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Clinical Trial Results:
A phase II, multicenter, open-label study of EGF816 in combination with Nivolumab in adult patients with EGFR mutated non-small cell lung cancer and of INC280 in combination with Nivolumab in adult patients with cMet positive non-small cell lung cancer

Summary
EudraCT number	2014-003731-20
Trial protocol	DE ES NL IT
Global end of trial date	05 Feb 2021

Results information
Results version number	v1(current)
This version publication date	16 Feb 2022
First version publication date	16 Feb 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

CEGF816X2201C

ISRCTN number

US NCT number

NCT02323126

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.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

05 Feb 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

05 Feb 2021

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objective of the trial was to estimate the clinical activity of nivolumab in combination with EGF816 or INC280.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

09 Feb 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 8

Country: Number of subjects enrolled

France: 2

Country: Number of subjects enrolled

Germany: 5

Country: Number of subjects enrolled

Italy: 18

Country: Number of subjects enrolled

Singapore: 6

Country: Number of subjects enrolled

Spain: 18

Country: Number of subjects enrolled

Switzerland: 5

Country: Number of subjects enrolled

United States: 2

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

Participants took part in 13 investigative sites in 8 countries.

Screening details

In the molecular pre-screening, tumor tissue was collected for determination and/or confirmation of protocol specific pre-requisite genetic alterations. After the molecular pre-screening, screening evaluations were performed within 28 days prior to the first dose of study medication. The treatment period started on Cycle 1 Day 1.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Nivolumab and EGF816

Arm description

Group 1: EGF816 150 mg QD + Nivolumab 3 mg/kg Q2W

Arm type

Experimental

Investigational medicinal product name

EGF816

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

EGF816 150 mg once daily (QD) administered orally

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 3 mg/kg every 2 weeks (Q2W) administered by intravenous infusion

Nivolumab and INC280, high cMet

Arm description

Group 2A: INC280 400 mg BID, High cMET + Nivolumab 3 mg/kg Q2W

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 3 mg/kg every 2 weeks (Q2W) administered by intravenous infusion

Investigational medicinal product name

INC280

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

INC280 400 mg twice daily (BID) administered orally

Nivolumab and INC280, low cMet

Arm description

Group 2B: INC280 400 mg BID, Low cMet + Nivolumab 3 mg/kg Q2W

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 3 mg/kg every 2 weeks (Q2W) administered by intravenous infusion

Investigational medicinal product name

INC280

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

INC280 400 mg twice daily (BID) administered orally

Number of subjects in period 1	Nivolumab and EGF816	Nivolumab and INC280, high cMet	Nivolumab and INC280, low cMet
Started	18	16	30
Completed	0	0	0
Not completed	18	16	30
Adverse event, serious fatal	1	1	4
Patient / guardian decision	-	1	2
Physician decision	-	1	3
Adverse event, non-fatal	3	5	7
Progressive disease	14	8	14

Baseline characteristics

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Reporting group title

Nivolumab and EGF816

Reporting group description

Group 1: EGF816 150 mg QD + Nivolumab 3 mg/kg Q2W

Reporting group title

Nivolumab and INC280, high cMet

Reporting group description

Group 2A: INC280 400 mg BID, High cMET + Nivolumab 3 mg/kg Q2W

Reporting group title

Nivolumab and INC280, low cMet

Reporting group description

Group 2B: INC280 400 mg BID, Low cMet + Nivolumab 3 mg/kg Q2W

Reporting group values	Nivolumab and EGF816	Nivolumab and INC280, high cMet	Nivolumab and INC280, low cMet	Total
Number of subjects	18	16	30	64
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	11	8	14	33
From 65-84 years	7	8	15	30
85 years and over	0	0	1	1
Age Continuous
Units: years
arithmetic mean (standard deviation)	62.6 ( 8.77 )	63.8 ( 13.05 )	64.9 ( 8.45 )	-
Sex: Female, Male
Units: participants
Female	12	8	15	35
Male	6	8	15	29
Race/Ethnicity, Customized
Units: Subjects
Asian	4	1	2	7
Caucasian	14	14	26	54
Other	0	0	1	1
Unknown	0	1	1	2

End points

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Reporting group title

Nivolumab and EGF816

Reporting group description

Group 1: EGF816 150 mg QD + Nivolumab 3 mg/kg Q2W

Reporting group title

Nivolumab and INC280, high cMet

Reporting group description

Group 2A: INC280 400 mg BID, High cMET + Nivolumab 3 mg/kg Q2W

Reporting group title

Nivolumab and INC280, low cMet

Reporting group description

Group 2B: INC280 400 mg BID, Low cMet + Nivolumab 3 mg/kg Q2W

Primary: Progression-Free Survival (PFS) rate at 6 months per RECIST v1.1

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End point title

Progression-Free Survival (PFS) rate at 6 months per RECIST v1.1 ^[1]

End point description

PFS rate represents the percentage of participants without a first documented progression or death due to any cause after the start of study treatment. Tumor response was based on local investigator assessment as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). PFS was modeled using a Weibull distribution and the PFS rate at 6 months was estimated from the posterior distribution.

