Leclaza-Rybrevant Boosts Survival – Hopes for Lung Cancer Cure
OS improve by over 12 months vs. Tagrisso — a practice-changing therapy
The combination therapy of Leclaza (lazertinib) and Rybrevant (amivantamab) is offering new hope to patients with stage IV EGFR-mutant non-small cell lung cancer (NSCLC), with real-world reports and trial data pointing to the potential for long-term remission and even cure.
Leclaza was added to Korea’s reimbursement list in January 2024 as a first-line monotherapy for EGFR-mutant NSCLC. Since then, the Leclaza-Rybrevant combination has been approved in major markets including the U.S. (FDA) and Europe (EMA), and its indication was expanded in Korea as of January 2025.
At the European Lung Cancer Congress (ELCC) held on March 26 in Paris, final overall survival (OS) results from the Phase 3 MARIPOSA trial were unveiled. The study compared the Leclaza-Rybrevant combination with Tagrisso (osimertinib) monotherapy in patients with locally advanced or metastatic EGFR-mutant NSCLC.
After a median follow-up of 37.8 months, the combination group had not yet reached median OS (95% CI: 42.9–NE), while the Tagrisso group showed 36.7 months (95% CI: 33.4–41.0). The combination reduced the risk of death by 25% (HR=0.75, 95% CI: 0.61–0.92, p<0.005). At 42 months, survival was 56% with the combination versus 44% with Tagrisso—a consistent trend seen through 48 months.
Experts praised the results, marking the first OS benefit over Tagrisso since its introduction as standard of care. The study’s significance lies in extending survival by over a year—something no other therapy has achieved to date.
It’s been a year since Leclaza monotherapy has been included in the reimbursement criteria. How has the lung cancer treatment landscape changed since then?
“Leclaza’s reimbursement has transformed first-line treatment options for EGFR-mutant NSCLC in Korea. Previously, insurance limitations restricted many physicians to older-generation TKIs. Now, we’re seeing better outcomes from the start, and more robust real-world data will become available later this year.”
Comparing Leclaza to Tagrisso, Dr. Lim noted: “Both have similar efficacy as monotherapies, but Leclaza shows particular strength in patients with the L858R mutation, and in those with brain or leptomeningeal metastases. Leclaza also demonstrates superior blood-brain barrier penetration and had a progression-free survival (PFS) of 23.3 months in Korean patients with Exon 19 deletion.”
Regarding toxicity, Tagrisso carries cardiotoxicity risks, while Leclaza may cause peripheral neuropathy in about a third of patients. “In my practice, I prescribe Leclaza more frequently—about 70% compared to 30% for Tagrisso.”
Leclaza and Tagrisso are both leading third-generation TKIs. What are the key differences between the two?
"In terms of monotherapy, both drugs show similar efficacy data overall.
However, Leclaza is particularly effective against the EGFR L858R mutation, based on both clinical trial data and real-world treatment experience. It also shows disease control benefits in patients with extensive brain metastases or leptomeningeal metastases, and a related investigator-initiated study is currently underway in Korea.
When comparing global randomized clinical trial data, Leclaza has demonstrated superior blood-brain barrier (BBB) penetration. In Korean patients with an Exon 19 deletion, the progression-free survival (PFS) reached 23.3 months—a very encouraging result, consistent across all EGFR subtypes.
That said, each drug has its own distinct toxicity profile. Tagrisso can cause cardiotoxicity by reducing myocardial contractility, which may lead to discontinuation if reported. Leclaza, on the other hand, has been associated with peripheral neuropathy, such as tingling in the hands and feet, in about one-third of patients, so careful monitoring is required.
In terms of actual prescribing patterns, academic discussions suggest a 50:50 usage ratio. Personally, I prescribe Leclaza over Tagrisso at about a 70:30 ratio."
The final overall survival (OS) results from the MARIPOSA trial were presented at ELCC 2025. How would you evaluate the key findings?
"The MARIPOSA study delivered meaningful results at this year’s conference. The median OS for the Tagrisso monotherapy group was 36.7 months, whereas the Leclaza combination group had not yet reached median OS. Some experts are speculating it could exceed 50 months.
This reflects a 25% reduction in the risk of death with the Leclaza combination therapy compared to Tagrisso—statistically significant. While we’ve seen improvements in progression-free survival (PFS) or objective response rate (ORR) in previous lung cancer studies, no therapy has extended OS by over 12 months until now. In that sense, the Leclaza combination is truly a practice-changing treatment.
The study also reported separate data on brain metastases. The 3-year intracranial PFS (IC-PFS)—the rate of patients without progression in the brain—was more than double in the Leclaza combination group compared to the Tagrisso monotherapy group. This suggests that Leclaza may offer not only systemic control of lung cancer but also better management of brain metastases."
In the MARIPOSA trial, beyond PFS, the PFS2 data has also been highlighted. Could you elaborate on its significance?
