Tepotinib With Gefitinib in Participants With Locally Advanced or Metastatic NSCLC (INSIGHT)

• Sponsor: Merck KGaA, Darmstadt, Germany (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01982955
• Collaborator: (none)
• Enrollment: 88
• Locations: 44
• Arms: 5
• Actual Duration (Months): 93.7
• Patients Per Site: 2
• Patients Per Site Per Month: 0

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Non-small Cell Lung Cancer	Drug: Tepotinib; Drug: Gefitinib; Drug: Pemetrexed; Drug: Cisplatin; Drug: Carboplatin	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 88 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase Ib/II Multicenter, Randomized, Open Label Trial to Compare Tepotinib (MSC2156119J) Combined With Gefitinib Versus Chemotherapy as Second-Line Treatment in Subjects With MET Positive, Locally Advanced or Metastatic NSCLC Harboring EGFR Mutation and Having Acquired Resistance to Prior EGFR-TKI Therapy (INSIGHT)
• Actual Study Start Date: Dec 23, 2013
• Actual Primary Completion Date: Dec 12, 2017
• Actual Study Completion Date: Oct 14, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1b: Tepotinib 300 milligram (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.	Drug: Tepotinib; 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.; Drug: Gefitinib; 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.
Experimental: Phase 1b: Tepotinib 500 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.	Drug: Tepotinib; 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.; Drug: Gefitinib; 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.
Experimental: Phase 2: Tepotinib and Gefitinib 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.	Drug: Tepotinib; 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.; Drug: Gefitinib; 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.
Experimental: Phase 2: Pemetrexed and Cisplatin/Carboplatin Participants randomized to receive 500 milligram per square meter (mg/m^2) of Pemetrexed as intravenous infusion over 10 minutes in combination with Cisplatin (75 mg/m2 as an intravenous infusion over 2 hours) or Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Premetrexed maintenance monotherapy.	Drug: Pemetrexed; 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.; Drug: Cisplatin; 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.; Drug: Carboplatin; 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.
Experimental: 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.	Drug: Tepotinib; 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.; Drug: Gefitinib; 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.

Outcome Measures

Primary Outcome Measures

1. 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.

2. Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs [Up to 259 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.

3. Phase 2 (Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by the Investigator [Up to 187 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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).

9. 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).

10. 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.

11. 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.

12. 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.

13. 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 259 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.

14. 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 259 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

15. 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 259 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.

16. 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 259 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.

17. Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation [Up to 259 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.

18. Phase 1b: Number of Participants With Death and Reasons [Up to 259 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.

19. 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 259 weeks]

    The laboratory measurements included hematology and coagulation, biochemistry and urinalysis.

20. Phase 1b: Number of Participants With Clinically Significant Abnormalities in Vital Signs [Up to 259 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.

21. Phase 1b: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings [Up to 259 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.

22. Phase 1b: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2 [Up to 259 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.

23. 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 187 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.

24. 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 187 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.

25. Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation [Up to 187 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.

26. Phase 2: Number of Participants With Death and Reasons [Up to 187 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.

27. 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 187 weeks]

    The laboratory measurements included hematology and coagulation, biochemistry and urinalysis.

28. Phase 2: Number of Participants With Clinically Significant Abnormalities in Vital Signs [Up to 187 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.

29. Phase 2: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings [Up to 187 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.

30. Phase 2: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2 [Up to 187 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.

31. Phase 2 (Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Independent Review Committee (IRC) [Up to 187 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.

32. Phase 2: (Randomized Part Only): Overall Survival (OS) Time [Up to 187 weeks]

    Overall survival time was measured as time in months between the date of randomization and the date of death.

33. 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 187 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.

34. 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 187 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.

35. Phase 2 (Non-Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Investigator [Up to 117 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.

36. Phase 2 (Non-Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Independent Review Committee (IRC) [Up to 117 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.

37. Phase 2: (Non-Randomized Part Only): Overall Survival (OS) Time [Up to 117 weeks]

    Overall survival time was measured as time in months between the date of randomization and the date of death.

38. 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 117 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.

39. 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 117 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.

40. 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.

41. Phase 2: Time-to-Symptom Progression (TTSP) [Up to 110 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 exclusion criteria could apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beijing Cancer Hospital	Beijing		China
2	Beijing Chest Hospital	Beijing		China
3	Peking Union Medical College Hospital	Beijing		China
4	Jilin Cancer Hospital	Changchun		China
5	Jilin University	Changchun		China
6	Fuzhou General Hospital	Fuzhou		China
7	Guangdong Provincial People's Hospital	Guangzhou		China
8	Sir Run Run Shaw Hospital Cardiology	Hangzhou		China
9	The First Affiliated Hospital of College of Medicine	Hangzhou		China
10	Shanghai Chest Hospital	Shanghai		China
11	Tongji Hospital	Wuhan		China
12	Fourth Military Medical University	Xi'an		China
13	Zhejiang Cancer Hospital	Zhejiang		China
14	Azienda Ospedaliero Universitaria Mater Domini-Campus Universitario	Catanzaro		Italy
15	IEO Istituto Europeo di Oncologia	Milano		Italy
16	Chungbuk National University Hospital	Cheongju-si		Korea, Republic of
17	Kyungpook National University Hospital	Daegu		Korea, Republic of
18	Chonnam National University Hwasun Hospital	Hwasun		Korea, Republic of
19	CHA Bundang Medical Center, CHA University	Seongnam-si		Korea, Republic of
20	Seoul National University Bundang Hospital	Seongnam-si		Korea, Republic of
21	Severance Hospital Yonsei University Health System	Seongnam-si		Korea, Republic of
22	Asan medical Centre	Seoul		Korea, Republic of
23	Gangnam Severance Hospital Yonsei University	Seoul		Korea, Republic of
24	Korea University Anam Hospital	Seoul		Korea, Republic of
25	Samsung Medical Center	Seoul		Korea, Republic of
26	Seoul National Universtiy Hospital	Seoul		Korea, Republic of
27	The Catholic University of Korea St Mary s Hospital	Seoul		Korea, Republic of
28	The Catholic University of Korea St. Vincent's Hospital	Suwon		Korea, Republic of
29	University Malaya Medical Centre	Kuala Lumpur		Malaysia
30	Beacon International Specialist Centre Sdn Bhd	Petaling Jaya		Malaysia
31	National Cancer Center	Singapore		Singapore
32	National University Hospital	Singapore		Singapore
33	Raffles Hospital	Singapore		Singapore
34	Hospital Universitari Vall d'Hebron	Barcelona		Spain
35	Hospital General Universitario Gregorio Marañon	Madrid		Spain
36	Hospital Clinico Universitario	Valencia		Spain
37	Hospital Alvaro Cunqueiro	Vigo		Spain
38	Chang Gung Memorial Hospital-Kaohsiung	Kaohsiung		Taiwan
39	China Medical University Hospital	Taichung		Taiwan
40	Taichung Veterans General Hospital	Taichung		Taiwan
41	National Taiwan University Hospital	Taipei		Taiwan
42	Taipei Veterans General Hospital	Taipei		Taiwan
43	Tri-Service General Hospital	Taipei		Taiwan
44	Chang Gung Memorial Hospital Linkou	Taoyuan		Taiwan

Sponsors and Collaborators

• Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Medical Responsible, Merck KGaA, Darmstadt, Germany

Study Documents (Full-Text)

• Study Protocol - Nov 27, 2017
• Statistical Analysis Plan - Jul 10, 2017

More Information

Additional Information:

• Trial Awareness and Transparency website
• Redacted Clinical study report, redacted clinical study protocol and redacted statistical analysis plan for this study is also available at the HC-PRCI portal (Health Canada-Public release of clinical information)

Publications

None provided.

