Non-small Cell Lung Cancer
Conditions
Keywords
MSC2156119J, Gefitinib, Pemetrexed, Cisplatin, MET positive, Tepotinib, Carboplatin, INSIGHT
Brief summary
This is a multi-center, open-label, randomized, Phase 1b/2 study to determine the recommended phase 2 dose (RP2D) and to evaluate the efficacy in terms of progression free survival (PFS) of Tepotinib when used in combination with gefitinib in partcipants with T790M negative, MET positive locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation and having acquired resistance to Prior EGFR-Tyrosine Kinase Inhibitor (EGFR-TKI) Therapy. This study has 2:1 randomization (Tepotinib/Gefitinib arm versus Chemotherapy arm).
Interventions
DRUGTepotinib
Tepotinib was administered at a dose range of 300 or 500 milligram (mg) (Phase 1b) and the recommended phase II dose (RP2D) determined in the Phase 1b in Phase II orally once daily over a 21-day cycle until progressive disease, intolerable toxicity, participants withdrawal from treatment. RP2D was determined as per safety monitoring committee (SMC) discretion.
DRUGGefitinib
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.
DRUGPemetrexed
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.
DRUGCisplatin
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.
DRUGCarboplatin
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.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Phase Ib Inclusion Criteria: * Histologically or cytologically confirmed advanced non-small cell lung cancer (NSCLC), regardless of histology subtype, which failed on gefitinib for reasons other than toxicity or compliance; * Availability of a fresh or archived pre treatment tumor biopsy (excluding fine needle aspiration and cytology samples). For participants who have had at least 1 prior anticancer treatment, a biopsy obtained between failure of the most recent anticancer treatment and enrolment is mandatory; * Mesenchymal-epithelial transition diagnostic-positive (status) (MET+ status), as determined by the central laboratory * Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 * Other protocol defined inclusion criteria could apply. Phase II Inclusion criteria: * Locally advanced or metastatic NSCLC other than predominantly squamous histology (confirmed by either histology or cytology); * Activating mutation of the epidermal growth factor (EGFR) receptor (documented, or as determined by the central laboratory) * Acquired resistance on first-line EGFR-Tyrosine Kinase Inhibitors (EGFR-TKI) therapy including gefitinib, erlotinib, icotinib, or afatinib * EGFR T790M status after acquired resistance to first line EGFR-TKI therapy including gefitinib, erlotinib, icotinib, or afatinib treatment (as determined by the central laboratory, using a validated PCR test); * T790M negative status for the randomized part * T790M positive status for the single-arm cohort (mainland China sites only) * Availability of a fresh or archived tumor tissue (excluding fine needle aspiration and cytology samples) obtained between documentation of acquired resistance to gefitinib, erlotinib, icotinib, or afatinib and enrollment is mandatory * MET+ status, as determined by the central laboratory i.e. c-Met overexpression as determined by IHC (i.e., IHC 2+ or IHC 3+) and/or c-Met amplification and/or increased c-Met gene copy number (GCN), both determined by ISH; * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Other protocol defined inclusion criteria could apply
Exclusion criteria
(Phase I and II): * Estimated life expectancy less than (\<) 3 months * Inadequate bone marrow, liver or renal functions * Prior chemotherapy, biological therapy, radiation therapy, or other investigational anticancer therapy (not including palliative radiotherapy at focal sites) within 21 days prior to the first dose of study treatment (Phase 1b only) * Prior systemic anticancer treatment with chemotherapy or other agents targeting the EGFR pathway excluding gefitinib, erlotinib, icotinib, and afatinib for advanced NSCLC (one course of chemotherapy regimen for \[neo\] adjuvant purpose, or one course of chemoradiation for Stage IIIa disease is allowed) (Phase 2 only) * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Number of Participants Experiencing at Least One Dose Limiting Toxicity (DLT) | Day 1 to Day 21 of Cycle 1 (each cycle is 21 days) | 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. |
| Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Up to 175 weeks | 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. |
| Phase 2 (Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by the Investigator | Up to 328 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Average Observed Plasma Concentration (Cavg) of Tepotinib, Its Metabolites and Gefitinib | Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 15 of Cycle 1 (each Cycle is 21 days) | Cavg is the average plasma concentration within 1 dosing interval obtained directly from the concentration versus time curve. |
| Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib, Its Metabolites and Gefitinib | Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 15 of Cycle 1 (each Cycle is 21 days) | Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve. |
| Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, Its Metabolites and Gefitinib | Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days) | Tmax is time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve. |
| Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, Its Metabolites and Gefitinib | Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days) | The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. |
| Phase 1b: Apparent Total Body Clearance From Plasma (CL/F) of Tepotinib and Gefitinib | Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 15 of Cycle 1 (each Cycle is 21 days) | The CL/f is a measure of the rate at which it was metabolized or eliminated by normal biological processes. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed. The CL/F from plasma was calculated using the formula: Dose divided by area under the concentration time curve from time zero to infinity (AUC0-inf). |
| Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, Its Metabolites and Gefitinib | Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days) | The Vz/f was defined as the theoretical volume in which the total amount of required to uniformly distribute to produce the desired plasma concentration. Apparent volume of distribution after oral dose (Vz/F) was influenced by the fraction absorbed. The Vz/f was calculated by dividing the dose with area under the concentration time curve from time zero to infinity multiplied with terminal elimination rate constant Lambda(z). Vz/f=Dose/AUC(0-inf) multiply Lambda(z). |
| Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, Its Metabolites and Gefitinib | Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days) | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss/f after oral dose was influenced by the fraction absorbed. |
| Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, Its Metabolites and Gefitinib | Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days) | Lambda(z) was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. |
| Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, Its Metabolites and Gefitinib | Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days) | Apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination. |
| Phase 1b: Percentage of Participants With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria | Up to 328 weeks | Objective response (OR) was defined as the percentage of participants who had achieved complete response (CR) or partial response (PR) as the best overall response according to local radiological assessments from randomization/the first administration of the study treatment to the first observation of disease progression (PD). 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 mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as 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 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 mm. |
| Phase 1b: Percentage of Participants With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria | Up to 328 weeks | Disease control defined as CR, PR, or stable disease(SD) as the best overall response according to local radiological assessments from the date of randomization/the first administration of the study treatment to the first observation of PD. CR: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 mm. PR:at least 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD: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 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 5mm. SD:as any cases that do not qualify for either PR or PD at minimum interval of 42 days after randomization/start of study treatment |
| Phase 1b: Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Up to 175 weeks | An adverse event (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. Term TEAE was defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. Treatment-related AE was defined as having a Possible or Related relationship to study treatment, as assessed by the Investigator. |
| Phase 1b: Number of Participants With Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) and Grade 3/4 Treatment-Related TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Up to 175 weeks | An adverse event (AE) was defined as any untoward medical occurrence in participant which does not necessarily have casual relationship with treatment was any unfavorable and unintended sign(including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal product, whether/not considered related to medicinal product. Term TEAE was defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. Treatment-related TEAE was defined as having a Possible or Related relationship to study treatment, as assessed by the Investigator. As per NCI-CTCAE, Grade 3 is Severe, Grade 4 is Life-threatening and Grade 5 or Death. Number of participants with Grade 3/4 TEAEs and Grade 3/4 treatment-related TEAEs were reported. |
| Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation | Up to 175 weeks | An adverse event (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. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. Number of participants with TEAEs leading to permanent treatment discontinuation were reported. |
| Phase 1b: Number of Participants With Death and Reasons | Up to 175 weeks | Number of participants with death due to progressive disease (PD), adverse event (AE) related to study treatment, AE not related to study treatment 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. PD defined as 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 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 mm. Number of participants with deaths due to PD, AE related to study treatment, AE not related to study treatment were reported. |
| Phase 1b: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Up to 175 weeks | The laboratory measurements included hematology and coagulation, biochemistry and urinalysis. |
| Phase 1b: Number of Participants With Clinically Significant Abnormalities in Vital Signs | Up to 175 weeks | Vital signs assessment included blood pressure, heart rate, respiratory rate and body temperature. Number of Participants with any clinically significant abnormalities in vital signs were reported. Clinical significance was determined by the investigator. |
| Phase 1b: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings | Up to 175 weeks | ECG parameters included heart rhythm, pulse rate intervals, QRS, QT intervals, RR intervals and corrected QT(QTc) intervals. Clinical significance was determined by the investigator. Number of participants with clinically significant abnormalities in 12-lead ECG were reported. |
| Phase 1b: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2 | Up to 175 weeks | ECOG PS score is widely used by doctors and researchers to assess how a participants' disease is progressing, and is used to assess how the disease affects the daily living abilities of the participant, and determine appropriate treatment and prognosis. The score ranges from Grade 0 to Grade 5, where Grade 0 = Fully active, able to carry on all pre-disease performance without restriction, Grade 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade 2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair, Grade 5 = Death. Number of participants with ECOG performance status score of 2 or higher than 2 were reported. |
| Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Treatment-Related TEAEs and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Up to 328 weeks | 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. TEAEs was defined as AEs that started or worsened in severity within the first dosing day of study treatment after the last dose of study treatment. TEAEs include both Serious TEAEs and non-serious TEAEs Treatment related AE was defined as having a Possible or Related relationship to study treatment, as assessed by the Investigator. |
| Phase 2: Number of Participants With Greater Than or Equal to (>=) Grade 3 Treatment-Emergent Adverse Events (TEAEs) and >= Grade 3 Treatment-Related TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Up to 328 weeks | An adverse event (AE) was defined as any untoward medical occurrence in participant which does not necessarily have casual relationship with treatment was any unfavorable and unintended sign(including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal product, whether/not considered related to medicinal product. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. Treatment-related AE was defined as having a Possible or Related relationship to study treatment, as assessed by the Investigator. As per NCI-CTCAE, Grade 3 is Severe, Grade 4 is Life-threatening and Grade 5 or Death. Number of Participants With \>= Grade 3 TEAEs and \>= Grade 3 treatment-related TEAEs were reported. |
| Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation | Up to 328 weeks | An adverse event (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. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. Number of participants with TEAEs leading to permanent treatment discontinuation were reported. |
| Phase 2: Number of Participants With Death and Reasons | Up to 328 weeks | An AE was defined as any unfavorable 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. PD defined as 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 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 mm. Number of participants with deaths due to progression disease (PD), AE related to study treatment, unknown reason was reported. |
| Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Up to 328 weeks | The laboratory measurements included hematology and coagulation, biochemistry and urinalysis. |
| Phase 2: Number of Participants With Clinically Significant Abnormalities in Vital Signs | Up to 328 weeks | Vital signs assessment included blood pressure, heart rate, respiratory rate and body temperature. Number of Participants with any clinically significant abnormalities in vital signs were reported. Clinical significance was determined by the investigator. |
| Phase 2: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings | Up to 328 weeks | ECG parameters included heart rhythm, pulse rate intervals, QRS, QT intervals, RR intervals and corrected QT(QTc) intervals. Clinical significance was determined by the investigator. Number of participants with clinically significant abnormalities in 12-lead ECG were reported. |
| Phase 2: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2 | Up to 328 weeks | ECOG PS score is widely used by doctors and researchers to assess how a participants' disease is progressing, and is used to assess how the disease affects the daily living abilities of the participant, and determine appropriate treatment and prognosis. The score ranges from Grade 0 to Grade 5, where Grade 0 = Fully active, able to carry on all pre-disease performance without restriction, Grade 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade 2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair, Grade 5 = Death. Number of participants with ECOG performance status score of 2 or higher than 2 were reported. |
| Phase 2 (Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Independent Review Committee (IRC) | Up to 328 weeks | Progression-free survival (assessed by Independent Review Committee) time was defined as the time in months from randomization to either first observation of radiologically confirmed progression disease (PD) by the IRC 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 mm. PFS was measured using Kaplan-Meier (KM) estimates. |
| Phase 2: (Randomized Part Only): Overall Survival (OS) Time | Up to 328 weeks | Overall survival time was measured as time in months between the date of randomization and the date of death. |
| Phase 2 (Randomized Part Only): Percentage of Participants With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria | Up to 328 weeks | Objective response (OR) was defined as the percentage of participants who had achieved complete response (CR) or partial response (PR) as the best overall response according to local radiological assessments from randomization/the first administration of the study treatment to the first observation of disease progression (PD). 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 mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as 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 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 mm. |
| Phase 2 (Randomized Part Only): Percentage of Participants With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria | Up to 328 weeks | Disease control defined as CR, PR, or stable disease(SD) as the best overall response according to local radiological assessments from the date of randomization/the first administration of the study treatment to the first observation of PD. CR: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 mm. PR:at least 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD: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 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 5mm. SD:as any cases that do not qualify for either PR/PD at minimum interval of 42 days after randomization/start of study treatment. |
| Phase 2 (Non-Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Investigator | Up to 328 weeks | Progression-free survival (assessed by Investigator) time was defined as the time in months from randomization to either first observation of radiologically confirmed progression disease 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 mm. PFS was measured using Kaplan-Meier (KM) estimates. |
| Phase 2 (Non-Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Independent Review Committee (IRC) | Up to 328 weeks | Progression-free survival (assessed by Independent Review Committee) time was defined as the time in months from randomization to either first observation of radiologically confirmed progression disease by the IRC 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 mm. PFS was measured using Kaplan-Meier (KM) estimates. |
| Phase 2: (Non-Randomized Part Only): Overall Survival (OS) Time | Up to 328 weeks | Overall survival time was measured as time in months between the date of randomization and the date of death. |
