Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication TEPMETKO is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal-epithelial transition ( MET ) exon 14 skipping alterations. TEPMETKO is a kinase inhibitor indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal-epithelial transition ( MET ) exon 14 skipping alterations. ( 1 ) FDA label
Also known as Tepotinib test, Tepotinib (HydroChloride hydrate), MSC2156119J
Tepotinib · 9 trials · 9 indications
DLTs are defined as any of the following toxicities and judged by the Investigator and/or the Sponsor to be not attributable to the disease or disease-related processes under investigation: Grade 4 neutropenia for more than 7 days; Grade greater than or equal to (\>=) 3 febrile neutropenia; Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with non-traumatic bleeding; Grade \>= 3 nausea/vomiting and/or diarrhea that has not improved within 72 hours despite adequate and optimal treatment; Any other Grade \>= 3 non-hematological AE, except alopecia or Grade 3 nauseas/vomiting and/or diarrhea that has improved within 72 hours with optimal treatment.
Objective response was defined as percentage of participants with either a confirmed complete response (CR) or partial response (PR) from first administration of study treatment to first observation of progressive disease (PD) .CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Objective response will be determined according to RECIST 1.1 and as per IRC. Objective response was defined as number of participants with either a confirmed complete response (CR) or partial response (PR) from first administration of study treatment to first observation of progressive disease (PD) .CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Objective response will be determined according to RECIST 1.1 and as per IRC. Objective response was defined as number of participants with either a confirmed complete response (CR) or partial response (PR) from first administration of study treatment to first observation of progressive disease (PD) .CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Objective response will be determined according to RECIST 1.1 and as per IRC. Objective response was defined as number of participants with either a confirmed complete response (CR) or partial response (PR) from first administration of study treatment to first observation of progressive disease (PD) .CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Assessing the antitumour activity of tepotinib in combination with pembrolizumab using the overall response rate as defined by disease response using iRECIST
The area under the plasma concentration time curve (AUC) from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at the last sampling time (tlast), as estimated using the linear regression from lambda z determination. AUC(0- inf)=AUC0-t plus Clastpred/lambda z where Clastpred was last predicted concentration. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve.
The AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification (LLOQ). Calculated using the mixed log-linear trapezoidal rule (linear up, log down).
Maximum observed plasma concentration (Cmax) was taken directly from the observed concentration-time profile.
DLT: defined using NCI-CTCAE for AEs Version 4.0, as any of following toxicities: Grade 4 neutropenia for more than 7 days; greater than or equal to (\>=) Grade 3 febrile neutropenia for more than 1 day; Grade 4 or Grade 3 thrombocytopenia with nontraumatic bleeding; \>=Grade 3 uncontrolled nausea/vomiting and/or diarrhoea despite adequate treatment for more than 3 days; \>=Grade 3 any non-hematological AE. (DLT defined specifically for following cases: \>=Grade 3 liver AE requiring recovery period of more than 7 days or to Grade 1 or less or Grade 2 with liver metastases ; \>=Grade 3 lipase and/or amylase elevation with confirmation of pancreatitis. An isolated lipase and/or amylase elevation of \>=Grade 3 without clinical/radiological evidence of pancreatitis was not classified as DLT); and AEs assessed by investigators to be exclusively related to the participant's underlying disease or medical condition/concomitant treatment are not considered as DLTs.
PFS status was evaluated by the number of participants who were progression-free at 12 weeks according to RECIST Version 1.1. Participants were considered to be progression-free if the participant had a tumor assessment of Complete Response (CR) defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 millimeter (mm). Partial response (PR) defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters, or Stable Disease (SD) defined as any cases that do not qualify for either partial response or progressive disease (an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started)12 weeks after start of treatment or later.
Dose limiting toxicity (DLT) was defined as toxicities at any dose level and judged to be related to the study treatment by investigator and/or the sponsor. DLTs included Grade 4 neutropenia for more than 7 days; Grade greater than or equal to (\>=) 3 febrile neutropenia for more than 1 day; Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with non-traumatic bleeding; Grade \>= 3 uncontrolled nausea/vomiting and/or diarrhea despite adequate and optimal treatment and Grade \>= 3 any non-hematological adverse event (AE), except the aforementioned gastrointestinal events and alopecia. Number of participants who experienced DLT during phase 1b were reported.
An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug and assessed up to 94 weeks. TEAEs include both Serious TEAEs and non-serious TEAEs.
TTP was defined as the time in months from randomization to date of the observation of radiological progressive disease (PD) (based on Response Evaluation Criteria in Solid Tumors \[RECIST\] v1.1) assessed by an IRC. PD is defined as at least 20 percent (%) increase in sum of diameters of target lesions, taking as reference as smallest sum on study; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must demonstrate an absolute increase of at least 5 millimeter (mm).
