"Leclaza+Rybrevant shifts the EGFR lung cancer trt paradigm"

OS benefit was reconfirmed through an Asian sub-analysis…adverse response is also manageable

Significance of the role of combination therapy for high-risk groups…at the stage of specifying treatment strategy

"The Leclaza + Rybrevant combination therapy confirmed improvement to survival in high-risk patient group with EGFR-mutant lung cancer. The result shifted the existing treatment strategy centered around monotherapy to combination therapy."

During a recent meeting with DailyPharm, Professor Ji-Youn Han from the Division of Hematology-Oncology at the National Cancer Center explained the clinical significance of the Leclaza + Rybrevant combination therapy and the changes in EGFR-mutant non-small-cell lung cancer (NSCLC).

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

'Leclaza (lazertinib)' is an EGFR-mutant NSCLC treatment developed by Yuhan Corp. It is a third-generation tyrosine kinase inhibitor (TKI) that targets exon 19 deletions and the exon 21 (L858R) mutation. Johnson & Johnson secured the global rights to Leclaza and has been conducting clinical research on its combination therapy with 'Rybrevant (amivantamab).'

Rybrevant is a fully human bispecific antibody that fundamentally blocks tumor growth pathways by simultaneously inhibiting active EGFR mutations and MET mutations·amplification. This drug inhibits various resistance pathways observed in EGFR-mutated lung cancer by blocking ligand binding and promoting receptor degradation.

The Leclaza + Rybrevant combination therapy demonstrated improvement in overall survival (OS) in the global Phase 3 MARIPOSA study. In an Asian sub-analysis presented at the European Society for Medical Oncology Asia Congress (ESMO Asia 2025) this year, the combination therapy reaffirmed an OS effect consistent with the global clinical data.

A total of 858 participants were enrolled in the MARIPOSA study, including 501 Asian patients. In an analysis at a median follow-up of 38.7 months, the combination therapy reduced the risk of death in Asian patients by 26%. While the median OS for the combination group was not reached, it was 38.4 months for the control group receiving 'Tagrisso (osimertinib)' monotherapy, suggesting the survival benefit of the combination could exceed one year. The 36-month survival rate also remained higher for the combination group at 61% compared to the Tagrisso group.

Since Asian patients have a higher prevalence of EGFR mutations and different disease characteristics compared to Western populations, shifts in treatment strategies have a more significant impact on clinical practice. This analysis, which confirmed survival-improvement effects identical to those in the global data, once again demonstrated that Leclaza + Rybrevant has sufficient efficacy in Asian patients.

Currently, Leclaza + Rybrevant is approved as a first-line treatment in major countries, including South Korea, the United States, Europe, Japan, and China. Given the high prevalence of EGFR mutations among Korean patients, this Asian analysis is expected to significantly influence clinical guidelines and first-line treatment strategies. Furthermore, the fact that major adverse events (paronychia and rash) of the combination therapy can be managed preventively through the COCOON study is emerging as a competitive advantage.

Professor Han assessed, "Leclaza + Rybrevant combination therapy clearly demonstrated consistency in therapeutic effect by showing results in the Asian patient group identical to those of the global clinical trial," adding, "I believe the paradigm shift toward combination therapy-centered treatment has begun."

Q. Sub-analysis data from MARIPOSA were recently released. What is your evaluation of the results?

Research on combination therapy for the treatment of EGFR-mutated NSCLC has shown a complete shift in the first-line treatment paradigm. Clinically significant improvements in progression-free survival (PFS), the primary endpoint, and OS, the secondary endpoint, were confirmed. These results clearly suggest that combination therapy rather than monotherapy should be adopted as a treatment strategy.

However, it is difficult to see combination therapy in its current form as the definitive answer. While there is an OS benefit, it does not manifest identically in all patients. Depending on the mechanism of action, some patients may find the Rybrevant combination therapy more advantageous, while others may prefer 'Alimta (pemetrexed)'-based treatment. Additionally, the possibility remains open for new drugs with different mechanisms to be added as combination partners in the future.

What is clear is that a distinct unmet need for monotherapy has existed. Specifically, the limitations of existing treatments were evident in high-risk patients, underscoring the need for a breakthrough therapeutic. Leclaza + Rybrevant presented a meaningful alternative for high-risk patient groups and further clearly demonstrated OS improvement. Based on this evidence, I assess that the treatment paradigm has now completely shifted.

Q. How do you interpret the reason why the survival improvement effect of Leclaza + Rybrevant appeared consistently in Asian patients?

If the global and Asian data are consistent across all subgroups and show no significant differences, this is the ideal clinical result.

As a bispecific antibody, Rybrevant has the advantage of simultaneously inhibiting both the EGFR and MET pathways. Clinically, approximately 10–15% of patients exhibit MET-dependent resistance pathways. This patient group has a relatively poor prognosis, and Rybrevant has the potential to show long-term survival benefits in these patients.

Q. Is it the ideal direction to proceed with combination therapy as the standard of care?

While it is an ideal direction, I do not believe that combination therapy must be applied to every single patient.

