Clinical trialPhase 3Lung cancer

Overall Survival with Amivantamab–Lazertinib in EGFR -Mutated Advanced NSCLC

N Engl J Med · 20251074 patients (429 amivantamab-lazertinib, 429 osimertinib and 216 lazertinib; lazertinib group size from the original MARIPOSA paper)

Yang JCH, Lu S, Hayashi H, Felip E, Spira AI, Girard N, et al. N Engl J Med. 2025. 393:1681-1693

Study type: Clinical trial
Study name: MARIPOSA
Phase: Phase 3
Design: Randomised phase 3 trial with 2:2:1 randomisation (protocol-specified final overall survival analysis)
Sample size: 1074 patients (429 amivantamab-lazertinib, 429 osimertinib and 216 lazertinib; lazertinib group size from the original MARIPOSA paper)
Source: N Engl J Med · 2025
Trial registration: NCT04487080

In plain words

In this study, patients with advanced non-small cell lung cancer with an EGFR mutation who had not yet been treated received either the combination of amivantamab and lazertinib or the drug osimertinib. Patients who received the amivantamab-lazertinib combination lived significantly longer; after 3 years, 60% of them were alive compared with 51% in the osimertinib group. On the other hand, more serious side effects (including skin problems, blood clots in the veins and reactions during the infusion) were more common with the combination. The choice of treatment should be made with the treating doctor, taking each patient's situation into account.

Key results

0.75 (95% CI 0.61–0.92)

Overall survival (hazard ratio for death)

P = 0.005; amivantamab-lazertinib vs osimertinib

60% vs 51%

3-year overall survival

Amivantamab-lazertinib vs osimertinib

37.8 months

Median follow-up

38% vs 28%

Still on treatment at data cut-off

Amivantamab-lazertinib vs osimertinib

Drugs in this study:Osimertinib (Tagrisso)

Dose and schedule cards

Amivantamab + lazertinib (MARIPOSA)

Locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R; first-lineEach drug’s schedule in the tableOn the page “Lung cancer” · Advanced NSCLC with an EGFR mutation or ALK rearrangement

Locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R; first-line

Drug	Dose	Route	Schedule
Lazertinib	240 mg	Oral, with or without food	Once daily, continuous (on infusion days, before amivantamab)
Amivantamab	1050 mg (body weight less than 80 kg) or 1400 mg (≥80 kg)	IV (via a peripheral vein in weeks 1 and 2)	Weekly in weeks 1 to 5 (week 1 dose split: 350 mg on day 1 and the remainder on day 2); no dose in week 6; then every 2 weeks from week 7

Cycle schedule: Amivantamab weekly (5 doses), then every 2 weeks; lazertinib daily and continuously
Duration: Until disease progression or intolerable toxicity

Source: FDA labels for amivantamab and lazertinib; trial. Premedication (infusion-related reactions): dexamethasone 8 mg orally twice daily on days −2 and −1, and one dose 1 hour before the infusion on day 1; dexamethasone 20 mg IV on day 1 and dexamethasone 10 mg IV on day 2; with all infusions, diphenhydramine 25–50 mg and acetaminophen 650–1000 mg. Thromboembolism prophylaxis: prophylactic anticoagulation for the first 4 months. Skin prophylaxis: doxycycline or minocycline 100 mg twice daily from day 1 for 12 weeks, then clindamycin 1% lotion on the scalp for 9 months; a non-comedogenic moisturizer, washing hands and feet with 4% chlorhexidine, and sun protection.

On the page “Lung cancer” · Advanced NSCLC with an EGFR mutation or ALK rearrangement

Amivantamab + lazertinib

Advanced EGFR-positive lung cancerEach drug’s schedule in the tableOn the page “Amivantamab with lazertinib (MARIPOSA)”

Advanced EGFR-positive lung cancer

Drug	Dose	Route	Schedule
Lazertinib	240 mg once a day	Oral	Daily
Amivantamab (weight below 80 kg)	1050 mg	IV	Weekly in weeks 1 to 5 (first dose split over days 1 and 2), then every 2 weeks from week 7
Amivantamab (weight 80 kg or more)	1400 mg	IV	Same schedule

Cycle schedule: Lazertinib daily; amivantamab weekly, then every 2 weeks
Duration: Until progression

As in MARIPOSA; dose source:.