Dose limiting toxicity (DLT) using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.0 was defined as toxicities at any dose level and judged to be related to the study treatment by investigator and/or the sponsor. DLTs included Grade 4 neutropenia for more than 7 days; Grade greater than or equal to (\>=) 3 febrile neutropenia for more than 1 day; Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with non-traumatic bleeding; Grade \>= 3 uncontrolled nausea/vomiting and/or diarrhea despite adequate and optimal treatment and Grade \>= 3 any non-hematological adverse event (AE), except the aforementioned gastrointestinal events and alopecia. Number of participants who experienced DLT during Phase 1b were reported.
An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs include both Serious TEAEs and non-serious TEAEs. Number of Participants with TEAEs and serious TEAEs were reported.
Progression-free survival (assessed by the Investigator) time was defined as the time in months from randomization to either first observation of radiologically confirmed progression disease (PD) by the investigator or occurrence of death due to any cause within 84 days of either randomization or the last tumor assessment. PD is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 millimeter (mm). PFS was measured using Kaplan-Meier (KM) estimates.
DLT: defined using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0, as any of following toxicities: Grade 4 neutropenia for more than 7 days; greater than or equal to (\>=) Grade 3 febrile neutropenia; Grade 4 or Grade 3 thrombocytopenia with bleeding; \>=Grade 3 nausea despite adequate treatment; \>=Grade 3 any non-hematological AE (DLT defined specifically for following cases: \>=Grade 3 liver adverse event \[AE\] requiring recovery period of more than 7 days or to Grade 1 without liver metastases or Grade 2 with liver metastases ; \>=Grade 3 lipase and/or amylase elevation with confirmation of pancreatitis. An isolated lipase and/or amylase elevation of \>=Grade 3 without clinical/radiological evidence of pancreatitis was not classified as DLT); and \>=Grade 2 any AE not otherwise defined as DLT that, due to prolonged recovery to Grade 1 (or less) or baseline status, led to delay of treatment with IMP for more than 21 days.
DLT was defined as one of the following adverse events (AEs) observed during Cycle1, regardless of MSC2156119J relationship, excluding AEs assessed by investigator exclusively related to subject's underlying disease or medical condition: Grade 4 neutropenia for \>7 days; Grade \>=3 febrile neutropenia for \>1 day; Grade 4 thrombocytopenia/Grade 3 with bleeding; Grade \>=3 nausea and emesis, despite optimal treatment; Grade \>=3 non-hematological AE, except emesis and nausea with no adequate therapy and alopecia, Grade \>= 3 liver AE with a recovery period of \>7 days or to Grade \<=1 for subjects without liver metastases or to \<=2 for subjects with liver metastases; Grade \>=3 lipase and/or amylase rise with pancreatitis confirmation, either based on clinical or radiological signs. Any AE not otherwise defined as a DLT that, due to prolonged recovery to Grade \<=1 or baseline status, leads to delay of above 21 days in planned administration of study drug.
MTD was defined as the dose level at which 2 out of 3 subjects or 2 out of 6 subjects experienced a DLT. The primary endpoint was to determine MTD of MSC2156119J for each of the 3 treatment regimens in subjects with advanced solid tumors. However, during the course of the trial it was established that the MTD could not be determined and instead, RP2D was to be determined.
Related AE was defined as any untoward medical occurrence which was considered to have a relationship with the study drug (suspected to be reasonably related to the study drug or AE was medically (pharmacologically/clinically) attributed to the study drug as per Investigator's assessment.