| Phase 2 (Non-Randomized Part Only): Percentage of Participants With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria | Up to 328 weeks | Objective response (OR) was defined as the percentage of participants who had achieved complete response (CR) or partial response (PR) as the best overall response according to local radiological assessments from randomization/the first administration of the study treatment to the first observation of disease progression (PD). 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 mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as 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 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 mm. |
| Phase 1b: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, Its Metabolites and Gefitinib | Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days) | Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration is at or above the lower limit of quantification (LLLQ). AUC(0-t) was calculated according to the mixed log-linear trapezoidal rule. |
| Phase 2: Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) Global Health Status Scale Score at End of Treatment (EOT) | Baseline and EOT (up to 110 weeks) | EORTC QLQ-C30 is a 30-question tool used to assess the overall quality of life (QoL) in cancer participants. It consisted of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, role, cognitive, emotional, social), and 9 symptom scales/items (Fatigue, nausea and vomiting, pain, dyspnoea, sleep disturbance, appetite loss, constipation, diarrhea, financial impact. The EORTC QLQ-C30 GHS/QoL score ranges from 0 to 100; High score indicates better GHS/QoL. Score 0 represents: very poor physical condition and QoL. Score 100 represents: excellent overall physical condition and QoL. |
| Phase 2: Time-to-Symptom Progression (TTSP) | Up to 328 weeks | TTSP was measured from randomization to symptomatic progression by lung cancer symptom scale (LCSS) used to measure symptom changes relevant to quality of life (QoL).It consisted of 9 items focused on cancer symptoms (loss of appetite, fatigue, cough, shortness of breath, blood in sputum, pain, symptoms of cancer, illness affecting normal activity, QoL).For each symptom score distance from left boundary to point where participant has marked line was measured in millimeters (mm).Total scale length was 100 mm. Symptomatic progression was defined as increase/worsening of average symptomatic burden index (ASBI) (mean of 6 major lung cancer specific symptom scores);Worsening defined as 10% increase of scale breadth from baseline. Score 0 indicate no/minimum symptoms;100 indicates maximum level of symptoms. |
| Phase 2 (Non-Randomized Part Only): Percentage of Participants With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria | Up to 328 weeks | Disease control defined as CR, PR, or stable disease(SD) as the best overall response according to local radiological assessments from the date of randomization/the first administration of the study treatment to the first observation of PD. CR: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 mm. PR:at least 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD: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 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 5mm. SD:as any cases that do not qualify for either PR/PD at minimum interval of 42 days after randomization/start of study treatment. |
| Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib | Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days) | AUC (0-tau) is the area under the plasma concentration time curve within 1 dosing interval. |
| Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib | Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days) | Cmax is the maximum observed plasma concentration obtained directly from the concentration versus time curve. |
Countries
China, Italy, Malaysia, Singapore, South Korea, Spain, Taiwan
Participant flow
Pre-assignment details
A total of 18 participants were enrolled in Phase 1b part of the study and a total of 70 participants were enrolled in phase 2 part of the study. Participants enrolled in phase 1b were not eligible for randomization in phase 2.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg 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. | 6 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg 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. | 12 |
| Phase 2: Tepotinib 500 mg + Gefitinib 250 mg (MET + T790 Negative) 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. | 31 |
| Phase 2: Pemetrexed and Cisplatin/Carboplatin (MET + T790 Negative) 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/m\^2 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. | 24 |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) 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. | 15 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Randomized but not treated | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Tepotinib 500 mg + Gefitinib 250 mg (MET + T790 Negative) | Phase 2: Pemetrexed and Cisplatin/Carboplatin (MET + T790 Negative) | Phase 2: Single-arm Cohort (MET+ T790M Positive) | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 6 Participants | 10 Participants | 7 Participants | 6 Participants | 32 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 6 Participants | 21 Participants | 17 Participants | 9 Participants | 56 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 12 Participants | 31 Participants | 24 Participants | 15 Participants | 88 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 3 Participants | 7 Participants | 20 Participants | 12 Participants | 10 Participants | 52 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 11 Participants | 12 Participants | 5 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 6 | 3 / 12 | 23 / 31 | 20 / 23 | 10 / 15 |
| other Total, other adverse events | 6 / 6 | 12 / 12 | 31 / 31 | 23 / 23 | 13 / 15 |
| serious Total, serious adverse events | 4 / 6 | 7 / 12 | 13 / 31 | 8 / 23 | 5 / 15 |
Outcome results
Primary
Phase 1b: Number of Participants Experiencing at Least One Dose Limiting Toxicity (DLT)
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.
Time frame: Day 1 to Day 21 of Cycle 1 (each cycle is 21 days)
Population: Dose Limiting Toxicity (DLT) set included all participants who experienced a DLT during Cycle 1, or received at least 80 percent of all planned doses of treatment during Cycle.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants Experiencing at Least One Dose Limiting Toxicity (DLT) | 0 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants Experiencing at Least One Dose Limiting Toxicity (DLT) | 0 Participants |
Primary
Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs
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.
Time frame: Up to 175 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Any Serious TEAEs | 4 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Any TEAEs | 6 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Any TEAEs | 12 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Any Serious TEAEs | 7 Participants |
Primary
Phase 2 (Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by the Investigator
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.
Time frame: Up to 328 weeks
Population: The Intent-to-treat analysis set in the Phase 2 part of the study included all participants with treatment group who were randomized to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2 (Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by the Investigator | 4.86 Months |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2 (Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by the Investigator | 4.37 Months |
Secondary
Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, Its Metabolites and Gefitinib
Lambda(z) was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Time frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days)
Population: The Pharmacokinetic set included all participants who had received at least 1 dose of the tepotinib or gefitinib and who had provided at least 1 plasma concentration measurement of tepotinib or gefitinib after the first dose.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 1 of Cycle 1 | NA 1 per hour |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 15 of Cycle 1 | NA 1 per hour |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 1 of Cycle 1 | NA 1 per hour |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 15 of Cycle 1 | NA 1 per hour |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 1 of Cycle 1 | NA 1 per hour |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 15 of Cycle 1 | NA 1 per hour |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 1 of Cycle 1 | NA 1 per hour |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 15 of Cycle 1 | NA 1 per hour |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 15 of Cycle 1 | NA 1 per hour |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 1 of Cycle 1 | NA 1 per hour |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 1 of Cycle 1 | NA 1 per hour |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 15 of Cycle 1 | NA 1 per hour |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 1 of Cycle 1 | NA 1 per hour |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 1 of Cycle 1 | NA 1 per hour |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 15 of Cycle 1 | NA 1 per hour |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 15 of Cycle 1 | NA 1 per hour |
Secondary
Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, Its Metabolites and Gefitinib
Apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination.
