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Clinical Trial Results:
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 Non-small Cell Lung Cancer (NSCLC) Harboring EGFR Mutation and Having Acquired Resistance to Prior EGFR-Tyrosine Kinase Inhibitor (EGFR-TKI) Therapy

Summary
EudraCT number	2016-001604-28
Trial protocol	ES SK BG NL IT
Global end of trial date	14 Oct 2021

Results information
Results version number	v1(current)
This version publication date	02 Nov 2022
First version publication date	02 Nov 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

EMR200095-006

ISRCTN number

US NCT number

NCT01982955

WHO universal trial number (UTN)

Sponsor organisation name

Merck Healthcare KGaA, Darmstadt,Germany

Sponsor organisation address

Frankfurter Strasse 250, Darmstadt, Germany, 64293

Public contact

Communication Center, Merck Healthcare KGaA, Darmstadt,Germany, +49 6151725200, service@merckgroup.com

Scientific contact

Communication Center, Merck Healthcare KGaA, Darmstadt,Germany, +49 6151725200, service@merckgroup.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

14 Oct 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

14 Oct 2021

Was the trial ended prematurely?

Main objective of the trial

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 subjects 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).

Protection of trial subjects

Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.

Background therapy

Evidence for comparator

Actual start date of recruitment

23 Dec 2013

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

6 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

China: 49

Country: Number of subjects enrolled

Taiwan: 10

Country: Number of subjects enrolled

Japan: 1

Country: Number of subjects enrolled

Korea, Republic of: 18

Country: Number of subjects enrolled

Malaysia: 3

Country: Number of subjects enrolled

Singapore: 7

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 18 subjects were enrolled in Phase 1b part of the study and a total of 70 subjects were enrolled in phase 2 part of the study. Subjects enrolled in phase 1b were not eligible for randomization in phase 2.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg

Arm description

Subjects 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.

Arm type

Experimental

Investigational medicinal product name

Tepotinib 300 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subejcts received Tepotinib 300 mg orally once daily over a 21-day treatment cycle until progressive disease, intolerable toxicity or withdrawal from treatment.

Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg

Arm description

Subjects received Tepotinib 500 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.

Arm type

Experimental

Investigational medicinal product name

Tepotinib 500 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received Tepotinib 500 mg tablet orally once daily over a 21-day treatment cycle until progressive disease, intolerable toxicity or withdrawal from treatment.

Phase 2: Tepotinib 500mg+Gefitinib250 mg (MET+ T790 negative)

Arm description

Subjects 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.

Arm type

Experimental

Investigational medicinal product name

Gefitinib 250 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects randomized to receive 250 mg Gefitinib tablets orally once daily over a 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment.

Investigational medicinal product name

Tepotinib 500 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects randomized to receive Tepotinib recommended Phase 2 dose 500 mg once daily over a 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment.

Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)

Arm description

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

Arm type

Experimental

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects randomized to receive 500 milligram per square meter (mg/m^2) of Pemetrexed as intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Pemetrexed maintenance monotherapy.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate and solvent for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects randomized to receive Carboplatin (intravenously at a dose of area under curve (AUC) 5 or AUC 6 at the discretion of the Investigator) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Pemetrexed maintenance monotherapy.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate and solvent for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects randomized to receive Cisplatin (75 mg/m^2 as an intravenous infusion over 2 hours) on Day 1 of each 21-day cycle until progressive disease, intolerable toxicity or withdrawal from treatment or up to 6 cycles if or 4 cycles followed by Pemetrexed maintenance monotherapy.

Phase 2: Single-arm Cohort (MET+ T790M positive)

Arm description

Subjects 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.

Arm type

Experimental

Investigational medicinal product name

Gefitinib 250 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects with MET+ T790M positive Non-small Cell Lung Cancer (NSCLC) received 250 mg Gefitinib tablets orally once daily over a 21-day treatment cycle until progressive disease, intolerable toxicity or withdrawal from treatment.

Investigational medicinal product name

Tepotinib 500 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects with MET+ T790M positive Non-small Cell Lung Cancer (NSCLC) received a Tepotinib recommended Phase 2 dose 500 mg once daily over a 21-day treatment cycle until progressive disease, intolerable toxicity or withdrawal from treatment.

Number of subjects in period 1	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg	Phase 2: Tepotinib 500mg+Gefitinib250 mg (MET+ T790 negative)	Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)	Phase 2: Single-arm Cohort (MET+ T790M positive)
Started	6	12	31	24	15
Treated	6	12	31	23	15
Completed	6	12	31	23	15
Not completed	0	0	0	1	0
Randomized but not treated	-	-	-	1	-

Baseline characteristics

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Reporting group title

Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg

Reporting group description

Reporting group title

Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg

Reporting group description

Subjects received Tepotinib 500 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.

Reporting group title

Phase 2: Tepotinib 500mg+Gefitinib250 mg (MET+ T790 negative)

Reporting group description

Reporting group title

Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)

Reporting group description

Reporting group title

Phase 2: Single-arm Cohort (MET+ T790M positive)

Reporting group description

Reporting group values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg	Phase 2: Tepotinib 500mg+Gefitinib250 mg (MET+ T790 negative)	Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)	Phase 2: Single-arm Cohort (MET+ T790M positive)	Total
Number of subjects	6	12	31	24	15	88
Age Categorical
Units: Subjects
<=18 years	0	0	0	0	0	0
Between 18 and 65 years	3	6	21	17	9	56
>=65 years	3	6	10	7	6	32
Sex: Female, Male
Units: Subjects
Female	3	7	20	12	10	52
Male	3	5	11	12	5	36
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0
Asian	6	12	31	24	15	88
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0
Black or African American	0	0	0	0	0	0
White	0	0	0	0	0	0
More than one race	0	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0	0

End points

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Reporting group title

Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg

Reporting group description

Reporting group title

Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg

Reporting group description

Subjects received Tepotinib 500 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.

Reporting group title

Phase 2: Tepotinib 500mg+Gefitinib250 mg (MET+ T790 negative)

Reporting group description

Reporting group title

Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)

Reporting group description

Reporting group title

Phase 2: Single-arm Cohort (MET+ T790M positive)

Reporting group description

Primary: Phase 1b: Number of Subjects Experiencing at least One Dose Limiting Toxicity (DLT)

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End point title

Phase 1b: Number of Subjects Experiencing at least One Dose Limiting Toxicity (DLT) ^[1] ^[2]

End point 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 subjects who experienced DLT during Phase 1b were reported. Dose Limiting Toxicity (DLT) set included all subjects who experienced a DLT during Cycle 1, or received at least 80 percent of all planned doses of treatment during Cycle.

End point type

Primary

End point timeframe

Day 1 to Day 21 of Cycle 1 (each cycle is 21 days)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	3	12
Units: Subjects	0	0

No statistical analyses for this end point

Primary: Phase 1b: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs

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End point title

Phase 1b: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs ^[3] ^[4]

End point 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 subjects with TEAEs and serious TEAEs were reported. The safety analysis set included all subjects who had received any dose of the study medication.

End point type

Primary

End point timeframe

Up to 175 Weeks

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	12
Units: subjects
Any TEAEs	6	12
Any Serious TEAEs	4	7

No statistical analyses for this end point

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

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End point title

Phase 2 (Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by the Investigator ^[5] ^[6]

End point 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. The Intent-to-treat analysis set in the Phase 2 part of the study included all subjects with treatment group who were randomized to study treatment.

End point type

Primary

End point timeframe

Up to 328 weeks

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 2. Therefore, other arms have not been selected.

End point values	Phase 2: Tepotinib 500mg+Gefitinib250 mg (MET+ T790 negative)	Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)
Number of subjects analysed	31	24
Units: Months
median (confidence interval 90%)	4.86 (3.88 to 6.87)	4.37 (4.17 to 6.80)

No statistical analyses for this end point

Secondary: Phase 1b: Area Under the Plasma Concentration Versus Time Curve from Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, its Metabolites and Gefitinib

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End point 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 ^[7]

End point 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. The Pharmacokinetic (PK) set included all subjects 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 “n=Number Analyzed” signifies those subjects who were evaluable for specified category. Here, "99999" indicate that value was not determined because only 2 subjects had evaluable AUC(0-t) at time point. For statistical reasons, calculation of summary statistics does not make sense for this low sample size. Individual values were 3830 and 3980 ng*h/mL.