• Responsible Party: Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT01982955
• Other Study ID Numbers: EMR 200095-006; 2016-001604-28
• First Posted: Nov 13, 2013
• Last Update Posted: Aug 24, 2022
• Last Verified: Aug 1, 2022

• Keywords provided by Merck KGaA, Darmstadt, Germany: MSC2156119J; Gefitinib; Pemetrexed; Cisplatin; MET positive; Tepotinib; Carboplatin; INSIGHT
• Additional relevant MeSH terms: Carcinoma, Non-Small-Cell Lung; Carboplatin; Pemetrexed; Gefitinib; Tepotinib

Study Results

Participant Flow

Recruitment Details	First participant enrolled on 23 Dec 2013. Clinical data cut-off:12 Dec 2018.
Pre-assignment Detail	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.

Arm/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)	Phase 2: Tepotinib and Gefitinib	Phase 2: Pemetrexed and Cisplatin/Carboplatin	Phase 2: Single-arm Cohort (MET+ T790M Positive)
Arm/Group Description	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.	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.	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.	Participants randomized to receive 500 milligram per square meter (mg/m^2) of Pemetrexed as intravenous infusion over 10 minutes in combination with Cisplatin (75 mg/m2 as an intravenous infusion over 2 hours) or Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Premetrexed maintenance monotherapy.	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.
Period Title: Overall Study
STARTED	6	12	31	24	15
Treated	6	12	31	23	15
COMPLETED	6	12	27	23	15
NOT COMPLETED	0	0	4	1	0

Baseline Characteristics

Arm/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)	Phase 2: Tepotinib and Gefitinib	Phase 2: Pemetrexed and Cisplatin/Carboplatin	Phase 2: Single-arm Cohort (MET+ T790M Positive)	Total
Arm/Group Description	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.	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.	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.	Participants randomized to receive 500 milligram per square meter (mg/m^2) of Pemetrexed as intravenous infusion over 10 minutes in combination with Cisplatin (75 mg/m2 as an intravenous infusion over 2 hours) or Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Premetrexed maintenance monotherapy.	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.	Total of all reporting groups
Overall Participants	6	12	31	24	15	88
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	3 50%	6 50%	21 67.7%	17 70.8%	9 60%	56 63.6%
>=65 years	3 50%	6 50%	10 32.3%	7 29.2%	6 40%	32 36.4%
Sex: Female, Male (Count of Participants)
Female	3 50%	7 58.3%	20 64.5%	12 50%	10 66.7%	52 59.1%
Male	3 50%	5 41.7%	11 35.5%	12 50%	5 33.3%	36 40.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	6 100%	12 100%	31 100%	24 100%	15 100%	88 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Phase 1b: Number of Participants Experiencing at Least One Dose Limiting Toxicity (DLT)
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	3	12
Count of Participants [Participants]	0 0%	0 0%

2. Primary Outcome

Title	Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs
Description	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 259 Weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	12
Any TEAEs	6 100%	12 100%
Any Serious TEAEs	4 66.7%	7 58.3%

3. Primary Outcome

Title	Phase 2 (Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by the Investigator
Description	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 187 weeks

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 2: Tepotinib and Gefitinib	Phase 2: Pemetrexed and Cisplatin/Carboplatin
Arm/Group Description	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.	Participants randomized to receive 500 milligram per square meter (mg/m^2) of Pemetrexed as intravenous infusion over 10 minutes in combination with Cisplatin (75 mg/m2 as an intravenous infusion over 2 hours) or Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Premetrexed maintenance monotherapy.
Measure Participants	31	24
Median (90% Confidence Interval) [Months]	4.86	4.37

4. Secondary Outcome

Title	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
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	12
Tepotinib: Day 1 of Cycle 1	6280 (25.4)	9210 (48.4)
Tepotinib: Day 15 of Cycle 1	15600 (19.6)	22200 (43.3)
MSC2571109A: Day 1 of Cycle 1	1680 (11.8)	1770 (56.7)
MSC2571109A Day15 of Cycle 1	4420 (25.7)	7530 (52.6)
MSC2571107A Day 1 of Cycle 1	248 (49.3)	324 (57.3)
MSC2571107A Day 15 of Cycle 1	872 (38.5)	1880 (76.0)
Gefitinib: Day 1 of Cycle 1	NA (NA)	2930 (45.8)
Gefitinib: Day 15 of Cycle 1	7690 (44.1)	7080 (29.0)

5. Secondary Outcome

Title	Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	12
Tepotinib: Day 1 of Cycle 1	6280 (25.4)	9210 (48.4)
Tepotinib: Day 15 of Cycle 1	15600 (19.6)	22200 (43.3)
MSC2571109A: Day 1 of Cycle 1	1680 (11.8)	1770 (56.7)
MSC2571109A: Day 15 of Cycle 1	4420 (25.7)	7530 (52.6)
MSC2571107A: Day 1 of Cycle 1	248 (49.3)	324 (57.3)
MSC2571107A: Day 15 of Cycle 1	872 (38.5)	1880 (76.0)
Gefitinib: Day 1 of Cycle 1	NA (NA)	2930 (45.8)
Gefitinib: Day 15 of Cycle 1	7690 (44.1)	7080 (29.0)

6. Secondary Outcome

Title	Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	12
Tepotinib: Day 1 of Cycle 1	375 (30.4)	575 (62.6)
Tepotinib: Day 15 of Cycle 1	763 (22.0)	1050 (44.1)
MSC2571109A: Day 1 of Cycle 1	132 (14.7)	149 (56.5)
MSC2571109A: Day 15 of Cycle 1	280 (32.0)	444 (45.8)
MSC2571107A: Day 1 of Cycle 1	16.8 (56.5)	24.3 (62.5)
MSC2571107A: Day 15 of Cycle 1	44.9 (40.5)	94.9 (70.8)
Gefitinib: Day 1 of Cycle 1	NA (NA)	215 (48.7)
Gefitinib: Day 15 of Cycle 1	432 (38.3)	366 (32.6)

