Clinical trialPhase 3Lung cancer

Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC

N Engl J Med · 20241074 patients

Cho BC, Lu S, Felip E, Spira AI, Girard N, Lee JS, et al. N Engl J Med. 2024. 391:1486-1498

A newer report of this study has been published: Overall Survival with Amivantamab–Lazertinib in EGFR -Mutated Advanced NSCLC (2025)

Study type: Clinical trial
Study name: MARIPOSA
Phase: Phase 3
Design: International randomised trial (2:2:1); amivantamab–lazertinib open-label, osimertinib and lazertinib double-blind
Sample size: 1074 patients
Source: N Engl J Med · 2024
Trial registration: NCT04487080

In plain words

Amivantamab is an antibody given by infusion that blocks two targets at once (EGFR and MET), and it is given together with lazertinib tablets. In this study, compared with osimertinib tablets, this combination kept the disease under control about 7 months longer, and in the final analysis more patients were alive after 3 years (60% versus 51%). On the other hand, skin side effects, infusion reactions and blood clots are more common, and regular visits for the infusions are needed.

Key results

23.7 vs 16.6 months

Median progression-free survival

HR 0.70; 95% CI 0.58–0.85; P<0.001

86% vs 85%

Objective response

25.8 vs 16.8 months

Median duration of response

HR 0.80

Overall survival (interim analysis, this paper)

95% CI 0.61–1.05

HR 0.75; 3-year survival 60% vs 51%

Overall survival (final analysis, separate paper)

95% CI 0.61–0.92; P=0.005; median follow-up 37.8 months — Yang JC et al., N Engl J Med 2025; DOI: 10.1056/NEJMoa2503001

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

Primary endpoint: progression-free survival (PFS) of amivantamab–lazertinib versus osimertinib by blinded independent central review. Key secondary: overall survival; also response, duration of response and safety.

Safety and side effects

The predominant adverse events were those related to EGFR inhibition (skin, nail, mucosal). Discontinuation of all drugs due to treatment-related adverse events: 10% with amivantamab–lazertinib versus 3% with osimertinib. In the final analysis (2025), grade 3 or higher adverse events were 80% versus 52%, especially skin events, venous thromboembolism and infusion-related reactions.

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

MARIPOSA led to FDA approval of amivantamab–lazertinib for first-line treatment of advanced EGFR-mutated NSCLC (August 2024), and by showing an overall survival benefit in the final analysis (2025) it became, alongside FLAURA2, one of the two standard intensified strategies. In updated guidelines this combination is listed as a first-line option alongside osimertinib (with or without chemotherapy); the choice between them depends on toxicity, access and patient preference.

Limitations

The amivantamab–lazertinib arm was open-label; grade 3 or higher adverse events, especially thromboembolism and skin toxicity, were considerably more frequent; there is no direct comparison with osimertinib plus chemotherapy; cost and the burden of visits for IV infusion are practical challenges.

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.