A Phase II Study of Amivantamab SC (subcutaneous) in Participants Previously Treated with High MET-Amplification for Stage IV or Recurrent Non-Small-Cell Lung Cancer (Lung-MAP Sub-Study)

5.1 Disease Related Criteria

a. Participants must have been assigned to S1900J by the SWOG Statistics and Data Management Center (SDMC). Assignment to S1900J is determined by the LUNGMAP protocol.

b. Participants must have documentation of NSCLC with MET amplification determined by FMI tissue-based NGS assay.

c. Participants must have measurable disease (Section 10.1) documented by CT or MRI. The CT from a combined PET/CT may be used to document measurable disease ONLY if it is of diagnostic quality as defined in Section 10.1c.3: otherwise, it may be used to document non-measurable disease only. Measurable disease must be assessed within 28 days prior to sub-study registration. Pleural effusions, ascites and laboratory parameters are not acceptable as the only evidence of disease. Non-measurable disease must be assessed within 42 days prior to sub-study registration. All known sites of disease must be assessed and documented on the Baseline Tumor Assessment Form. Participants whose only measurable disease is within a previous radiation therapy port must demonstrate clearly progressive disease (in the opinion of the treating investigator) prior to sub-study registration to be considered measurable.

d. Participants must have a CT or MRI scan of the brain to evaluate for CNS disease within 42 days prior to sub-study registration.

e. Participants with asymptomatic CNS metastasis (brain metastases or leptomeningeal disease) must be clinically stable and asymptomatic for at least 14 days prior to sub-study registration.

NOTE: Participants can be on a low-dose corticosteroid treatment (≤10 mg prednisone or equivalent) for at least 14 days prior to study treatment.

f. Participants must not have other known actionable oncogenic alterations, such as (but not limited to) EGFR sensitizing mutations, EGFR T790M mutation, MET Exon-14 skipping mutant NSCLC, ALK gene fusion, ROS1 gene rearrangement, RET gene rearrangement, NTRK rearrangement, HER2 mutation, KRAS activating mutations, and BRAF V600E mutation.

5.2 Prior/Concurrent Therapy Criteria

a. Participants must have progressed (in the opinion of the treating physician) following the most recent line of therapy.

b. Participants must have received at least one line of systemic treatment for Stage IV or recurrent NSCLC.

c. Participants must have recovered (≤ Grade 1) from any side effects of prior therapy. The exception is if a side effect from a prior treatment is known to be permanent without expected further recovery or resolution (i.e., endocrinopathy from immunotherapy or cisplatin neurotoxicity).

d. Participants must not have been previously treated for any cancer with MET TKIs such as tepotinib, capmatinib, and crizotinib.

e. Participants must not have received any prior systemic therapy (systemic chemotherapy, immunotherapy or investigational drug) within 21 days prior to sub-study registration.

f. Participants must not have a prior treatment with anti-PD-1 or anti-PD-L1 antibody within 6 weeks of sub-study registration.

g. Participants must not have received any radiation therapy within 14 days prior to sub-study registration.

h. Participants must not be planning to receive any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment while receiving treatment on this study.

i. Participants must not have had major surgery excluding placement of vascular access or tumor biopsy, or had significant traumatic injury within 28 days prior to sub-study registration, or will not have fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study.

NOTE: Participants with planned surgical procedures to be conducted under local anesthesia may participate.

j. Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the investigational regimen.

5.3 Clinical/Laboratory Criteria

a. Participants must have adequate organ and marrow function as defined below within 28 days prior to sub-study registration:

- absolute neutrophil count ≥1.5 x 10^3/uL
- hemoglobin >= 10.0 g/dL
- platelets ≥75 x 10^3/uL
- total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) unless history of Gilbert’s disease. Participants with history of Gilbert’s disease must have total bilirubin ≤ 5 x institutional ULN.
- AST and ALT ≤ 3 × institutional ULN. Participants with history of liver metastasis must have AST and ALT ≤ 5 x ULN

b. Participants must have a serum creatinine ≤ the IULN or calculated creatinine clearance ≥ 45 mL/min using the following Cockcroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to sub-study registration. For creatinine clearance formula see the tools on the CRA Workbench https://txwb.crab.org/TXWB/Tools.aspx.

c. Participants’ most recent Zubrod performance status must be 0-2 (Section 10.4) and be documented within 28 days prior to sub-study registration.

d. Participants must have a completed medical history and physical exam within 28 days prior to sub-study registration.

e. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification (see Section 18.1). To be eligible for this trial, participants must be class 2B or better.

f. Participants with known human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy and have undetectable viral load test on the most recent test results obtained within 6 months prior to sub-study registration.

g. Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load while on suppressive therapy on the most recent test results obtained within 6 months prior to sub-study registration.

h. Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants currently being treated for HCV infection must have undetectable HCV viral load test on the most recent test results obtained within 6 months prior to sub-study registration.

i. Participants with known diabetes as determined by the treating investigator must show evidence of controlled disease within 14 days prior to sub-study registration.

j. Participants of reproductive potential must have a negative serum pregnancy test within 7 days prior to sub-study registration.

k. Participants must not have other clinically active infectious liver disease.

l. Participants must not have clinically significant hypertension within 28 days prior to sub-study registration as determined by the treating investigator.

m. Participants must not have a history of pneumonitis that required drug therapy or an active symptomatic ILD/pneumonitis, including drug-induced or radiation ILD/pneumonitis.

n. Participants must not have ongoing or active infection or be diagnosed or suspected viral infection as determined by the treating investigator. NOTE: Participants that have an infection requiring antimicrobial therapy will be required to complete antibiotics 1 week prior to starting treatment.

o. Participants must not have active bleeding diathesis as determined by the treating investigator.

p. Participants must not have impaired oxygenation requiring continuous oxygen supplementation as determined by the treating investigator.

q. Participants must not have psychiatric illness, social situation, or any other circumstances that would limit compliance with study requirements as determined by the treating investigator.

r. Participants must not have any ophthalmologic condition that is unstable in the opinion of the treating investigator.

s. Participants must not be pregnant or breastfeeding (nursing includes breast milk fed to an infant by any means, including from the breast, milk expressed by hand, or pumped). Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen.

5.4 Specimen Submission Criteria

a. Participants must agree to have blood specimens submitted for circulating tumor DNA (ctDNA) as outlined in Section 15.2.

b. Participants must also be offered participation in specimen banking as outlined in Section 15.2. With participant consent, specimens must be collected and submitted via the SWOG Specimen Tracking System as outlined in Section 15.4.

5.5 Regulatory Criteria

NOTE: As a part of the OPEN registration process (see Section 13 for OPEN access instructions) the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system.

a. Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines.

NOTE: Participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and CIRB regulations.