End point type

Secondary

End point timeframe

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)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	12
Units: nanogramhour per milliliter (ngh/mL)
geometric mean (geometric coefficient of variation)
Tepotinib: Day 1 of Cycle 1 (n=5, 12)	6280 ( 25.4 )	9210 ( 48.4 )
Tepotinib: Day 15 of Cycle 1 (n=6, 9)	15600 ( 19.6 )	22200 ( 43.3 )
MSC2571109A: Day 1 of Cycle 1 (n=5, 11)	1680 ( 11.8 )	1770 ( 56.7 )
MSC2571109A Day15 of Cycle 1 (n=6, 8)	4420 ( 25.7 )	7530 ( 52.6 )
MSC2571107A Day 1 of Cycle 1 (n=5, 11)	248 ( 49.3 )	324 ( 57.3 )
MSC2571107A Day 15 of Cycle 1 (n=6, 8)	872 ( 38.5 )	1880 ( 76.0 )
Gefitinib: Day 1 of Cycle 1 (n=2, 11)	99999 ( 99999 )	2930 ( 45.8 )
Gefitinib: Day 15 of Cycle 1 (n=6, 9)	7690 ( 44.1 )	7080 ( 29.0 )

No statistical analyses for this end point

Secondary: Phase 1b: Area Under the Plasma Concentration-Time Curve within 1 Dosing Interval (AUC 0-tau) of Tepotinib, its Metabolites and Gefitinib

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End point title

Phase 1b: Area Under the Plasma Concentration-Time Curve within 1 Dosing Interval (AUC 0-tau) of Tepotinib, its Metabolites and Gefitinib ^[8]

End point description

AUC (0-tau) is the area under the plasma concentration time curve within 1 dosing interval. The PK set included all subjects 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 “n=Number Analyzed” signifies those subjects who were evaluable for specified category. Here, "99999" indicate that value was not determined because only 2 subjects had evaluable AUC(0-tau) at time point. For statistical reasons, calculation of summary statistics does not make sense for this low sample size. Individual values were 3830 and 3980 ng*h/mL.

End point type

Secondary

End point timeframe

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)

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	12
Units: ng*h/mL
geometric mean (geometric coefficient of variation)
Tepotinib: Day 1 of Cycle 1 (n=5, 12)	6280 ( 25.4 )	9210 ( 48.4 )
Tepotinib: Day 15 of Cycle 1 (n=6, 9 )	15600 ( 19.6 )	22200 ( 43.3 )
MSC2571109A: Day 1 of Cycle 1 (n=5, 11 )	1680 ( 11.8 )	1770 ( 56.7 )
MSC2571109A: Day 15 of Cycle 1 (n=6, 8)	4420 ( 25.7 )	7530 ( 52.6 )
MSC2571107A: Day 1 of Cycle 1 (n=5, 11)	248 ( 49.3 )	324 ( 57.3 )
MSC2571107A: Day 15 of Cycle 1 (n=6, 8)	872 ( 38.5 )	1880 ( 76.0 )
Gefitinib: Day 1 of Cycle 1 (n=2, 11)	99999 ( 99999 )	2930 ( 45.8 )
Gefitinib: Day 15 of Cycle 1 (n=6, 9)	7690 ( 44.1 )	7080 ( 29.0 )

No statistical analyses for this end point

Secondary: Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, its Metabolites and Gefitinib

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End point title

Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, its Metabolites and Gefitinib ^[9]

End point description

Cmax is the maximum observed plasma concentration obtained directly from the concentration versus time curve. The PK set included all subjects 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 “n=Number Analyzed” signifies those subjects who were evaluable for specified category. Here, "99999" indicate that value was not determined because only 2 subjects had evaluable Cmax at time point. For statistical reasons, calculation of summary statistics does not make sense for this low sample size. Individual values were 302 and 305 ng/mL.

End point type

Secondary

End point timeframe

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)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	12
Units: Nanogram per Milliliter (ng/mL)
geometric mean (geometric coefficient of variation)
Tepotinib: Day 1 of Cycle 1 (n=5, 12)	375 ( 30.4 )	575 ( 62.6 )
Tepotinib: Day 15 of Cycle 1 (n=6, 10)	763 ( 22.0 )	1050 ( 44.1 )
MSC2571109A: Day 1 of Cycle 1 (n=5, 11)	132 ( 14.7 )	149 ( 56.5 )
MSC2571109A: Day 15 of Cycle 1 (n=6, 9)	280 ( 32.0 )	444 ( 45.8 )
MSC2571107A: Day 1 of Cycle 1 (n=5, 11)	16.8 ( 56.5 )	24.3 ( 62.5 )
MSC2571107A: Day 15 of Cycle 1 (n=6, 9)	44.9 ( 40.5 )	94.9 ( 70.8 )
Gefitinib: Day 1 of Cycle 1 (n=2, 11)	99999 ( 99999 )	215 ( 48.7 )
Gefitinib: Day 15 of Cycle 1 (n=6, 10)	432 ( 38.3 )	366 ( 32.6 )

No statistical analyses for this end point

Secondary: Phase 1b: Average Observed Plasma Concentration (Cavg) of Tepotinib, its Metabolites and Gefitinib

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End point title

Phase 1b: Average Observed Plasma Concentration (Cavg) of Tepotinib, its Metabolites and Gefitinib ^[10]

End point description

Cavg is the average plasma concentration within 1 dosing interval obtained directly from the concentration versus time curve. The PK analysis set employed here. "Number of subjects analyzed" signifies subjects who were evaluable for this outcome measure and "n=Number Analyzed" signifies those subjects who were evaluable for specified category.

End point type

Secondary

End point timeframe

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)

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	9
Units: ng/mL
geometric mean (geometric coefficient of variation)
Tepotinib (n=6, 9)	654 ( 19.4 )	924 ( 43.3 )
MSC2571109A (n=6, 8)	185 ( 25.4 )	314 ( 52.6 )
MSC2571107A (n=6, 8)	36.4 ( 38.2 )	78.3 ( 76.0 )
Gefitinib (n=6, 9)	321 ( 43.9 )	295 ( 29.0 )

No statistical analyses for this end point

Secondary: Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib, its Metabolites and Gefitinib

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End point title

Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib, its Metabolites and Gefitinib ^[11]

End point description

Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve. The PK analysis set employed here. "Number of subjects analyzed" signifies subjects who were evaluable for this outcome measure and "n=Number Analyzed" signifies those subjects who were evaluable for specified category.

End point type

Secondary

End point timeframe

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)

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	9
Units: ng/mL
geometric mean (geometric coefficient of variation)
Tepotinib (n=6, 9)	534 ( 18.8 )	735 ( 47.6 )
MSC2571109A (n=6, 8)	156 ( 28.8 )	270 ( 58.5 )
MSC2571107A (n=6, 8)	32.8 ( 40.1 )	68.7 ( 80.1 )
Geftinib (n=6, 9)	231 ( 57.3 )	190 ( 43.5 )

No statistical analyses for this end point

Secondary: Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, its Metabolites and Gefitinib

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End point title

Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, its Metabolites and Gefitinib ^[12]

End point description

Tmax is time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve. The Pharmacokinetic set included all subjects 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 subjects who were evaluable for specified category. Here "99999" indicate that value can not be determined as only 2 subjects had evaluable tmax at time point. For statistical reasons, calculation of summary statistics does not make sense for this low sample size. Individual values were 4.00 and 4.00 hour.

