• In this study, we hypothesized that immune engagement by amivantamab will enhance antitumor efficacy by modulating the immune microenvironment in combination with lazertinib in patients with untreated EGFR-mutant NSCLC or with chemotherapy (carboplatin plus pemetrexed) after progression with 3rd generation (3G) EGFR TKI.
• The primary objective of this study is to examine the patients' tumors for immunomodulatory effects of amivantamab-based regimens.
• In a phase 2, two cohort clinical trial, treatment naïve patients with EGFR-mutant NSCLC will be treated with amivantamab SC plus oral lazertinib (Cohort 1, n=30) or patients with EGFR-mutant NSCLC progressed on or after 3G EGFR TKI treated with amivantamab SC plus chemotherapy (Cohort 2, n=30).

Inclusion Criteria:

1. 19 years and older

2. Provision of informed consent prior to any study specific procedures

3. Histologically or cytologically confirmed Locally advanced, Recurrent, or Metastatic NSCLC, performed on a biopsy and able to do a paired biopsy during treatment (C3D1)

4. Documented activating EGFR mutation (Exon 19 deletion or L858R)

5. Measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria

6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-1

7. Resolution of all acute toxic effects of prior chemotherapy, radiotherapy or surgical procedures to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0: ≤ grade 1

8. Patient should meet following requirements.

   • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN)
   • Bilirubin ≤ 1.5 x ULN, (Patients with documented Gilbert's syndrome and conjugated bilirubin within the normal range may be allowed into the study; in this event, it will be documented that the patient was eligible based on conjugated bilirubin levels)
   • Leukocytes ≥ 3.0 x 10^3/μL
   • Hemoglobin ≥ 9.0 g/dL, with no blood transfusions in the 28 days prior to study entry
   • Absolute neutrophil count ≥ 1.5 x 10^3/μL
   • Platelets ≥ 75 x 10^3/μL
   • Creatinine ≤ 1.5 x upper limit of normal (ULN) OR creatinine clearance (details in Appendix 10. Cockcroft-Gault Formula for Estimated Creatinine Clearance) >50 mL/min for patients with creatinine levels >1.5 x upper limit above institutional normal

9. Ability to swallow oral medications

10. Male or female (according to their reproductive organs and functions assigned by chromosomal complement at birth).

11. A female using oral contraceptivesmust use an additional barrier contraceptive method (details in Appendix 5: Contraceptive Guidance). A female participant must be either of the following (as defined in Appendix 5: Contraceptive Guidance)

    1. Not of childbearing potential: premenarchal; postmenopausal (>45 years of age with amenorrhea for at least 12 months); permanently sterilized (eg, bilateral tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy); or otherwise, be incapable of pregnancy.

    2. Of childbearing potential and practicing at least 1 highly effective method(s) of birth control consistent with local regulations regarding the use of birth control methods for participants participating in clinical studies, as described below:

       • Practicing true abstinence (when this is in line with the preferred and usual lifestyle of the participant), which is defined as refraining from heterosexual intercourse during the entire period of the study, and for 7 months after the last dose of the study treatment. Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not considered an acceptable contraceptive method.
       • Have a sole partner who is vasectomized.
       • Practicing 2 methods of contraception, including one highly effective method (ie, established use of oral, intravaginal, transdermal, injected or implanted hormonal methods of contraception; placement of an intrauterine device [IUD] or intrauterine system [IUS], tubal ligation procedures as consistent with local regulations), AND, a second method, (eg, condom with spermicidal foam/gel/film/cream/suppository or occlusive cap [diaphragm or cervical/vault caps] with spermicidal foam/gel/film/cream/suppository).
       • Participants must agree to continue contraception throughout the study and continuing through 7 months after the last dose of the study treatment.

    Note: If the childbearing potential changes after start of the study (eg, woman who is not heterosexually active becomes active, premenarchal woman experiences menarche) the woman must begin a method of birth control, including 1 highly effective method, as described above.

12. A female participant of childbearing potential must have a negative serum (b-human chorionic gonadotropin [b-hCG]) at screening (within 72 hours of the first dose of study treatment administration) and must agree to further serum or urine pregnancy tests during the study prior to Day 1 of each cycle and at End of Study.

13. A female must agree not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction during the study and for a period of 7 months after the last dose of the study treatment. Female participants should consider preservation of eggs prior to study treatment as anti-cancer treatments may impair fertility.

14. A male participant must wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study and for 6 months after the last dose of the study treatment.

15. If the male participant's partner is a female of childbearing potential, the male participant must use condom with or without spermicide and the female partner of the male participant must also be practicing a highly effective method of contraception (see Appendix 5: Contraceptive Guidance). A male participant who is vasectomized must still use a condom (with or without spermicide), but the partner is not required to use contraception.

16. A male participant must agree not to donate sperm for the purposes of reproduction during the study and for 6 months after the last dose of the study treatment (whichever comes last). Male participants should consider preservation of sperm prior to study treatment as anti-cancer treatments may impair fertility.

17. A male participant must agree not to plan to father a child while enrolled in this study and for 7 months after the last dose of the study treatment (whichever comes last).