Time frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days)
Population: The Pharmacokinetic set included all participants who had received at least 1 dose of the tepotinib or gefitinib and who had provided at least 1 plasma concentration measurement of tepotinib or gefitinib after the first dose.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 15 of Cycle 1 | NA Hours |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 1 of Cycle 1 | NA Hours |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 1 of Cycle 1 | NA Hours |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 15 of Cycle 1 | NA Hours |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 1 of Cycle 1 | NA Hours |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 1 of Cycle 1 | NA Hours |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 15 of Cycle 1 | NA Hours |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 15 of Cycle 1 | NA Hours |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 15 of Cycle 1 | NA Hours |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 1 of Cycle 1 | NA Hours |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 15 of Cycle 1 | NA Hours |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 1 of Cycle 1 | NA Hours |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 15 of Cycle 1 | NA Hours |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 1 of Cycle 1 | NA Hours |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 15 of Cycle 1 | NA Hours |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 1 of Cycle 1 | NA Hours |
Secondary
Phase 1b: Apparent Total Body Clearance From Plasma (CL/F) of Tepotinib and Gefitinib
The CL/f is a measure of the rate at which it was metabolized or eliminated by normal biological processes. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed. The CL/F from plasma was calculated using the formula: Dose divided by area under the concentration time curve from time zero to infinity (AUC0-inf).
Time frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 15 of Cycle 1 (each Cycle is 21 days)
Population: The Pharmacokinetic set included all participants who had received at least 1 dose of the tepotinib or gefitinib and who had provided at least 1 plasma concentration measurement of tepotinib or gefitinib after the first dose. Here, Number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Total Body Clearance From Plasma (CL/F) of Tepotinib and Gefitinib | Gefitinib | 32.5 liter per hour (L/h) | Geometric Coefficient of Variation 44.1 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Total Body Clearance From Plasma (CL/F) of Tepotinib and Gefitinib | Tepotinib | 17.3 liter per hour (L/h) | Geometric Coefficient of Variation 19.6 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Total Body Clearance From Plasma (CL/F) of Tepotinib and Gefitinib | Gefitinib | 35.3 liter per hour (L/h) | Geometric Coefficient of Variation 29 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Total Body Clearance From Plasma (CL/F) of Tepotinib and Gefitinib | Tepotinib | 20.3 liter per hour (L/h) | Geometric Coefficient of Variation 43.3 |
Secondary
Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, Its Metabolites and Gefitinib
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss/f after oral dose was influenced by the fraction absorbed.
Time frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days)
Population: The Pharmacokinetic set included all participants who had received at least 1 dose of the tepotinib or gefitinib and who had provided at least 1 plasma concentration measurement of tepotinib or gefitinib after the first dose.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 1 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 15 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 1 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 15 of cycle 1 | NA Liter |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 1 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 15 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 1 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 15 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 15 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 1 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 1 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 15 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 1 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 1 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 15 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 15 of cycle 1 | NA Liter |
Secondary
Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, Its Metabolites and Gefitinib
The Vz/f was defined as the theoretical volume in which the total amount of required to uniformly distribute to produce the desired plasma concentration. Apparent volume of distribution after oral dose (Vz/F) was influenced by the fraction absorbed. The Vz/f was calculated by dividing the dose with area under the concentration time curve from time zero to infinity multiplied with terminal elimination rate constant Lambda(z). Vz/f=Dose/AUC(0-inf) multiply Lambda(z).
Time frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days)
Population: The Pharmacokinetic set included all participants who had received at least 1 dose of the tepotinib or gefitinib and who had provided at least 1 plasma concentration measurement of tepotinib or gefitinib after the first dose.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 1 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 1 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 15 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 15 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 1 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 15 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 1 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 15 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 15 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 1 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 1 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 1 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 15 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 1 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 15 of Cycle 1 | NA Liter |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 15 of Cycle 1 | NA Liter |
Secondary
Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, Its Metabolites and Gefitinib
The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.
Time frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days)
Population: The Pharmacokinetic set included all participants who had received at least 1 dose of the tepotinib or gefitinib and who had provided at least 1 plasma concentration measurement of tepotinib or gefitinib after the first dose.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 1 of Cycle 1 | NA ng*h/mL |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 15 of Cycle 1 | NA ng*h/mL |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 1 of Cycle 1 | NA ng*h/mL |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 15 of Cycle 1 | NA ng*h/mL |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 1 of Cycle 1 | NA ng*h/mL |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 15 of Cycle 1 | NA ng*h/mL |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 1 of Cycle 1 | NA ng*h/mL |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 15 of Cycle 1 | NA ng*h/mL |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 15 of Cycle 1 | NA ng*h/mL |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 1 of Cycle 1 | NA ng*h/mL |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 1 of Cycle 1 | NA ng*h/mL |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 15 of Cycle 1 | NA ng*h/mL |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 1 of Cycle 1 | NA ng*h/mL |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 1 of Cycle 1 | NA ng*h/mL |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 15 of Cycle 1 | NA ng*h/mL |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 15 of Cycle 1 | NA ng*h/mL |
Secondary
Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib
AUC (0-tau) is the area under the plasma concentration time curve within 1 dosing interval.
Time frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days)
Population: The PK set included all participants who had received at least 1 dose of the tepotinib or gefitinib and who had provided at least 1 plasma concentration measurement of tepotinib or gefitinib after the first dose. Here Number Analyzed signifies those participants who were evaluable for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 1 of Cycle 1 | 6280 ng*h/mL | Geometric Coefficient of Variation 25.4 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 1 of Cycle 1 | 248 ng*h/mL | Geometric Coefficient of Variation 49.3 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 1 of Cycle 1 | 1680 ng*h/mL | Geometric Coefficient of Variation 11.8 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 15 of Cycle 1 | 872 ng*h/mL | Geometric Coefficient of Variation 38.5 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 15 of Cycle 1 | 15600 ng*h/mL | Geometric Coefficient of Variation 19.6 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 1 of Cycle 1 | NA ng*h/mL | — |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 15 of Cycle 1 | 4420 ng*h/mL | Geometric Coefficient of Variation 25.7 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 15 of Cycle 1 | 7690 ng*h/mL | Geometric Coefficient of Variation 44.1 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 15 of Cycle 1 | 7530 ng*h/mL | Geometric Coefficient of Variation 52.6 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 1 of Cycle 1 | 9210 ng*h/mL | Geometric Coefficient of Variation 48.4 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 15 of Cycle 1 | 22200 ng*h/mL | Geometric Coefficient of Variation 43.3 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 1 of Cycle 1 | 1770 ng*h/mL | Geometric Coefficient of Variation 56.7 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 15 of Cycle 1 | 7080 ng*h/mL | Geometric Coefficient of Variation 29 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 1 of Cycle 1 | 324 ng*h/mL | Geometric Coefficient of Variation 57.3 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 15 of Cycle 1 | 1880 ng*h/mL | Geometric Coefficient of Variation 76 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 1 of Cycle 1 | 2930 ng*h/mL | Geometric Coefficient of Variation 45.8 |
Secondary
Phase 1b: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, Its Metabolites and Gefitinib
Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration is at or above the lower limit of quantification (LLLQ). AUC(0-t) was calculated according to the mixed log-linear trapezoidal rule.
