Amivantamab in Combination with Tyrosine Kinase Inhibitors for the Treatment of Patients with Locally Advanced, Unresectable, or Metastatic Non-Small Cell Lung Carcinoma Harboring ALK, ROS1, and RET Gene Fusions

Inclusion Criteria

• Provision to sign and date the informed consent form
• Stated willingness to comply with all study procedures and be available for the duration of the study
• Participant is >= 18 years of age
• Participant has histologic or cytologic confirmation of locally advanced (unresectable) or metastatic NSCLC with a known (and documented) ALK, ROS1, or RET fusion based on approved diagnostic testing methods specified below. Note that next generation sequencing NGS testing (using either archival or pre-treatment tissue biopsy) is required for all participants, but screening if any of tests below are positive * Immunohistochemistry (IHC): For ALK NSCLC only using the ALK D5F3 antibody * Fluorescence in situ hybridization (FISH) with >= 15% of 100 cells sampled constituting positivity * NGS using a Clinical Laboratory Improvement Act (CLIA)-certified test
• Participants must have clinical progression on at least one prior Food and Drug Administration (FDA)-approved TKI. They must be on a TKI at the same dose for at least 8 weeks without radiographic progression or clinical intolerance of the TKI prior to enrolling on this study. TKIs that will be considered include (but not limited to): * ALK fusions – alectinib, brigatinib, lorlatinib * ROS1 fusions – entrectinib, lorlatinib * RET fusions – selpercatinib, pralsetinib
• Participants must have at least 1 measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria using computed tomography (CT) scan or magnetic resonance imaging (MRI) * Measurable Central Nervous System (CNS) lesions >= 10mm must be captured as overall and intracranial RECIST target lesions. CNS lesions 5-9mm may be included in the intra-cranial data set alone but must be listed as non-target lesions * Measurable, treated brain metastases (>= 10mm) growing after whole-brain radiotherapy (WBRT) or resection are allowed as target lesions, but lesions growing after stereotactic radiosurgery (SRS) are allowed as target lesions only if radiation necrosis or pseudoprogression is ruled out
• Participant has an Eastern Cooperative Oncology Group (ECOG) score of 0-2
• Participant has a life expectancy of greater than 12 weeks, per investigator discretion
• Participant can ingest oral medications
• Participant has received the final dose of any of the following treatments/procedures with the specified minimum intervals before first dose of study drug (unless in the opinion of sponsor-investigator, the medication will not interfere with study or compromise participant safety) * The patient cannot have received an EGFR TKI (e.g. osimertinib, afatinib), EGFR-directed monoclonal antibody (e.g. cetuximab), MET-inhibitor (e.g., tepotinib, capmatinib, telisotuzumab vedotin, etc.) at any point prior to study entry. For patients with ALK and ROS1 NSCLC, crizotinib cannot be used within 3 months of screening * Patients will be allowed to remain on their prior TKI without need for a washout therapy * Chemotherapy: 21 days ** Chemotherapy washout period will be 21 days or 5 half-lives, whichever is longer. As patients are required to be on a stable dose of TKI for at least 8 weeks prior to study entry, this criterion would rarely (if ever) apply to any participant in this study * Antibody-drug conjugate (ADC): 28 days * Immune checkpoint inhibitors (ICI): 28 days * Locally ablative radiotherapy: 28 days ** Locally ablative therapy will be considered as any form of radiotherapy with the intent of providing ablative doses for oligoprogressive lesions while on TKI therapy. * Palliative radiotherapy: 14 days ** Palliative radiotherapy will be considered as any form of radiotherapy with the intent of alleviating symptomatic lesions. * Major surgery: 28 days
• Absolute neutrophil count (ANC) > 1.0 x 10^9 / L * Participants cannot be receiving growth factor support using granulocyte-stimulating colony factor (G-CSF) during the screening visit
