Amivantamab, Lazertinib, and Pemetrexed for First-line Treatment of Recurrent/Metastatic Non-small Cell Lung Cancers With Epidermal Growth Factor Receptor Mutations

Inclusion Criteria:

1. Participant must be ≥18 years of age;

2. Participant must have histologically or cytologically confirmed locally advanced ormetastatic NSCLC not amenable to curative therapy. Participants must betreatment-naïve for metastatic NSCLC. Prior adjuvant and neo-adjuvant therapy forearly-stage disease is permitted, prior systemic therapy for potentially curablelocally advanced disease is also permitted;

3. Participant must have a tumor that was previously determined to have Exon 19del orExon 21 L858R substitution, as detected by a validated test in accordance with sitestandard of care. Note: A copy of the test report documenting the EGFR mutation mustbe included in the participant records and must also be submitted to the sponsorprior to enrollment;

4. Unstained tumor tissue and blood (for ctDNA, biomarker), both collected prior totreatment initiation, must be provided. Unstained FFPE tumor tissue blocks must beprovided whenever possible. Alternatively, re-cut unstained sections from FFPE tumortissue block, presented on slides must be provided (recommended 10-15 slides);

5. Subject must have specific organ and bone marrow function;

6. Participant must have ECOG status of 0 to 2;

7. Any toxicities from prior anticancer therapy must have resolved to CTCAE Grade 1 orbaseline level;

8. Participant must have at least 1 measurable lesion, according to RECIST v1.1 thathas not been previously irradiated. Target lesions situated in a previouslyirradiated area are considered measurable if progression has been demonstrated insuch lesions.

Exclusion Criteria:

1. Participant has received any prior systemic treatment for metastatic disease (priorsystemic therapy for potentially curable locally advanced disease, adjuvant orneoadjuvant therapy are allowed, if administered more than 12 months prior to thedevelopment of the recurrent disease);

2. Participant has symptomatic brain metastases. A participant with asymptomatic orpreviously treated and stable brain metastases may participate in this study.Participants who have received definitive radiation or surgical treatment forsymptomatic or unstable brain metastases and have been clinically stable andasymptomatic for at least 2 weeks before Screening are eligible, provided they havebeen either off corticosteroid treatment or are receiving low-dose corticosteroidtreatment (≤10 mg/day prednisone or equivalent) for at least 2 weeks prior toenrollment;

3. Participant has severe co-morbidities that in the opinion of the investigator posethe patient at undue risk from participating in the study;

4. Participant has an active or past medical history of leptomeningeal disease;

5. Participant has spinal cord compression that has not been definitively treated withsurgery or radiation or requires steroid treatment within 2 weeks prior toenrollment. Low-dose corticosteroid treatment ≤10mg/day prednisone or equivalent isallowed;

6. Participant has an active or past medical history of Interstitial lung disease (ILD)/pneumonitis, including drug-induced or radiation ILD/pneumonitis;

7. Immune-mediated rash from checkpoint inhibitors that has not resolved prior toenrollment;

8. Subject has uncontrolled inter-current illness;

9. Participant has active cardiovascular disease;

10. Participant is currently receiving medications or herbal supplements known to bepotent CYP3A4/5 inhibitors or inducers and is unable to stop use for an appropriatewashout period prior to enrollment (see Appendix 8: Prohibited and RestrictedMedications and Therapies That Induce, Inhibit, or Are Substrates of CYP3A4/5);

11. Participant has received any prior treatment with an EGFR TKI;

12. Known positive hepatitis B (hepatitis B virus [HBV]) surface antigen (HBsAg);

13. Known positive hepatitis C antibody (anti-HCV). Note: Subjects with a prior historyof HCV, who have completed antiviral treatment and have subsequently documented HCVRNA below the lower limit of quantification per local testing are eligible;

14. Other clinically active or chronic liver disease;

15. Known active infection including tuberculosis (clinical evaluation that includesclinical history, physical examination and radiographic findings, and TB testing inline with local practice), Patients positive for human immunodeficiency virus (HIV)can be eligible if receiving highly active antiretroviral therapy (ART) and CD4count >350 within 6 months of the start of treatment (consultation of MedicalMonitor is required in this case). Screening for tuberculosis, hepatitis B,hepatitis C, and/or HIV infections is not required, unless there is clinicalsuspicion of these infections;

16. Participant had major surgery (e.g., requiring general anesthesia), excludingplacement of vascular access or tumor biopsy, or had significant traumatic injurywithin 2 weeks before signing the ICF, or will not have fully recovered fromsurgery, or has surgery planned during the time the participant is expected toparticipate in the study.