A Study of Amivantamab and Lazertinib Combination Therapy Versus Osimertinib in Locally Advanced or Metastatic Non-Small Cell Lung Cancer

The purpose of this study is to assess the efficacy of the amivantamab and lazertinib combination, compared with osimertinib, in participants with epidermal growth factor receptor (EGFR) mutation (Exon 19 deletions \[Exon 19del\] or Exon 21 L858R substitution) positive, locally advanced or metastatic non-small cell lung cancer (NSCLC).

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* Participant must have newly diagnosed histologically or cytologically confirmed, locally advanced or metastatic non-small cell lung cancer (NSCLC) that is treatment naive and not amenable to curative therapy including surgical resection or chemoradiation
* The tumor harbors exon 19 deletions (Exon 19del) or Exon 21 L858R substitution, as detected by an food and drug administration (FDA)-approved or other validated test in a clinical laboratory improvement amendments (CLIA) certified laboratory (sites in the United states \[US\]) or an accredited local laboratory (sites outside of the US) in accordance with site standard of care
* Mandatory submission of unstained tissue from tumor (in a quantity sufficient to allow for central analysis of EGFR mutation status and blood (for circulating tumor deoxyribonucleic acid \[ctDNA\], digital droplet polymerase chain reaction \[ddPCR\], and pharmacogenomic analysis)
* Any toxicities from prior anticancer therapy must have resolved to common terminology criteria for adverse events (CTCAE) Grade 1 or baseline level
* Participant must have at least 1 measurable lesion, according to response evaluation criteria in solid tumors (RECIST) v1.1 that has not been previously irradiated. Measurable lesions should not have been biopsied during screening, but if only 1 non-irradiated measurable lesion exists, it may undergo a diagnostic biopsy and be acceptable as a target lesion, provided the baseline tumor assessment scans are performed at least 14 days after the biopsy

Exclusion Criteria:

* Participant has received any prior systemic treatment at any time for locally advanced Stage III or metastatic Stage IV disease (adjuvant or neoadjuvant therapy for Stage I or II disease is allowed, if administered more than 12 months prior to the development of locally advanced or metastatic disease)
* Participant has an active or past medical history of leptomeningeal disease
* Participant with untreated spinal cord compression. A participant that has been definitively treated with surgery or radiation and has a stable neurological status for at least 2 weeks prior to randomization is eligible provided they are off corticosteroid treatment or receiving low-dose corticosteroid treatment less than or equal to (\<=) 10 milligrams per day (mg/day) prednisone or equivalent
* Participant has an active or past medical history of interstitial lung disease (ILD)/pneumonitis, including drug-induced or radiation ILD/pneumonitis
* Participant has known allergy, hypersensitivity, or intolerance to the excipients used in formulation of amivantamab, lazertinib, or osimertinib, or any contraindication to the use of osimertinib
* Participant has symptomatic brain metastases. A participant with asymptomatic or previously treated and stable brain metastases may participate in this study

• DERIVEDYang JC, Lu S, Hayashi H, Felip E, Spira AI, Girard N, Kim YJ, Lee SH, Ostapenko Y, Danchaivijitr P, Liu B, Alip A, Korbenfeld E, Mourao Dias J, Besse B, Passaro A, Lee KH, Xiong H, How SH, Cheng Y, Chang GC, Yoshioka H, Thomas M, Nguyen D, Ou SI, Mukhedkar S, Prabhash K, D'Arcangelo M, Alatorre-Alexander J, Vazquez Limon JC, Alves S, Stroyakovskiy D, Peregudova M, Sendur MAN, Yazici O, Califano R, Gutierrez Calderon V, de Marinis F, Kim SW, Gadgeel SM, Owen S, Xie J, Sun T, Mehta J, Venkatasubramanian R, Ennis M, Fennema E, Daksh M, Roshak A, Man J, Knoblauch RE, Bauml JM, Baig M, Shah S, Sethi S, Cho BC; MARIPOSA Investigators. Overall Survival with Amivantamab-Lazertinib in EGFR-Mutated Advanced NSCLC. N Engl J Med. 2025 Oct 30;393(17):1681-1693. doi: 10.1056/NEJMoa2503001. Epub 2025 Sep 7. PMID 40923797
• DERIVEDLee SH, Lu S, Hayashi H, Felip E, Spira AI, Girard N, Kim YJ, Ostapenko Y, Danchaivijitr P, Liu B, Alip A, Korbenfeld E, Dias JM, Lee KH, Xiong H, How SH, Cheng Y, Chang GC, Chih-Hsin Yang J, Besse B, Thomas M, Shah S, Baig M, Curtin JC, Zhang J, Xie J, Sun T, Sethi S, Wang M, Fennema E, Daksh M, Ennis M, Bauml JM, Cho BC. Lazertinib Versus Osimertinib in Previously Untreated EGFR-Mutant Advanced NSCLC: A Randomized, Double-Blind, Exploratory Analysis From MARIPOSA. J Thorac Oncol. 2025 Nov;20(11):1655-1668. doi: 10.1016/j.jtho.2025.06.030. Epub 2025 Jul 3. PMID 40617394
• DERIVEDCho BC, Lu S, Felip E, Spira AI, Girard N, Lee JS, Lee SH, Ostapenko Y, Danchaivijitr P, Liu B, Alip A, Korbenfeld E, Mourao Dias J, Besse B, Lee KH, Xiong H, How SH, Cheng Y, Chang GC, Yoshioka H, Yang JC, Thomas M, Nguyen D, Ou SI, Mukhedkar S, Prabhash K, D'Arcangelo M, Alatorre-Alexander J, Vazquez Limon JC, Alves S, Stroyakovskiy D, Peregudova M, Sendur MAN, Yazici O, Califano R, Gutierrez Calderon V, de Marinis F, Passaro A, Kim SW, Gadgeel SM, Xie J, Sun T, Martinez M, Ennis M, Fennema E, Daksh M, Millington D, Leconte I, Iwasawa R, Lorenzini P, Baig M, Shah S, Bauml JM, Shreeve SM, Sethi S, Knoblauch RE, Hayashi H; MARIPOSA Investigators. Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC. N Engl J Med. 2024 Oct 24;391(16):1486-1498. doi: 10.1056/NEJMoa2403614. Epub 2024 Jun 26. PMID 38924756
• DERIVEDCho BC, Felip E, Hayashi H, Thomas M, Lu S, Besse B, Sun T, Martinez M, Sethi SN, Shreeve SM, Spira AI. MARIPOSA: phase 3 study of first-line amivantamab + lazertinib versus osimertinib in EGFR-mutant non-small-cell lung cancer. Future Oncol. 2022 Feb;18(6):639-647. doi: 10.2217/fon-2021-0923. Epub 2021 Dec 16.