7. Secondary Outcome

Title	Phase 1b: Average Observed Plasma Concentration (Cavg) of Tepotinib, Its Metabolites and Gefitinib
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	9
Tepotinib	654 (19.4)	924 (43.3)
MSC2571109A	185 (25.4)	314 (52.6)
MSC2571107A	36.4 (38.2)	78.3 (76.0)
Gefitinib	321 (43.9)	295 (29.0)

8. Secondary Outcome

Title	Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib, Its Metabolites and Gefitinib
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	9
Tepotinib	534 (18.8)	735 (47.6)
MSC2571109A	156 (28.8)	270 (58.5)
MSC2571107A	32.8 (40.1)	68.7 (80.1)
Geftinib	231 (57.3)	190 (43.5)

9. Secondary Outcome

Title	Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, Its Metabolites and Gefitinib
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	12
Tepotinib: Day 1 of Cycle 1	8.00	9.01
Tepotinib: Day 15 of Cycle 1	6.00	9.00
MSC2571109A: Day 1 of Cycle 1	24.00	24.00
MSC2571109A: Day 15 of Cycle 1	0.00	0.00
MSC2571107A: Day 1 of Cycle 1	24.00	24.00
MSC2571107A: Day 15 of Cycle 1	0.13	0.25
Gefitinib: Day 1 of Cycle 1	NA	8.00
Gefitinib: Day 15 of Cycle 1	4.00	8.00

10. Secondary Outcome

Title	Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, Its Metabolites and Gefitinib
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	12
Tepotinib: Day 1 of Cycle 1	NA (NA)	NA (NA)
Tepotinib: Day 15 of Cycle 1	NA (NA)	NA (NA)
MSC2571109A: Day 1 of Cycle 1	NA (NA)	NA (NA)
MSC2571109A: Day 15 of Cycle 1	NA (NA)	NA (NA)
MSC2571107A: Day 1 of Cycle 1	NA (NA)	NA (NA)
MSC2571107A: Day 15 of Cycle 1	NA (NA)	NA (NA)
Gefitinib: Day 1 of Cycle 1	NA (NA)	NA (NA)
Gefitinib: Day 15 of Cycle 1	NA (NA)	NA (NA)

11. Secondary Outcome

Title	Phase 1b: Apparent Total Body Clearance From Plasma (CL/F) of Tepotinib and Gefitinib
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	9
Tepotinib	17.3 (19.6)	20.3 (43.3)
Gefitinib	32.5 (44.1)	35.3 (29.0)

12. Secondary Outcome

Title	Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, Its Metabolites and Gefitinib
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	12
Tepotinib: Day 1 of Cycle 1	NA (NA)	NA (NA)
Tepotinib: Day 15 of Cycle 1	NA (NA)	NA (NA)
MSC2571109A: Day 1 of Cycle 1	NA (NA)	NA (NA)
MSC2571109A: Day 15 of Cycle 1	NA (NA)	NA (NA)
MSC2571107A: Day 1 of Cycle 1	NA (NA)	NA (NA)
MSC2571107A: Day 15 of Cycle 1	NA (NA)	NA (NA)
Gefitinib: Day 1 of Cycle 1	NA (NA)	NA (NA)
Gefitinib: Day 15 of Cycle 1	NA (NA)	NA (NA)

13. Secondary Outcome

Title	Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, Its Metabolites and Gefitinib
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	12
Tepotinib: Day 1 of Cycle 1	NA (NA)	NA (NA)
Tepotinib: Day 15 of Cycle 1	NA (NA)	NA (NA)
MSC2571109A: Day 1 of Cycle 1	NA (NA)	NA (NA)
MSC2571109A: Day 15 of cycle 1	NA (NA)	NA (NA)
MSC2571107A: Day 1 of Cycle 1	NA (NA)	NA (NA)
MSC2571107A: Day 15 of Cycle 1	NA (NA)	NA (NA)
Gefitinib: Day 1 of Cycle 1	NA (NA)	NA (NA)
Gefitinib: Day 15 of Cycle 1	NA (NA)	NA (NA)

14. Secondary Outcome

Title	Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, Its Metabolites and Gefitinib
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	12
Tepotinib: Day 1 of Cycle 1	NA (NA)	NA (NA)
Tepotinib: Day 15 of Cycle 1	NA (NA)	NA (NA)
MSC2571109A: Day 1 of Cycle 1	NA (NA)	NA (NA)
MSC2571109A: Day 15 of Cycle 1	NA (NA)	NA (NA)
MSC2571107A: Day 1 of Cycle 1	NA (NA)	NA (NA)
MSC2571107A: Day 15 of Cycle 1	NA (NA)	NA (NA)
Gefitinib: Day 1 of Cycle 1	NA (NA)	NA (NA)
Gefitinib: Day 15 of Cycle 1	NA (NA)	NA (NA)

15. Secondary Outcome

Title	Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, Its Metabolites and Gefitinib
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	12
Tepotinib: Day 1 of Cycle 1	NA	NA
Tepotinib: Day 15 of Cycle 1	NA	NA
MSC2571109A: Day 1 of Cycle 1	NA	NA
MSC2571109A: Day 15 of Cycle 1	NA	NA
MSC2571107A: Day 1 of Cycle 1	NA	NA
MSC2571107A: Day 15 of Cycle 1	NA	NA
Gefitinib: Day 1 of Cycle 1	NA	NA
Gefitinib: Day 15 of Cycle 1	NA	NA

16. Secondary Outcome

Title	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
Description	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 259 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	12
Number (90% Confidence Interval) [Percentage of Participants]	33.3 555%	33.3 277.5%

17. Secondary Outcome

Title	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
Description	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 259 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	12
Number (90% Confidence Interval) [Percentage of Participants]	50.0 833.3%	58.3 485.8%

18. Secondary Outcome

Title	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
Description	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 259 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	12
Any TEAE Related to Tepotinib	6 100%	9 75%
Any TEAE Related to Gefitinib	5 83.3%	11 91.7%
Any Serious TEAE Related to Tepotinib	0 0%	0 0%
Any Serious TEAE Related to Gefitinib	0 0%	0 0%

19. Secondary Outcome

Title	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
Description	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 259 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	12
Any Grade 3/4 TEAE	5 83.3%	9 75%
Any Grade 3/4 TEAE Related to Tepotinib	2 33.3%	4 33.3%
Any Grade 3/4 TEAE Related to Gefitinib	0 0%	0 0%

20. Secondary Outcome

Title	Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation
Description	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 259 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	12
TEAE Leading Permanent Tepotinib Discontinuation	0 0%	2 16.7%
TEAE Leading Permanent Gefitinib Discontinuation	0 0%	1 8.3%

21. Secondary Outcome

Title	Phase 1b: Number of Participants With Death and Reasons
Description	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 259 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	12
Death due to PD	0 0%	3 25%
Death due to AE related to study treatment	0 0%	0 0%
Death due to AE not related to study treatment	1 16.7%	0 0%

