Tepotinib Alone or in Combination with Tyrosine Kinase Inhibitors for the Treatment of MET-driven Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Inclusion Criteria

• ARM 1 (MONOTHERAPY): Participant has histologic or cytologic confirmation of NSCLC with evaluable CNS metastases and an activating MET alteration which will be defined by presence of one of the following: * MET Exon 14 skipping mutation as determined by Clinical Laboratory Improvement Act (CLIA) certified next-generation sequencing (NGS) assay. This can be ascertained either by circulating tumor deoxyribonucleic acid (ctDNA) based assay or through local testing of tissue samples * MET amplifications (defined as MET/CEP7 >= 4 using fluorescence in situ hybridisation [FISH]) * MET fusions as determined by CLIA certified NGS assay. This can be ascertained either by ctDNA based assay or through local testing for tissue samples * Other MET driven cases may be considered after consultation and approval by the principal investigator (PI)
• ARM 2 (COMBINATION): Participant has histologic or cytologic confirmation of locally advanced or metastatic NSCLC with documented other driver (e.g. EGFR, ALK, ROS1 alterations) in which there is evidence of MET-driven acquired resistance (including any of the MET mechanisms noted for Arm 1). Due to the potential sub-clonal nature of acquired resistance, a lower threshold of MET amplification (using MET/CEP7 >= 3 or equivalent) will explicitly be permitted. Other cases with plausible biological evidence of MET resistance may be considered after consultation and approval by PI). TKIs that will be considered for Arm 2 include: * EGFR mutations – osimertinib * ALK rearrangements – alectinib, brigatinib, lorlatinib * ROS1 rearrangements – entrectinib, lorlatinib Patients must be on their TKI at the same dose for at least 3 months prior to enrolling in Arm 2
• The participant is able to understand and voluntarily sign a written informed consent and is willing and able to comply with the protocol requirements
• Participant is a male or female and at least 18 years of age
• Participant has at least 1 measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criterion using computed tomography (CT) scan or magnetic resonance imaging (MRI). For Arm 1, evaluable disease (defined as the presence of any CNS disease identified prior to study entry), will be permitted in the dose escalation cohort. For Arm 1, in the dose expansion cohort, participants must have at least one measurable intracranial lesion that is >= 10mm. Measurable CNS lesions >= 10mm in any cohort must be captured as overall and intracranial RECIST target lesions. CNS lesions 5-9mm may be included in intracranial data set alone
• Participant has an Eastern Cooperative Oncology Group (ECOG) score of 0-2 or Karnofsky score of >= 60
• Participant has a life expectancy of greater than 12 weeks
• Participant is able to 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 Investigator and Medical Monitor, the medication will not interfere with study or compromise participant safety). * Chemotherapy 28 days * Antibody drug conjugate (ADC)** 28 days * Immune checkpoint inhibitors (ICI) 28 days * Stereotactic radiotherapy (SRS) 14 days * Tyrosine kinase inhibitor (TKI)** 7 days **The patient cannot have received a prior MET-inhibitor (e.g., crizotinib, capamatinib, telisotuzumab, vedotin, etc.) for Arm 1. **For patients in Arm 2, patients will be allowed to remain on their prior TKI without need for a washout therapy. No prior MET therapy within 1 year prior to study start will be allowed for patients being considered for Arm 2.
• Absolute neutrophil count (ANC) >= 1,500/mm^3 (>= 1.5 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 (>= 50 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
• Serum creatinine =< 2 x upper limit normal (ULN)
• Liver transaminases (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
• Participant must meet following conditions prior to enrollment in Arm 1: * Measurable, untreated brain metastases (>= 5mm) will be considered target lesions provided: ** Patient is asymptomatic from these lesions ** Patient is on less than 20 mg prednisolone equivalents daily prior to enrolling on study * 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 * Leptomeningeal disease (confirmed through either MRI or CSF sampling) is permitted provided this is not the only site of disease. If leptomeningeal disease is present, it will not count as measurable disease
• 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 2 negative pregnancy tests as verified by the 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 2 effective methods of contraception without interruption 28 days prior to starting investigational product, during the study therapy (including dose interruptions), and for 120 days after discontinuation (or longer if required by local requirements) of study therapy. The 2 methods of contraception can either be 2 barrier methods or a barrier method plus a hormonal method to prevent pregnancy * 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
• Male participant must practice true abstinence* (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions, and for at least 3 months following investigational product discontinuation (or longer if required by local requirements), even if he has undergone a successful vasectomy *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

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 Investigator and Medical Monitor, the medication will not interfere with the study procedures or compromise subject safety
• The patient cannot have received a prior MET-inhibitor (e.g., crizotinib, capamatinib, telisotuzumab vedotin, etc.) for Arm 1. No prior MET therapy within 1 year prior to study start will be allowed for patients being considered for Arm 2. For Arm 2 patients on current dose of TKI for less than 3 months are not eligible
• Participants with isolated leptomeningeal disease are not eligible. Patients with symptomatic brain metastases may be potentially eligible provided that all the following criteria are met: 1) they are not on prednisolone 20mg equivalents daily prior to enrolling in the study and 2) anticonvulsants will be permitted provided the patient has been on a stable dose for a period of 2 weeks prior to the first dose of study drug. Patients without evidence of CNS metastases are not permitted in Arm 1 Monotherapy
• 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 New York Association Class III or IV heart failure
• Participant has 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 1 month 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)
• Participant has active/chronic, uncontrolled pancreatitis with serum amylase / lipase >= 1.5 ULN
• Participant has untreated known human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). Patients with treated and stable HIV (defined as CD4 count >200 cells/mm^3 and undetectable HIV viral load) with active, chronic, known outpatient follow up with an HIV specialist will be eligible
• Participant has active/chronic, known, untreated, hepatitis B or C infection
• 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, 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 significant reversible toxicities from prior 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 has preexisting clinically significant (in the opinion of the investigator) interstitial lung disease or history of pneumonitis that required steroid treatment