Time frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days)
Population: The Pharmacokinetic (PK) set included all participants who had received at least 1 dose of the tepotinib or gefitinib and who had provided at least 1 plasma concentration measurement of tepotinib or gefitinib after the first dose. Here Number Analyzed signifies those participants who were evaluable for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 1 of Cycle 1 | 6280 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 25.4 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 15 of Cycle 1 | 15600 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 19.6 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 1 of Cycle 1 | 1680 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 11.8 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A Day15 of Cycle 1 | 4420 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 25.7 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A Day 1 of Cycle 1 | 248 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 49.3 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A Day 15 of Cycle 1 | 872 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 38.5 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 1 of Cycle 1 | NA nanogram*hour per milliliter (ng*h/mL) | — |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 15 of Cycle 1 | 7690 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 44.1 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 15 of Cycle 1 | 7080 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 29 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 1 of Cycle 1 | 9210 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 48.4 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A Day 1 of Cycle 1 | 324 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 57.3 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 15 of Cycle 1 | 22200 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 43.3 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 1 of Cycle 1 | 2930 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 45.8 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 1 of Cycle 1 | 1770 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 56.7 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A Day 15 of Cycle 1 | 1880 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 76 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A Day15 of Cycle 1 | 7530 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 52.6 |
Secondary
Phase 1b: Average Observed Plasma Concentration (Cavg) of Tepotinib, Its Metabolites and Gefitinib
Cavg is the average plasma concentration within 1 dosing interval obtained directly from the concentration versus time curve.
Time frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 15 of Cycle 1 (each Cycle is 21 days)
Population: The PK analysis set employed here. Number of participants analyzed signifies participants who were evaluable for this outcome measure and Number Analyzed signifies those participants who were evaluable for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Average Observed Plasma Concentration (Cavg) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib | 654 ng/mL | Geometric Coefficient of Variation 19.4 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Average Observed Plasma Concentration (Cavg) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A | 185 ng/mL | Geometric Coefficient of Variation 25.4 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Average Observed Plasma Concentration (Cavg) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib | 321 ng/mL | Geometric Coefficient of Variation 43.9 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Average Observed Plasma Concentration (Cavg) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A | 36.4 ng/mL | Geometric Coefficient of Variation 38.2 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Average Observed Plasma Concentration (Cavg) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib | 295 ng/mL | Geometric Coefficient of Variation 29 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Average Observed Plasma Concentration (Cavg) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib | 924 ng/mL | Geometric Coefficient of Variation 43.3 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Average Observed Plasma Concentration (Cavg) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A | 314 ng/mL | Geometric Coefficient of Variation 52.6 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Average Observed Plasma Concentration (Cavg) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A | 78.3 ng/mL | Geometric Coefficient of Variation 76 |
Secondary
Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib
Cmax is the maximum observed plasma concentration obtained directly from the concentration versus time curve.
Time frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days)
Population: The PK set included all participants who had received at least 1 dose of the tepotinib or gefitinib and who had provided at least 1 plasma concentration measurement of tepotinib or gefitinib after the first dose. Here Number Analyzed signifies those participants who were evaluable for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 1 of Cycle 1 | 375 Nanogram per Milliliter (ng/mL) | Geometric Coefficient of Variation 30.4 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 15 of Cycle 1 | 763 Nanogram per Milliliter (ng/mL) | Geometric Coefficient of Variation 22 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 1 of Cycle 1 | 132 Nanogram per Milliliter (ng/mL) | Geometric Coefficient of Variation 14.7 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 15 of Cycle 1 | 280 Nanogram per Milliliter (ng/mL) | Geometric Coefficient of Variation 32 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 1 of Cycle 1 | 16.8 Nanogram per Milliliter (ng/mL) | Geometric Coefficient of Variation 56.5 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 15 of Cycle 1 | 44.9 Nanogram per Milliliter (ng/mL) | Geometric Coefficient of Variation 40.5 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 1 of Cycle 1 | NA Nanogram per Milliliter (ng/mL) | — |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 15 of Cycle 1 | 432 Nanogram per Milliliter (ng/mL) | Geometric Coefficient of Variation 38.3 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 15 of Cycle 1 | 366 Nanogram per Milliliter (ng/mL) | Geometric Coefficient of Variation 32.6 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 1 of Cycle 1 | 575 Nanogram per Milliliter (ng/mL) | Geometric Coefficient of Variation 62.6 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 1 of Cycle 1 | 24.3 Nanogram per Milliliter (ng/mL) | Geometric Coefficient of Variation 62.5 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 15 of Cycle 1 | 1050 Nanogram per Milliliter (ng/mL) | Geometric Coefficient of Variation 44.1 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 1 of Cycle 1 | 215 Nanogram per Milliliter (ng/mL) | Geometric Coefficient of Variation 48.7 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 1 of Cycle 1 | 149 Nanogram per Milliliter (ng/mL) | Geometric Coefficient of Variation 56.5 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 15 of Cycle 1 | 94.9 Nanogram per Milliliter (ng/mL) | Geometric Coefficient of Variation 70.8 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 15 of Cycle 1 | 444 Nanogram per Milliliter (ng/mL) | Geometric Coefficient of Variation 45.8 |
Secondary
Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib, Its Metabolites and Gefitinib
Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve.
Time frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 15 of Cycle 1 (each Cycle is 21 days)
Population: The PK analysis set employed here. Number of participants analyzed signifies participants who were evaluable for this outcome measure and Number Analyzed signifies those participants who were evaluable for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib | 534 ng/mL | Geometric Coefficient of Variation 18.8 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A | 156 ng/mL | Geometric Coefficient of Variation 28.8 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A | 32.8 ng/mL | Geometric Coefficient of Variation 40.1 |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib, Its Metabolites and Gefitinib | Geftinib | 231 ng/mL | Geometric Coefficient of Variation 57.3 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib, Its Metabolites and Gefitinib | Geftinib | 190 ng/mL | Geometric Coefficient of Variation 43.5 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib | 735 ng/mL | Geometric Coefficient of Variation 47.6 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A | 68.7 ng/mL | Geometric Coefficient of Variation 80.1 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A | 270 ng/mL | Geometric Coefficient of Variation 58.5 |
Secondary
Phase 1b: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings
ECG parameters included heart rhythm, pulse rate intervals, QRS, QT intervals, RR intervals and corrected QT(QTc) intervals. Clinical significance was determined by the investigator. Number of participants with clinically significant abnormalities in 12-lead ECG were reported.
Time frame: Up to 175 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings | 0 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings | 0 Participants |
Secondary
Phase 1b: Number of Participants With Clinically Significant Abnormalities in Vital Signs
Vital signs assessment included blood pressure, heart rate, respiratory rate and body temperature. Number of Participants with any clinically significant abnormalities in vital signs were reported. Clinical significance was determined by the investigator.
Time frame: Up to 175 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Clinically Significant Abnormalities in Vital Signs | 0 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Clinically Significant Abnormalities in Vital Signs | 0 Participants |
Secondary
Phase 1b: Number of Participants With Death and Reasons
Number of participants with death due to progressive disease (PD), adverse event (AE) related to study treatment, AE not related to study treatment 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. PD defined as 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 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 mm. Number of participants with deaths due to PD, AE related to study treatment, AE not related to study treatment were reported.