• Platelets >= 75,000/mm^3 (>= 75 x 10^9/L) * Participants cannot receive transfusion support up to one week prior to the screening period
• Hemoglobin >= 9 g/dL * Participants cannot receive transfusion support up to one week prior to the screening period
• Renal function: Serum creatinine =< 1.5 x upper limit normal (ULN) OR creatinine clearance >= 50 mL/min/1.73 m^2 via Cockcroft-Gault
• Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 3 x ULN * =< 5 x ULN, if liver metastases are present on screening
• Bilirubin =< 1.5 x ULN * =< 3.0 x ULN, if patient has Gilbert’s disease
• Amylase and lipase =< 1.5 x ULN
• Female participant of childbearing potential (defined as a sexually mature woman who has not undergone a hysterectomy [surgical removal of the uterus] or bilateral oophorectomy [surgical removal of both ovaries], or if >= 45 years old, has not been naturally postmenopausal for at least 24 consecutive months [i.e., has had menses at any time during the preceding 24 consecutive months]) must: * Have 1 negative pregnancy test as verified by an Investigator prior to starting study therapy. This applies even if the subject practices true abstinence** from heterosexual contact * Either commit to true abstinence** from heterosexual contact (which must be reviewed on a monthly basis) or agree to use and be able to comply with a barrier method plus a hormonal method of contraception without interruption 28 days prior to starting investigational product, during the study therapy (including dose interruptions), and for 3 months after discontinuation (or longer if required by local requirements) of study therapy. The method of contraception must be a barrier method plus a hormonal method to prevent pregnancy * Participants must agree to continue contraception throughout the study and continuing through 3 months after the last dose of study drug. Note: If the childbearing potential changes after start of the study (e.g., woman who is not heterosexually active becomes active, premenarchal woman experiences menarche) the woman must begin a highly effective method of birth control, as described above * A woman of childbearing potential must have a negative serum or urine (b- human chorionic gonadotropin [b-hCG]) at screening * A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 6 months after receiving the last dose of study drug * A female participant must agree not to be pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study treatment ** True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Note: Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
• A man who is sexually active with a woman of childbearing potential must agree to use a condom with spermicidal foam/gel/film/cream/suppository and his partner must also be practicing a highly effective method of contraception (i.e., established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device [IUD] or intrauterine system [IUS]). If the subject is vasectomized, he must still use a condom (with or without spermicide), but his female partner is not required to use contraception. The subject must also not donate sperm during the study and for 6 months after receiving the last dose of study drug, even if he has undergone a successful vasectomy

Exclusion Criteria

• Participant has received an investigational drug within a 28-day period (or within 5 half-lives, whichever is shorter) before the first dose of study drug or is currently participating in another interventional clinical trial, unless in the opinion of the sponsor-investigator, the medication will not interfere with the study procedures or compromise subject safety
• The patient cannot have ever received an EGFR TKI (e.g. osimertinib), EGFR- directed monoclonal antibody (e.g. cetuximab), MET TKI (e.g. capmatinib, tepotinib), MET-directed monoclonal antibody (e.g. amivantamab) or MET- directed antibody drug conjugate (e.g. telisotuzumab vedotin) prior to study entry. For patients with ALK or ROS1 NSCLC, crizotinib cannot be used within 3 months of screening.