| Arm | Type | Description |
|---|---|---|
| Tepotinib and Osimertinib | EXPERIMENTAL | Participants received a single oral dose of Tepotinib 500 milligrams (mg) followed by Omisertinib 80 mg once daily until disease progression, death, adverse event leading to discontinuation, study withdrawal or consent withdrawal. |
| Tepotinib Mono-therapy | EXPERIMENTAL | Participants received a single oral dose of Tepotinib 500 mg until disease progression, death, adverse event leading to discontinuation, study withdrawal or consent withdrawal. |
| Part 1: Cohort A: METex14 Skipping Alterations | OTHER | Participants received 500 milligram (mg) of tepotinib once daily in cycles of 21-day duration until disease progression, death, adverse event (AE) leading to discontinuation or withdrawal of consent. |
| Part 1: Cohort B: MET Amplification | OTHER | Participants received 500 milligram (mg) of tepotinib once daily in cycles of 21-day duration until disease progression, death, adverse event (AE) leading to discontinuation or withdrawal of consent. |
| Part 2: Cohort C: Confirmatory Part for METex14 Skipping Alterations | OTHER | Participants received 500 milligram (mg) of tepotinib once daily in cycles of 21-day duration until disease progression, death, adverse event (AE) leading to discontinuation or withdrawal of consent. |
| Part A- Escalation | EXPERIMENTAL | The safety run-in part of the study will enrol 6-12 patients. Tepotinib will be given to patients daily for three weeks. After thee weeks, patients will be given pembrolizumab immunotherapy on a 21-day cycle along side tepotinib daily. Dose de-escalation of Tepotinib only will be performed in in Part A.. Should dose level 1 (500mg OD) be deemed non-tolerable by the SRC then a single dose de-escalation to dose level -1 (250mg OD) may be performed. Alternative dosing schedules may be explored. Recruitment into Part A will be staggered such that at least 7 days elapse between treatment of the 1st and 2nd patient of each dose level. In the dose confirmation phase, the study will first evaluate the dose level 1 with 3 patients, expanding to a maximum of 6 evaluable patients. If needed, a maximum of 6 patients will be evaluate in the dose level -1. Recruitment to this arm is closed. |
| Part B- Expansion | EXPERIMENTAL | The expansion part of the study will enrol 13-26 patients with NSCLC and MET exon 14 skipping mutations. The combination of tepotinib and pembrolizumab will be tested throughout this part of the study. The first cycle will test the safety run-in of tepotinib followed by the introduction of combination with pembrolizumab from cycle 2 onwards. Recruitment to this arm is open. |
| Healthy Participants (Control) | EXPERIMENTAL | Participants with normal hepatic function matched to moderate hepatic impairment received single oral dose of 500 milligrams (mg) of tepotinib film-coated tablet on Day 1 after a standard breakfast. |
| Mild Hepatic Impairment (Child-Pugh Class A) | EXPERIMENTAL | Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received single oral dose of 500 mg tepotinib film-coated tablet on Day 1 after a standard breakfast. |
| Moderate Hepatic Impairment (Child-Pugh Class B) | EXPERIMENTAL | Participants with moderate hepatic impairment (Child-Pugh Class B, score 7 to 9) received single oral dose of 500 mg tepotinib film-coated tablet on Day 1 after a standard breakfast. |
| Phase 1b: Tepotinib 300 mg | EXPERIMENTAL | - |
| Phase 1b: Tepotinib 500 mg | EXPERIMENTAL | - |
| Phase 2: Tepotinib 500 mg | EXPERIMENTAL | - |
| Phase 1b: Tepotinib 1000 mg | EXPERIMENTAL | Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Phase 2: Tepotinib | EXPERIMENTAL | Participants randomized to receive Tepotinib recommended Phase 2 dose (RP2D) determined from Phase 1b over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Phase 2 Sorafenib | EXPERIMENTAL | Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | EXPERIMENTAL | Participants received Tepotinib 300 milligram (mg) along with 250 mg Gefitinib tablets orally once daily over a 21-day treatment cycle until progressive disease, intolerable toxicity or withdrawal from treatment. |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | EXPERIMENTAL | Participants received Tepotinib 500 milligram (mg) along with 250 mg Gefitinib tablets orally once daily over a 21-day treatment cycle until progressive disease, intolerable toxicity or withdrawal from treatment. |
| Phase 2: Tepotinib 500 mg + Gefitinib 250 mg (MET + T790 negative) | EXPERIMENTAL | Participants randomized to receive Tepotinib recommended Phase 2 dose 500 mg once daily along with 250 mg Gefitinib tablets orally once daily over a 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment. |
| Phase 2: Pemetrexed and Cisplatin/Carboplatin (MET + T790 negative) | EXPERIMENTAL | Participants randomized to receive 500 milligram per square meter (mg/m\^2) of Pemetrexed as intravenous infusion over 10 minutes in combination with Cisplatin (75 mg/m2 as an intravenous infusion over 2 hours) or Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Pemetrexed maintenance monotherapy. |
