"Era of precision therapy for lung cancer"… Leclaza-based treatment strategy

Paradigm has shifted to a strategy considering patient risk profiles after the establishment of third-generation TKI as a first-line treatment

"Treatment intensity must be modulated based on individual patient risk profiles…quality of life must also be considered"

Professor Tae-Hwan Kim of Ajou University Hospital·Professor Ji-Youn Han of the National Cancer Center (from left)

The therapeutic paradigm for epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) is shifting. While treatment was previously centered on third-generation EGFR tyrosine kinase inhibitor (TKI) monotherapy, the introduction of combination therapies such as Leclaza plus Rybrevant, alongside integrated local consolidative therapies like radiation, has shifted the clinical approach toward modulating treatment intensity based on individual patient risk profiles.

In particular, as Leclaza expands its clinical utility from a frontline monotherapy to a foundational component of combination regimens, a personalized treatment paradigm is becoming established. This approach simultaneously addresses long-term survival, resistance mitigation, and the management of central nervous system (CNS) metastases. Professor Ji-Youn Han of the Department of Hematology-Oncology at the National Cancer Center and Professor Tae-Hwan Kim of the Department of Medical Oncology and Hematology at Ajou University Hospital shared their insights into the evolving dynamics of Leclaza-based treatment strategies, patient selection criteria, and optimal protocols for managing CNS metastases.

Leclaza is a third-generation EGFR TKI that was approved as South Korea's 31st novel drug in January 2021. Subsequently, in August 2024, the combination of Leclaza + Rybrevant secured approval from the U.S. Food and Drug Administration (FDA) as a first-line treatment for adult patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations.

The starting point of this shift in the EGFR-mutant lung cancer landscape is the use of multifaceted, customized therapeutic approaches in the first-line treatment setting. Previously, the clinical utility of third-generation agents was limited to patients who developed the T790M resistance mutation after progression on first- or second-generation targeted therapies. Today, clinicians can evaluate various combination strategies anchored by a third-generation EGFR TKI right from initial diagnosis.

Professor Han stated, "The advanced care began when third-generation therapeutics became accessible as a first-line treatment for all patients confirmed with EGFR mutations," and added, "With the clinical efficacy of combination therapies now robustly validated, the current therapeutic approach focuses on stratifying treatment strategies based on specific patient risk factors.

The introduction of third-generation EGFR TKIs has allowed clinicians to design therapeutic strategies aimed at long-term overall survival rather than merely extending progression-free intervals. Professor Kim said "Previously, many patients lost subsequent therapeutic opportunities before ever receiving a third-generation agent if they failed to demonstrate the T790M resistance mutation post-progression," and he emphasized that "Using third-generation agents as a first-line intervention reduces these treatment gaps and establishes a baseline survival expectation of over 3 years. It is a profoundly meaningful clinical advancement in real-world practice.

Recently, the treatment paradigm has advanced further, moving away from using monotherapy approach for all patients toward differentiating between monotherapy and combination therapies based on baseline disease severity. This shift is supported by data from the MARIPOSA and FLAURA2 trials, which indicate that combination strategies have the potential to further optimize progression-free survival (PFS) and overall survival (OS) compared with third-generation EGFR TKI monotherapies.

Professor Han said, "Third-generation EGFR TKIs should not be viewed as the definitive endpoint of EGFR-mutant lung cancer therapy, but rather as the foundational starting point," and added, "While monotherapy outcomes have improved, combination therapies must be actively considered for patient cohorts characterized by persistent unmet medical needs, such as those presenting with baseline brain or liver metastases and the EGFR L858R mutation.

In real-world clinical settings, the primary criteria for prioritizing combination therapy are baseline brain and liver metastases, the EGFR L858R mutation, and a high baseline tumor burden. Patients with detectable circulating tumor DNA (ctDNA) in their blood profile are also stratified into the high tumor-burden category. Clinical consensus indicates that for patients presenting with these distinct risk factors, upfront combination regimens should take precedence over single-agent interventions.