End point type

Secondary

End point timeframe

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)

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	12
Units: Hours
median (full range (min-max))
Tepotinib: Day 1 of Cycle 1 (n=5, 12)	8.00 (4.00 to 8.00)	9.01 (4.00 to 10.00)
Tepotinib: Day 15 of Cycle 1 (n=6, 10)	6.00 (0.00 to 8.00)	9.00 (4.00 to 24.00)
MSC2571109A: Day 1 of Cycle 1 (n=5, 11)	24.00 (23.75 to 24.00)	24.00 (24.00 to 24.00)
MSC2571109A: Day 15 of Cycle 1 (n=6, 9)	0.00 (0.00 to 24.00)	0.00 (0.00 to 24.00)
MSC2571107A: Day 1 of Cycle 1 (n=5, 11)	24.00 (23.75 to 24.00)	24.00 (24.00 to 24.00)
MSC2571107A: Day 15 of Cycle 1 (n=6, 9)	0.13 (0.00 to 8.00)	0.25 (0.00 to 24.00)
Gefitinib: Day 1 of Cycle 1 (n=2, 11)	99999 (99999 to 99999)	8.00 (4.00 to 8.02)
Gefitinib: Day 15 of Cycle 1 (n=6, 10)	4.00 (4.00 to 10.00)	8.00 (4.00 to 10.12)

No statistical analyses for this end point

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

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End point title

Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, its Metabolites and Gefitinib ^[13]

End point description

The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. The Pharmacokinetic set included all subjects 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, "99999" indicate that value was not determined. Study drug administered once daily with rich PK sampling up to 24 hours. As half-life of study drug exceeding the PK sampling time, Lambda(z) could not be reliably estimated. Therefore, AUC(0-inf) which is dependent on Lambda(z) was not determined.

End point type

Secondary

End point timeframe

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)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	12
Units: ng*h/mL
geometric mean (geometric coefficient of variation)
Tepotinib: Day 1 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
Tepotinib: Day 15 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
MSC2571109A: Day 1 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
MSC2571109A: Day 15 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
MSC2571107A: Day 1 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
MSC2571107A: Day 15 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
Gefitinib: Day 1 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
Gefitinib: Day 15 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )

No statistical analyses for this end point

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

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End point title

Phase 1b: Apparent Total Body Clearance From Plasma (CL/F) of Tepotinib and Gefitinib ^[14]

End point 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). The Pharmacokinetic set included all subjects 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 subjects analyzed" signifies subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

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)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	9
Units: liter per hour (L/h)
geometric mean (geometric coefficient of variation)
Tepotinib	17.3 ( 19.6 )	20.3 ( 43.3 )
Gefitinib	32.5 ( 44.1 )	35.3 ( 29.0 )

No statistical analyses for this end point

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

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End point title

Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, its Metabolites and Gefitinib ^[15]

End point 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). The Pharmacokinetic set included all subjects 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, "99999" indicate that values was not determined. Study drug administered once daily with rich PK sampling up to 24 hours. As half-life of study drug exceeding the PK sampling time, Lambda(z) could not be reliably estimated. Therefore, Vz/F which is dependent on Lambda(z) was not determined.

End point type

Secondary

End point timeframe

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)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	12
Units: Liter
geometric mean (geometric coefficient of variation)
Tepotinib: Day 1 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
Tepotinib: Day 15 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
MSC2571109A: Day 1 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
MSC2571109A: Day 15 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
MSC2571107A: Day 1 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
MSC2571107A: Day 15 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
Gefitinib: Day 1 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
Gefitinib: Day 15 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )

No statistical analyses for this end point

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

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End point title

Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, its Metabolites and Gefitinib ^[16]

End point 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. The Pharmacokinetic set included all subjects 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, "99999" indicate that value was not determined. Study drug administered once daily with rich PK sampling up to 24 hours. As half-life of study drug exceeding the PK sampling time, Lambda(z) could not be reliably estimated. Therefore, Vss/F which is dependent on Lambda(z) was not determined.

End point type

Secondary

End point timeframe

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)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	12
Units: Liter
geometric mean (geometric coefficient of variation)
Tepotinib: Day 1 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
Tepotinib: Day 15 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
MSC2571109A: Day 1 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
MSC2571109A: Day 15 of cycle 1	99999 ( 99999 )	99999 ( 99999 )
MSC2571107A: Day 1 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
MSC2571107A: Day 15 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
Gefitinib: Day 1 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
Gefitinib: Day 15 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, its Metabolites and Gefitinib

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End point title

Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, its Metabolites and Gefitinib ^[17]

End point description

Lambda(z) was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. The Pharmacokinetic set included all subjects 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, "99999" indicate that value was not determined. Study drug administered once daily with rich PK sampling up to 24 hours. As half-life of study drug exceeding the PK sampling time, Lambda(z) could not be reliably estimated. Therefore, Lambda (z) was not determined.

End point type

Secondary

End point timeframe

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)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	12
Units: 1 per hour
geometric mean (geometric coefficient of variation)
Tepotinib: Day 1 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
Tepotinib: Day 15 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
MSC2571109A: Day 1 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
MSC2571109A: Day 15 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
MSC2571107A: Day 1 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
MSC2571107A: Day 15 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
Gefitinib: Day 1 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )
Gefitinib: Day 15 of Cycle 1	99999 ( 99999 )	99999 ( 99999 )

No statistical analyses for this end point

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

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End point title

Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, its Metabolites and Gefitinib ^[18]

End point 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. The Pharmacokinetic set included all subjects 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, "99999" indicate that value was not determined. Study drug administered once daily with rich PK sampling up to 24 hours. As half-life of study drug exceeding the PK sampling time, Lambda(z) could not be reliably estimated. Therefore, t1/2 which is dependent on Lambda(z) was not determined.

End point type

Secondary

End point timeframe

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)

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	12
Units: Hours
median (full range (min-max))
Tepotinib: Day 1 of Cycle 1	99999 (99999 to 99999)	99999 (99999 to 99999)
Tepotinib: Day 15 of Cycle 1	99999 (99999 to 99999)	99999 (99999 to 99999)
MSC2571109A: Day 1 of Cycle 1	99999 (99999 to 99999)	99999 (99999 to 99999)
MSC2571109A: Day 15 of Cycle 1	99999 (99999 to 99999)	99999 (99999 to 99999)
MSC2571107A: Day 1 of Cycle 1	99999 (99999 to 99999)	99999 (99999 to 99999)
MSC2571107A: Day 15 of Cycle 1	99999 (99999 to 99999)	99999 (99999 to 99999)
Gefitinib: Day 1 of Cycle 1	99999 (99999 to 99999)	99999 (99999 to 99999)
Gefitinib: Day 15 of Cycle 1	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Phase 1b: Percentage of Subjects With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria

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End point title

Phase 1b: Percentage of Subjects With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria ^[19]

End point description

Objective response (OR) was defined as percentage of subjects who had achieved complete response or partial response as best overall response according to local radiological assessments from randomization/ first administration of study treatment to 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 sum of diameters of target lesions taking as reference baseline sum diameters. PD defined as an increase of at least 20% in 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 presence of new lesions. Sum must also demonstrate an absolute increase of at least 5 mm. The safety analysis set was used.

End point type

Secondary

End point timeframe

Up to 328 weeks

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	12
Units: Percentage of subjects
number (confidence interval 90%)	33.3 (6.3 to 72.9)	33.3 (12.3 to 60.9)

No statistical analyses for this end point

Secondary: Phase 1b: Percentage of Subjects With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria

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End point title

Phase 1b: Percentage of Subjects With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria ^[20]

End point description

Disease control defined as CR, PR, or stable disease as best overall response according to local radiological assessments from date of randomization/the first administration of 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 sum of diameters of target lesions taking as reference baseline sum diameters. PD: an increase of at least 20% in sum of the diameters of target lesions, taking as reference smallest sum of the diameters of target lesions recorded since treatment started and/or unequivocal progression of existing non-target lesions and/or presence of new lesions. 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. The safety analysis set was used.

End point type

Secondary

End point timeframe

Up to 328 weeks

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	12
Units: Percentage of subjects
number (confidence interval 90%)	50.0 (15.3 to 84.7)	58.3 (31.5 to 81.9)

No statistical analyses for this end point

Secondary: Phase 1b: Number of Subjects 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

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End point title

Phase 1b: Number of Subjects 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 ^[21]

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

End point type

Secondary

End point timeframe

Up to 175 weeks

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	12
Units: Subjects
Any TEAE Related to Tepotinib	6	9
Any TEAE Related to Gefitinib	5	11
Any Serious TEAE Related to Tepotinib	0	0
Any Serious TEAE Related to Gefitinib	0	0

No statistical analyses for this end point

Secondary: Phase 1b: Number of Subjects 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

Top of page

End point title

Phase 1b: Number of Subjects 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 ^[22]

End point description

An adverse event (AE) was defined as any untoward medical occurrence in subject which does not necessarily have causal 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 subjects with Grade 3/4 TEAEs and Grade 3/4 treatment-related TEAEs were reported. The safety analysis set included all subjects who had received any dose of the study medication.