End point type

Primary

End point timeframe

6 months

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: No statistical analysis were planned for this primary endpoint.

End point values	Nivolumab and EGF816	Nivolumab and INC280, high cMet	Nivolumab and INC280, low cMet
Number of subjects analysed	18	16	30
Units: percentage of participants
number (confidence interval 95%)	63.4 (45.7 to 79.2)	68.9 (48.5 to 85.7)	50.9 (35.6 to 66.4)

No statistical analyses for this end point

Secondary: Overall Response Rate (ORR) per RECIST v1.1

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End point title

Overall Response Rate (ORR) per RECIST v1.1

End point description

Tumor response was based on local investigator assessment as per RECIST v1.1. ORR per RECIST 1.1 is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR). For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

End point type

Secondary

End point timeframe

From start of treatment until end of treatment, assessed up to 4.7 years

End point values	Nivolumab and EGF816	Nivolumab and INC280, high cMet	Nivolumab and INC280, low cMet
Number of subjects analysed	18	16	30
Units: percentage of participants
number (not applicable)	38.9	25.0	16.7

No statistical analyses for this end point

Secondary: Disease Control Rate (DCR) per RECIST v1.1

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End point title

Disease Control Rate (DCR) per RECIST v1.1

End point description

Tumor response was based on local investigator assessment as per RECIST v1.1. DCR per RECIST 1.1 is defined as the percentage of participants with a best overall response of Complete Response (CR), Partial Response (PR) or Stable Disease (SD). For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR= At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters; SD= Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression.

End point type

Secondary

End point timeframe

From start of treatment until end of treatment, assessed up to 4.7 years

End point values	Nivolumab and EGF816	Nivolumab and INC280, high cMet	Nivolumab and INC280, low cMet
Number of subjects analysed	18	16	30
Units: percentage of participants
number (not applicable)	94.4	81.3	43.3

No statistical analyses for this end point

Secondary: Median Progression-Free Survival (PFS) per RECIST v1.1

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End point title

Median Progression-Free Survival (PFS) per RECIST v1.1

End point description

PFS is the time from the date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. The median PFS was estimated using the Kaplan-Meier method. Tumor response was based on local investigator assessment as per RECIST v1.1

End point type

Secondary

End point timeframe

From start of treatment to first documented progression or death, assessed up to 5 years

End point values	Nivolumab and EGF816	Nivolumab and INC280, high cMet	Nivolumab and INC280, low cMet
Number of subjects analysed	18	16	30
Units: months
median (confidence interval 95%)	7.4 (3.7 to 11.1)	6.2 (3.5 to 19.2)	4.2 (1.8 to 7.4)

No statistical analyses for this end point

Secondary: Progression-Free Survival (PFS) rate at 3 months per RECIST v1.1

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End point title

Progression-Free Survival (PFS) rate at 3 months per RECIST v1.1

End point description

PFS rate represents the percentage of participants without a first documented progression or death due to any cause after the start of study treatment. Tumor response was based on local investigator assessment as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). The PFS rate at 3 months was estimated using the Kaplan-Meier method.

End point type

Secondary

End point timeframe

3 months

End point values	Nivolumab and EGF816	Nivolumab and INC280, high cMet	Nivolumab and INC280, low cMet
Number of subjects analysed	18	16	30
Units: percentage of participants
number (confidence interval 95%)	83.3 (56.8 to 94.3)	86.7 (56.4 to 96.5)	53.8 (33.3 to 70.6)

No statistical analyses for this end point

Secondary: Overall Survival (OS) at 1 year

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End point title

Overall Survival (OS) at 1 year

End point description

OS represents the percentage of participants who are alive after the start of study treatment. OS at 1 year was estimated using the Kaplan-Meier method.