• Participants who have progressed on most recent TKI in less than 8 weeks
• The patient has evidence of neuroendocrine differentiation or small cell transformation on the screening biopsy
• The patient has no evidence of an ALK, ROS1, and RET gene fusion as determined by molecular testing. Acquired resistance mechanisms detected through NGS (or FISH) testing for which alternative therapies exist may potentially be eligible after consultation with the principal investigator (PI)
• Participants with active, symptomatic, central nervous system disease defined as follows: * Leptomeningeal disease * Symptomatic cord compression from metastatic disease * Untreated, symptomatic brain metastases * Patients with brain metastases may be potentially eligible provided that all the following criteria are met: ** They are not on prednisolone 20mg equivalents daily prior to enrolling in the study ** Anticonvulsants will be permitted provided the patient has been on a stable dose for a period of 2 weeks prior to study day 1. ** Procedural interventions (such as ventriculoperitoneal shunt) greater than 12 weeks prior to study day 1 ** Palliative radiotherapy (either whole brain radiotherapy or stereotactic radiosurgery) >= 28 days prior to screening
• Participant has active cardiovascular disease defined as the following: * Congestive heart failure (CHF), defined as New York Heart Association (NYHA) class III-IV or hospitalization for CHF (any NYHA class) within 6 months of study day 1 * Symptomatic acute coronary syndrome, unstable angina, or active ischemia requiring coronary artery stenting, angioplasty, or bypass grafting within 12 weeks prior to starting investigational drug * Participant has evidence of current, uncontrolled, clinically significant, unstable arrhythmias. Participants receiving active anti-arrhythmic therapy are not eligible with the following exceptions: ** Participants with atrial fibrillation medically controlled for greater than 4 weeks prior to study day 1 ** Participants who have medical pacemakers for control of arrhythmias * Participant has medically uncontrolled hypertension (defined as >= 160 mmHg systolic blood pressure [SBP] and >= 100 mmHg diastolic blood pressure [DBP]) * Clinically significant, acute deep vein thrombosis or pulmonary embolism within 6 months prior to first dose of study drug. Clinically non-significant thrombosis, such as non-obstructive catheter-associated clots or incidentally detected, asymptomatic, subsegmental pulmonary emboli are not considered exclusionary * History of cerebrovascular accident or transient ischemic attack within 12 weeks of enrollment * QT interval corrected by Fridericia’s formula (QTcF) prolongation to > 470ms based on a 12-lead electrocardiogram
• Participant has any history of interstitial lung disease (ILD), including drug- induced ILD or radiation pneumonitis requiring treatment with prolonged steroids or other immune suppressive agents that is unresolved or resolved within the last 3 months
• Participant has clinical evidence or history of ongoing significant bowel obstruction limiting oral intake, active uncontrolled malabsorption syndromes, or any other gastrointestinal disorder or defect that would interfere with absorption, distribution, metabolism, or excretion of the study drug and/or predispose the subject to an increased risk of gastrointestinal toxicity
• Participant has an additional primary malignancy within 2 years prior to enrollment with following exceptions: * Adequately resected non-melanoma skin cancer * Superficial bladder tumors (Ta, Tis, or T1) * Adequately treated intraepithelial carcinoma of the cervix uteri * Low risk, non-metastatic prostate cancer following local treatment or ongoing active surveillance * Any other curatively treated in situ disease
• Participant is positive for human immunodeficiency virus (HIV), with 1 or more of the following: * Receiving antiretroviral therapy (ART) that may interfere with study treatment (consult sponsor- investigator for review of medication prior to enrollment) * CD4 count =< 350 at screening * Acquired immunodeficiency syndrome (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)
• Participant has active/chronic, known, untreated, hepatitis B as demonstrated by a positive hepatitis B surface antigen (HBsAg). Note: Subjects with a prior history of hepatitis B virus (HBV) demonstrated by positive hepatitis B core antibody are eligible if they have the following at screening: * Negative HBsAg * HBV DNA (viral load) below the lower limit of quantification, per local testing * Subjects 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
• Participant has active/chronic, known, untreated, hepatitis C infection as demonstrated by a positive hepatitis C virus (HCV) antibody with detectable HCV viral load. Note: Subjects with a prior history of HCV, who have completed antiviral treatment and have subsequently documented HCV ribonucleic acid (RNA) below the lower limit of quantification per local testing are eligible
• Participant has a concurrent and uncontrolled medical illness which would preclude study conduct and assessment, including, but not limited to the following medical conditions: an active infection requiring systemic therapy, bleeding disorder, clinically unstable ophthalmologic condition, diabetes mellitus with end organ damage, pulmonary diseases, or alcoholic liver disease
• Participant is a pregnant or lactating woman
• Participant has a history of severe allergic reactions to any of the study intervention components
• Participant has a medical or psychiatric condition, which might compromise their ability to give written informed consent or to comply with the study protocol visits and procedures
• Participant has immune-mediated rash from checkpoint inhibitors that has not resolved prior to enrollment
• Use of live or live-attenuated vaccines within 30 days of screening
• Participant has significant reversible toxicities from prior anti-cancer therapy that have not recovered to grade 1 or baseline (higher grades of alopecia and neuropathy up to grade 2 will be permitted)
• Participant had major surgery excluding placement of vascular access or tumor biopsy, or had significant traumatic injury within 4 weeks before enrollment, 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