End point type

Secondary

End point timeframe

Up to 175 weeks

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	12
Units: Subjects
Any Grade 3/4 TEAE	5	9
Any Grade 3/4 TEAE Related to Tepotinib	2	4
Any Grade 3/4 TEAE Related to Gefitinib	0	0

No statistical analyses for this end point

Secondary: Phase 1b: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation

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End point title

Phase 1b: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation ^[23]

End point 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 subjects with TEAEs leading to permanent treatment discontinuation were reported. The safety analysis set included all subjects who had received any dose of the study medication.

End point type

Secondary

End point timeframe

Up to 175 weeks

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	12
Units: Subjects
TEAE Leading Permanent Tepotinib Discontinuation	0	2
TEAE Leading Permanent Gefitinib Discontinuation	0	1

No statistical analyses for this end point

Secondary: Phase 1b: Number of Subjects With Death and Reasons

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End point title

Phase 1b: Number of Subjects With Death and Reasons ^[24]

End point description

Number of subjects 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 subjects with deaths due to PD, AE related to study treatment, AE not related to study treatment were reported. The safety analysis set included all subjects who had received any dose of the study medication.

End point type

Secondary

End point timeframe

Up to 175 weeks

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	12
Units: Subjects
Death due to PD	0	3
Death due to AE related to study treatment	0	0
Death due to AE not related to study treatment	1	0

No statistical analyses for this end point

Secondary: Phase 1b: Number of Subjects With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs)

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End point title

Phase 1b: Number of Subjects With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) ^[25]

End point description

The laboratory measurements included hematology and coagulation, biochemistry and urinalysis. The safety analysis set included all subjects who had received any dose of the study medication.

End point type

Secondary

End point timeframe

Up to 175 weeks

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	12
Units: Subjects
Amylase increased	2	2
Lipase increased	1	2
Neutrophil count decreased	0	1
Hyperglycemia	0	2
Hypocalcemia	1	0
Hyponatremia	0	2
Hypoproteinemia	1	0

No statistical analyses for this end point

Secondary: Phase 1b: Number of Subjects With Clinically Significant Abnormalities in Vital Signs

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End point title

Phase 1b: Number of Subjects With Clinically Significant Abnormalities in Vital Signs ^[26]

End point description

Vital signs assessment included blood pressure, heart rate, respiratory rate and body temperature. Number of subjects with any clinically significant abnormalities in vital signs were reported. Clinical significance was determined by the investigator. The safety analysis set included all subjects who had received any dose of the study medication.

End point type

Secondary

End point timeframe

Up to 175 weeks

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	12
Units: subjects	0	0

No statistical analyses for this end point

Secondary: Phase 1b: Number of Subjects With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings

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End point title

Phase 1b: Number of Subjects With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings ^[27]

End point 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 subjects with clinically significant abnormalities in 12-lead ECG were reported. The safety analysis set included all subjects who had received any dose of the study medication.

End point type

Secondary

End point timeframe

Up to 175 weeks

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	12
Units: Subjects	0	0

No statistical analyses for this end point

Secondary: Phase 1b: Number of Subjects With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2

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End point title

Phase 1b: Number of Subjects With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2 ^[28]

End point description

ECOG PS score is widely used by doctors and researchers to assess how a subject's disease is progressing and is used to assess how the disease affects the daily living abilities of the subject 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 subjects with ECOG performance status score of 2 or higher than 2 were reported. The safety analysis set was used.

End point type

Secondary

End point timeframe

Up to 175 weeks

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 1b. Therefore, other arms have not been selected.

End point values	Phase 1b: Tepotinib 300 mg + Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg
Number of subjects analysed	6	12
Units: Subjects	2	6

No statistical analyses for this end point

Secondary: Phase 2: Number of Subjects 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

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End point title

Phase 2: Number of Subjects 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 ^[29]

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

End point type

Secondary

End point timeframe

Up to 328 weeks

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 2. Therefore, other arms have not been selected.

End point values	Phase 2: Tepotinib 500mg+Gefitinib250 mg (MET+ T790 negative)	Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)	Phase 2: Single-arm Cohort (MET+ T790M positive)
Number of subjects analysed	31	23	15
Units: Subjects
Any TEAE	31	23	13
Any Treatment-Related TEAE	30	23	11
Any Serious TEAE	13	8	5
Any Treatment-Related Serious TEAE	6	7	1

No statistical analyses for this end point

Secondary: Phase 2: Number of Subjects 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

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End point title

Phase 2: Number of Subjects 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 ^[30]

End point description

An adverse event (AE) was defined as any untoward medical occurrence in subject which does not necessarily have causal 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 subjects with >= Grade 3 TEAEs and >= Grade 3 treatment-related TEAEs were reported. The safety analysis set included all subjects who had received any dose of the study medication.

End point type

Secondary

End point timeframe

Up to 328 weeks

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 2. Therefore, other arms have not been selected.

End point values	Phase 2: Tepotinib 500mg+Gefitinib250 mg (MET+ T790 negative)	Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)	Phase 2: Single-arm Cohort (MET+ T790M positive)
Number of subjects analysed	31	23	15
Units: Subjects
Any TEAE of >= Grade 3	20	14	7
Any Treatment-related TEAE of >= Grade 3	16	12	1

No statistical analyses for this end point

Secondary: Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation

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End point title

Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation ^[31]

End point 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 subjects with TEAEs leading to permanent treatment discontinuation were reported. The safety analysis set included all subjects who had received any dose of the study medication.

End point type

Secondary

End point timeframe

Up to 328 weeks

Notes
[31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 2. Therefore, other arms have not been selected.

End point values	Phase 2: Tepotinib 500mg+Gefitinib250 mg (MET+ T790 negative)	Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)	Phase 2: Single-arm Cohort (MET+ T790M positive)
Number of subjects analysed	31	23	15
Units: Subjects	3	1	2

No statistical analyses for this end point

Secondary: Phase 2: Number of Subjects With Death and Reasons

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End point title

Phase 2: Number of Subjects With Death and Reasons ^[32]

End point description

An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. PD defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 mm. Number of subjects with deaths due to PD, AE related to study treatment, unknown reason was reported. The safety analysis set included all subjects who had received any dose of the study medication.

End point type

Secondary

End point timeframe

Up to 328 weeks

Notes
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 2. Therefore, other arms have not been selected.

End point values	Phase 2: Tepotinib 500mg+Gefitinib250 mg (MET+ T790 negative)	Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)	Phase 2: Single-arm Cohort (MET+ T790M positive)
Number of subjects analysed	31	23	15
Units: Subjects
Death due to disease progression	21	15	8
Death due to AE related to study treatment	0	0	0
Unknown	2	5	2

No statistical analyses for this end point

Secondary: Phase 2: Number of Subjects with Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs)

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End point title

Phase 2: Number of Subjects with Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs) ^[33]

End point description

The laboratory measurements included hematology and coagulation, biochemistry and urinalysis. The safety analysis set included all subjects who had received any dose of the study medication.

End point type

Secondary

End point timeframe

Up to 328 weeks

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 2. Therefore, other arms have not been selected.

End point values	Phase 2: Tepotinib 500mg+Gefitinib250 mg (MET+ T790 negative)	Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)	Phase 2: Single-arm Cohort (MET+ T790M positive)
Number of subjects analysed	31	23	15
Units: Subjects
Anaemia	0	7	0
Neutropenia	0	1	0
Alanine aminotransferase increased	1	0	0
Amylase increased	7	2	2
Gamma-glutamyltransferase increased	0	1	0
Lipase increased	4	2	1
Neutrophil count decreased	2	3	0
White blood cell count decreased	1	2	0
Hyponatremia	1	3	0
Hypokalemia	0	2	0
hypophosphatemia	0	1	0
Hypoalbuminemia	1	0	0

No statistical analyses for this end point

Secondary: Phase 2: Number of Subjects With Clinically Significant Abnormalities in Vital Signs

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End point title

Phase 2: Number of Subjects With Clinically Significant Abnormalities in Vital Signs ^[34]

End point description

End point type

Secondary

End point timeframe

Up to 328 weeks

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 2. Therefore, other arms have not been selected.