22. Secondary Outcome

Title	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)
Description	The laboratory measurements included hematology and coagulation, biochemistry and urinalysis.
Time Frame	Up to 259 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	12
Amylase increased	2 33.3%	2 16.7%
Lipase increased	1 16.7%	2 16.7%
Neutrophil count decreased	0 0%	1 8.3%

23. Secondary Outcome

Title	Phase 1b: Number of Participants With Clinically Significant Abnormalities in Vital Signs
Description	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 259 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	12
Count of Participants [Participants]	0 0%	0 0%

24. Secondary Outcome

Title	Phase 1b: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings
Description	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 259 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	12
Count of Participants [Participants]	0 0%	0 0%

25. Secondary Outcome

Title	Phase 1b: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2
Description	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 259 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 1b: Tepotinib (300 mg)	Phase 1b: Tepotinib (500 mg)
Arm/Group Description	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.	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.
Measure Participants	6	12
Count of Participants [Participants]	1 16.7%	9 75%

26. Secondary Outcome

Title	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
Description	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 187 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 2: Tepotinib and Gefitinib	Phase 2: Pemetrexed and Cisplatin/Carboplatin	Phase 2: Single-arm Cohort (MET+ T790M Positive)
Arm/Group Description	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.	Participants randomized to receive 500 milligram per square meter (mg/m^2) of Pemetrexed as intravenous infusion over 10 minutes in combination with Cisplatin (75 mg/m2 as an intravenous infusion over 2 hours) or Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Premetrexed maintenance monotherapy.	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.
Measure Participants	31	23	15
Any TEAE	31 516.7%	23 191.7%	13 41.9%
Any Treatment-Related TEAE	30 500%	23 191.7%	11 35.5%
Any Serious TEAE	13 216.7%	8 66.7%	5 16.1%
Any Treatment-Related Serious TEAE	6 100%	7 58.3%	1 3.2%

27. Secondary Outcome

Title	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
Description	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 187 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 2: Tepotinib and Gefitinib	Phase 2: Pemetrexed and Cisplatin/Carboplatin	Phase 2: Single-arm Cohort (MET+ T790M Positive)
Arm/Group Description	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.	Participants randomized to receive 500 milligram per square meter (mg/m^2) of Pemetrexed as intravenous infusion over 10 minutes in combination with Cisplatin (75 mg/m2 as an intravenous infusion over 2 hours) or Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Premetrexed maintenance monotherapy.	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.
Measure Participants	31	23	15
Any TEAE of >= Grade 3	20 333.3%	14 116.7%	7 22.6%
Any Treatment-related TEAE of >= Grade 3	16 266.7%	12 100%	1 3.2%

28. Secondary Outcome

Title	Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation
Description	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 187 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 2: Tepotinib and Gefitinib	Phase 2: Pemetrexed and Cisplatin/Carboplatin	Phase 2: Single-arm Cohort (MET+ T790M Positive)
Arm/Group Description	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.	Participants randomized to receive 500 milligram per square meter (mg/m^2) of Pemetrexed as intravenous infusion over 10 minutes in combination with Cisplatin (75 mg/m2 as an intravenous infusion over 2 hours) or Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Premetrexed maintenance monotherapy.	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.
Measure Participants	31	23	15
Count of Participants [Participants]	3 50%	1 8.3%	2 6.5%

29. Secondary Outcome

Title	Phase 2: Number of Participants With Death and Reasons
Description	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 187 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 2: Tepotinib and Gefitinib	Phase 2: Pemetrexed and Cisplatin/Carboplatin	Phase 2: Single-arm Cohort (MET+ T790M Positive)
Arm/Group Description	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.	Participants randomized to receive 500 milligram per square meter (mg/m^2) of Pemetrexed as intravenous infusion over 10 minutes in combination with Cisplatin (75 mg/m2 as an intravenous infusion over 2 hours) or Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Premetrexed maintenance monotherapy.	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.
Measure Participants	31	23	15
Death due to PD	15 250%	11 91.7%	6 19.4%
Death due to AE related to study treatment	0 0%	0 0%	0 0%
Death due to AE not related to study treatment	1 16.7%	5 41.7%	2 6.5%

30. Secondary Outcome

Title	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)
Description	The laboratory measurements included hematology and coagulation, biochemistry and urinalysis.
Time Frame	Up to 187 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 2: Tepotinib and Gefitinib	Phase 2: Pemetrexed and Cisplatin/Carboplatin	Phase 2: Single-arm Cohort (MET+ T790M Positive)
Arm/Group Description	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.	Participants randomized to receive 500 milligram per square meter (mg/m^2) of Pemetrexed as intravenous infusion over 10 minutes in combination with Cisplatin (75 mg/m2 as an intravenous infusion over 2 hours) or Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Premetrexed maintenance monotherapy.	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.
Measure Participants	31	23	15
Anaemia	0 0%	7 58.3%	0 0%
Neutropenia	0 0%	1 8.3%	0 0%
Alanine aminotransferase increased	1 16.7%	0 0%	0 0%
Amylase increased	5 83.3%	1 8.3%	0 0%
Gamma-glutamyltransferase increased	0 0%	1 8.3%	0 0%
Lipase increased	4 66.7%	2 16.7%	1 3.2%
Neutrophil count decreased	0 0%	3 25%	0 0%
White blood cell count decreased	0 0%	2 16.7%	0 0%
Hyponatremia	1 16.7%	1 8.3%	0 0%
Hypokalemia	0 0%	2 16.7%	0 0%
hypophosphatemia	0 0%	1 8.3%	0 0%

31. Secondary Outcome

Title	Phase 2: Number of Participants With Clinically Significant Abnormalities in Vital Signs
Description	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 187 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 2: Tepotinib and Gefitinib	Phase 2: Pemetrexed and Cisplatin/Carboplatin	Phase 2: Single-arm Cohort (MET+ T790M Positive)
Arm/Group Description	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.	Participants randomized to receive 500 milligram per square meter (mg/m^2) of Pemetrexed as intravenous infusion over 10 minutes in combination with Cisplatin (75 mg/m2 as an intravenous infusion over 2 hours) or Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Premetrexed maintenance monotherapy.	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.
Measure Participants	31	23	15
Count of Participants [Participants]	0 0%	0 0%	0 0%

32. Secondary Outcome

Title	Phase 2: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings
Description	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 187 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 2: Tepotinib and Gefitinib	Phase 2: Pemetrexed and Cisplatin/Carboplatin	Phase 2: Single-arm Cohort (MET+ T790M Positive)
Arm/Group Description	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.	Participants randomized to receive 500 milligram per square meter (mg/m^2) of Pemetrexed as intravenous infusion over 10 minutes in combination with Cisplatin (75 mg/m2 as an intravenous infusion over 2 hours) or Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Premetrexed maintenance monotherapy.	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.
Measure Participants	31	23	15
Count of Participants [Participants]	2 33.3%	1 8.3%	0 0%