Time frame: Up to 175 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Death and Reasons | Death due to PD | 0 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Death and Reasons | Death due to AE related to study treatment | 0 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Death and Reasons | Death due to AE not related to study treatment | 1 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Death and Reasons | Death due to PD | 3 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Death and Reasons | Death due to AE related to study treatment | 0 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Death and Reasons | Death due to AE not related to study treatment | 0 Participants |
Secondary
Phase 1b: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2
ECOG PS score is widely used by doctors and researchers to assess how a participants' disease is progressing, and is used to assess how the disease affects the daily living abilities of the participant, and determine appropriate treatment and prognosis. The score ranges from Grade 0 to Grade 5, where Grade 0 = Fully active, able to carry on all pre-disease performance without restriction, Grade 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade 2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair, Grade 5 = Death. Number of participants with ECOG performance status score of 2 or higher than 2 were reported.
Time frame: Up to 175 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2 | 1 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2 | 9 Participants |
Secondary
Phase 1b: Number of Participants With Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) and Grade 3/4 Treatment-Related TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.03
An adverse event (AE) was defined as any untoward medical occurrence in participant which does not necessarily have casual relationship with treatment was any unfavorable and unintended sign(including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal product, whether/not considered related to medicinal product. Term TEAE was defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. Treatment-related TEAE was defined as having a Possible or Related relationship to study treatment, as assessed by the Investigator. As per NCI-CTCAE, Grade 3 is Severe, Grade 4 is Life-threatening and Grade 5 or Death. Number of participants with Grade 3/4 TEAEs and Grade 3/4 treatment-related TEAEs were reported.
Time frame: Up to 175 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) and Grade 3/4 Treatment-Related TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Any Grade 3/4 TEAE | 5 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) and Grade 3/4 Treatment-Related TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Any Grade 3/4 TEAE Related to Tepotinib | 2 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) and Grade 3/4 Treatment-Related TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Any Grade 3/4 TEAE Related to Gefitinib | 0 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) and Grade 3/4 Treatment-Related TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Any Grade 3/4 TEAE | 9 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) and Grade 3/4 Treatment-Related TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Any Grade 3/4 TEAE Related to Tepotinib | 4 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) and Grade 3/4 Treatment-Related TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Any Grade 3/4 TEAE Related to Gefitinib | 0 Participants |
Secondary
Phase 1b: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs)
The laboratory measurements included hematology and coagulation, biochemistry and urinalysis.
Time frame: Up to 175 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Hypoproteinemia | 1 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Lipase increased | 1 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Hypocalcemia | 1 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Neutrophil count decreased | 0 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Amylase increased | 2 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Hyperglycemia | 0 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Hyponatremia | 0 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Hyperglycemia | 2 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Hypocalcemia | 0 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Hyponatremia | 2 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Hypoproteinemia | 0 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Amylase increased | 2 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Lipase increased | 2 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Neutrophil count decreased | 1 Participants |
Secondary
Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation
An adverse event (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. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. Number of participants with TEAEs leading to permanent treatment discontinuation were reported.
Time frame: Up to 175 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation | TEAE Leading Permanent Tepotinib Discontinuation | 0 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation | TEAE Leading Permanent Gefitinib Discontinuation | 0 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation | TEAE Leading Permanent Tepotinib Discontinuation | 2 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation | TEAE Leading Permanent Gefitinib Discontinuation | 1 Participants |
Secondary
Phase 1b: Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03
An adverse event (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. Term TEAE was defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. Treatment-related AE was defined as having a Possible or Related relationship to study treatment, as assessed by the Investigator.
Time frame: Up to 175 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any TEAE Related to Tepotinib | 6 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any TEAE Related to Gefitinib | 5 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any Serious TEAE Related to Tepotinib | 0 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any Serious TEAE Related to Gefitinib | 0 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any Serious TEAE Related to Gefitinib | 0 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any TEAE Related to Tepotinib | 9 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any Serious TEAE Related to Tepotinib | 0 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any TEAE Related to Gefitinib | 11 Participants |
Secondary
Phase 1b: Percentage of Participants With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria
Disease control defined as CR, PR, or stable disease(SD) as the best overall response according to local radiological assessments from the date of randomization/the first administration of the study treatment to the first observation of PD. CR: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 mm. PR:at least 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD: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 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 5mm. SD:as any cases that do not qualify for either PR or PD at minimum interval of 42 days after randomization/start of study treatment
Time frame: Up to 328 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Percentage of Participants With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria | 50.0 Percentage of Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Percentage of Participants With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria | 58.3 Percentage of Participants |
Secondary
Phase 1b: Percentage of Participants With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria
Objective response (OR) was defined as the percentage of participants who had achieved complete response (CR) or partial response (PR) as the best overall response according to local radiological assessments from randomization/the first administration of the study treatment to the first observation of disease progression (PD). 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 mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as 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 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 mm.
Time frame: Up to 328 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Percentage of Participants With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria | 33.3 Percentage of Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Percentage of Participants With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria | 33.3 Percentage of Participants |
Secondary
Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, Its Metabolites and Gefitinib
Tmax is time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve.
Time frame: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days)
Population: The Pharmacokinetic set included all participants who had received at least 1 dose of the tepotinib or gefitinib and who had provided at least 1 plasma concentration measurement of tepotinib or gefitinib after the first dose. Here Number Analyzed signifies those participants who were evaluable for specified category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 1 of Cycle 1 | 8.00 Hours |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 15 of Cycle 1 | 6.00 Hours |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 1 of Cycle 1 | 24.00 Hours |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 15 of Cycle 1 | 0.00 Hours |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 1 of Cycle 1 | 24.00 Hours |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 15 of Cycle 1 | 0.13 Hours |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 1 of Cycle 1 | NA Hours |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 15 of Cycle 1 | 4.00 Hours |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 15 of Cycle 1 | 8.00 Hours |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 1 of Cycle 1 | 9.01 Hours |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 1 of Cycle 1 | 24.00 Hours |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, Its Metabolites and Gefitinib | Tepotinib: Day 15 of Cycle 1 | 9.00 Hours |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, Its Metabolites and Gefitinib | Gefitinib: Day 1 of Cycle 1 | 8.00 Hours |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 1 of Cycle 1 | 24.00 Hours |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, Its Metabolites and Gefitinib | MSC2571107A: Day 15 of Cycle 1 | 0.25 Hours |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, Its Metabolites and Gefitinib | MSC2571109A: Day 15 of Cycle 1 | 0.00 Hours |
Secondary
Phase 2: Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) Global Health Status Scale Score at End of Treatment (EOT)
EORTC QLQ-C30 is a 30-question tool used to assess the overall quality of life (QoL) in cancer participants. It consisted of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, role, cognitive, emotional, social), and 9 symptom scales/items (Fatigue, nausea and vomiting, pain, dyspnoea, sleep disturbance, appetite loss, constipation, diarrhea, financial impact. The EORTC QLQ-C30 GHS/QoL score ranges from 0 to 100; High score indicates better GHS/QoL. Score 0 represents: very poor physical condition and QoL. Score 100 represents: excellent overall physical condition and QoL.