Exclusion Criteria:

1. Leptomeningeal carcinomatosis or uncontrolled central nervous system (CNS) metastases

2. Symptomatic spinal cord compression that has not been treated definitively with surgery or radiation

3. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease

4. Patients who are known to be serologically positive for human immunodeficiency virus (HIV)

5. Participant has concurrent or prior malignancy other than the disease under study. The following exceptions require consultation with the Principal Investigator:

   1. Non-muscle invasive bladder cancer (NMIBC) treated within the last 24 months that is considered completely cured.

   2. Skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured.

   3. Non-invasive cervical cancer treated within the last 24 months that is considered completely cured.

   4. Localized prostate cancer (N0M0):

      • with a Gleason score of 6, treated within the last 24 months or untreated and under surveillance,
      • with a Gleason score of 3+4 that has been treated more than 6 months prior to full study screening and considered to have a very low risk of recurrence,
      • or history of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence.

   5. Breast cancer:

      - lobular carcinoma in situ or ductal carcinoma in situ that is considered completely cured.

   6. Participant has undergone curative therapy and is considered cured after 5 years with no evidence of disease recurrence since initiation of that therapy.

6. Any of the following cardiac criteria:

   • Patient with any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, electrolyte abnormalities (including: Serum/plasma potassium < LLN; Serum/plasma magnesium < LLN; Serum/plasma calcium < LLN) congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause Torsades de Pointes. (details in Appendix 11: Medications With Potential for QT Interval Prolongation)

7. Treatment with prohibited medications (concurrent anticancer therapy including chemotherapy, radiation, hormonal treatment [except corticosteroids and megesterol acetate], or immunotherapy) ≤ 14 days prior to treatment with an investigational drug

8. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, or known active infection (within 2 weeks prior to first day of study drug treament); screening for chronic conditions is not required

9. Participant has at Screening:

   • Positive hepatitis B (hepatitis B virus [HBV]) surface antigen (HBsAg) Note: Participants with a prior history of HBV demonstrated by positive core antibody are eligible if they have at Screening 1) a negative HBsAg and 2) an HBV DNA (viral load) below the lower limit of quantification, per local testing. Participants with a positive HBsAg due to recent vaccination are eligible if HBV DNA (viral load) is below the lower limit of quantification, per local testing.
   • Positive hepatitis C (hepatitis C virus [HCV]) antibody (anti-HCV) Note: Participants with a prior history of HCV who have completed antiviral treatment and have subsequently documented HCV RNA below the lower limit of quantification per local testing are eligible.
   • Other clinically active infectious liver disease

10. Participant is positive for human immunodeficiency virus (HIV), with 1 or more of the following:

    • Not receiving highly active antiretroviral therapy (ART)
    • Had a change in ART within 6 months of the start of screening
    • Receiving ART that may interfere with study treatment
    • CD4 count <350 at screening
    • AIDS-defining opportunistic infection within 6 months of start of screening
    • Not agreeing to start ART and be on ART>4 weeks plus having HIV viral load <400 copies/mL at end of 4-week period (to ensure ART is tolerated and HIV controlled).

11. Treatment with an investigational drug within three half-lives of the compound or 3 months, whichever is greater.

12. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of study drug.

13. Active tuberculosis

14. Females who are pregnant or breastfeeding

15. Presence of active gastrointestinal (GI) disease (including GI bleeding or ulceration) or other condition that could affect GI absorption (e.g. malabsorption syndrome, history of biliary tract disease), including refractory nausea or vomiting, or chronic GI disease which may affect absorption or tolerance to oral medications

16. History of hypersensitivity or intolerance to active or inactive excipients of study drug or drugs with a similar chemical structure or class

17. Involvement in the planning and/or conduct of the study (applies to both investigator staff and/or staff at the study site)

18. Uncontrolled medical, psychological, familial, sociological, or geographical conditions that interfere with the patient's safety, ability to provide informed consent, or ability to comply with the protocol.

19. Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.

20. Participant has a history of clinically significant cardiovascular disease including, but not limited to the following:

    • Diagnosis of deep vein thrombosis or pulmonary embolism within 4 weeks prior to enrollment, or any of the following within 24 weeks prior to enrollment: myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary/peripheral artery bypass graft, or acute coronary syndrome (Note: clinically non-significant thrombosis, such as non-obstructive catheter-associated thrombus, or incidental or asymptomatic pulmonary embolism, is not exclusionary)
    • Participant has a significant genetic predisposition to venous thromboembolic events (VTE; such as Factor V Leiden).
    • Participant has a prior history of VTE and is not on appropriate therapeutic anticoagulation as per NCCN or local guidelines.
    • Uncontrolled hypokalemia or clinically significant cardiac arrythmia or electrophysiologic disease (eg, placement if implantable cardioverter defibrillator or atrial fibrillation with uncontrolled rate).
    • Uncontrolled (persistent) hypertension despite optimal treatment: systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg.
    • Congestive heart failure (CHF) defined as New York Heart Association (NYHA) class III-IV (see Appendix 8: New York Heart Association Criteria) or hospitalization for CHF (any NYHA class) within 6 months of enrollment.
    • Pericarditis, pericardial effusion, or myocarditis that is clinically unstable. Pericardial effusion considered due to the disease under study is permitted if clinically stable at screening.

21. Participant is currently receiving a medication or herbal supplement known to be a strong cytochrome P450 (CYP) 3A4/5 inducer and is not able to stop use for an appropriate washout period prior to enrollment (details in Appendix 12: Prohibited or Restricted Medications and Therapies).