On the page “Amivantamab with lazertinib (MARIPOSA)”

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Amivantamab + lazertinib

IV amivantamab by baseline weight: 1050 mg (weight below 80 kg) or 1400 mg (weight 80 kg or more), in 28-day cycles: weekly in cycle 1 (weeks 1 to 4; the first-week dose split over days 1 and 2) and then every 2 weeks from cycle 2 (week 5) onwards; with lazertinib 240 mg orally once daily (open-label), until disease progression or unacceptable toxicity. (429 patients)

Notes from the current FDA labels (Rybrevant and Lazcluze, 2026): first-week split dose: day 1, 350 mg; day 2, 700 mg (weight below 80) or 1050 mg (weight 80 or more). Weeks 2 to 5 weekly, no dose in week 6, every 2 weeks from week 7. On shared days, lazertinib is given before the amivantamab infusion. Week 1 and 2 infusions via a peripheral line (first infusion about 4 to 6 hours on day 1 and 6 to 8 hours on day 2; later ones about 2 hours).

Premedication before each infusion: diphenhydramine 25 to 50 mg (or equivalent) and paracetamol (acetaminophen) 650 to 1000 mg; dexamethasone before the first-week infusions (the current label also recommends oral dexamethasone 8 mg twice daily on the 2 days before starting) and optionally for later infusions.
Anticoagulant prophylaxis during the first 4 months of combination therapy to reduce venous thromboembolism.
Skin prophylaxis: doxycycline or minocycline 100 mg orally twice daily from day 1 for 12 weeks, then clindamycin 1% lotion on the scalp once daily for the next 9 months; non-comedogenic moisturiser for the face and body; daily washing of hands and feet with chlorhexidine 4%; sun avoidance and sunscreen during treatment and for 2 months afterwards.
Dose reduction: amivantamab 1050 → 700 → 350 mg (for 1400 mg per the label table); lazertinib 240 → 160 → 80 mg. For an adverse event requiring dose reduction, the amivantamab dose is reduced first. Liver tests (ALT, AST, bilirubin) before starting and during treatment.

2Osimertinib

Osimertinib 80 mg orally once daily with lazertinib placebo (double-blind), until disease progression or unacceptable toxicity. (429 patients)

3Lazertinib (to assess the contribution of the treatment components)

Lazertinib 240 mg orally once daily with osimertinib placebo (double-blind). (216 patients)

Source of the regimen details: ClinicalTrials.gov NCT04487080 (arms and doses) and the FDA labels for Rybrevant and Lazcluze (DailyMed, 2026 version; split dosing, premedication, anticoagulant and skin prophylaxis, dose-reduction levels); the full text of the paper was not available in PMC

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with newly diagnosed, histologically or cytologically confirmed locally advanced or metastatic NSCLC not amenable to curative therapy (surgery or chemoradiotherapy) and previously untreated; with an EGFR exon 19 deletion or L858R substitution; at least one measurable lesion (RECIST 1.1). Adjuvant or neoadjuvant therapy for stage I or II disease was allowed if completed more than 12 months before the development of advanced disease. Asymptomatic, or treated and stable, brain metastases were allowed.

Key exclusion criteria: any prior systemic therapy for advanced stage III or stage IV disease, history or presence of leptomeningeal disease, symptomatic brain metastases, untreated spinal cord compression, and history of ILD/pneumonitis (including drug-‎ or radiation-induced).

Endpoints

Overall survival (time from randomisation to death from any cause) in the amivantamab-lazertinib group compared with the osimertinib group was the key secondary endpoint. Other endpoints included safety.

Safety and side effects

Grade 3 or higher adverse events were more common with amivantamab-lazertinib (80% versus 52% with osimertinib), especially skin events, venous thromboembolism and infusion-related reactions. These findings were consistent with the known safety profile of each treatment, and no new safety signals were observed with longer follow-up.

According to the FDA labels (MARIPOSA data, 421 patients receiving the combination): infusion-related reactions 63% (grade 3: 5%, grade 4: 1%; mostly with the first infusion); venous thromboembolism 36% (grade 3: 10%; 2 fatal cases; median time to onset 84 days); ILD/pneumonitis 3.1% (one fatal case); hepatotoxicity 49% (grade 3: 9.3%). Serious adverse events 49% and fatal adverse events 7%. For lazertinib: dose interruption 72%, dose reduction 42% (mainly rash and nail toxicity) and permanent discontinuation 21%.

Clinical significance and place in guidelines

This final analysis shows that amivantamab-lazertinib in first-line treatment of advanced EGFR-mutated NSCLC, in addition to the improvement in progression-free survival in the earlier report, also increases overall survival compared with osimertinib. This advantage comes with a greater burden of grade 3 or higher adverse events, and treatment choice must balance survival benefit and tolerability. The status of drug approvals and formal clinical guideline recommendations should be checked separately, because the abstract does not address them.

Limitations

Based on the abstract, grade 3 or higher adverse events were noticeably more frequent in the combination group. Overall survival was the key secondary endpoint. Other limitations are not mentioned in the abstract and should be checked in the full text of the paper.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.