"Yes, PFS2 refers to the progression-free survival after failure of first-line treatment and initiation of second-line therapy. In this metric as well, the Leclaza combination therapy showed improved outcomes compared to Tagrisso monotherapy.
In the MARIPOSA trial, the PFS2 rate was 57% for the Leclaza combination group and 49% for the Tagrisso group—a difference of about 10%. Interestingly, this gap appeared to widen gradually over time.
This trend is likely due to the contribution of Rybrevant, which is administered alongside Leclaza. Rybrevant is a bispecific antibody targeting both EGFR and MET, and it goes beyond traditional targeted therapy by also exhibiting immunotherapeutic properties. It’s believed to activate memory T cells, allowing the immune system to retain long-term memory—creating a synergistic effect that enhances durability of response."
Based on all this data, how would you summarize the clinical significance of the MARIPOSA trial?
"I would describe it as a study with the potential to cure patients.
To share a real-world example, one of my patients diagnosed with stage IV lung cancer enrolled in the MARIPOSA trial and has now survived for over five years.
This patient personally described the Leclaza combination therapy as life-changing. Although a small 1 cm lesion remains visible on CT, it shows no activity, and we consider the patient to be in near-complete remission (CR).
Currently, the patient is experiencing some difficulty with mobility due to bleeding from nail bed inflammation. As a result, we reduced and eventually stopped Rybrevant, and the patient is now continuing on Leclaza monotherapy."
What are the resistance and toxicity concerns associated with the Leclaza combination therapy?
"Current treatment trends are shifting toward combination therapies. While monotherapies are effective, resistance typically develops within 18 to 20 months, which is a key consideration.
In line with this, studies are underway to better understand the resistance mechanisms of the Leclaza combination. Data so far show that Rybrevant suppresses both the EGFR and MET pathways, which helps reduce traditional resistance. However, we are now observing new resistance patterns, such as HER2 amplification, CDK-related cell cycle mutations, and TPO13 expression.
As for side effects, patients receiving Leclaza combination therapy may experience skin issues, diarrhea, and inflammation around the nails. However, these adverse events are generally manageable through dose adjustments or discontinuation of Rybrevant. It’s important to communicate this clearly to patients upfront, as it helps in building trust and ensuring adherence.
Physicians in Korea, who have extensive experience prescribing Leclaza monotherapy, are often consulted by their international peers for advice in managing these side effects."
With four treatment options now available—Leclaza monotherapy, Leclaza combination therapy, Tagrisso monotherapy, and Tagrisso plus chemotherapy—how should clinicians decide which to use?
"Tagrisso monotherapy, Tagrisso with chemotherapy, and Leclaza combination therapy are all listed in global guidelines such as the NCCN as standard treatments. Including Leclaza monotherapy, clinicians now face a choice among four treatment options. There’s ongoing discussion about which option is most appropriate for which patients.
Leclaza combination therapy shows a very dramatic tumor shrinkage effect early in treatment. Still, a recent Korean clinical study evaluating Leclaza monotherapy in EGFR-mutant NSCLC patients with five or fewer metastatic lesions showed a PFS of about 23 months—identical to the MARIPOSA trial results. This suggests that even monotherapy can provide excellent outcomes in patients with a limited number of metastases. These findings will be presented at the World Conference on Lung Cancer (WCLC) in November 2025.
On the other hand, for patients with both brain and liver metastases, Leclaza combination therapy is essential. Among five high-risk markers—including TPO13 and CTDZ positivity—even the presence of just one indicates poor prognosis, making combination therapy more suitable for high-risk groups.
In the U.S., preferences vary depending on the physician. This is partly because Leclaza has not yet been approved as monotherapy in the U.S., and physicians may be less familiar with it. There’s also some reluctance due to the intravenous (IV) formulation of Rybrevant, which can be inconvenient.
However, within the academic community, data is the most critical factor. So, regardless of familiarity, if the clinical data continues to show strong results, use of Leclaza will likely increase. If a subcutaneous (SC) formulation of Rybrevant is approved in the future, it may further shift preferences in favor of the MARIPOSA regimen."
What additional efforts are needed to further improve the lung cancer treatment landscape?
"Patients with EGFR-mutant non-small cell lung cancer (NSCLC) generally do not respond well to PD-1/PD-L1-based immunotherapies and are often classified as having 'cold tumors.' If we can accurately identify the small subset of patients who do respond, it could significantly improve outcomes in second-line treatment.
While targeted therapies like TKIs remain the standard in first-line treatment, developing combination regimens that incorporate immunotherapy is urgently needed to extend survival in second- and third-line settings. Beyond antibody-drug conjugates (ADCs), I hope to see the emergence of more diverse immunotherapeutic strategies.
Additionally, quickly gathering Korean real-world data (RWD) on these newer treatments will be a great support for clinicians as these therapies enter clinical practice. From an academic standpoint, I would also like to see more educational initiatives and symposiums hosted to support the integration of new treatments."