Recently, researchers have redefined high-risk patient groups for whom combination therapy should be applied, thereby refining the first-line treatment approach strategy, which I view as an essential step. In my opinion, the patient groups to whom I recommend combination therapy are those with a high tumor burden. For example, high-risk groups with confirmed bone, liver, or central nervous system (CNS) metastases.

This also includes patients who show biologically aggressive characteristics, such as mutations being detected in circulating tumor DNA (ctDNA) tests. Additionally, because patients with the EGFR L858R mutation often do not achieve long-term response with monotherapy, combination therapy is considered.

Looking at the distribution of EGFR mutations that constitute the high-risk patient group, exon 19 deletions and L858R substitution mutations are roughly split half-and-half. Specifically, I estimate exon 19 deletions at about 60% and L858R at about 40%. Among these, patient groups with high tumor burdens include those accompanied by bone or brain metastases. Among these patients, about 30–40% are high-risk EGFR-mutated NSCLC patients.

Q. Overall, how do you evaluate the safety data regarding the adverse events of the Rybrevant combination therapy?

Looking at the entire development process, from CHRYSALIS to MARIPOSA and MARIPOSA-2, the journey to find the proper indications was long. Because the drug's adverse events were clear, Johnson & Johnson conducted extensive research on them and simultaneously developed educational programs to help medical staff using the drug in clinical settings do so safely. The COCOON study was also conducted in this context.

The COCOON study is significant in that it presented a standardized protocol for systematic management. Whereas management methods previously varied by medical staff or institution, a standardized management strategy that anyone can apply has now been introduced with the COCOON regimen.

Rybrevant tends to have more adverse events than Alimta-based treatment. Since it is a drug targeting EGFR, there are areas where EGFR-related adverse events partially overlap when combined with Leclaza. In fact, combining Rybrevant and Leclaza for patients with exon 19 deletions or exon 21 (L858R) mutations may be more challenging than combining Rybrevant and chemotherapy for patients with exon 20 insertion mutations. This is particularly true for adverse events directly associated with EGFR mutation inhibition.

A standardized adverse event management strategy was established through the COCOON study, which was designed to preventively manage skin-related adverse events associated with the Rybrevant combination therapy. For example, detailing the active use of chlorhexidine preparations or topical treatments when paronychia occurs is a novel part organized by the COCOON study.

Overall, it was a very consistent and determined development strategy. The study did not avoid the drug's adverse events but addressed them directly, ultimately building a clinically applicable management system.

Q. The subcutaneous (SC) formulation of Rybrevant was approved in the United States. What impact do you think it will have on clinical practice if introduced in Korea in the future?

The characteristic of an SC formulation for anticancer drugs differs from that of methods such as insulin injections, which are administered in small volumes. Anticancer drugs require a specific dose to be administered, and a process is needed to wait for the drug to be absorbed by the body after administration. In cases like exon 20 insertion mutations, where it is combined with intravenous (IV) chemotherapy, a method of simultaneously administering IV and SC drugs during treatment may not be feasible.

While there might be a possibility of administering the SC formulation alone with an oral targeted therapy, even in this case, the volume of drug to be injected is not small, and the local volume after administration is significant. Considering that one must wait for the drug to be absorbed into the local area after administration, we need to wait and see how applicable it will be in actual clinical practice. For these reasons, the application of the SC formulation in combination therapy is likely to be more limited compared to monotherapy.

Q. With treatment options diversifying and long-term survival being expected, how do you view the issue of reimbursement for combination therapy?

Currently, there are quite a few patients who maintain long-term treatment for over five years while taking an EGFR-TKI. In fact, there is a patient who has continued taking the same EGFR-TKI since the early days of our hospital's founding. Because these patients have a great fear of recurrence if they stop the drug, they continue treatment, having become accustomed to it.

As the emergence of targeted therapies has led to an increase in stage 4 lung cancer patients surviving long-term at levels similar to patients who have undergone surgery, the 'Special Case Medical Expense Coverage System' is not being fully applied. There are cases where the exception ends after taking an EGFR-TKI for more than 5 years, and a realistic consideration is becoming necessary about how long the subsequent treatment can be recognized by insurance.

Q.How do you expect the first-line treatment paradigm for EGFR-mutated lung cancer to change in the future?

The MARIPOSA study shifted the paradigm for first-line treatment of EGFR-mutated NSCLC. In particular, it demonstrated the consistency of the therapeutic effect, as results identical to the global data were confirmed in the Asian patient group.

Rybrevant’s mechanism of action clearly shows an overall survival benefit by comprehensively blocking not only the major signaling pathways centered on EGFR mutations but also MET-dependent bypass pathways, which occur in about 10–15% of cases. Considering these mechanistic characteristics, one can also expect a "long-tail effect," showing long-term survival after administration, in the latter half of the survival curve for the Rybrevant combination therapy.

Of course, the possibility of accompanying adverse events is higher in combination therapy since two agents are used together. However, through studies like COCOON, an excellent protocol for adverse event management has been developed, establishing a foundation for easier application in the real world.