End point type

Secondary

End point timeframe

1 year

End point values	Nivolumab and EGF816	Nivolumab and INC280, high cMet	Nivolumab and INC280, low cMet
Number of subjects analysed	18	16	30
Units: percentage of participants
number (confidence interval 95%)	55.6 (30.5 to 74.8)	72.3 (41.5 to 88.7)	32.5 (15.8 to 50.5)

No statistical analyses for this end point

Secondary: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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End point title

Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

End point description

Number of participants with AEs and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

End point type

Secondary

End point timeframe

From first dose of study medication up to 100 days after last dose of study medication, with a maximum duration of 5 years

End point values	Nivolumab and EGF816	Nivolumab and INC280, high cMet	Nivolumab and INC280, low cMet
Number of subjects analysed	18	16	30
Units: participants
AEs	18	16	30
Treatment-related AEs	17	16	27
AEs with grade 3/4	18	14	24
Treatment-related AEs with grade 3/4	13	12	16
SAEs	14	8	18
Treatment-related SAEs	6	4	7
Fatal SAEs	4	1	4
Treatment related fatal SAEs	2	0	0
AEs leading to discontinuation	5	7	11
Treatment-related AEs leading to discontinuation	5	7	9
AEs leading to dose adjustment/interruption	15	14	23

No statistical analyses for this end point

Secondary: Number of participants with dose reductions and dose interruptions of EGF816, INC280 and nivolumab

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End point title

Number of participants with dose reductions and dose interruptions of EGF816, INC280 and nivolumab

End point description

Number of participants with at least one dose reduction of EGF816, INC280 or nivolumab and number of participants with at least one dose interruption of EGF816, INC280 or nivolumab. Dose reduction was not allowed for nivolumab in this study. Due to EudraCT system limitations, data fields cannot be blank if the number of subjects analyzed in the corresponding column is greater than 0. Therefore, not applicable values (eg. dose reduction or interruption of EGF816 in Groups 2A and 2B) are indicated as ‘999’.

End point type

Secondary

End point timeframe

From first dose of study treatment until last dose of study treatment, up to maximum 4.7 years

End point values	Nivolumab and EGF816	Nivolumab and INC280, high cMet	Nivolumab and INC280, low cMet
Number of subjects analysed	18	16	30
Units: participants
EGF816, dose reduction (n=18, 0, 0)	5	999	999
EGF816, dose interruption (n=18, 0, 0)	14	999	999
INC280, dose reduction (n=0, 16, 30)	999	7	10
INC280, dose interruption (n=0, 16, 30)	999	14	25
Nivolumab, dose reduction (n=18, 16, 30)	0	0	0
Nivolumab, dose interruption (n=18, 16, 30)	12	10	15

No statistical analyses for this end point

Secondary: Dose intensity of EGF816 and INC280

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End point title

Dose intensity of EGF816 and INC280

End point description

Dose intensity (mg/day) of EGF816 and INC280 was calculated as actual cumulative dose in milligrams divided by duration of exposure in days. Due to EudraCT system limitations, data fields cannot be blank if the number of subjects analyzed in the corresponding column is greater than 0. Therefore, not applicable values (eg. dose intensity of EGF816 in Groups 2A and 2B) are indicated as ‘999’.

End point type

Secondary

End point timeframe

From first dose of study treatment until last dose of study treatment, up to maximum 4.7 years

End point values	Nivolumab and EGF816	Nivolumab and INC280, high cMet	Nivolumab and INC280, low cMet
Number of subjects analysed	18	16	30
Units: mg/day
median (full range (min-max))
EGF816 (n=18, 0, 0)	141.5 (81 to 150)	999 (999 to 999)	999 (999 to 999)
INC280 (n=0, 16, 30)	999 (999 to 999)	609.4 (254 to 800)	636.7 (240 to 800)

No statistical analyses for this end point

Secondary: Dose intensity of nivolumab

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End point title

Dose intensity of nivolumab

End point description

Dose intensity (mg/kg biweekly) of nivolumab was calculated as actual cumulative dose in mg/kg divided by duration of exposure in days and then multiplied by 14 days (2 weeks).

End point type

Secondary

End point timeframe

From first dose of study treatment until last dose of study treatment, up to maximum 4.7 years

End point values	Nivolumab and EGF816	Nivolumab and INC280, high cMet	Nivolumab and INC280, low cMet
Number of subjects analysed	18	16	30
Units: mg/kg/2-week
median (full range (min-max))	3.0 (3 to 3)	3.0 (3 to 3)	3.0 (3 to 3)

No statistical analyses for this end point

Secondary: Maximum observed plasma concentration (Cmax) of EGF816

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End point title

Maximum observed plasma concentration (Cmax) of EGF816 ^[2]

End point description

Pharmacokinetic (PK) parameters were calculated based on EGF816 plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose.

End point type

Secondary

End point timeframe

pre-dose, 1, 3, 6 and 8 hours post EGF816 dose on Cycle 1 Day 15. The duration of one cycle was 28 days.

Notes
[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: This endpoint is only applicable for Group 1.

End point values	Nivolumab and EGF816
Number of subjects analysed	11
Units: ng/mL
geometric mean (geometric coefficient of variation)	935 ( 40.8 )

No statistical analyses for this end point

Secondary: Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of EGF816

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End point title

Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of EGF816 ^[3]

End point description

Pharmacokinetic (PK) parameters were calculated based on EGF816 plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.

