Leclaza–Rybrevant Trial Achieves Record Survival, Signals New Treatment Era

At this year’s European Lung Cancer Congress (ELCC) and World Conference on Lung Cancer (WCLC 2025), the final overall survival (OS) results from the Phase 3 MARIPOSA trial were unveiled, alongside new insights into resistance mechanisms and adverse event management. The findings are expected to mark a major shift in the treatment paradigm for patients with stage IV EGFR-mutant non–small cell lung cancer (NSCLC).

For patients with stage IV, or metastatic, disease, the core objective remains extending survival. The MARIPOSA trial demonstrated that the combination of Leclaza (lazertinib), a third-generation EGFR-TKI, and Rybrevant (amivantamab), a bispecific antibody targeting EGFR and MET, improved overall survival by more than one year compared to Tagrisso (osimertinib) monotherapy. The results, first presented at ELCC 2025 on March 26, represent the first instance of a treatment regimen for advanced NSCLC achieving a median survival exceeding four years.

Subsequent updates shared at WCLC 2025 reinforced these findings, confirming the combination’s ability to overcome key EGFR and MET resistance mutations. The full results were simultaneously published in the New England Journal of Medicine (NEJM), underscoring the study’s global scientific impact.

Supporting studies—including the COCOON trial, which investigates dermatologic adverse event management, and PALOMA-2, evaluating the subcutaneous (SC) formulation of Rybrevant—further highlight improvements in treatment convenience and tolerability for both patients and clinicians.

To explore the clinical significance of these findings and their implications for Korean practice, Hit News interviewed Professor Byoung Chul Cho, principal investigator of the MARIPOSA trial at Yonsei Cancer Center, and Professor Sun Min Lim, who presented the PALOMA-2 results at WCLC 2025. The discussion delves into the evolving role of the Leclaza–Rybrevant regimen and its potential to reshape the standard of care.

Prof. Byoung Chul Cho: “The MARIPOSA trial, which evaluated the combination of Leclaza (lazertinib) and Rybrevant (amivantamab) as first-line treatment for metastatic NSCLC, marks the first chemo-free regimen to demonstrate a clear overall survival (OS) benefit. Achieving this level of efficacy without traditional chemotherapy represents a major milestone in lung cancer treatment.

Until now, discussions around first-line combinations have centered on progression-free survival (PFS), as no regimen had shown a significant OS advantage. With the release of MARIPOSA’s final OS data at ELCC 2025, we are now witnessing a real potential for a paradigm shift in clinical practice.

However, widespread adoption may take time. When Tagrisso (osimertinib) first showed superior OS over earlier EGFR-TKIs eight years ago, many physicians transitioned gradually rather than immediately. Given Tagrisso’s long-standing role as the global standard, a similar gradual shift toward the Leclaza combination is expected.”

Prof. Sun Min Lim: “As Prof. Cho mentioned, OS improvement remains the primary endpoint in any phase 3 trial. Both MARIPOSA and FLAURA-2—which evaluated Tagrisso combined with chemotherapy—have demonstrated meaningful survival benefits, establishing new standards of care.

We are already observing these combination regimens being prescribed in real-world clinical settings, signaling that this paradigm shift has already begun.”

Prof. Byoung Chul Cho: “The median OS for Tagrisso monotherapy is roughly 36 months. While 20–30% of patients maintain a long-term response, about 70% experience disease progression within three years and eventually require cytotoxic chemotherapy—many of whom die within a year. By contrast, the Leclaza combination therapy has extended median OS by more than 12 months.

While several factors guide treatment selection, survival duration remains the most meaningful outcome from a patient’s perspective. Recently, I met a patient under 40 newly diagnosed with stage IV lung cancer who specifically requested the Leclaza combination after learning about the MARIPOSA results. As patients become more informed and proactive in treatment decisions, physicians must increasingly consider these preferences.

That said, this does not lessen the importance of monotherapy options like Tagrisso or Leclaza. Oral EGFR-TKIs remain a key part of the treatment landscape due to their simple dosing and convenience in outpatient care.”

Prof. Sun Min Lim: “In real-world practice, combination regimens involving Leclaza or Tagrisso often produce rapid tumor responses and notable symptom relief. As long as early adverse effects are managed effectively, treatment can be safely maintained in outpatient settings, providing both efficacy and quality-of-life benefits.”

Prof. Byoung Chul Cho: “The MARIPOSA study, recently published in the New England Journal of Medicine (NEJM), confirmed that the Leclaza (lazertinib)–Rybrevant (amivantamab) combination delivers not only a significant overall survival (OS) benefit but also robust efficacy across multiple endpoints.

The regimen achieved an objective response rate (ORR) of approximately 80%, along with substantial improvement in progression-free survival (PFS). It also demonstrated strong central nervous system (CNS) control, maintaining intracranial responses in nearly three times as many patients as Tagrisso (osimertinib) monotherapy.

Most notably, the resistance mechanism analysis revealed both quantitative and qualitative improvements. Among patients treated with the Leclaza combination, the frequency of resistance mutations was reduced, and their genetic and biological characteristics were distinctly altered. These findings—validated through circulating tumor DNA (ctDNA) analysis—mark the first documented qualitative transformation in resistance biology for any EGFR-targeted therapy.