Time frame: Baseline and EOT (up to 110 weeks)
Population: Quality of life (Qol) evaluable population set included ITT participants in the treatment group in which they actually received the treatment with a baseline and at least 1 evaluable on-treatment QoL questionnaire. Here Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) Global Health Status Scale Score at End of Treatment (EOT) | -16.29 Units on a Scale | Standard Deviation 30.691 |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) Global Health Status Scale Score at End of Treatment (EOT) | -2.78 Units on a Scale | Standard Deviation 22.869 |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) Global Health Status Scale Score at End of Treatment (EOT) | -24.19 Units on a Scale | Standard Deviation 24.673 |
Secondary
Phase 2: (Non-Randomized Part Only): Overall Survival (OS) Time
Overall survival time was measured as time in months between the date of randomization and the date of death.
Time frame: Up to 328 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: (Non-Randomized Part Only): Overall Survival (OS) Time | 25.86 Months |
Secondary
Phase 2 (Non-Randomized Part Only): Percentage of Participants With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria
Disease control defined as CR, PR, or stable disease(SD) as the best overall response according to local radiological assessments from the date of randomization/the first administration of the study treatment to the first observation of PD. CR: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 mm. PR:at least 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD: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 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 5mm. SD:as any cases that do not qualify for either PR/PD at minimum interval of 42 days after randomization/start of study treatment.
Time frame: Up to 328 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2 (Non-Randomized Part Only): Percentage of Participants With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria | 40 Percentage of Participants |
Secondary
Phase 2 (Non-Randomized Part Only): Percentage of Participants With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria
Objective response (OR) was defined as the percentage of participants who had achieved complete response (CR) or partial response (PR) as the best overall response according to local radiological assessments from randomization/the first administration of the study treatment to the first observation of disease progression (PD). 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 mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as 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 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 mm.
Time frame: Up to 328 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2 (Non-Randomized Part Only): Percentage of Participants With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria | 0 Percentage of Participants |
Secondary
Phase 2 (Non-Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Independent Review Committee (IRC)
Progression-free survival (assessed by Independent Review Committee) time was defined as the time in months from randomization to either first observation of radiologically confirmed progression disease by the IRC 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 mm. PFS was measured using Kaplan-Meier (KM) estimates.
Time frame: Up to 328 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2 (Non-Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Independent Review Committee (IRC) | 2.63 Months |
Secondary
Phase 2 (Non-Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Investigator
Progression-free survival (assessed by Investigator) time was defined as the time in months from randomization to either first observation of radiologically confirmed progression disease 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 mm. PFS was measured using Kaplan-Meier (KM) estimates.
Time frame: Up to 328 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2 (Non-Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Investigator | 1.41 Months |
Secondary
Phase 2: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings
ECG parameters included heart rhythm, pulse rate intervals, QRS, QT intervals, RR intervals and corrected QT(QTc) intervals. Clinical significance was determined by the investigator. Number of participants with clinically significant abnormalities in 12-lead ECG were reported.
Time frame: Up to 328 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings | 2 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings | 1 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings | 0 Participants |
Secondary
Phase 2: Number of Participants With Clinically Significant Abnormalities in Vital Signs
Vital signs assessment included blood pressure, heart rate, respiratory rate and body temperature. Number of Participants with any clinically significant abnormalities in vital signs were reported. Clinical significance was determined by the investigator.
Time frame: Up to 328 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Clinically Significant Abnormalities in Vital Signs | 0 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Clinically Significant Abnormalities in Vital Signs | 0 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Clinically Significant Abnormalities in Vital Signs | 0 Participants |
Secondary
Phase 2: Number of Participants With Death and Reasons
An AE was defined as any unfavorable 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. PD defined as 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 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 mm. Number of participants with deaths due to progression disease (PD), AE related to study treatment, unknown reason was reported.
Time frame: Up to 328 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Death and Reasons | Death due to AE related to study treatment | 0 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Death and Reasons | Death due to disease progression | 21 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Death and Reasons | Death due to unknown reason | 2 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Death and Reasons | Death due to AE related to study treatment | 0 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Death and Reasons | Death due to disease progression | 15 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Death and Reasons | Death due to unknown reason | 5 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Death and Reasons | Death due to disease progression | 8 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Death and Reasons | Death due to unknown reason | 2 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Death and Reasons | Death due to AE related to study treatment | 0 Participants |
Secondary
Phase 2: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2
ECOG PS score is widely used by doctors and researchers to assess how a participants' disease is progressing, and is used to assess how the disease affects the daily living abilities of the participant, and determine appropriate treatment and prognosis. The score ranges from Grade 0 to Grade 5, where Grade 0 = Fully active, able to carry on all pre-disease performance without restriction, Grade 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade 2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair, Grade 5 = Death. Number of participants with ECOG performance status score of 2 or higher than 2 were reported.
Time frame: Up to 328 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2 | 6 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2 | 1 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2 | 1 Participants |
Secondary
Phase 2: Number of Participants With Greater Than or Equal to (>=) Grade 3 Treatment-Emergent Adverse Events (TEAEs) and >= Grade 3 Treatment-Related TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03
An adverse event (AE) was defined as any untoward medical occurrence in participant which does not necessarily have casual relationship with treatment was any unfavorable and unintended sign(including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal product, whether/not considered related to medicinal product. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. Treatment-related AE was defined as having a Possible or Related relationship to study treatment, as assessed by the Investigator. As per NCI-CTCAE, Grade 3 is Severe, Grade 4 is Life-threatening and Grade 5 or Death. Number of Participants With \>= Grade 3 TEAEs and \>= Grade 3 treatment-related TEAEs were reported.
Time frame: Up to 328 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Greater Than or Equal to (>=) Grade 3 Treatment-Emergent Adverse Events (TEAEs) and >= Grade 3 Treatment-Related TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any TEAE of >= Grade 3 | 20 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Greater Than or Equal to (>=) Grade 3 Treatment-Emergent Adverse Events (TEAEs) and >= Grade 3 Treatment-Related TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any Treatment-related TEAE of >= Grade 3 | 16 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Greater Than or Equal to (>=) Grade 3 Treatment-Emergent Adverse Events (TEAEs) and >= Grade 3 Treatment-Related TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any TEAE of >= Grade 3 | 14 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Greater Than or Equal to (>=) Grade 3 Treatment-Emergent Adverse Events (TEAEs) and >= Grade 3 Treatment-Related TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any Treatment-related TEAE of >= Grade 3 | 12 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Greater Than or Equal to (>=) Grade 3 Treatment-Emergent Adverse Events (TEAEs) and >= Grade 3 Treatment-Related TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any TEAE of >= Grade 3 | 7 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Greater Than or Equal to (>=) Grade 3 Treatment-Emergent Adverse Events (TEAEs) and >= Grade 3 Treatment-Related TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any Treatment-related TEAE of >= Grade 3 | 1 Participants |
Secondary
Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs)
The laboratory measurements included hematology and coagulation, biochemistry and urinalysis.