33. Secondary Outcome

Title	Phase 2: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2
Description	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 187 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 2: Tepotinib and Gefitinib	Phase 2: Pemetrexed and Cisplatin/Carboplatin	Phase 2: Single-arm Cohort (MET+ T790M Positive)
Arm/Group Description	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.	Participants randomized to receive 500 milligram per square meter (mg/m^2) of Pemetrexed as intravenous infusion over 10 minutes in combination with Cisplatin (75 mg/m2 as an intravenous infusion over 2 hours) or Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Premetrexed maintenance monotherapy.	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.
Measure Participants	31	23	15
Count of Participants [Participants]	6 100%	1 8.3%	1 3.2%

34. Secondary Outcome

Title	Phase 2 (Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Independent Review Committee (IRC)
Description	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 187 weeks

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 2: Tepotinib and Gefitinib	Phase 2: Pemetrexed and Cisplatin/Carboplatin
Arm/Group Description	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.	Participants randomized to receive 500 milligram per square meter (mg/m^2) of Pemetrexed as intravenous infusion over 10 minutes in combination with Cisplatin (75 mg/m2 as an intravenous infusion over 2 hours) or Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Premetrexed maintenance monotherapy.
Measure Participants	31	24
Median (90% Confidence Interval) [Months]	10.15	4.37

35. Secondary Outcome

Title	Phase 2: (Randomized Part Only): Overall Survival (OS) Time
Description	Overall survival time was measured as time in months between the date of randomization and the date of death.
Time Frame	Up to 187 weeks

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 2: Tepotinib and Gefitinib	Phase 2: Pemetrexed and Cisplatin/Carboplatin
Arm/Group Description	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.	Participants randomized to receive 500 milligram per square meter (mg/m^2) of Pemetrexed as intravenous infusion over 10 minutes in combination with Cisplatin (75 mg/m2 as an intravenous infusion over 2 hours) or Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Premetrexed maintenance monotherapy.
Measure Participants	31	24
Median (90% Confidence Interval) [Months]	17.25	18.69

36. Secondary Outcome

Title	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
Description	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 187 weeks

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 2: Tepotinib and Gefitinib	Phase 2: Pemetrexed and Cisplatin/Carboplatin
Arm/Group Description	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.	Participants randomized to receive 500 milligram per square meter (mg/m^2) of Pemetrexed as intravenous infusion over 10 minutes in combination with Cisplatin (75 mg/m2 as an intravenous infusion over 2 hours) or Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Premetrexed maintenance monotherapy.
Measure Participants	31	24
Number (90% Confidence Interval) [Percentage of Participants]	45.2 753.3%	33.3 277.5%

37. Secondary Outcome

Title	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
Description	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 187 weeks

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 2: Tepotinib and Gefitinib	Phase 2: Pemetrexed and Cisplatin/Carboplatin
Arm/Group Description	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.	Participants randomized to receive 500 milligram per square meter (mg/m^2) of Pemetrexed as intravenous infusion over 10 minutes in combination with Cisplatin (75 mg/m2 as an intravenous infusion over 2 hours) or Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Premetrexed maintenance monotherapy.
Measure Participants	31	24
Number (90% Confidence Interval) [Percentage of Participants]	83.9 1398.3%	70.8 590%

38. Secondary Outcome

Title	Phase 2 (Non-Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Investigator
Description	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 117 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 2: Single-arm Cohort (MET+ T790M Positive)
Arm/Group Description	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.
Measure Participants	15
Median (90% Confidence Interval) [Months]	1.41

39. Secondary Outcome

Title	Phase 2 (Non-Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Independent Review Committee (IRC)
Description	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 117 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 2: Single-arm Cohort (MET+ T790M Positive)
Arm/Group Description	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.
Measure Participants	15
Median (90% Confidence Interval) [Months]	2.63

40. Secondary Outcome

Title	Phase 2: (Non-Randomized Part Only): Overall Survival (OS) Time
Description	Overall survival time was measured as time in months between the date of randomization and the date of death.
Time Frame	Up to 117 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 2: Single-arm Cohort (MET+ T790M Positive)
Arm/Group Description	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.
Measure Participants	15
Median (90% Confidence Interval) [Months]	25.86

41. Secondary Outcome

Title	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
Description	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 117 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 2: Single-arm Cohort (MET+ T790M Positive)
Arm/Group Description	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.
Measure Participants	15
Number (90% Confidence Interval) [Percentage of Participants]	0 0%

42. Secondary Outcome

Title	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
Description	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 117 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received any dose of the study medication.

Arm/Group Title	Phase 2: Single-arm Cohort (MET+ T790M Positive)
Arm/Group Description	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.
Measure Participants	15
Number (90% Confidence Interval) [Percentage of Participants]	40 666.7%

43. Secondary Outcome

Title	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)
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 2: Tepotinib and Gefitinib	Phase 2: Pemetrexed and Cisplatin/Carboplatin	Phase 2: Single-arm Cohort (MET+ T790M Positive)
Arm/Group Description	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.	Participants randomized to receive 500 milligram per square meter (mg/m^2) of Pemetrexed as intravenous infusion over 10 minutes in combination with Cisplatin (75 mg/m2 as an intravenous infusion over 2 hours) or Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Premetrexed maintenance monotherapy.	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.
Measure Participants	22	21	10
Mean (Standard Deviation) [Units on a Scale]	-16.29 (30.691)	-2.78 (22.869)	-24.19 (24.673)

44. Secondary Outcome

Title	Phase 2: Time-to-Symptom Progression (TTSP)
Description	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 110 weeks

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 2: Tepotinib and Gefitinib	Phase 2: Pemetrexed and Cisplatin/Carboplatin	Phase 2: Single-arm Cohort (MET+ T790M Positive)
Arm/Group Description	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.	Participants randomized to receive 500 milligram per square meter (mg/m^2) of Pemetrexed as intravenous infusion over 10 minutes in combination with Cisplatin (75 mg/m2 as an intravenous infusion over 2 hours) or Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Premetrexed maintenance monotherapy.	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.
Measure Participants	29	22	15
Median (90% Confidence Interval) [Months]	5.75	7.95	2.63