End point values	Phase 2: Tepotinib 500mg+Gefitinib250 mg (MET+ T790 negative)	Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)	Phase 2: Single-arm Cohort (MET+ T790M positive)
Number of subjects analysed	31	23	15
Units: Subjects	0	0	0

No statistical analyses for this end point

Secondary: Phase 2: Number of Subjects With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings

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End point title

Phase 2: Number of Subjects With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings ^[35]

End point description

End point type

Secondary

End point timeframe

Up to 328 weeks

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 2. Therefore, other arms have not been selected.

End point values	Phase 2: Tepotinib 500mg+Gefitinib250 mg (MET+ T790 negative)	Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)	Phase 2: Single-arm Cohort (MET+ T790M positive)
Number of subjects analysed	31	23	15
Units: Subjects	2	1	0

No statistical analyses for this end point

Secondary: Phase 2: Number of Subjects With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2

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End point title

Phase 2: Number of Subjects With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2 ^[36]

End point description

ECOG PS score is widely used by doctors and researchers to assess how a subject's disease is progressing, and is used to assess how the disease affects the daily living abilities of the subject, 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 subjects with ECOG performance status score of 2 or higher than 2 were reported. The safety analysis set was used.

End point type

Secondary

End point timeframe

Up to 328 weeks

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 2. Therefore, other arms have not been selected.

End point values	Phase 2: Tepotinib 500mg+Gefitinib250 mg (MET+ T790 negative)	Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)	Phase 2: Single-arm Cohort (MET+ T790M positive)
Number of subjects analysed	31	23	15
Units: Subjects	6	1	1

No statistical analyses for this end point

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

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End point title

Phase 2 (Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Independent Review Committee (IRC) ^[37]

End point 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. The Intent-to-treat analysis set in the Phase 2 part of the study included all subjects with treatment group who were randomized to study treatment.

End point type

Secondary

End point timeframe

Up to 328 weeks

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 2. Therefore, other arms have not been selected.

End point values	Phase 2: Tepotinib 500mg+Gefitinib250 mg (MET+ T790 negative)	Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)
Number of subjects analysed	31	24
Units: Months
median (confidence interval 90%)	10.15 (4.24 to 19.32)	4.34 (4.11 to 6.97)

No statistical analyses for this end point

Secondary: Phase 2: (Randomized Part Only): Overall Survival (OS) Time

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End point title

Phase 2: (Randomized Part Only): Overall Survival (OS) Time ^[38]

End point description

Overall survival time was measured as time in months between the date of randomization and the date of death. The Intent-to-treat analysis set in the Phase 2 part of the study included all subjects with treatment group who were randomized to study treatment.

End point type

Secondary

End point timeframe

Up to 328 weeks

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 2. Therefore, other arms have not been selected.

End point values	Phase 2: Tepotinib 500mg+Gefitinib250 mg (MET+ T790 negative)	Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)
Number of subjects analysed	31	24
Units: Months
median (confidence interval 90%)	17.25 (12.12 to 29.14)	19.48 (15.90 to 21.82)

No statistical analyses for this end point

Secondary: Phase 2 (Randomized Part Only): Percentage of Subjects With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria

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End point title

Phase 2 (Randomized Part Only): Percentage of Subjects With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria ^[39]

End point description

Objective response was defined as percentage of subjects who had achieved complete response or partial response as best overall response according to local radiological assessments from randomization/the first administration of the study treatment to first observation of disease progression. 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 sum of diameters of target lesions taking as reference baseline sum diameters. PD defined as an increase of at least 20% in the sum of diameters of target lesions, taking as reference the smallest sum of diameters of target lesions recorded since treatment started and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. Sum must also demonstrate an absolute increase of at least 5 mm. Intent-to-treat analysis set was used.

End point type

Secondary

End point timeframe

Up to 328 weeks

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 2. Therefore, other arms have not been selected.

End point values	Phase 2: Tepotinib 500mg+Gefitinib250 mg (MET+ T790 negative)	Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)
Number of subjects analysed	31	24
Units: Percentage of Subjects
number (confidence interval 90%)	45.2 (29.7 to 61.3)	33.3 (17.8 to 52.1)

No statistical analyses for this end point

Secondary: Phase 2 (Randomized Part Only): Percentage of Subjects With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria

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End point title

Phase 2 (Randomized Part Only): Percentage of Subjects With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria ^[40]

End point description

Disease control defined as CR, PR, or stable disease as best overall response according to local radiological assessments from date of randomization/the first administration of study treatment to 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 sum of diameters of target lesions taking as reference baseline sum diameters. PD: an increase of at least 20% in sum of the diameters of target lesions, taking as reference smallest sum of diameters of target lesions recorded since treatment started and/or unequivocal progression of existing non-target lesions and/or presence of new lesions. 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. The Intent-to-treat analysis set was used.

End point type

Secondary

End point timeframe

Up to 328 weeks

Notes
[40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 2. Therefore, other arms have not been selected.

End point values	Phase 2: Tepotinib 500mg+Gefitinib250 mg (MET+ T790 negative)	Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)
Number of subjects analysed	31	24
Units: Percentage of Subjects
number (confidence interval 90%)	83.9 (69.0 to 93.4)	70.8 (52.1 to 85.4)

No statistical analyses for this end point

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

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End point title

Phase 2 (Non-Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Independent Review Committee (IRC) ^[41]

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

End point type

Secondary

End point timeframe

Up to 328 weeks

Notes
[41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 2. Therefore, other arms have not been selected.

End point values	Phase 2: Single-arm Cohort (MET+ T790M positive)
Number of subjects analysed	15
Units: Months
median (confidence interval 90%)	2.63 (1.38 to 2.73)

No statistical analyses for this end point

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

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End point title

Phase 2 (Non-Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Investigator ^[42]

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

End point type

Secondary

End point timeframe

Up to 328 weeks

Notes
[42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 2. Therefore, other arms have not been selected.

End point values	Phase 2: Single-arm Cohort (MET+ T790M positive)
Number of subjects analysed	15
Units: Months
median (confidence interval 90%)	1.41 (1.35 to 4.90)

No statistical analyses for this end point

Secondary: Phase 2: (Non-Randomized Part Only): Overall Survival (OS) Time

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End point title

Phase 2: (Non-Randomized Part Only): Overall Survival (OS) Time ^[43]

End point description

Overall survival time was measured as time in months between the date of randomization and the date of death. The safety analysis set included all subjects who had received any dose of the study medication.

End point type

Secondary

End point timeframe

Up to 328 weeks

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 2. Therefore, other arms have not been selected.

End point values	Phase 2: Single-arm Cohort (MET+ T790M positive)
Number of subjects analysed	15
Units: Months
median (confidence interval 90%)	25.86 (13.08 to 39.66)

No statistical analyses for this end point

Secondary: Phase 2 (Non-Randomized Part Only): Percentage of Subjects With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria

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End point title

Phase 2 (Non-Randomized Part Only): Percentage of Subjects With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria ^[44]

End point description

Objective response (OR) was defined as percentage of subjects who had achieved complete response (CR) or partial response (PR) as best overall response according to local radiological assessments from randomization/the first administration of study treatment to 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 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 diameters of target lesions, taking as reference smallest sum of 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. Safety analysis set was used.

End point type

Secondary

End point timeframe

Up to 328 weeks

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 2. Therefore, other arms have not been selected.

End point values	Phase 2: Single-arm Cohort (MET+ T790M positive)
Number of subjects analysed	15
Units: Percentage of Subjects
number (confidence interval 90%)	0 (0.0 to 18.1)

No statistical analyses for this end point

Secondary: Phase 2 (Non-Randomized Part Only): Percentage of Subjects With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria

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End point title

Phase 2 (Non-Randomized Part Only): Percentage of Subjects With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria ^[45]

End point description

Disease control defined as CR, PR, or stable disease(SD) as best overall response according to local radiological assessments from date of randomization/the first administration of study treatment to 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 sum of diameters of target lesions taking as reference baseline sum diameters. PD: an increase of at least 20% in sum of the diameters of target lesions, taking as reference smallest sum of diameters of target lesions recorded since treatment started and/or unequivocal progression of existing non-target lesions and/or presence of new lesions. 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. Safety analysis set was used.

