"Leclaza comb included in the U.S. guideline"

Professor Se Hoon Lee of the Division of Hematology-Oncology at Samsung Medical Center

In MARIPOSA trial, the risk of death was reduced by 25%...statistical significance of OS confirmed

"Choosing between different combination therapies, rather than whether to use combination or not"

Professor Se Hoon Lee of the Division of Hematology-Oncology at Samsung Medical Center

The global status of Korea-made novel anticancer drug 'Leclaza' (ingredient: lazertinib) is shifting. The shift was brought by the 2026 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for Non-Small Cell Lung Cancer (NSCLC), which included the combination therapy of Leclaza + 'Rybrevant' (ingredient: amivantamab) as a 'Preferred Regimen' for first-line treatment, while Leclaza monotherapy was included as an option that is 'Useful in Certain Circumstances.'

Analysis suggests that this is highly significant as the first Korea-made novel drug has been included in the NCCN Category 1 first-line treatment bracket. DailyPharm met with Professor Se Hoon Lee of the Division of Hematology-Oncology at Samsung Medical Center, who led the follow-up studies of the Phase 3 MARIPOSA trial, to discuss the significance of this guideline revision and the evolving treatment strategies in clinical practice.

OS data changed the standard... "Combination therapy enters the stage of discussion"

Yuhan's Leclaza and Janssen's Rybrevant

Leclaza is a third-generation NSCLC treatment targeting Epidermal Growth Factor Receptor (EGFR) mutations, which received domestic approval in January 2021 as South Korea's 31st novel drug. The Leclaza-Rybrevant combination therapy was approved by the U.S. Food and Drug Administration (FDA) in August 2024 as a first-line treatment for adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations.

Professor Lee identified the foundation of this revision in the Overall Survival (OS) data.

Professor Lee stated, "The Phase 3 MARIPOSA trial, which served as the basis for this revision, was a study comparing the Leclaza-Rybrevant combination therapy against the existing standard of care, 'Tagrisso' (ingredient: osimertinib) monotherapy. Given that monotherapy has already established itself as the standard treatment, demonstrating whether clinical benefits actually translate into OS improvement was paramount, especially considering the inevitable toxicity burden of combination therapy."

Professor Lee added, "If it were a comparison between monotherapies with similar efficacy and toxicity profiles, a shift in the standard could be discussed based on Progression-Free Survival (PFS) results alone. However, for combination therapies, the criteria for decision differ," and added, "It is meaningful that by confirming statistical significance for OS through this study, the grounds for discussing combination therapy as a standard treatment option have been established."

According to the Phase 3 MARIPOSA OS results presented at the European Lung Cancer Congress (ELCC) last March, the Leclaza-Rybrevant combination therapy demonstrated statistical significance, reducing the risk of death by approximately 25% (HR 0.75, 95% CI 0.61–0.92) compared with Tagrisso monotherapy.

The median Overall Survival (mOS) has not yet been reached (not reached). This means that more than half of the patients in the combination therapy group survived during the follow-up period, and a sufficient number of death events did not occur to calculate a median value. Considering that the mOS of Tagrisso monotherapy was confirmed at 36.7 months, there are projections that once the mOS for the Leclaza-Rybrevant combination therapy is finalized in the future, the gap between the two groups could widen to more than a year.

Professor Lee also expected that this revision could serve as a starting point for restructuring international treatment guidelines. He noted, "The NCCN guidelines are be revised relatively quickly among global guidelines, so this change is highly likely to become the starting point for revisions of other international guidelines in the future. While European guidelines may take a more cautious approach as they consider economic evaluations simultaneously, I expect the general direction itself to unfold similarly."

Changes in the guidelines are also influencing the domestic clinical field.

Professor Lee stated, "Following the changes in global guidelines, a shift in perception regarding first-line treatment strategies is emerging in the domestic medical field. Since OS has improved by more than a year, many medical professionals believe that combination therapy should be considered a priority."

He added, "Compared to when the MARIPOSA study's PFS data was first released, I can feel that the perception of medical staff is changing over time. While individual opinions vary, it is a clear trend that as more experts gather to discuss, the proportion of those considering combination therapy is gradually expanding."

