"Personalized first-line therapy for EGFR-mutated NSCLC"

Differentiating trend of third-generation EGFR TKI that provides CNS inhibition and toxicity management

LASER201·301 integrated analysis provided evidence for patients with brain metastases

Differentiated strategy with toxicity management…Leclaza becomes a treatment option for drug switching

The treatment paradigm for EGFR-mutated Non-Small Cell Lung Cancer (NSCLC) is changing.

Given the high incidence of brain metastases at diagnosis in EGFR-mutated NSCLC, the key criteria for first-line treatment selection are now centered around Central Nervous System (CNS) inhibition and a favorable toxicity for long-term administration.

The integrated analysis of LASER201 and LASER301, published recently in 'Clinical Lung Cancer,' provides additional evidence supporting the intracranial efficacy of the domestically developed third-generation EGFR TKI, Leclaza (lazertinib). The study is providing evidence for redefining the treatment strategy for patients with EGFR mutations.

DailyPharm met with Professor Ji-Youn Han, from the Division of Hematology-Oncology at the National Cancer Center, a co-author of the paper mentioned above, to hear about the latest trends in the treatment of EGFR-mutated Non-Small Cell Lung Cancer (NSCLC), the CNS strategy, and the direction of customized therapy in the era of combination therapies.

"Brain metastases account for 40% at diagnosis…key determining factor for prognosis"

Professor Ji-Youn Han, Division of Hematology-Oncology at the National Cancer Center

First, Professor Han emphasizes that "CNS management is now the starting point of treatment, rather than simply an additional factor."

Professor Han stated, "Approximately 20-25% of all lung cancer patients already have brain metastases at diagnosis, but this rate rises to as high as 40% in patients with EGFR·ALK·HER2 mutations or who are non-smokers," and added, "Recent global Phase 3 (MARIPOSA·FLAURA2) trials also reported that 40% of patients have baseline brain metastases."

These data indicate that not only are baseline brain metastases common, but a significant number of participating patients with good performance status have accompanying brain metastases.

However, the prognosis varies significantly depending on symptom status. While approximately 40% of brain metastases cases are detected while still asymptomatic, the prognosis rapidly worsens once neurological deficits occur.

Professor Han stated, "Symptoms of brain metastases include persistent headaches, nausea/vomiting, visual impairment, dizziness, and stroke-like symptoms, which severely limit daily life. Ultimately, symptomatic brain metastases is regarded as a major worsening factor that significantly decreases the patient's Quality of Life."

Integrated Analysis of ​LASER201/301...reconfirming Leclaza's effect on suppressing the CNS

Professor Han summarized the limitations of existing first- and second-generation EGFR TKIs as being 'not initially designed to target the EGFR mutation itself.'

Professor Han explained that side effects from inhibiting normal EGFR made it difficult to achieve sufficiently high drug concentrations, resulting in restricted BBB permeability and, consequently, a structural limitation in CNS management.

In contrast, third-generation EGFR TKIs were developed from the start to enhance mutant EGFR selectivity and BBB permeability. This gained attention because it opened an era where much more stable and consistent effects on CNS can be expected, even in patients with brain metastases.

Furthermore, the differences in toxicity profiles are evident. Professor Han said, "If the clinically perceived toxicity severity of first·second generation agents is rated at 10, the third generation is at the 2–3 level, which significantly improves their suitability for long-term use."

Regarding the results of the LASER201 and LASER301 integrated analysis released, Professor Han evaluated them as additional evidence supporting Leclaza's global competitiveness.

Professor Han stated, "The key finding is that this study provided objective data confirming that Leclaza has intracranial efficacy comparable to Tagrisso (osimertinib), the Korean standard of care, in EGFR-mutated lung cancer patients with brain metastases." She found this consistent with the trend from the MARIPOSA study, in which lazertinib monotherapy showed a Hazard Ratio (HR) of less than 0.9 compared to osimertinib in this patient group.

Professor Han also mentioned, "Although the two drugs have generally similar efficacy, their side effect profiles do not entirely overlap. The fact that an option exists for patients to switch to the other drug if they cannot tolerate a specific adverse event is a major clinical advantage."

Consequently, the availability of two third-generation EGFR TKIs is viewed as having significance for expanding the treatment strategy.

Leclaza has a demonstrated advantage for suppressing brain metastases, supported by clear data proving the BBB permeability in preclinical studies.

Professor Han stated, "This integrated analysis strengthens Leclaza's intracranial evidence, enhancing its global credibility, and expands the treatment strategy by enabling customized drug selection based on the patient's side effects and status. It is significant because it lays the foundation for broadening the scope of clinical judgment amid the future flow of combination therapies and new drug development."

Toxicity management and drug switching...differentiating strategy garners attention

Professor Han stressed that 'toxicity management' is a critical factor in determining the actual clinical treatment strategy, as EGFR-mutated lung cancer is a disease that requires long-term use of agents from the same class.

In the case of Tagrisso, specified severe side effects, such as thrombocytopenia, ILD (interstitial lung disease), and cardiac toxicity like QTc prolongation, may necessitate dose reduction.

"According to the current guidelines, dose must be reduced to 40 mg if the same adverse event recurs. However, the evidence for maintaining drug efficacy at the 40 mg reduced dose is extremely limited, and the lack of data ensuring sufficient CNS control in patients with brain metastases is the biggest concern in the clinical setting," she said.

Professor Han said, "Since CNS progression in EGFR-mutated lung cancer is directly linked to treatment failure, disease progression during dose reduction significantly limits the scope of subsequent drug switching strategies." She emphasized, "The medically recommended option in this scenario is a switch to Leclaza monotherapy, whose efficacy and tolerability have already been proven at the standard dose (240 mg)."

Professor Han also suggested that the reimbursement criteria need be improved.

The current reimbursement criteria require a Tagrisso dose reduction before switching to Leclaza, forcing the patient to risk the same side effects again. 

Professor Han also pointed out that if the disease progresses during the dose reduction, reimbursement for the subsequent switch to Leclaza may be denied.

Professor Han concluded, "Since there is little difference in the drug price between the two agents, and Leclaza is sometimes even cheaper, there is insufficient evidence to mandate dose reduction for financial reasons," and added, "Ultimately, these regulations are criticized as being unreasonable from the perspectives of patient safety, treatment continuity, and insurance finances."