End point type

Secondary

End point timeframe

Up to 328 weeks

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 2. Therefore, other arms have not been selected.

End point values	Phase 2: Single-arm Cohort (MET+ T790M positive)
Number of subjects analysed	15
Units: Percentage of Subjects
number (confidence interval 90%)	40 (19.1 to 64.0)

No statistical analyses for this end point

Secondary: Phase 2: Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) Global Health Status Scale Score at end of Treatment (EOT)

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End point 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) ^[46]

End point description

EORTC QLQ-C30 is a 30-question tool used to assess the overall quality of life (QoL) in cancer subjects. 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, dyspnea, 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. Quality of life (Qol) evaluable population set included ITT subjects 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 subjects analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline and EOT (up to 110 weeks)

Notes
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 2. Therefore, other arms have not been selected.

End point values	Phase 2: Tepotinib 500mg+Gefitinib250 mg (MET+ T790 negative)	Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)	Phase 2: Single-arm Cohort (MET+ T790M positive)
Number of subjects analysed	22	21	10
Units: Units on a Scale
arithmetic mean (standard deviation)	-16.29 ( 30.691 )	-2.78 ( 22.869 )	-24.19 ( 24.673 )

No statistical analyses for this end point

Secondary: Phase 2: Time-to-Symptom Progression (TTSP)

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End point title

Phase 2: Time-to-Symptom Progression (TTSP) ^[47]

End point 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. It consisted of 9 items focused on cancer symptoms (loss of appetite, fatigue, cough, shortness of breath, blood in sputum, symptoms of cancer, illness affecting normal activity, QoL). For each symptom score distance from left boundary to point where subject has marked line was measured in millimeters. Total scale length was 100 mm. Symptomatic progression was defined as increase/worsening of average symptomatic burden index (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. Quality of life evaluable population set included ITT subjects in treatment group in which they actually received treatment with a baseline and at least 1 evaluable on-treatment QoL questionnaire.

End point type

Secondary

End point timeframe

Up to 328 weeks

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only Phase 2. Therefore, other arms have not been selected.

End point values	Phase 2: Tepotinib 500mg+Gefitinib250 mg (MET+ T790 negative)	Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)	Phase 2: Single-arm Cohort (MET+ T790M positive)
Number of subjects analysed	29	22	15
Units: Months
median (confidence interval 90%)	5.75 (1.41 to 11.86)	8.61 (2.83 to 19.42)	2.63 (1.41 to 8.31)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to 328 weeks

Adverse event reporting additional description

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

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

20.0, 24.0

Reporting group title

Phase 1b: Tepotinib 300 mg +Gefitinib 250 mg

Reporting group description

Reporting group title

Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg

Reporting group description

Subjects 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.

Reporting group title

Phase 2: Tepotinib 500mg+Gefitinib250mg (MET+T790 negative)

Reporting group description

Reporting group title

Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)

Reporting group description

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

Reporting group title

Phase 2: Single-arm Cohort (MET+ T790M positive)