Adverse Events

Time Frame	Phase 1b: Up to 259 weeks Phase 2: Up to 187 weeks
Adverse Event Reporting Description	The safety analysis set included all participants who had received any dose of the study medication.
Arm/Group Title	Phase 1b: Tepotinib (300 mg)		Phase 1b: Tepotinib (500 mg)		Phase 2: Tepotinib and Gefitinib		Phase 2: Pemetrexed and Cisplatin/Carboplatin		Phase 2: Single-arm Cohort (MET+ T790M Positive)
Arm/Group Description	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.		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.		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.		Participants randomized to receive 500 milligram per square meter (mg/m^2) of Pemetrexed as intravenous infusion over 10 minutes in combination with Cisplatin (75 mg/m2 as an intravenous infusion over 2 hours) or Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Premetrexed maintenance monotherapy.		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.
All Cause Mortality
	Phase 1b: Tepotinib (300 mg)		Phase 1b: Tepotinib (500 mg)		Phase 2: Tepotinib and Gefitinib		Phase 2: Pemetrexed and Cisplatin/Carboplatin		Phase 2: Single-arm Cohort (MET+ T790M Positive)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/6 (16.7%)		3/12 (25%)		16/31 (51.6%)		16/23 (69.6%)		8/15 (53.3%)
Serious Adverse Events
	Phase 1b: Tepotinib (300 mg)		Phase 1b: Tepotinib (500 mg)		Phase 2: Tepotinib and Gefitinib		Phase 2: Pemetrexed and Cisplatin/Carboplatin		Phase 2: Single-arm Cohort (MET+ T790M Positive)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/6 (66.7%)		7/12 (58.3%)		13/31 (41.9%)		8/23 (34.8%)		5/15 (33.3%)
Blood and lymphatic system disorders
Anaemia	0/6 (0%)		0/12 (0%)		0/31 (0%)		2/23 (8.7%)		0/15 (0%)
Cardiac disorders
Arrhythmia supraventricular	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Gastrointestinal disorders
Abdominal distension	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Abdominal pain	0/6 (0%)		1/12 (8.3%)		1/31 (3.2%)		0/23 (0%)		0/15 (0%)
Constipation	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Vomiting	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		1/23 (4.3%)		0/15 (0%)
Ascites	0/6 (0%)		0/12 (0%)		1/31 (3.2%)		0/23 (0%)		0/15 (0%)
Nausea	0/6 (0%)		0/12 (0%)		0/31 (0%)		1/23 (4.3%)		0/15 (0%)
General disorders
Chest discomfort	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		1/23 (4.3%)		0/15 (0%)
Disease progression	0/6 (0%)		1/12 (8.3%)		1/31 (3.2%)		1/23 (4.3%)		1/15 (6.7%)
Fatigue	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Non-cardiac chest pain	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Chest Pain	0/6 (0%)		0/12 (0%)		1/31 (3.2%)		0/23 (0%)		0/15 (0%)
Face Oedema	0/6 (0%)		0/12 (0%)		0/31 (0%)		1/23 (4.3%)		0/15 (0%)
Malaise	0/6 (0%)		0/12 (0%)		0/31 (0%)		1/23 (4.3%)		0/15 (0%)
Oedema peripheral	0/6 (0%)		0/12 (0%)		2/31 (6.5%)		0/23 (0%)		0/15 (0%)
Infections and infestations
Cellulitis	1/6 (16.7%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Pneumonia	1/6 (16.7%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Atypical pneumonia	0/6 (0%)		0/12 (0%)		1/31 (3.2%)		0/23 (0%)		0/15 (0%)
Herpes virus infection	0/6 (0%)		0/12 (0%)		0/31 (0%)		1/23 (4.3%)		0/15 (0%)
Lower respiratory tract infection	0/6 (0%)		0/12 (0%)		0/31 (0%)		1/23 (4.3%)		0/15 (0%)
Lung infection	0/6 (0%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		1/15 (6.7%)
Pneumonia	0/6 (0%)		0/12 (0%)		0/31 (0%)		1/23 (4.3%)		0/15 (0%)
Investigations
Amylase increased	0/6 (0%)		0/12 (0%)		1/31 (3.2%)		1/23 (4.3%)		0/15 (0%)
Lipase increased	0/6 (0%)		0/12 (0%)		0/31 (0%)		1/23 (4.3%)		0/15 (0%)
Neutrophil count decreased	0/6 (0%)		0/12 (0%)		1/31 (3.2%)		2/23 (8.7%)		0/15 (0%)
White blood cell count decreased	0/6 (0%)		0/12 (0%)		1/31 (3.2%)		1/23 (4.3%)		0/15 (0%)
Metabolism and nutrition disorders
Hyperglycaemia	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Decreased appetite	0/6 (0%)		0/12 (0%)		1/31 (3.2%)		1/23 (4.3%)		0/15 (0%)
Hypoalbuminaemia	0/6 (0%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		1/15 (6.7%)
Hypophosphataemia	0/6 (0%)		0/12 (0%)		0/31 (0%)		1/23 (4.3%)		0/15 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/6 (16.7%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Back pain	1/6 (16.7%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Myalgia	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to central nervous system	0/6 (0%)		1/12 (8.3%)		1/31 (3.2%)		0/23 (0%)		1/15 (6.7%)
Tumour pain	0/6 (0%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		1/15 (6.7%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/6 (16.7%)		0/12 (0%)		0/31 (0%)		1/23 (4.3%)		0/15 (0%)
Dyspnoea exertional	0/6 (0%)		2/12 (16.7%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Dyspnoea paroxysmal nocturnal	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Haemoptysis	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Pleural effusion	0/6 (0%)		1/12 (8.3%)		3/31 (9.7%)		1/23 (4.3%)		1/15 (6.7%)
Dyspnoea at rest	0/6 (0%)		0/12 (0%)		0/31 (0%)		1/23 (4.3%)		0/15 (0%)
Skin and subcutaneous tissue disorders
Dermatitis acneiform	0/6 (0%)		0/12 (0%)		1/31 (3.2%)		0/23 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Phase 1b: Tepotinib (300 mg)		Phase 1b: Tepotinib (500 mg)		Phase 2: Tepotinib and Gefitinib		Phase 2: Pemetrexed and Cisplatin/Carboplatin		Phase 2: Single-arm Cohort (MET+ T790M Positive)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		12/12 (100%)		31/31 (100%)		23/23 (100%)		13/15 (86.7%)