Rybrevant offers a distinct mechanistic advantage as a bispecific antibody simultaneously targeting EGFR and MET, concurrently inhibiting both downstream signaling pathways. Professor Han explained that "While the MARIPOSA study did not present a granular analysis stratified by specific EGFR co-mutations, separate literature identifies MET activation as a critical therapeutic target within the EGFR L858R mutant population," and added, "Despite the necessary financial considerations, the Leclaza + Rybrevant combination therapy represents a highly tailored clinical choice for patients in whom MET signaling plays a dominant pathological role, such as those with liver metastases or L858R mutations.

Conversely, Leclaza monotherapy remains an essential standard of care for elderly patients, those with compromised performance status, or individuals facing a high baseline burden of comorbidities and potential adverse events. Professor Kim pointed out that "While combination therapy yields high efficacy, it requires patients to visit clinical sites every two to three weeks for intravenous infusions, expanding the overall toxicity management burden," and added, "In contrast, stable monotherapy allows clinicians to extend outpatient follow-up intervals up to 3-4 months, offering distinct advantages regarding patient quality of life and long-term treatment persistence."

Then, how can cumulative toxicities be managed during long-term Leclaza monotherapy?

Clinicians utilize dose titration to manage treatment-induced side effects. For instance, if a patient experiences severe peripheral neuropathy while on the standard 240mg dose, the daily intake is down-titrated to 160mg to maintain treatment continuity. Professor Kim said, "Retrospective data indicate limited evidence of significant efficacy loss following programmatic dose reductions", adding that "The clinical community has accumulated extensive experience in maintaining long-term therapeutic durability through customized dose adjustments.

The CNS metastases is a critical variable in overall treatment intensity. Approximately 25% to 30% of EGFR-mutant lung cancer patients present with brain metastases at initial diagnosis, and even when successfully controlled via upfront therapy, a significant proportion experience intracranial disease progression during long-term follow-up. In a pooled analysis of 64 patients with baseline CNS metastases from the LASER201 and LASER301 trials, the median intracranial progression-free survival (iPFS) with Leclaza was 27.7 months. Among patients with measurable baseline CNS lesions, the intracranial objective response rate (iORR) reached 92%, accompanied by a disease control rate (DCR) of 96%.

For patients presenting with limited metastases, a strategy combining Leclaza monotherapy with localized radiation is frequently deployed. Professor Kim explained that "For oligometastatic patients presenting with fewer than five intracranial lesions, clinicians can utilize a strategy that pairs oral Leclaza with stereotactic body radiotherapy (SBRT) rather than initiating systemic combination infusions," and adding that "This combined approach effectively sustains clinical efficacy while successfully mitigating the burden of frequent hospital visits and combination-induced systemic toxicities."

The clinical scope of Leclaza-based treatment strategies is projected to broaden further through ongoing Investigator-Initiated Trials (IITs) within South Korea. These trials are actively validating the drug's therapeutic potential across niche clinical segments that were underrepresented in registration trials, including T790M-negative cohorts, active brain and leptomeningeal metastases, and uncommon atypical EGFR mutations. Professor Han said, "IITs have been a critical role in developing real-world clinical strategies and establishing standards of care, and they will continue to serve as the engine for advancing novel therapeutic pathways in populations with high unmet needs."

Professor Han emphasized the necessity of optimizing clinical efficacy as well as expanding patient access to the market. Professor Han explained that even when a novel therapeutic demonstrates exceptional clinical value, patients cannot derive real-world benefits if health insurance reimbursement is delayed or if long-term treatment generates unsustainable financial toxicity. Yuhan Corporation operated a nationwide Early Access Program (EAP) to provide the drug compassionately before formal national reimbursement and has recently implemented price reductions to systematically lower the long-term economic burden on patients with chronic conditions.

Professor Han concluded by noting that "Given the limited pipeline of innovative, domestically developed innovative oncology agents in South Korea, Yuhan Corporation’s successful development of Leclaza presents a highly significant milestone for the domestic pharmaceutical industry," and added, "We hope that the company will draw its century-long corporate legacy to continue evolving into a global biopharmaceutical leader, driving innovation in foreign drug discovery."