An ideal therapy should demonstrate consistent efficacy regardless of race, prior treatment, or clinical background, and MARIPOSA stands out precisely because it achieved such uniformity across all subgroups.”

Prof. Byoung Chul Cho: “The benefits of the combination are clearly seen even in elderly patients, though it’s important to recognize that older participants in clinical trials typically represent a healthier subset with strong family or caregiver support. Real-world patient populations can differ significantly.

Since the average age of patients with EGFR-mutant lung cancer is in the mid-60s—roughly a decade younger than the general lung cancer population—extra caution is warranted when considering combination therapy for those aged 80 or older.

In clinical decision-making, factors such as treatment motivation, self-management ability, comorbidities, and metastatic patterns often matter more than chronological age. For example, if a patient with brain metastases is motivated and capable of managing their care, the Leclaza combination should be actively considered.

While some clinicians continue to favor monotherapy, increasing patient awareness and demand, coupled with accumulating clinical evidence, indicate that the Leclaza–Rybrevant combination is on track to become the future standard of care.”

Prof. Sun Min Lim: “In the recent FLAURA-2 presentation, Asian participants were analyzed separately for the first time as Chinese and non-Chinese groups. Among roughly 100 non-Chinese Asian patients—including Koreans—no OS benefit was observed, with a hazard ratio (HR) of 1.0, showing a clear contrast to the survival advantage seen in Western patients.

Interestingly, even in the earlier FLAURA monotherapy trial, Asian patients did not exhibit significant OS improvement. These findings indicate that ethnic differences may remain a critical discussion point in future analyses.”

Prof. Byoung Chul Cho: “There are two main issues to consider. First, in FLAURA-2, the duration of chemotherapy lacked clear standardization. The WCLC 2025 data showed a median of eight cycles of pemetrexed, but the actual range varied widely—from three to twelve—depending on the physician. Such variability could lead to confusion, with some mistaking the Tagrisso combination for a chemo-free regimen, even though it remains a chemotherapy-based combination. Standardized protocols will be essential for consistency.

Second, there was a notable rise in subsequent therapy rates. At ELCC 2025, only about 40% of patients in the Tagrisso arm had received post-progression treatment, but the latest update shows an increase to over 60%. Without detailed definitions or data on treatment timing and composition, interpretation is limited. However, this increase might reflect temporary interruptions and later resumption of chemotherapy.

Moving forward, greater transparency and consistency in data reporting are needed to accurately assess the clinical benefit.”

Prof. Byoung Chul Cho: “In earlier generations of EGFR-TKIs, skin toxicities were managed reactively—using antibiotics or ointments after rashes appeared. However, with the Leclaza–Rybrevant combination, which is administered long-term as a first-line therapy, rashes often occur during the first 12 weeks of Rybrevant treatment.

The COCOON study investigated proactive prevention and showed that preemptive management—using oral antibiotics, scalp creams, and nail care—reduced rash and paronychia incidence by three- to fivefold, while significantly improving quality of life.

Importantly, patient-reported outcomes (PROs) indicated that patients themselves experienced greater comfort and symptom relief, not merely lower physician-graded scores. These findings confirm that structured, proactive management can meaningfully improve real-world treatment experience.”

Prof. Sun Min Lim: “In the COCOON study, patients who received enhanced skin, scalp, and nail care showed a marked reduction in severe (Grade 3 or higher) dermatologic adverse events compared to controls.

Such management is valuable because it allows patients to continue long-term therapy safely and comfortably using simple, low-cost interventions. This requires physicians to be actively engaged in patient and caregiver education from the start of treatment.

At Yonsei Cancer Center, we already provide educational booklets on managing adverse events to both patients and caregivers at treatment initiation.”'

Prof. Byoung Chul Cho: “Those concerns are largely overstated. For example, paraesthesia—tingling or numbness in the hands and feet—is relatively common among Korean patients but rare in Western populations. This likely reflects pharmacokinetic and dermatologic differences between ethnic groups. In Korean monotherapy studies, about 30% of patients reported paraesthesia, compared with less than 5% globally.

Patients are often sensitive to even mild symptoms, so consistent reassurance and communication from healthcare providers are crucial. Most side effects can be managed easily through dose adjustments or supportive care, and it is extremely rare for patients to discontinue therapy.

With studies like PALOMA-2 and COCOON confirming the manageability of adverse events, there is no substantial reason to avoid the Leclaza combination—aside from cost considerations.”

Prof. Byoung Chul Cho: “I feel deeply honored to have served as both first and corresponding author on three NEJM publications, including the latest MARIPOSA results. When we first published the PFS findings last year, I was so overwhelmed that I cried for nearly an hour—perhaps less this time, but it remains profoundly meaningful.

Above all, I’m grateful that Leclaza’s development journey became a catalyst for my own growth. Drug development is long and challenging—a process where both the drug itself and the researcher evolve together. In Korea, every step forward requires persistence and teamwork.

It took ten years for Leclaza to move from concept to clinical success. Watching an inanimate compound transform into a therapy that saves lives has been one of the most rewarding experiences of my career.

To younger researchers, I’d say this: stay patient, stay curious, and find meaning in the process itself—because one day, your work may also touch lives in ways you never imagined.”