Blood and lymphatic system disorders
Anaemia	0/6 (0%)		0/12 (0%)		5/31 (16.1%)		16/23 (69.6%)		4/15 (26.7%)
Leukopenia	0/6 (0%)		0/12 (0%)		0/31 (0%)		1/23 (4.3%)		1/15 (6.7%)
Neutropenia	0/6 (0%)		0/12 (0%)		0/31 (0%)		7/23 (30.4%)		1/15 (6.7%)
Thrombocytopenia	0/6 (0%)		0/12 (0%)		1/31 (3.2%)		1/23 (4.3%)		1/15 (6.7%)
Cardiac disorders
Supraventricular extrasystoles	0/6 (0%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		1/15 (6.7%)
Atrial fibrillation	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Cardiac discomfort	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Pericardial effusion	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Ear and labyrinth disorders
Tinnitus	0/6 (0%)		0/12 (0%)		0/31 (0%)		2/23 (8.7%)		0/15 (0%)
Hypoacusis	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Endocrine disorders
Inappropriate antidiuretic hormone secretion	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Eye disorders
Eyelids pruritus	0/6 (0%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		1/15 (6.7%)
Keratitis	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Gastrointestinal disorders
Abdominal distension	0/6 (0%)		0/12 (0%)		3/31 (9.7%)		2/23 (8.7%)		0/15 (0%)
Abdominal pain	1/6 (16.7%)		3/12 (25%)		1/31 (3.2%)		2/23 (8.7%)		0/15 (0%)
Abdominal pain upper	0/6 (0%)		2/12 (16.7%)		3/31 (9.7%)		1/23 (4.3%)		0/15 (0%)
Cheilitis	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		1/15 (6.7%)
Constipation	0/6 (0%)		3/12 (25%)		6/31 (19.4%)		6/23 (26.1%)		3/15 (20%)
Diarrhoea	4/6 (66.7%)		10/12 (83.3%)		18/31 (58.1%)		4/23 (17.4%)		7/15 (46.7%)
Dyspepsia	1/6 (16.7%)		2/12 (16.7%)		2/31 (6.5%)		0/23 (0%)		1/15 (6.7%)
Epigastric discomfort	0/6 (0%)		0/12 (0%)		4/31 (12.9%)		1/23 (4.3%)		0/15 (0%)
Nausea	2/6 (33.3%)		2/12 (16.7%)		7/31 (22.6%)		14/23 (60.9%)		2/15 (13.3%)
Stomatitis	0/6 (0%)		1/12 (8.3%)		2/31 (6.5%)		0/23 (0%)		0/15 (0%)
Vomiting	2/6 (33.3%)		3/12 (25%)		8/31 (25.8%)		11/23 (47.8%)		3/15 (20%)
Abdominal discomfort	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Gingival bleeding	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Haemorrhoidal haemorrhage	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
General disorders
Asthenia	1/6 (16.7%)		0/12 (0%)		5/31 (16.1%)		5/23 (21.7%)		2/15 (13.3%)
Axillary pain	0/6 (0%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		1/15 (6.7%)
Chest discomfort	0/6 (0%)		1/12 (8.3%)		2/31 (6.5%)		0/23 (0%)		1/15 (6.7%)
Chest pain	0/6 (0%)		0/12 (0%)		6/31 (19.4%)		1/23 (4.3%)		1/15 (6.7%)
Fatigue	1/6 (16.7%)		5/12 (41.7%)		2/31 (6.5%)		3/23 (13%)		0/15 (0%)
Malaise	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		2/23 (8.7%)		1/15 (6.7%)
Oedema	0/6 (0%)		1/12 (8.3%)		5/31 (16.1%)		0/23 (0%)		1/15 (6.7%)
Oedema peripheral	2/6 (33.3%)		3/12 (25%)		12/31 (38.7%)		1/23 (4.3%)		0/15 (0%)
Pyrexia	1/6 (16.7%)		2/12 (16.7%)		4/31 (12.9%)		1/23 (4.3%)		2/15 (13.3%)
Local swelling	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Non-cardiac chest pain	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Pain	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Peripheral swelling	1/6 (16.7%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Hepatobiliary disorders
Hepatic function abnormal	0/6 (0%)		0/12 (0%)		0/31 (0%)		1/23 (4.3%)		1/15 (6.7%)
Liver injury	0/6 (0%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		1/15 (6.7%)
Infections and infestations
Conjunctivitis	0/6 (0%)		0/12 (0%)		3/31 (9.7%)		0/23 (0%)		1/15 (6.7%)
Gingivitis	0/6 (0%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		1/15 (6.7%)
Influenza	0/6 (0%)		0/12 (0%)		1/31 (3.2%)		0/23 (0%)		1/15 (6.7%)
Localised infection	0/6 (0%)		0/12 (0%)		1/31 (3.2%)		0/23 (0%)		1/15 (6.7%)
Lung infection	0/6 (0%)		0/12 (0%)		1/31 (3.2%)		0/23 (0%)		1/15 (6.7%)
Nasopharyngitis	0/6 (0%)		0/12 (0%)		2/31 (6.5%)		1/23 (4.3%)		0/15 (0%)
Oral herpes	0/6 (0%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		1/15 (6.7%)
Paronychia	0/6 (0%)		0/12 (0%)		7/31 (22.6%)		0/23 (0%)		1/15 (6.7%)
Pneumonia	0/6 (0%)		0/12 (0%)		1/31 (3.2%)		0/23 (0%)		2/15 (13.3%)
Upper respiratory tract infection	0/6 (0%)		0/12 (0%)		3/31 (9.7%)		0/23 (0%)		1/15 (6.7%)
Urinary tract infection	0/6 (0%)		0/12 (0%)		2/31 (6.5%)		0/23 (0%)		1/15 (6.7%)
Cellulitis	1/6 (16.7%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Folliculitis	1/6 (16.7%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Influenza	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Paronychia	2/6 (33.3%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Pneumonia	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Investigations
Activated partial thromboplastin time prolonged	0/6 (0%)		0/12 (0%)		3/31 (9.7%)		2/23 (8.7%)		0/15 (0%)
Alanine aminotransferase increased	1/6 (16.7%)		0/12 (0%)		9/31 (29%)		2/23 (8.7%)		1/15 (6.7%)
Amylase increased	4/6 (66.7%)		2/12 (16.7%)		11/31 (35.5%)		4/23 (17.4%)		4/15 (26.7%)
Aspartate aminotransferase increased	1/6 (16.7%)		0/12 (0%)		5/31 (16.1%)		3/23 (13%)		2/15 (13.3%)
Blood albumin decreased	0/6 (0%)		0/12 (0%)		2/31 (6.5%)		1/23 (4.3%)		3/15 (20%)
Blood alkaline phosphatase increased	3/6 (50%)		0/12 (0%)		2/31 (6.5%)		5/23 (21.7%)		2/15 (13.3%)
Blood creatinine increased	2/6 (33.3%)		0/12 (0%)		4/31 (12.9%)		6/23 (26.1%)		2/15 (13.3%)
Blood urea increased	0/6 (0%)		0/12 (0%)		0/31 (0%)		3/23 (13%)		0/15 (0%)
C-reactive protein increased	0/6 (0%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		1/15 (6.7%)
Creatinine renal clearance decreased	2/6 (33.3%)		0/12 (0%)		3/31 (9.7%)		3/23 (13%)		1/15 (6.7%)