Comparison of monotherapies…attention on safety differences

The double-blind, Head-to-Head direct-comparison data between Leclaza and Tagrisso monotherapy are gaining attention.

Generally, it has been perceived that studies directly comparing two drugs with proven efficacy are difficult to establish. Regarding a standard treatment that has already preempted the market, a result showing inferiority could pose significant commercial risks, and the practice of randomly assigning patients when a standard treatment is established can provoke ethical controversies.

Professor Lee explained, "As the FDA required the individual contribution of each component drug in the combination therapy study to be proven, a design involving a direct comparison of monotherapies within the same study could be included," added, "This data is unique globally and is precious data that will be difficult to replicate in the future."

As this was an exploratory analysis, it has limitations regarding the number of patients. However, the professor explained that the reliability of the interpretation is enhanced by the fact that the two drugs were directly compared under the same conditions within the same clinical trial, rather than through indirect methods that compare results from different studies. Such data can serve as evidence for fine-tuning treatment strategies in clinical practice.

The direct comparison showed that the two drugs had similar efficacy, as evidenced by their survival curves, but differences in their safety profiles were observed. Among these, the point of clinical interest is cardiac toxicity.

Professor Lee stated, "Tagrisso showed a tendency toward more reports of cardiac-related adverse events such as heart failure or QT prolongation compared to Leclaza," added, "It has been suggested that this may be due to Tagrisso's characteristic of more broadly inhibiting HER2 (ERBB2), which is associated with cardioprotection."

Professor Lee further explained, "While the incidence of cardiac toxicity itself is low at less than 2%, it is a clinically important consideration as it is a life-threatening adverse event," added, "Peripheral neuropathy is observed more frequently in Leclaza monotherapy, but this is not a life-threatening adverse event, and its clinical impact tends to be limited."

Consistent survival benefit confirmed in Asian patients... "Combination will become the basic option"

Leclaza is also securing consistent clinical data in the Asian patient population. This contrasts with the FLAURA2 study, which evaluated the Tagrisso-chemotherapy combination, where the efficacy in the Asian subgroup excluding China appeared limited.

In the FLAURA2 study, the OS Hazard Ratio (HR) for the Asian subgroup excluding China was 1.00 (95% CI 0.71–1.40), showing no additional survival benefit compared to monotherapy. In contrast, the MARIPOSA study reported an OS HR of approximately 0.77 for the total population, including Asian patients, confirming a death risk reduction effect.

Professor Lee stated, "The mechanism explaining the HR difference observed in the Asian patient population is not yet clear, making it difficult to draw conclusions based on subgroup analysis alone. However, since consistent OS improvement was confirmed in the total population, including Asian patients, in the MARIPOSA study, these differences need to be scrutinized through further research in the future."

Professor Lee believes the focus on first-line treatment strategies is gradually shifting toward combination therapy.

Professor Lee said, "In the past, monotherapy was the default, with combination therapy considered for some patients; however, recently, there is a spreading view that combination therapy should be the baseline strategy, with monotherapy applied selectively," added, "This is similar to the trend where the combination of immunotherapy and chemotherapy has become the standard of care in NSCLC."

Furthermore, Professor Lee stated, "In my opinion, a strategy of first checking the response with monotherapy for about three to six weeks and then switching to combination therapy for patients who need it is desirable," added, "However, in a reimbursement system, it is important to secure the option of combination therapy, so an approach starting with combination therapy whenever possible can be rational."

Ultimately, Professor Lee predicted that future first-line treatment strategies will be restructured as a matter of choice between combination therapies. He concluded, "If both Leclaza + Rybrevant and Tagrisso + chemotherapy combination therapies are included in the reimbursement system, the focus of discussion will move beyond simply whether to use combination therapy to which of the two combination strategies to choose,'' and concluded, "At that stage, further discussions will be necessary, considering not only survival indicators but also the mechanistic differences, immunological changes, and molecular biological characteristics of each treatment strategy."