to EGFR but are more selective for EGFR T790M mutations than for WT EGFR.^2,5,6

MECHANISM OF ACTION OF LAZERTINIB

Lazertinib is an orally administered, third-generation, irreversible EGFR-TKI.¹ In preclinical studies, lazertinib selectively inhibited both primary activating EGFR mutations (Exon19del, Exon21 L858R substitution) and the EGFR T790M resistance mutation, and showed less activity against WT EGFR. Lazertinib inhibited EGFR phosphorylation and EGFR downstream signaling pathways, induced apoptosis in EGFR-mutant NSCLC cell lines, and showed a high degree of BBB penetration with intracranial tumor suppression in brain metastasis mouse models. Data from the preclinical studies reported by Yun et al (2019) that evaluated the mechanism of action of lazertinib are summarized below.⁴

In Vitro Inhibitory Activity Against Mutant EGFR Kinases

Lazertinib at a concentration of 1 μmol/L inhibited kinase activities of EGFRs, with percentages of inhibition >85% in vitro (Table: Inhibition of EGFR Kinases by Lazertinib in Kinome Profiling).⁴

Lazertinib demonstrated strong inhibitory activity against mutant EGFR kinases, with IC₅₀ values in the low nanomolar range (1.7-20.6nmol/L) compared with WT EGFR in vitro
(IC₅₀: 76 nmol/L) (Table: Inhibitory Activity of Lazertinib Against Mutant EGFR Kinases).⁴

In Vitro Inhibition of EGFR Phosphorylation

In Ba/F3 cells in vitro, lazertinib at concentrations of 5 nmol/L, 10 nmol/L, and 100 nmol/L showed a dose-dependent inhibition of EGFR phosphorylation in cells harboring Del19, L858R, Del19/T790M, and L858R/T790M mutations.⁴

In Vitro Reduction of Viability of Cells with Mutant EGFRs

In Ba/F3 cells in vitro, lazertinib reduced the viability of cells harboring mutant EGFRs, with mean IC₅₀ values in the low nanomolar range (3.3-5.7 nmol/L) compared with WT EGFR (IC₅₀: 722.7 nmol/L) (Table: Viability of Ba/F3 Cells Harboring Mutant EGFRs Treated with Lazertinib).⁴

In Vitro and in Vivo Inhibition of EGFR Downstream Signaling

Lazertinib inhibited EGFR downstream signaling, including phospho-EGFR (p-EGFR), phospho-protein kinase B (p-AKT), and phospho-extracellular signal-regulated kinase
(p-ERK) in various lung cancer cell lines harboring PC9(Del19), YUX-1024(L858R), and H1975 (L858R/T790M) mutations, but not in a WT EGFR cell line (H2291).⁴

In tumor lysates of H1975 (L858R/T790M) xenograft mice treated with lazertinib, there was complete inhibition of EGFR downstream signaling, including pEGFR, pAKT, and pERK1/2.⁴

In Vitro Inhibition of Cell Proliferation and Induction of Apoptosis

In an vitro assay that evaluated the effect on cell proliferation in several NSCLC cell lines
(6 from patient-derived cells) with sensitizing, resistant, or uncommon EGFR mutations, lazertinib inhibited the proliferation of Del19- and/or T790M- mutant NSCLC cells with IC₅₀ values in the low nanomolar range (1.9-12.4 nmol/L) (Table: Inhibition of Cell Proliferation in EGFR-Mutant NSCLC Cell Lines). Lazertinib was also shown to induce apoptosis in EGFR-mutant cell lines (H1975 and PC9).⁴

In Vivo Reduction of Tumor Growth

In EGFR (Del19)-mutant NSCLC patient-derived tumor-bearing mice, treatment with lazertinib significantly inhibited tumor growth compared with a thirdgeneration EGFR-TKI, osimertinib (87.5% vs 83.6%; P<0.001).⁴

In H1975 (L858R/T790M) tumor-bearing mice, treatment with lazertinib 3 mg/kg/day and 10 mg/kg/day resulted in 87% and 90% of tumor reduction, respectively. Similarly, near complete tumor reduction in PC9 (Del19) tumor-bearing mice was seen with lazertinib treatment.⁴

In Vivo Intracranial Tumor Suppression and Blood Brain Barrier Penetration

Intracranial tumor growth and BBB penetration was evaluated using luciferase-transfected EGFR-mutant H1975 (H1975-luc) brain metastasis mouse model. Treatment with lazertinib 10 mg/kg once daily and 25 mg/kg once daily significantly inhibited intracranial tumor growth compared with osimertinib 10 mg/kg once daily and 25 mg/kg once daily, respectively (P=0.0125 and P=0.0274, respectively).⁴

In the H1975-luc brain metastasis mouse model, the maximum concentration of lazertinib in plasma, brain, and intracranial tumor was detected after 4 hours after a single dose; uptake was higher in the intracranial tumor than in plasma and the brain (area under the plasma drug concentration-time curve from time 0 to the last measurable concentration [AUC_0-last] ratio: intracranial tumor/plasma, 7.0; intracranial tumor/brain, 7.9).⁴

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 19 August 2024.