Electrocardiogram QT prolonged	3/6 (50%)		1/12 (8.3%)		3/31 (9.7%)		2/23 (8.7%)		1/15 (6.7%)
Gamma-glutamyltransferase increased	1/6 (16.7%)		0/12 (0%)		1/31 (3.2%)		4/23 (17.4%)		1/15 (6.7%)
Haemoglobin decreased	0/6 (0%)		0/12 (0%)		2/31 (6.5%)		1/23 (4.3%)		1/15 (6.7%)
International normalised ratio increased	3/6 (50%)		0/12 (0%)		0/31 (0%)		1/23 (4.3%)		1/15 (6.7%)
Lipase increased	2/6 (33.3%)		2/12 (16.7%)		8/31 (25.8%)		3/23 (13%)		2/15 (13.3%)
Neutrophil count decreased	0/6 (0%)		1/12 (8.3%)		2/31 (6.5%)		9/23 (39.1%)		1/15 (6.7%)
Platelet count decreased	1/6 (16.7%)		0/12 (0%)		2/31 (6.5%)		6/23 (26.1%)		0/15 (0%)
Prothrombin time prolonged	3/6 (50%)		0/12 (0%)		1/31 (3.2%)		2/23 (8.7%)		1/15 (6.7%)
Weight decreased	0/6 (0%)		3/12 (25%)		6/31 (19.4%)		6/23 (26.1%)		3/15 (20%)
White blood cell count decreased	1/6 (16.7%)		0/12 (0%)		2/31 (6.5%)		12/23 (52.2%)		2/15 (13.3%)
Bacterial test positive	1/6 (16.7%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Blood glucose increased	1/6 (16.7%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Metabolism and nutrition disorders
Decreased appetite	2/6 (33.3%)		4/12 (33.3%)		9/31 (29%)		10/23 (43.5%)		3/15 (20%)
Hyperglycaemia	0/6 (0%)		2/12 (16.7%)		2/31 (6.5%)		4/23 (17.4%)		0/15 (0%)
Hyperkalaemia	0/6 (0%)		0/12 (0%)		2/31 (6.5%)		2/23 (8.7%)		0/15 (0%)
Hypermagnesaemia	0/6 (0%)		0/12 (0%)		0/31 (0%)		2/23 (8.7%)		0/15 (0%)
Hypoalbuminaemia	2/6 (33.3%)		1/12 (8.3%)		8/31 (25.8%)		1/23 (4.3%)		2/15 (13.3%)
Hypocalcaemia	2/6 (33.3%)		1/12 (8.3%)		6/31 (19.4%)		3/23 (13%)		2/15 (13.3%)
Hypochloraemia	0/6 (0%)		0/12 (0%)		0/31 (0%)		2/23 (8.7%)		0/15 (0%)
Hypokalaemia	0/6 (0%)		1/12 (8.3%)		2/31 (6.5%)		6/23 (26.1%)		2/15 (13.3%)
Hypomagnesaemia	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		2/23 (8.7%)		0/15 (0%)
Hyponatraemia	1/6 (16.7%)		2/12 (16.7%)		2/31 (6.5%)		3/23 (13%)		0/15 (0%)
Hypoproteinaemia	2/6 (33.3%)		0/12 (0%)		3/31 (9.7%)		5/23 (21.7%)		2/15 (13.3%)
Hypoglycaemia	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Hypophosphataemia	1/6 (16.7%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/6 (16.7%)		2/12 (16.7%)		4/31 (12.9%)		1/23 (4.3%)		1/15 (6.7%)
Bone pain	0/6 (0%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		1/15 (6.7%)
Muscle twitching	0/6 (0%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		1/15 (6.7%)
Musculoskeletal chest pain	0/6 (0%)		2/12 (16.7%)		2/31 (6.5%)		0/23 (0%)		1/15 (6.7%)
Pain in extremity	1/6 (16.7%)		1/12 (8.3%)		2/31 (6.5%)		0/23 (0%)		1/15 (6.7%)
Arthralgia	1/6 (16.7%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Myalgia	1/6 (16.7%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain	0/6 (0%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		1/15 (6.7%)
Nervous system disorders
Dizziness	0/6 (0%)		2/12 (16.7%)		3/31 (9.7%)		4/23 (17.4%)		0/15 (0%)
Headache	0/6 (0%)		1/12 (8.3%)		6/31 (19.4%)		3/23 (13%)		0/15 (0%)
Cognitive disorder	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Dysgeusia	1/6 (16.7%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Memory impairment	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Psychiatric disorders
Innsomnia	1/6 (16.7%)		1/12 (8.3%)		5/31 (16.1%)		2/23 (8.7%)		0/15 (0%)
Renal and urinary disorders
Haematuria	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		1/23 (4.3%)		1/15 (6.7%)
Hydronephrosis	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Ureterolithiasis	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/6 (0%)		2/12 (16.7%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Vulvovaginal dryness	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	3/6 (50%)		1/12 (8.3%)		8/31 (25.8%)		5/23 (21.7%)		3/15 (20%)
Dyspnoea	0/6 (0%)		1/12 (8.3%)		7/31 (22.6%)		2/23 (8.7%)		3/15 (20%)
Haemoptysis	1/6 (16.7%)		1/12 (8.3%)		4/31 (12.9%)		0/23 (0%)		3/15 (20%)
Pleural effusion	0/6 (0%)		1/12 (8.3%)		2/31 (6.5%)		1/23 (4.3%)		1/15 (6.7%)
Productive cough	1/6 (16.7%)		0/12 (0%)		2/31 (6.5%)		3/23 (13%)		0/15 (0%)
Rhinorrhoea	0/6 (0%)		1/12 (8.3%)		2/31 (6.5%)		2/23 (8.7%)		0/15 (0%)
Dyspnoea exertional	3/6 (50%)		5/12 (41.7%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Dyspnoea paroxysmal nocturnal	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Hiccups	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Pulmonary thrombosis	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Skin and subcutaneous tissue disorders
Dermatitis acneiform	1/6 (16.7%)		0/12 (0%)		4/31 (12.9%)		0/23 (0%)		0/15 (0%)
Dry skin	0/6 (0%)		4/12 (33.3%)		3/31 (9.7%)		0/23 (0%)		0/15 (0%)
Palmar-plantar erythrodysaesthesia syndrome	0/6 (0%)		0/12 (0%)		2/31 (6.5%)		0/23 (0%)		0/15 (0%)
Pruritus	2/6 (33.3%)		4/12 (33.3%)		4/31 (12.9%)		2/23 (8.7%)		2/15 (13.3%)
Rash	3/6 (50%)		5/12 (41.7%)		8/31 (25.8%)		0/23 (0%)		4/15 (26.7%)
Seborrhoeic dermatitis	0/6 (0%)		0/12 (0%)		2/31 (6.5%)		0/23 (0%)		0/15 (0%)
Skin fissures	0/6 (0%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		1/15 (6.7%)
Skin hyperpigmentation	0/6 (0%)		0/12 (0%)		2/31 (6.5%)		0/23 (0%)		0/15 (0%)
Acne	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Erythema	1/6 (16.7%)		0/12 (0%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Intertrigo	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)
Social circumstances
Inadequate diet	0/6 (0%)		0/12 (0%)		1/31 (3.2%)		2/23 (8.7%)		0/15 (0%)
Vascular disorders
Peripheral embolism	0/6 (0%)		1/12 (8.3%)		0/31 (0%)		0/23 (0%)		0/15 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.