The 2025 European Lung Cancer Congress (ELCC) officially opened on March 26 in Paris, France. On the very first day, during the Proffered Paper Session 1, the highly anticipated final overall survival (OS) results from the MARIPOSA study (Abstract 4O) were presented.Oncology Frontier invited Professor Rui Ma of Liaoning Cancer Hospital to provide an in-depth expert analysis of the updated data and its implications for clinical practice.

Professor Rui Ma：Osimertinib was the first third-generation EGFR-TKI to achieve regulatory approval. Its dual benefit in progression-free survival (PFS) and overall survival (OS) in the FLAURA trial established it as the standard first-line therapy for patients with EGFR-mutant advanced NSCLC.

In China, six domestically developed third-generation EGFR-TKIs have also been approved, including amecetinib, furmonertinib, befotinib, rezivertinib, rezivantinib, and lefitinib. All of these are structural optimizations based on osimertinib’s molecular backbone, designed to enhance anti-tumor potency, improve blood–brain barrier penetration, reduce off-target effects, and improve safety profiles.

However, based on currently available phase III clinical data, these drugs have not demonstrated clear superiority over osimertinib in first-line settings. The median PFS across trials remains around 20 months, showing no significant breakthrough. Furthermore, none of these agents have yet reported OS data, leaving it unproven whether these modified third-generation TKIs offer a meaningful clinical advantage. As the Chinese saying goes, “just when the road seems blocked”—this represents the bottleneck we’re facing.

The heterogeneity of EGFR-mutant advanced NSCLC is considerable. Many patients present with co-mutations and are at higher risk for brain or liver metastases. Additionally, patients with the L858R mutation often have poorer responses to EGFR-TKI therapy. This suggests that a “one-size-fits-all” approach is insufficient, and has led to the exploration of combination strategies, which aim to target broader tumor subclones and delay the onset of resistance.

Combination Strategy Exploration

Among combination approaches, the most common strategies have involved anti-angiogenic agents or chemotherapy. However, in studies combining third-generation EGFR-TKIs with anti-angiogenic drugs, most have failed to demonstrate PFS benefit, suggesting that further refinement—such as identifying predictive biomarkers—is necessary.

In contrast, combining third-generation EGFR-TKIs with chemotherapy has shown promise. The FLAURA2 trial, for example, demonstrated that osimertinib plus chemotherapy achieved a positive PFS result over osimertinib monotherapy, though final OS data have not yet been published. As such, the clinical community still awaits clarity on whether chemotherapy should be used upfront or reserved for later lines.

The MARIPOSA study adopted a “chemo-free” strategy, using the amivantamab plus lazertinib regimen. Importantly, this approach preserves the option of chemotherapy for later use and allows patients to transition into regimens like ORIENT-31 or HARMONi-A if needed.

Notably, MARIPOSA is the first and only phase III study to date to demonstrate a significant OS benefit over osimertinib. The estimated median OS improvement exceeded one year, breaking the survival ceiling set by the FLAURA study and marking a new milestone in EGFR-mutant NSCLC treatment—a true “light at the end of the tunnel.”

This success can be attributed to the unique mechanism of action of the amivantamab–lazertinib combination:

1. Amivantamab is a fully human bispecific antibody targeting EGFR and MET. By binding to the extracellular domains of both targets, it blocks ligand binding, induces receptor degradation, and inhibits MET-driven resistance mechanisms.
2. The combination offers dual inhibition of EGFR signaling at both the extracellular (amivantamab) and intracellular (lazertinib) levels, which may strengthen EGFR blockade and delay the emergence of EGFR-related resistance.
3. Amivantamab also has immune-mediated mechanisms, including ADCC and ADCP, through its Fc domain. Notably, its low fucosylation profile enhances recruitment of immune effector cells, amplifying its immunological activity.

Managing Adverse Events in Combination Therapy

As with any combination therapy, increased adverse events (AEs) are an expected challenge. In the MARIPOSA study, AEs associated with EGFR and MET inhibition, as well as infusion-related reactions (IRRs) and venous thromboembolism (VTE), were observed.

Interestingly, only 5% of patients received prophylactic anticoagulation, and 21% received baseline skin prophylaxis. Johnson & Johnson has acknowledged these AE challenges and is conducting multiple studies to mitigate them.

For example, the PALOMA-2 study found that VTE incidence was 11% in patients who received preventive anticoagulation, compared to 20% in those who did not. Similarly, the SKIPirr study showed that adding 8 mg dexamethasone premedication (administered five times) reduced IRR incidence from 67.4% to 22.5%.

At ELCC 2025, a new study—COCOON—was presented, evaluating whether enhanced skin prophylaxis could reduce grade ≥2 dermatologic AEs (DAEIs) within the first 12 weeks. Results showed that enhanced skin care reduced grade ≥2 skin AEs from 76.5% to 38.6%, successfully meeting the study’s primary endpoint.

Amivantamab combined with lazertinib significantly prolonged both PFS and OS compared to osimertinib. With the support of new prophylactic strategies to improve the safety of the combination regimen, this approach not only offers enhanced efficacy but also better tolerability, paving the way for its potential to become a new standard of care in the future.

Director, Department of Thoracic Medical Oncology II, Liaoning Cancer Hospital

PhD in Oncology

Master’s Supervisor at China Medical University and Dalian Medical University

Academic Affiliations:

• Member of the Board of Directors, Chinese Society of Clinical Oncology (CSCO)
• Executive Committee Member, Geriatric Oncology Committee, Chinese Geriatrics Society
• Standing Member, Lung Cancer Subcommittee, Geriatric Oncology Committee, Chinese Geriatrics Society
• Standing Member, Pulmonary Oncology Committee, Chinese Medical Education Association
• Executive Director, Liaoning Society for Life Sciences
• Member, Lung Cancer Committee, Chinese Anti-Cancer Association
• Council Member, Liaoning Anti-Cancer Association
• Chair, Lung Cancer Committee, Liaoning Society for Life Sciences
• Chair, Tumor Metastasis Committee, Liaoning Anti-Cancer Association
• Vice Chair, Tumor Biomarkers Committee, Liaoning Anti-Cancer Association
• Standing Committee Member, Internal Medicine Branch, Liaoning Medical Association
• Standing Committee Member, Geriatric Oncology Committee, Liaoning Society for Life Sciences
• Editorial board member and peer reviewer for several journals, including: Chinese Journal of Cancer Biotherapy, Chinese Journal of Practical Internal Medicine, Medicine and Philosophy, and Journal of Shenyang Medical College

Research Achievements:

Professor Ma has led 9 research projects at the provincial and municipal levels, received two third-class awards for Scientific and Technological Progress from Liaoning Province, and one second-class award from the Shenyang Municipal Government. As first or corresponding author, she has published over 40 peer-reviewed articles.