The combination of amivantamab (Rybrevant) and lazertinib (Lazcluze) has demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) compared to osimertinib (Tagrisso) alone as a first-line treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or L858R substitution mutations. This was shown in the phase 3 MARIPOSA trial (NCT04487080). The findings suggest a potential shift in the treatment paradigm for this patient population, addressing a significant unmet need in EGFR-positive lung cancer. The study's results could extend median OS by more than a year, offering transformative benefits for patients. The combination of amivantamab and lazertinib has already been approved by the FDA and European Commission as a frontline treatment for patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations. These approvals were based on earlier data from the MARIPOSA trial. The primary endpoint was PFS per RECIST 1.1 criteria as assessed by blinded independent central review. Secondary end points included OS, objective response rate, duration of response, time to second progression, and intracranial PFS.
Efficacy Outcomes in MARIPOSA
The MARIPOSA trial, a phase 3 study, randomized 1074 patients with newly diagnosed EGFR-mutated NSCLC to receive either amivantamab plus lazertinib, osimertinib alone, or lazertinib alone. The primary endpoint was progression-free survival (PFS). Key findings from the trial include:
- Progression-Free Survival (PFS): The combination of amivantamab and lazertinib significantly improved PFS compared to osimertinib alone (HR, 0.70; 95% CI, 0.58-0.85; P < .001). Median PFS was 23.7 months in the combination arm compared to 16.6 months in the osimertinib arm.
- Overall Survival (OS): Updated findings presented at the 2024 IASLC World Conference on Lung Cancer demonstrated a continued trend toward improved OS with the combination compared to osimertinib alone (HR, 0.77; 95% CI, 0.61-0.96; P = .019). At 3 years, 61% of patients in the amivantamab plus lazertinib arm were alive, compared to 53% in the osimertinib arm.
- Intracranial PFS: The combination showed a sustained benefit in intracranial PFS, with a 3-year landmark of 38% for amivantamab plus lazertinib compared to 18% for osimertinib alone.
- Objective Response Rate (ORR): The ORR was similar between the arms, 86% for amivantamab/lazertinib and 85% for osimertinib.
- Duration of Response (DOR): The DOR was longer in the amivantamab/lazertinib arm at 25.8 months vs 16.8 months in the osimertinib arm.
Dr. Stephen Liu, MD, associate professor of medicine at Georgetown University School of Medicine, stated, "Seeing this increase in OS in a trial with mature data is powerful and reaffirms that first-line treatment with amivantamab and lazertinib can lead to better patient outcomes."
Safety and Tolerability
The safety profile of the amivantamab plus lazertinib regimen was generally consistent with the known profiles of each agent. However, venous thromboembolic events were observed, which could be mitigated with prophylactic anticoagulation. Common adverse events included rash, infusion-related reactions, and paronychia. The COCOON trial (NCT06120140) investigated enhanced dermatologic management to reduce skin-related adverse events. Interim results showed a reduction in the frequency of moderate-to-severe skin and nail adverse effects with the enhanced regimen.
Implications for Clinical Practice
The MARIPOSA trial results, along with the FLAURA2 trial data on osimertinib plus chemotherapy, provide clinicians with more options for first-line treatment of EGFR-mutated NSCLC. Treatment decisions should consider patient-specific factors, including performance status, disease burden, and patient preferences. The amivantamab plus lazertinib combination offers a chemotherapy-free option with a demonstrated OS benefit, while osimertinib plus chemotherapy may be preferred for patients who can tolerate chemotherapy-related toxicities. Ongoing research is focused on optimizing sequencing strategies and identifying biomarkers to guide treatment selection.
Managing Adverse Events
Effective management of adverse events is crucial for optimizing treatment outcomes with amivantamab plus lazertinib. Strategies include:
- Prophylactic Anticoagulation: Consider prophylactic oral anticoagulation during the initial 4 months of treatment to mitigate the risk of venous thromboembolic events.
- Dermatologic Management: Implement proactive strategies for managing skin toxicities, such as prophylactic topical corticosteroids and antibiotics. The COCOON trial demonstrated that enhanced dermatologic care could reduce the incidence of skin-related adverse events.
- Infusion-Related Reaction (IRR) Management: Utilize premedication with dexamethasone and antihistamines to reduce the incidence and severity of IRRs. Splitting the first dose over two days and considering subcutaneous administration may also help.
The Future of EGFR-Mutated NSCLC Treatment
The treatment landscape for EGFR-mutated NSCLC continues to evolve, with ongoing research focused on novel therapeutic strategies and personalized approaches. The MARIPOSA trial represents a significant step forward, providing a new first-line option with a demonstrated OS benefit. As more data emerge, clinicians will be better equipped to tailor treatment to individual patients, improving outcomes and quality of life.