Reporting group description

Serious adverse events	Phase 1b: Tepotinib 300 mg +Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg	Phase 2: Tepotinib 500mg+Gefitinib250mg (MET+T790 negative)	Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)	Phase 2: Single-arm Cohort (MET+ T790M positive)
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 6 (66.67%)	7 / 12 (58.33%)	13 / 31 (41.94%)	8 / 23 (34.78%)	5 / 15 (33.33%)
number of deaths (all causes)	1	3	23	20	10
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to central nervous system
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	1 / 31 (3.23%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Amylase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 31 (3.23%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lipase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 31 (3.23%)	2 / 23 (8.70%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
White blood cell count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 31 (3.23%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Arrhythmia supraventricular
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest discomfort
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Disease progression
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	2 / 31 (6.45%)	1 / 23 (4.35%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest Pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 31 (3.23%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Face Oedema
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	2 / 31 (6.45%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	2 / 23 (8.70%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	1 / 31 (3.23%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 31 (3.23%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 31 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	0 / 6 (0.00%)	2 / 12 (16.67%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea paroxysmal nocturnal
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	3 / 31 (9.68%)	1 / 23 (4.35%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea at rest
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermatitis acneiform
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 31 (3.23%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 31 (3.23%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes virus infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	1 / 23 (4.35%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 31 (3.23%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoalbuminaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Phase 1b: Tepotinib 300 mg +Gefitinib 250 mg	Phase 1b: Tepotinib 500 mg + Gefitinib 250 mg	Phase 2: Tepotinib 500mg+Gefitinib250mg (MET+T790 negative)	Phase 2: Pemetrexed+Cisplatin/Carboplatin (MET+T790 negative)	Phase 2: Single-arm Cohort (MET+ T790M positive)
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 6 (100.00%)	12 / 12 (100.00%)	31 / 31 (100.00%)	23 / 23 (100.00%)	13 / 15 (86.67%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
Vascular disorders
Peripheral embolism
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	5 / 31 (16.13%)	5 / 23 (21.74%)	2 / 15 (13.33%)
occurrences all number	1	0	5	5	2
Axillary pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
Chest discomfort
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	2 / 31 (6.45%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	1	2	0	1
Chest pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	6 / 31 (19.35%)	1 / 23 (4.35%)	1 / 15 (6.67%)
occurrences all number	0	0	6	1	1
Fatigue
subjects affected / exposed	1 / 6 (16.67%)	5 / 12 (41.67%)	2 / 31 (6.45%)	3 / 23 (13.04%)	0 / 15 (0.00%)
occurrences all number	1	5	2	3	0
Malaise
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	1 / 31 (3.23%)	2 / 23 (8.70%)	1 / 15 (6.67%)
occurrences all number	0	1	1	2	1
Oedema
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	4 / 31 (12.90%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	1	4	0	1
Oedema peripheral
subjects affected / exposed	2 / 6 (33.33%)	3 / 12 (25.00%)	12 / 31 (38.71%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	2	3	12	1	0
Pyrexia
subjects affected / exposed	1 / 6 (16.67%)	2 / 12 (16.67%)	4 / 31 (12.90%)	1 / 23 (4.35%)	2 / 15 (13.33%)
occurrences all number	1	2	4	1	2
Local swelling
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Non−cardiac chest pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Peripheral swelling
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	2 / 31 (6.45%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	2	0	0
Social circumstances
Inadequate diet
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 31 (3.23%)	2 / 23 (8.70%)	0 / 15 (0.00%)
occurrences all number	0	0	1	2	0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 6 (0.00%)	2 / 12 (16.67%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	2	0	0	0
Vulvovaginal dryness
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 6 (50.00%)	1 / 12 (8.33%)	8 / 31 (25.81%)	5 / 23 (21.74%)	3 / 15 (20.00%)
occurrences all number	3	1	8	5	3
Dyspnoea
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	8 / 31 (25.81%)	2 / 23 (8.70%)	3 / 15 (20.00%)
occurrences all number	0	1	8	2	3
Haemoptysis
subjects affected / exposed	1 / 6 (16.67%)	1 / 12 (8.33%)	4 / 31 (12.90%)	0 / 23 (0.00%)	3 / 15 (20.00%)
occurrences all number	1	1	4	0	3
Pleural effusion
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	2 / 31 (6.45%)	1 / 23 (4.35%)	1 / 15 (6.67%)
occurrences all number	0	1	2	1	1
Productive cough
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	3 / 31 (9.68%)	3 / 23 (13.04%)	0 / 15 (0.00%)
occurrences all number	1	0	3	3	0
Rhinorrhoea
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	2 / 31 (6.45%)	2 / 23 (8.70%)	0 / 15 (0.00%)
occurrences all number	0	1	2	2	0
Dyspnoea paroxysmal nocturnal
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Dyspnoea exertional
subjects affected / exposed	3 / 6 (50.00%)	5 / 12 (41.67%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	3	5	0	0	0
Hiccups
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Pulmonary thrombosis
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Psychiatric disorders
Innsomnia
subjects affected / exposed	1 / 6 (16.67%)	1 / 12 (8.33%)	5 / 31 (16.13%)	2 / 23 (8.70%)	0 / 15 (0.00%)
occurrences all number	1	1	5	2	0
Investigations
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	3 / 31 (9.68%)	2 / 23 (8.70%)	0 / 15 (0.00%)
occurrences all number	0	0	3	2	0
Alanine aminotransferase increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	10 / 31 (32.26%)	2 / 23 (8.70%)	1 / 15 (6.67%)
occurrences all number	1	0	10	2	1
Amylase increased
subjects affected / exposed	4 / 6 (66.67%)	2 / 12 (16.67%)	11 / 31 (35.48%)	4 / 23 (17.39%)	4 / 15 (26.67%)
occurrences all number	4	2	11	4	4
Aspartate aminotransferase increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	5 / 31 (16.13%)	3 / 23 (13.04%)	2 / 15 (13.33%)
occurrences all number	1	0	5	3	2
Blood albumin decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	3 / 31 (9.68%)	1 / 23 (4.35%)	3 / 15 (20.00%)
occurrences all number	0	0	3	1	3
Blood alkaline phosphatase increased
subjects affected / exposed	3 / 6 (50.00%)	0 / 12 (0.00%)	2 / 31 (6.45%)	5 / 23 (21.74%)	2 / 15 (13.33%)
occurrences all number	3	0	2	5	2
Blood creatinine increased
subjects affected / exposed	2 / 6 (33.33%)	0 / 12 (0.00%)	4 / 31 (12.90%)	6 / 23 (26.09%)	2 / 15 (13.33%)
occurrences all number	2	0	4	6	2
Blood urea increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	3 / 23 (13.04%)	0 / 15 (0.00%)
occurrences all number	0	0	0	3	0
C-reactive protein increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
Creatinine renal clearance decreased
subjects affected / exposed	2 / 6 (33.33%)	0 / 12 (0.00%)	3 / 31 (9.68%)	3 / 23 (13.04%)	1 / 15 (6.67%)
occurrences all number	2	0	3	3	1
Electrocardiogram QT prolonged
subjects affected / exposed	3 / 6 (50.00%)	1 / 12 (8.33%)	3 / 31 (9.68%)	2 / 23 (8.70%)	1 / 15 (6.67%)
occurrences all number	3	1	3	2	1
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	1 / 31 (3.23%)	4 / 23 (17.39%)	1 / 15 (6.67%)
occurrences all number	1	0	1	4	1
Haemoglobin decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	2 / 31 (6.45%)	1 / 23 (4.35%)	1 / 15 (6.67%)
occurrences all number	0	0	2	1	1
International normalised ratio increased
subjects affected / exposed	3 / 6 (50.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	1 / 23 (4.35%)	1 / 15 (6.67%)
occurrences all number	3	0	0	1	1
Lipase increased
subjects affected / exposed	2 / 6 (33.33%)	2 / 12 (16.67%)	8 / 31 (25.81%)	3 / 23 (13.04%)	2 / 15 (13.33%)
occurrences all number	2	2	8	3	2
Neutrophil count decreased
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	2 / 31 (6.45%)	9 / 23 (39.13%)	1 / 15 (6.67%)
occurrences all number	0	1	2	9	1
Platelet count decreased
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	2 / 31 (6.45%)	6 / 23 (26.09%)	0 / 15 (0.00%)
occurrences all number	1	0	2	6	0
Prothrombin time prolonged
subjects affected / exposed	3 / 6 (50.00%)	0 / 12 (0.00%)	1 / 31 (3.23%)	2 / 23 (8.70%)	1 / 15 (6.67%)
occurrences all number	3	0	1	2	1
Weight decreased
subjects affected / exposed	0 / 6 (0.00%)	3 / 12 (25.00%)	6 / 31 (19.35%)	6 / 23 (26.09%)	3 / 15 (20.00%)
occurrences all number	0	3	6	6	3
White blood cell count decreased
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	2 / 31 (6.45%)	12 / 23 (52.17%)	2 / 15 (13.33%)
occurrences all number	1	0	2	12	2
Bacterial test positive
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
Blood glucose increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
Cardiac disorders
Supraventricular extrasystoles
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
Atrial fibrillation
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Pericardial effusion
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Cardiac discomfort
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 6 (0.00%)	2 / 12 (16.67%)	3 / 31 (9.68%)	4 / 23 (17.39%)	0 / 15 (0.00%)
occurrences all number	0	2	3	4	0
Headache
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	7 / 31 (22.58%)	3 / 23 (13.04%)	0 / 15 (0.00%)
occurrences all number	0	1	7	3	0
Cognitive disorder
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Dysgeusia
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
Memory impairment
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	5 / 31 (16.13%)	16 / 23 (69.57%)	4 / 15 (26.67%)
occurrences all number	0	0	5	16	4
Leukopenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	1 / 23 (4.35%)	1 / 15 (6.67%)
occurrences all number	0	0	0	1	1
Neutropenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	7 / 23 (30.43%)	1 / 15 (6.67%)
occurrences all number	0	0	0	7	1
Thrombocytopenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 31 (3.23%)	1 / 23 (4.35%)	1 / 15 (6.67%)
occurrences all number	0	0	1	1	1
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	2 / 23 (8.70%)	0 / 15 (0.00%)
occurrences all number	0	0	0	2	0
Hypoacusis
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Eye disorders
Eyelids pruritus
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
Keratitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	4 / 31 (12.90%)	2 / 23 (8.70%)	0 / 15 (0.00%)
occurrences all number	0	0	4	2	0
Abdominal pain
subjects affected / exposed	1 / 6 (16.67%)	3 / 12 (25.00%)	1 / 31 (3.23%)	2 / 23 (8.70%)	0 / 15 (0.00%)
occurrences all number	1	3	1	2	0
Abdominal pain upper
subjects affected / exposed	0 / 6 (0.00%)	2 / 12 (16.67%)	3 / 31 (9.68%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	2	3	1	0
Cheilitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	1	0	0	1
Constipation
subjects affected / exposed	0 / 6 (0.00%)	3 / 12 (25.00%)	6 / 31 (19.35%)	6 / 23 (26.09%)	3 / 15 (20.00%)
occurrences all number	0	3	6	6	3
Diarrhoea
subjects affected / exposed	4 / 6 (66.67%)	10 / 12 (83.33%)	18 / 31 (58.06%)	4 / 23 (17.39%)	7 / 15 (46.67%)
occurrences all number	4	10	18	4	7
Dyspepsia
subjects affected / exposed	1 / 6 (16.67%)	2 / 12 (16.67%)	2 / 31 (6.45%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	1	2	2	0	1
Epigastric discomfort
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	4 / 31 (12.90%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	0	4	1	0
Nausea
subjects affected / exposed	2 / 6 (33.33%)	2 / 12 (16.67%)	7 / 31 (22.58%)	14 / 23 (60.87%)	2 / 15 (13.33%)
occurrences all number	2	2	7	14	2
Stomatitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	2 / 31 (6.45%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	2	0	0
Vomiting
subjects affected / exposed	2 / 6 (33.33%)	3 / 12 (25.00%)	9 / 31 (29.03%)	11 / 23 (47.83%)	3 / 15 (20.00%)
occurrences all number	2	3	9	11	3
Abdominal discomfort
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Gingival bleeding
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Hepatobiliary disorders
Hepatic function abnormal
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	1 / 23 (4.35%)	1 / 15 (6.67%)
occurrences all number	0	0	0	1	1
Liver injury
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
Skin and subcutaneous tissue disorders
Dermatitis acneiform
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	4 / 31 (12.90%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	4	0	0
Dry skin
subjects affected / exposed	0 / 6 (0.00%)	4 / 12 (33.33%)	3 / 31 (9.68%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	4	3	0	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	2 / 31 (6.45%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	2	0	0
Pruritus
subjects affected / exposed	2 / 6 (33.33%)	4 / 12 (33.33%)	4 / 31 (12.90%)	2 / 23 (8.70%)	2 / 15 (13.33%)
occurrences all number	2	4	4	2	2
Rash
subjects affected / exposed	3 / 6 (50.00%)	5 / 12 (41.67%)	8 / 31 (25.81%)	0 / 23 (0.00%)	4 / 15 (26.67%)
occurrences all number	3	5	8	0	4
Seborrhoeic dermatitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	2 / 31 (6.45%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	2	0	0
Skin fissures
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
Skin hyperpigmentation
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	2 / 31 (6.45%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	2	0	0
Acne
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Erythema
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
Intertrigo
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	1 / 23 (4.35%)	1 / 15 (6.67%)
occurrences all number	0	1	0	1	1
Hydronephrosis
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Ureterolithiasis
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Endocrine disorders
Inappropriate antidiuretic hormone secretion
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 6 (16.67%)	2 / 12 (16.67%)	4 / 31 (12.90%)	1 / 23 (4.35%)	1 / 15 (6.67%)
occurrences all number	1	2	4	1	1
Bone pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
Muscle twitching
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
Musculoskeletal chest pain
subjects affected / exposed	0 / 6 (0.00%)	2 / 12 (16.67%)	2 / 31 (6.45%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	2	2	0	1
Pain in extremity
subjects affected / exposed	1 / 6 (16.67%)	1 / 12 (8.33%)	2 / 31 (6.45%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	1	1	2	0	1
Arthralgia
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	3 / 31 (9.68%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	3	0	0
Myalgia
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
Neck pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	2 / 31 (6.45%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	2	0	0
Infections and infestations
Conjunctivitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	3 / 31 (9.68%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	3	0	1
Gingivitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
Localised infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 31 (3.23%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	1	0	1
Nasopharyngitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	3 / 31 (9.68%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	0	3	1	0
Oral herpes
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1
Upper respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	4 / 31 (12.90%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	4	0	1
Urinary tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	4 / 31 (12.90%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	4	0	1
Cellulitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
Folliculitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0
Influenza
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Paronychia
subjects affected / exposed	2 / 6 (33.33%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	2	1	0	0	0
Pneumonia
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 6 (33.33%)	4 / 12 (33.33%)	11 / 31 (35.48%)	10 / 23 (43.48%)	3 / 15 (20.00%)
occurrences all number	2	4	11	10	3
Hyperglycaemia
subjects affected / exposed	0 / 6 (0.00%)	2 / 12 (16.67%)	2 / 31 (6.45%)	4 / 23 (17.39%)	0 / 15 (0.00%)
occurrences all number	0	2	2	4	0
Hyperkalaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	2 / 31 (6.45%)	2 / 23 (8.70%)	0 / 15 (0.00%)
occurrences all number	0	0	2	2	0
Hypermagnesaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	2 / 23 (8.70%)	0 / 15 (0.00%)
occurrences all number	0	0	0	2	0
Hypoalbuminaemia
subjects affected / exposed	2 / 6 (33.33%)	1 / 12 (8.33%)	9 / 31 (29.03%)	1 / 23 (4.35%)	2 / 15 (13.33%)
occurrences all number	2	1	9	1	2
Hypocalcaemia
subjects affected / exposed	2 / 6 (33.33%)	1 / 12 (8.33%)	6 / 31 (19.35%)	3 / 23 (13.04%)	2 / 15 (13.33%)
occurrences all number	2	1	6	3	2
Hypochloraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 31 (0.00%)	2 / 23 (8.70%)	0 / 15 (0.00%)
occurrences all number	0	0	0	2	0
Hypokalaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	3 / 31 (9.68%)	6 / 23 (26.09%)	2 / 15 (13.33%)
occurrences all number	0	1	3	6	2
Hypomagnesaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	2 / 23 (8.70%)	0 / 15 (0.00%)
occurrences all number	0	1	0	2	0
Hyponatraemia
subjects affected / exposed	1 / 6 (16.67%)	2 / 12 (16.67%)	2 / 31 (6.45%)	3 / 23 (13.04%)	0 / 15 (0.00%)
occurrences all number	1	2	2	3	0
Hypoproteinaemia
subjects affected / exposed	2 / 6 (33.33%)	0 / 12 (0.00%)	3 / 31 (9.68%)	5 / 23 (21.74%)	2 / 15 (13.33%)
occurrences all number	2	0	3	5	2
Hypoglycaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0
Hypophosphataemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 31 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