| Phase 2: Single-arm Cohort (MET+ T790M positive) | EXPERIMENTAL | Participants with MET+ T790M positive Non-small Cell Lung Cancer (NSCLC) received a Tepotinib recommended Phase 2 dose 500 mg once daily along with 250 mg Gefitinib tablets orally once daily over a 21-day treatment cycle until progressive disease, intolerable toxicity or withdrawal from treatment. |
| MSC2156119J | EXPERIMENTAL | - |
| MSC2156119J Regimen 1 | EXPERIMENTAL | Subjects will be administered with micronized or non-micronized MSC2156119J in dose ranging from 30 mg to 400 mg (capsule formulation) once daily for 14 days, followed by 7 days with no treatment (21-day cycle) in Regimen 1. |
| MSC2156119J Regimen 2 | EXPERIMENTAL | Subjects will be administered with micronized or non-micronized MSC2156119J in dose ranging from 60 mg to 315 mg (capsule formulation) once daily 3 times per week for 3 weeks (21-day cycle) in Regimen 2. |
| MSC2156119J Regimen 3 | EXPERIMENTAL | Subjects will be administered with micronized MSC2156119J in dose ranging from 300 mg to 1400 mg (capsule or tablet formulation) once daily for 21 days (21-day cycle) in Regimen 3. |
| Name | Type | Description |
|---|---|---|
| Tepotinib | DRUG | Participants were administered with Tepotinib orally once daily at a dose of 500 mg. |
| Osimertinib | DRUG | Participants received Osimertinib at a dose of 80 mg orally once daily. |
| Pembrolizumab | DRUG | Pembrolizumab Solution for Infusion 100 mg/vial is a liquid drug product supplied as a clear to opalescent solution, essentially free of visible particles, in Type I glass vials and manufactured using the fully formulated drug substance with L-histidine as buffering agent, polysorbate 80 as surfactant, and sucrose as stabilizer/tonicity modifier. Pembrolizumab Solution for Infusion can be further diluted with normal saline or 5% dextrose in the concentration range of 1 to 10 mg/mL in IV containers made of polyvinyl chloride (PVC) or non-PVC material. |
| Tepotinib 300 mg | DRUG | Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Tepotinib 500 mg | DRUG | Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Tepotinib 1000 mg | DRUG | Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal |
| Sorafenib | DRUG | Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. |
| Gefitinib | DRUG | Gefitinib was administered at a dose of 250 mg orally as once daily over a 21-day cycle until progressive disease, intolerable toxicity, participants withdrawal from treatment. |
| Pemetrexed | DRUG | Pemetrexed was administered at a dose of 500 milligram per square meter (mg/m\^2) as intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity, participants withdrawal from treatment or up to 6 cycles if pemetrexed maintenance is not considered. |
| Cisplatin | DRUG | Cisplatin was administered at a dose of 75 mg/m\^2 as intravenous infusion over 2 hours on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity, participants withdrawal from treatment or up to 6 cycles if pemetrexed maintenance is not considered. |
| Carboplatin | DRUG | Carboplatin was administered intravenously on Day 1 of each 21-day cycle at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator until progressive disease, intolerable toxicity, participants withdrawal from treatment or up to 6 cycles if pemetrexed maintenance is not considered. |
| MSC2156119J | DRUG | Subjects will be administered with MSC2156119J 215 mg, 300 mg and 500 mg orally once daily for repeated 21-day cycles until disease progression or unacceptable toxicity. |
Inclusion Criteria: * Locally advanced or metastatic Non-small Cell Lung Cancer (NSCLC) histology (confirmed by either histology or cytology) with documented activating Epidermal Growth Factor Receptor (EGFR) mutation * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and a mi...
Tepotinib is used to treat advanced (Stage IIIB/IV) non-small cell lung cancer (NSCLC) with MET exon 14 (METex14) skipping alterations or MET amplification. It is also being studied in other advanced cancers, including hepatocellular carcinoma, and in patients with hepatic impairment. It is an oral small molecule developed by Merck KGaA.
Tepotinib targets MET, a receptor tyrosine kinase. It is a MET inhibitor, meaning it blocks MET signaling that drives tumor growth in cancers with MET exon 14 skipping alterations or MET amplification. This targeted action makes it relevant for biomarker-selected NSCLC patients.
Tepotinib is developed by Merck KGaA, which trades under the ticker MKGAF. Merck KGaA is the sponsor of the clinical trials evaluating tepotinib in NSCLC and other advanced cancers.
Tepotinib is in Phase 2 clinical development. It is investigational and has not been approved by the FDA for any indication. The Phase 2 program includes the VISION trial and the INSIGHT 2 trial, both currently active but not recruiting.
Tepotinib is being studied in several trials. The Phase 2 VISION trial (NCT02864992) evaluates tepotinib in NSCLC with MET alterations. The Phase 2 INSIGHT 2 trial (NCT03940703) tests tepotinib plus osimertinib in osimertinib-relapsed MET-amplified NSCLC. The Phase 1 POTENT trial (NCT05782361) combines tepotinib with pembrolizumab in NSCLC. A completed Phase 1 trial (NCT03546608) assessed tepotinib in hepatic impairment.