Collaborative Clinical-translational Cohort of Amivantamab Plus Lazertinib and Amivantamab Plus Chemotherapy in Patients With EGFR-mutant, Locally Advanced or Metastatic/Recurrent Non-Small Cell Lung Cancer (INSTAR Study) (INSTAR)

• 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).

Study Overview

• Status: Not yet recruiting
• Conditions: Non Small Cell Lung Cancer
• Intervention / Treatment: Drug: Amivantamab SC + Lazertinib PO; Drug: Amivantamab SC + Chemotherapy (Carboplatin IV & Pemetrexed IV)

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; • No prior exposure to 1st, 2nd, or 3rd EGFR TKIs	Drug: Amivantamab SC + Lazertinib PO; • Amivantamab SC plus Lazertinib PO: 28-day Cycles; Amivantamab 1600/2240 mg SC QW up to C2D1 and Q2W thereafter;; Lazertinib 240 mg PO QD
Experimental: Cohort 2; • Disease progression after prior treatment with 3rd generation (3G) EGFR TKI (including osimertinib, lazertinib)	Drug: Amivantamab SC + Chemotherapy (Carboplatin IV & Pemetrexed IV); Amivantamab SC plus Chemotherapy: 21-day Cycles 1-4Amivantamab 1600/2240 mg SC C1D1; 2400/3360 mg C1D8, C1D15, and Day 1 of Cycles 2, 3, 4Pemetrexced 500 mg/m2 IV Day 1Carboplatin AUC5 IV Day 1; Amivantamab SC plus Chemotherapy: 21-day Cycles 5+Amivantamab 2400/3360 mg SC Day 1Pemetrexed 500 mg/m2 IV Day 1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
• scRNA-seq and/or spatial RNA sequencing analysis. Multiplex IHC and/or FACS analysis.	• Molecular candidates associated with the activity of amivantamab-based regimens identified by analyzing scRNA-seq and/or spatial RNA sequencing from pre-treatment tumor biopsy specimens and tumor tissue acquired at the time of C3D1. Multiplex IHC and/or FACS analysis performed either pre-treatment or post-treatment.	through study completion, an average of 5 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response rate (ORR)	Objective Response rate (ORR): the proportion of participants who achieve a CR or PR, based on RECIST v1.1.	through study completion, an average of 5 year
Progression-free survival (PFS)	Progression-free survival (PFS): the time from the first dose of study treatment until the date of objective disease progression or death, whichever comes first, based on RECIST v1.1.	through study completion, an average of 5 year
Duration of response (DoR)	Duration of response (DoR): the time from the date of first documented response (PR or CR) until the date of documented progression or death, whichever comes first, for participants who have PR or CR	through study completion, an average of 5 year
circulating tumor DNA (ctDNA).	To assess EGFR mutations, MET alterations, and mutations in other key oncogenes, samples for ctDNA analysis will be collected	through study completion, an average of 5 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment (TRAE, Clinical laboratory test, Vital signs, Physical Examination, Weight)	Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment (TRAE, Clinical laboratory test, Vital signs, Physical Examination, Weight)	through study completion, an average of 5 year
The biomarker and ctDNA samples.	The biomarker and ctDNA samples may be used to explore the potential to predict clinical benefit, relapse, and/or identify mechanism of resistance to assigned treatment, and to enable the development of safer, more effective, and ultimately individualized therapies.	through study completion, an average of 5 year

Collaborators and Investigators

• Sponsor: Yonsei University

Study record dates

Study Major Dates

• Study Start (Estimated): April 6, 2026
• Primary Completion (Estimated): January 31, 2031
• Study Completion (Estimated): January 31, 2031

Study Registration Dates

• First Submitted: March 8, 2026
• First Submitted That Met QC Criteria: March 26, 2026
• First Posted (Actual): April 2, 2026

Study Record Updates

• Last Update Posted (Actual): April 2, 2026
• Last Update Submitted That Met QC Criteria: March 26, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; Therapeutics; Drug Therapy
• Other Study ID Numbers: 4-2025-0569

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No