27 Nov 2017

Protocol amendments, including administrative changes was filed by the Sponsor and at the site.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1b: Number of Subjects Experiencing at least One Dose Limiting Toxicity (DLT)

Primary: Phase 1b: Number of Subjects Experiencing at least One Dose Limiting Toxicity (DLT)

Primary: Phase 1b: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs

Primary: Phase 1b: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs

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

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

Secondary: Phase 1b: Area Under the Plasma Concentration Versus Time Curve from Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, its Metabolites and Gefitinib

Secondary: Phase 1b: Area Under the Plasma Concentration Versus Time Curve from Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, its Metabolites and Gefitinib

Secondary: Phase 1b: Area Under the Plasma Concentration-Time Curve within 1 Dosing Interval (AUC 0-tau) of Tepotinib, its Metabolites and Gefitinib

Secondary: Phase 1b: Area Under the Plasma Concentration-Time Curve within 1 Dosing Interval (AUC 0-tau) of Tepotinib, its Metabolites and Gefitinib

Secondary: Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, its Metabolites and Gefitinib

Secondary: Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, its Metabolites and Gefitinib

Secondary: Phase 1b: Average Observed Plasma Concentration (Cavg) of Tepotinib, its Metabolites and Gefitinib

Secondary: Phase 1b: Average Observed Plasma Concentration (Cavg) of Tepotinib, its Metabolites and Gefitinib

Secondary: Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib, its Metabolites and Gefitinib

Secondary: Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib, its Metabolites and Gefitinib

Secondary: Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, its Metabolites and Gefitinib

Secondary: Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, its Metabolites and Gefitinib

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

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

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

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

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

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

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

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

Secondary: Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, its Metabolites and Gefitinib

Secondary: Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, its Metabolites and Gefitinib

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

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

Secondary: Phase 1b: Percentage of Subjects With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria

Secondary: Phase 1b: Percentage of Subjects With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria

Secondary: Phase 1b: Percentage of Subjects With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria

Secondary: Phase 1b: Percentage of Subjects With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria

Secondary: Phase 1b: Number of Subjects 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

Secondary: Phase 1b: Number of Subjects 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

Secondary: Phase 1b: Number of Subjects 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

Secondary: Phase 1b: Number of Subjects 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

Secondary: Phase 1b: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation

Secondary: Phase 1b: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation

Secondary: Phase 1b: Number of Subjects With Death and Reasons

Secondary: Phase 1b: Number of Subjects With Death and Reasons

Secondary: Phase 1b: Number of Subjects With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs)

Secondary: Phase 1b: Number of Subjects With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs)

Secondary: Phase 1b: Number of Subjects With Clinically Significant Abnormalities in Vital Signs

Secondary: Phase 1b: Number of Subjects With Clinically Significant Abnormalities in Vital Signs

Secondary: Phase 1b: Number of Subjects With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings

Secondary: Phase 1b: Number of Subjects With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings

Secondary: Phase 1b: Number of Subjects With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2

Secondary: Phase 1b: Number of Subjects With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2

Secondary: Phase 2: Number of Subjects 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

Secondary: Phase 2: Number of Subjects 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

Secondary: Phase 2: Number of Subjects 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

Secondary: Phase 2: Number of Subjects 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

Secondary: Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation

Secondary: Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation

Secondary: Phase 2: Number of Subjects With Death and Reasons

Secondary: Phase 2: Number of Subjects With Death and Reasons

Secondary: Phase 2: Number of Subjects with Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs)

Secondary: Phase 2: Number of Subjects with Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs)

Secondary: Phase 2: Number of Subjects With Clinically Significant Abnormalities in Vital Signs

Secondary: Phase 2: Number of Subjects With Clinically Significant Abnormalities in Vital Signs

Secondary: Phase 2: Number of Subjects With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings

Secondary: Phase 2: Number of Subjects With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings

Secondary: Phase 2: Number of Subjects With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2

Secondary: Phase 2: Number of Subjects With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2

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

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

Secondary: Phase 2: (Randomized Part Only): Overall Survival (OS) Time

Secondary: Phase 2: (Randomized Part Only): Overall Survival (OS) Time

Secondary: Phase 2 (Randomized Part Only): Percentage of Subjects With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria