Lazertinib: on the Way to Its Throne

Treatment strategies for non-small cell lung cancer (NSCLC) haves transformed tremendously over the past decades. Surgical resection, radiation therapy, cytotoxic chemotherapies, immunotherapies, and targeted therapies have been adopted at different stages and according to the tumor biology. Among these advances, targeted therapy is the one which brought a paradigm shift in the treatment scheme for NSCLC patients with molecular alterations. It significantly improved response rates and survival outcomes for selected patients, compared to conventional cytotoxic chemotherapeutic agents.

Epidermal growth factor receptor (EGFR) is a transmembrane protein with cytoplasmic kinase activity that transduces signals leading to increased cell proliferation, angiogenesis, metastasis, and decreased apoptosis.1 Mutations in the EGFR tyrosine kinase domain lead to constitutive activation of its kinase activity and activation of downstream signaling pathways, including PI3K/AKT/mTOR and Ras/Raf/MEK/ERK, which result in the apoptosis prevention or cell cycle progression.1, 2

Despite the advent of EGFR tyrosine kinase inhibitors (TKI), early clinical trials without patient selection based on biomarkers have failed to demonstrate any superiority in survival outcomes over cytotoxic chemotherapy.3 Their therapeutic capabilities were only visible after the identification of patients harboring activating EGFR mutations who demonstrate a unique susceptibility to EGFR TKIs.4, 5

Resistance to first-[erlotinib, gefitinib, and icotinib (icotinib is approved only in China)] or second-generation (afatinib, dacomitinib) EGFR TKIs typically develops in 50%–80% of initially responding patients after a median progression-free survival (PFS) of 9–13 months.6 Among the many resistance mechanisms involved, the emergence of a secondary mutation in the gatekeeper residue T790M is the most commonly encountered, accounting for 50%–60% of patients who are resistant to first/second-generation EGFR-TKIs.7, 8 The T790M mutation leads to impaired binding of TKI via steric hindrance.9, 10 As such, targeted therapy in EGFR-mutant NSCLC patients has been dominated by the third-generation TKI osimertinib,11, 12, 13 which irreversibly and selectively inhibits both EGFR-sensitizing and T790M mutations.14 Nevertheless, the emergence of treatment resistance, a higher risk of cardiac toxicity, and the “financial burden” of osimertinib dictated a need for the development of novel third-generation EGFR TKI, which leads us to lazertinib.

Lazertinib (YH-25448, JNJ-73841937, Leclaza™) is an oral, irreversible, third-generation EGFR-TKI developed for the treatment of EGFR-mutant NSCLC (Fig. 1). It irreversibly binds to the Cys797 residue in the ATP-binding site of the EGFR kinase domain via covalent bond formation and exhibits high selectivity for sensitizing and T790M EGFR mutations while sparing EGFR WT tumors.15

Fig. 1
Chemical structures of lazertinib and osimertinib.

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In January 2021, lazertinib was first approved in Korea for the treatment of advanced or metastatic NSCLC patients with EGFR T790M who had previously received EGFR TKI therapy at a recommended dose of 240 mg, taken orally once daily as tablets and without regard to food.16

In its preclinical study, lazertinib significantly reduced the viability of Ba/F3 cells harboring Del19, L858R, Del19/T790M, and L858R/T790M mutations, with mean half-maximal inhibitory concentration (IC₅₀) values ranging from 3.3–5.7 nmol/L,15 similar to those obtained from osimertinib (IC₅₀ 3.5–4.3) but lower than those obtained from gefitinib (IC₅₀ 10.2–7625.2). Additionally, lazertinib demonstrated a higher IC₅₀ for EGFR WT, compared to osimertinib (722.7 nmol/L vs. 519.1 nmol/L).

Compatibly, a cell-free in vitro kinase inhibition assay has demonstrated that lazertinib inhibits the kinase activities of mutant EGFRs, including Del19, L858R, and T790M, with IC₅₀ values ranging between 1.7–20.6 nmol/L, and also uncommon EGFR mutants, such as G719X and L861Q. WT EGFR was less affected by lazertinib than osimertinib (IC₅₀ 60 nmol/L vs. 20 nmol/L).15

The strong tumor inhibitory capability of lazertinib was robustly replicated in PDX models.15 Lazertinib demonstrated a superior tumor regression percentage than osimertinib (86.85% vs. 7.24% using 3 mg/kg lazertinib and osimertinib, respectively) in H1975 tumor-bearing mice models without any compromise in body weight. At a higher dose of 10 mg/kg (clinically equivalent to 240 mg once daily), lazertinib achieved a near-complete tumor regression (90%).

Lazertinib suppressed EGFR downstream pathways, including phospho-EGFR, phospho-AKT, and phospho-ERK, with an inhibitory capacity comparable to or higher than that of osimertinib.15 Once again, lazertinib did not inhibit EGFR signaling in a WT EGFR cell line.

Lastly, mouse models with intracranial implantation of H1975 cells were used to evaluate the efficacy of lazertinib in tumors with brain metastases.15 Intracranial tumors demonstrated a higher uptake of lazertinib than plasma or brain tissue at a single dose of 10 mg/kg. The relative exposure ratios of brain-to-plasma, intracranial tumor-to-plasma, and intracranial tumor-to-brain were 0.9, 7.0, and 7.9, respectively. Lazertinib was determined not to be a BCRP substrate, but only a weak substrate of MDR1 and was less affected by efflux transporters and maintained higher drug concentrations in intracranial tumors. In in vivo models, lazertinib more effectively inhibited intratumor growth than osimertinib, with a significantly longer survival duration (the median survival duration of mice, 124 days vs. 65 days at 10 mg/kg).

EGFR is abundant in keratinocytes in the basal layer of the epidermis and undifferentiated keratinocytes proliferating in the external root sheath of hair follicles.40 Hence, EGFR inhibition with TKI treatments can severely disrupt the skin homeostasis and ultimately lead to cutaneous toxicity, such as xerosis, pruritus, acneiform or papulopustular eruption, nail changes, and paronychia.41 Such adverse events have been reported with EGFR TKI treatments, including osimertinib and lazertinib.

In a preclinical study, lazertinib demonstrated a high IC₅₀ for EGFR WT cells, implying that it poses a lower likelihood of manifesting off-target toxicities, including rash and paronychia.15 Lazertinib-treated mice showed minimal skin manifestation, while osimertinib-treated mice showed conspicuous skin changes, including keratosis on the face, neck, and abdomen.

Nonetheless, the actual incidence of skin-related adverse events, such as rash, pruritus, and paronychia, reported from patients did not differ between the two drugs (Table 2). Considering the interpretative challenges of cross-trial comparisons, further research on the incidence and management of adverse events related to lazertinib is warranted.

In addition, there are also concerns for cardiotoxicities, such as cardiac failure, atrial fibrillation, QT prolongation, myocardial infarction, and pericardial effusion, regarding osimertinib and other EGFR TKIs. Specifically, the risk of cardiac adverse events associated with osimertinib is a concern for clinicians.42, 43 The reported odds ratio for cardiac failure, atrial fibrillation, QT prolongation, myocardial infarction, and pericardial effusion when comparing osimertinib and other EGFR-TKIs were 2.2 (95% CI, 1.5–3.2), 2.1 (95% CI, 1.3–3.5), 6.6 (95% CI, 3.4–12.8), 1.2 (95% CI, 0.6–2.3), and 1.6 (95% CI, 0.8–3.3), respectively.44

Notwithstanding, the causal relationship between osimertinib and cardiac failure and the underlying mechanism thereof are not explicitly understood.45 A proposed mechanism suggests that the inhibition of ERBB2 or HER2 and the AMPK pathway leads to reduced contractility, mitochondrial energy depletion, and cardiomyocyte apoptosis. Meanwhile, researchers have shown that lazertinib selectivity for HER2 over EGFR was 275-fold, compared to 6.7-fold for osimertinib, which implies that lazertinib has lower cardiotoxicity.46

Consistent with this background, lazertinib has been found to exert minimal effects on cardiac function in both preclinical and clinical studies.46 No patients experienced clinically significant QT prolongation or decreased left ventricular ejection fraction. Considering that lazertinib demonstrated comparable anti-tumor efficacy to osimertinib, it may be considered a relatively safer option in terms of cardiotoxicity.47

Lastly, NSCLC patients with oncogenic-driven mutations such as EGFR are characterized by a high predilection for brain metastases, compared to unselected patients.48, 49 Brain metastasis is associated with deleterious effects on the patient’s quality of life and survival,50, 51 highlighting a need for novel TKI with improved intracranial efficacy. Although osimertinib has an improved BBB penetration, compared to early-generation EGFR TKIs,52 a significant proportion of patients (17%–20%) still experience disease progression in the brain after osimertinib treatment.53, 54 Lazertinib is not a substrate of BCRP and only a weak substrate of MDR1,55 as opposed to osimertinib, which is a substrate of both BCRP and MDR1.56 In LASER201, lazertinib demonstrated an encouraging intracranial activity with ORR of 87.5% and DCR of 100.0%, comparable to osimertinib from the AURA3 trial, which reported an intracranial ORR of 70.0% and DCR of 93.9%.52 Nonetheless, the sample sizes in these studies were limited, and real-world data with a larger number of patients on lazertinib should be investigated.

Despite the remarkable advances in targeted therapies for NSCLC with oncogenic mutations, the area of unmet need still remains. Lazertinib, a novel third-generation EGFR TKI, effectively inhibited extracranial lesions and demonstrated encouraging intracranial penetration and favorable safety profiles, including reduced skin or cardiac adverse events compared to osimertinib. Accordingly, it could be considered a sound option for the treatment of EGFR-mutant NSCLC patients. However, confirmatory phase 3 data or direct head-to-head comparisons with other EGFR TKIs are needed to finalize its position in the treatment scheme of EGFR-mutant NSCLC patients. The results from ongoing studies on front-line settings and in combination with amivantamab or cytotoxic chemotherapies are highly anticipated.