‘Leclaza combo extends survival without chemotherapy’

sets a new treatment standard

Byoung Chul Cho and Sun Min Lim, Professors of Medical Oncology, Yonsei Cancer Center

Overall survival extended by 12 months vs. Tagrisso; clinical evidence validated through NEJM publication

Subgroup analysis confirms consistent OS benefit regardless of ethnicity or baseline characteristics

Professors Sun Min Lim and Byoung Chul Cho of Yonsei Cancer Center’s Department of Medical Oncology

“The MARIPOSA study is the first clinical trial to significantly extend overall survival using two targeted therapies without chemotherapy.

 

Discussions on EGFR-mutated lung cancer treatment will now shift to focus on overall survival.” During a recent interview with Dailypharm, Professors Byoung Chul Cho and Sun Min Lim of Yonsei Cancer Center’s Department of Medical Oncology expressed so regarding the results of the MARIPOSA trial that evaluated the combined use of Leclaza (Lazertinib) and Rybrevant (amivantamab)’, agreeing it will trigger a paradigm shift in treatment.

 

Leclaza (lazertinib), developed by Yuhan Corporation, is a third-generation EGFR tyrosine kinase inhibitor (TKI) that targets exon 19 deletions and exon 21 L858R mutations in EGFR-positive non-small cell lung cancer (NSCLC).

 

Johnson & Johnson secured global rights to Leclaza and has conducted clinical studies evaluating the efficacy of Leclaza in combination with Rybrevant, a targeted therapy option targeting exon 20 and MET mutations.

 

In the trial, the Leclaza + Rybrevant group demonstrated a statistically significant improvement in survival duration compared to the Tagrisso (osimertinib) group (p-value less than 0.005).

 

Specifically, the median overall survival (OS) for the Leclaza + Rybrevant group was not reached (42.9-NE).

 

In contrast, the Tagrisso group showed an OS of 36.7 months.

 

Considering the survival rate distribution between the two groups, the Leclaza + Rybrevant group is expected to extend OS by at least 12 months compared to the Tagrisso group.

 

These study results were recently published in the New England Journal of Medicine (NEJM), drawing significant attention from the academic community.

 

Professor Cho explained, “The MARIPOSA study is the first clinical trial to significantly extend survival using only two targeted therapies without chemotherapy.

 

While discussions on EGFR-mutated lung cancer have previously focused on progression-free survival (PFS), the focus will now shift to OS.” Professor Lim also stated, “In actual clinical settings, the third-generation TKI combo regimen showed rapid response and early symptom relief.

 

If initial side effects are appropriately managed and prevented, treatment can be sufficiently continued on an outpatient basis.

 

Ultimately, helping patients survive long-term with effective drugs is the top priority of treatment.” The professors saw that the most significant distinguishing feature of this study was the confirmation of a ‘qualitative change in the mechanism of resistance.’

Professor Byoung Chul Cho of Yonsei Cancer Center’s Department of Medical Oncology

Professor Cho emphasized, “Not only did the frequency of resistance occurrence change, but the genetic and biological characteristics of the tumor itself changed.

 

This suggests that the treatment fundamentally altered tumor biology, contributing to improved OS beyond merely extending the duration of treatment.” He further explained, “The MARIPOSA study demonstrated consistent OS improvement in both Asian and non-Asian patient populations.

 

In contrast, the FLAURA2 study, which evaluated the efficacy of Tagrisso plus chemotherapy, showed a limited OS improvement in the Asian patient cohort.” He projected, “Combining chemotherapy has limitations in that it cannot fundamentally alter the biological characteristics of the tumor.

 

Therefore, the detailed Asian data from MARIPOSA to be presented at ESMO Asia is expected to show different results compared to FLAURA2.” Professor Lim said, “In the detailed analysis of FLAURA2, no OS improvement was observed in the Asian cohort, excluding Chinese patients.

 

Considering that the previous FLAURA study on Tagrisso monotherapy also failed to confirm OS improvement in Asian patients, racial differences may remain a persistent point of debate.

 

Differences in drug response between races will become an important discussion point going forward.” Side effect management and formulation improvements increase potential for sustained treatment...

 

“Combination therapy will ultimately become the standard” Researchers also note that recent studies have demonstrated manageability for skin-related adverse reactions, a common side effect of combination therapy.

 

For Leclaza + Rybrevant, skin rash and paronychia are identified as major adverse reactions.

 

Professor Cho stated, “According to the recently published COCOON study, preventive use of antibiotics, scalp lotions, and moisturizers reduced moderate to severe skin rashes by nearly half.

 

If managed well during the initial 12 weeks, patients' quality of life also improves significantly.” Professor Lim emphasized, “We provide a management manual to patients and caregivers from the initial stages of treatment,” stressing that “prevention-focused management is key to ensuring treatment adherence.” Also, Professor Lim believed that the convenience of administration would significantly improve with the introduction of the subcutaneous injection formulation of Rybrevant.

 

A drawback highlighted in the combination therapy of Leclaza + Rybrevant is that the injectable form of Rybrevant may reduce administration convenience.

 

EGFR-targeted therapies, including Leclaza, Tagrisso, Boehringer Ingelheim's Giotrif (Afatinib), Pfizer's Vizimpro (dacomitinib), Roche's Tarceva (Erlotinib), and AstraZeneca's Iressa (gefitinib), are all oral medications.

 

Rybrevant, however, is an intravenous (IV) formulation requiring a hospital visit once every three weeks for administration that lasts over an hour.

 

This has raised concerns that it may hinder treatment convenience for non-small cell lung cancer patients.

 

Janssen plans to maximize the synergy of combination therapy through the introduction of Rybrevant’s subcutaneous (SC) injection formulation.

 

Professor Sun Min Lim of Yonsei Cancer Center’s Department of Medical Oncology

Professor Lim stated, “In the PALOMA-2 study evaluating the potential of Rybrevant SC, the SC formulation showed infusion-related reactions reduced to one-seventh compared to IV, while demonstrating equivalent efficacy.

 

Approval has already been granted in Europe, and U.S.

 

approval is imminent.

 

If introduced in Korea as well, the new formulation will significantly reduce the burden on patients.” She continued, “Beyond simply reducing administration time and increasing convenience, the SC formulation has the potential to alter the patient's immune environment itself.

 

Our research team is currently preparing a study directly comparing the immunological differences between Rybrevant SC and IV administration.” She also noted, "The most important factor for patients is the survival period.

 

As long as the data supports this, change in the field is only a matter of time.

 

Delays in approval and reimbursement preventing patients from immediately benefiting from the latest treatments represent an institutional challenge that needs resolution.“ Professor Cho explained, ”While some hesitate to use combination therapy, citing concerns about Leclaza’s adverse reactions or reduced administration convenience, most issues can be resolved through dose adjustment and proactive management.

 

The results of the PALOMA-2 and COCOON studies support this." He added, “The average age of EGFR-mutated lung cancer patients is mid-60s, about 10 years younger than the general lung cancer patient population.

 

While caution is needed for combination therapy in those over 80, factors like treatment willingness, self-management capability, underlying conditions, and metastasis patterns are more critical criteria than age itself.” He stated, “If a patient has brain metastases but demonstrates strong treatment intent and good self-management capability, combination therapy should be prioritized.

 

When Tagrisso first improved OS by six months eight years ago, some initially urged caution, but it eventually became the global standard.

 

While some clinicians still prefer monotherapy, considering patient demand and the proliferation of data, combination therapy will likely establish itself as the new standard of care.”