Time frame: Up to 328 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Anaemia | 0 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Neutropenia | 0 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Alanine aminotransferase increased | 1 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Amylase increased | 7 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Gamma-glutamyltransferase increased | 0 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Lipase increased | 5 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Neutrophil count decreased | 2 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | White blood cell count decreased | 1 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Hyponatremia | 1 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Hypokalemia | 0 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | hypophosphatemia | 0 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Hypoalbuminemia | 1 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Hypoalbuminemia | 0 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Anaemia | 7 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Neutrophil count decreased | 3 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Hyponatremia | 3 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Neutropenia | 1 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Lipase increased | 2 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | hypophosphatemia | 1 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Alanine aminotransferase increased | 0 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | White blood cell count decreased | 2 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Gamma-glutamyltransferase increased | 1 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Amylase increased | 2 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Hypokalemia | 2 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Amylase increased | 2 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Gamma-glutamyltransferase increased | 0 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Hypokalemia | 0 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Lipase increased | 1 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Neutrophil count decreased | 0 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | White blood cell count decreased | 0 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | hypophosphatemia | 0 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Anaemia | 0 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Neutropenia | 0 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Hyponatremia | 0 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Alanine aminotransferase increased | 0 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) | Hypoalbuminemia | 0 Participants |
Secondary
Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation
An adverse event (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. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. Number of participants with TEAEs leading to permanent treatment discontinuation were reported.
Time frame: Up to 328 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation | 3 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation | 1 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation | 2 Participants |
Secondary
Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Treatment-Related TEAEs and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03
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. TEAEs was defined as AEs that started or worsened in severity within the first dosing day of study treatment after the last dose of study treatment. TEAEs include both Serious TEAEs and non-serious TEAEs Treatment related AE was defined as having a Possible or Related relationship to study treatment, as assessed by the Investigator.
Time frame: Up to 328 weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Treatment-Related TEAEs and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any TEAE | 31 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Treatment-Related TEAEs and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any Treatment-Related TEAE | 30 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Treatment-Related TEAEs and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any Serious TEAE | 13 Participants |
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Treatment-Related TEAEs and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any Treatment-Related Serious TEAE | 6 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Treatment-Related TEAEs and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any Treatment-Related Serious TEAE | 7 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Treatment-Related TEAEs and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any TEAE | 23 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Treatment-Related TEAEs and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any Serious TEAE | 8 Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Treatment-Related TEAEs and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any Treatment-Related TEAE | 23 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Treatment-Related TEAEs and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any Treatment-Related Serious TEAE | 1 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Treatment-Related TEAEs and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any Treatment-Related TEAE | 11 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Treatment-Related TEAEs and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any Serious TEAE | 5 Participants |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Treatment-Related TEAEs and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 | Any TEAE | 13 Participants |
Secondary
Phase 2: (Randomized Part Only): Overall Survival (OS) Time
Overall survival time was measured as time in months between the date of randomization and the date of death.
Time frame: Up to 328 weeks
Population: The Intent-to-treat analysis set in the Phase 2 part of the study included all participants with treatment group who were randomized to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: (Randomized Part Only): Overall Survival (OS) Time | 17.25 Months |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: (Randomized Part Only): Overall Survival (OS) Time | 19.48 Months |
Secondary
Phase 2 (Randomized Part Only): Percentage of Participants With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria
Disease control defined as CR, PR, or stable disease(SD) as the best overall response according to local radiological assessments from the date of randomization/the first administration of the study treatment to the first observation of PD. CR: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 mm. PR:at least 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD: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 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 5mm. SD:as any cases that do not qualify for either PR/PD at minimum interval of 42 days after randomization/start of study treatment.
Time frame: Up to 328 weeks
Population: The Intent-to-treat analysis set in the Phase 2 part of the study included all participants with treatment group who were randomized to study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2 (Randomized Part Only): Percentage of Participants With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria | 83.9 Percentage of Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2 (Randomized Part Only): Percentage of Participants With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria | 70.8 Percentage of Participants |
Secondary
Phase 2 (Randomized Part Only): Percentage of Participants With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria
Objective response (OR) was defined as the percentage of participants who had achieved complete response (CR) or partial response (PR) as the best overall response according to local radiological assessments from randomization/the first administration of the study treatment to the first observation of disease progression (PD). 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 mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as 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 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 mm.
Time frame: Up to 328 weeks
Population: The Intent-to-treat analysis set in the Phase 2 part of the study included all participants with treatment group who were randomized to study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2 (Randomized Part Only): Percentage of Participants With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria | 45.2 Percentage of Participants |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2 (Randomized Part Only): Percentage of Participants With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria | 33.3 Percentage of Participants |
Secondary
Phase 2 (Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Independent Review Committee (IRC)
Progression-free survival (assessed by Independent Review Committee) time was defined as the time in months from randomization to either first observation of radiologically confirmed progression disease (PD) by the IRC 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 mm. PFS was measured using Kaplan-Meier (KM) estimates.
Time frame: Up to 328 weeks
Population: The Intent-to-treat analysis set in the Phase 2 part of the study included all participants with treatment group who were randomized to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2 (Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Independent Review Committee (IRC) | 10.15 Months |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2 (Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Independent Review Committee (IRC) | 4.34 Months |
Secondary
Phase 2: Time-to-Symptom Progression (TTSP)
TTSP was measured from randomization to symptomatic progression by lung cancer symptom scale (LCSS) used to measure symptom changes relevant to quality of life (QoL).It consisted of 9 items focused on cancer symptoms (loss of appetite, fatigue, cough, shortness of breath, blood in sputum, pain, symptoms of cancer, illness affecting normal activity, QoL).For each symptom score distance from left boundary to point where participant has marked line was measured in millimeters (mm).Total scale length was 100 mm. Symptomatic progression was defined as increase/worsening of average symptomatic burden index (ASBI) (mean of 6 major lung cancer specific symptom scores);Worsening defined as 10% increase of scale breadth from baseline. Score 0 indicate no/minimum symptoms;100 indicates maximum level of symptoms.
Time frame: Up to 328 weeks
Population: Quality of life (Qol) evaluable population set included ITT participants in the treatment group in which they actually received the treatment with a baseline and at least 1 evaluable on-treatment QoL questionnaire.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg | Phase 2: Time-to-Symptom Progression (TTSP) | 5.75 Months |
| Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg | Phase 2: Time-to-Symptom Progression (TTSP) | 7.95 Months |
| Phase 2: Single-arm Cohort (MET+ T790M Positive) | Phase 2: Time-to-Symptom Progression (TTSP) | 2.63 Months |