End point type

Secondary

End point timeframe

pre-dose, 1, 3, 6 and 8 hours post EGF816 dose on Cycle 1 Day 15. The duration of one cycle was 28 days.

Notes
[3] - 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: This endpoint is only applicable for Group 1.

End point values	Nivolumab and EGF816
Number of subjects analysed	11
Units: hr*ng/mL
geometric mean (geometric coefficient of variation)	5560 ( 42.8 )

No statistical analyses for this end point

Secondary: Time to reach maximum plasma concentration (Tmax) of EGF816

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End point title

Time to reach maximum plasma concentration (Tmax) of EGF816 ^[4]

End point description

Pharmacokinetic (PK) parameters were calculated based on EGF816 plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) plasma concentration following a dose.

End point type

Secondary

End point timeframe

pre-dose, 1, 3, 6 and 8 hours post EGF816 dose on Cycle 1 Day 15. The duration of one cycle was 28 days.

Notes
[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: This endpoint is only applicable for Group 1.

End point values	Nivolumab and EGF816
Number of subjects analysed	11
Units: hours
median (full range (min-max))	3.00 (1.00 to 6.00)

No statistical analyses for this end point

Secondary: Maximum observed plasma concentration (Cmax) of INC280

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End point title

Maximum observed plasma concentration (Cmax) of INC280 ^[5]

End point description

Pharmacokinetic (PK) parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose.

End point type

Secondary

End point timeframe

pre-dose, 1, 3, 6 and 8 hours post INC280 dose on Cycle 1 Day 15. The duration of one cycle was 28 days.

Notes
[5] - 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: This endpoint is only applicable for Groups 2A and 2B.

End point values	Nivolumab and INC280, high cMet	Nivolumab and INC280, low cMet
Number of subjects analysed	5	0 ^[6]
Units: ng/mL
geometric mean (geometric coefficient of variation)	6190 ( 83.9 )	( )

Notes
[6] - In the Group 2B, no patients provided an INC280 evaluable PK profile.

No statistical analyses for this end point

Secondary: Minimum observed plasma concentration (Cmin) of EGF816

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End point title

Minimum observed plasma concentration (Cmin) of EGF816 ^[7]

End point description

Pharmacokinetic (PK) parameters were calculated based on EGF816 plasma concentrations by using non-compartmental methods. Cmin is defined as the minimum observed plasma concentration following a dose.

End point type

Secondary

End point timeframe

pre-dose, 1, 3, 6 and 8 hours post EGF816 dose on Cycle 1 Day 15. The duration of one cycle was 28 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: This endpoint is only applicable for Group 1.

End point values	Nivolumab and EGF816
Number of subjects analysed	11
Units: ng/mL
geometric mean (geometric coefficient of variation)	398 ( 48.8 )

No statistical analyses for this end point

Secondary: Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of INC280

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End point title

Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of INC280 ^[8]

End point description

Pharmacokinetic (PK) parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.

End point type

Secondary

End point timeframe

pre-dose, 1, 3, 6 and 8 hours post INC280 dose on Cycle 1 Day 15. The duration of one cycle was 28 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: This endpoint is only applicable for Groups 2A and 2B.

End point values	Nivolumab and INC280, high cMet	Nivolumab and INC280, low cMet
Number of subjects analysed	5	0 ^[9]
Units: hr*ng/mL
geometric mean (geometric coefficient of variation)	19300 ( 97.5 )	( )

Notes
[9] - In the Group 2B, no patients provided an INC280 evaluable PK profile.

No statistical analyses for this end point

Secondary: Time to reach maximum plasma concentration (Tmax) of INC280

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End point title

Time to reach maximum plasma concentration (Tmax) of INC280 ^[10]

End point description

Pharmacokinetic (PK) parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) plasma concentration following a dose. Actual recorded sampling times were considered for the calculations.

End point type

Secondary

End point timeframe

pre-dose, 1, 3, 6 and 8 hours post INC280 dose on Cycle 1 Day 15. The duration of one cycle was 28 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: This endpoint is only applicable for Groups 2A and 2B.

End point values	Nivolumab and INC280, high cMet	Nivolumab and INC280, low cMet
Number of subjects analysed	5	0 ^[11]
Units: hours
median (full range (min-max))	0.983 (0.667 to 1.08)	( to )

Notes
[11] - In the Group 2B, no patients provided an INC280 evaluable PK profile.

No statistical analyses for this end point

Secondary: Minimum observed plasma concentration (Cmin) of INC280

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End point title

Minimum observed plasma concentration (Cmin) of INC280 ^[12]

End point description

Pharmacokinetic (PK) parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods. Cmin is defined as the minimum observed plasma concentration following a dose.

End point type

Secondary

End point timeframe

pre-dose, 1, 3, 6 and 8 hours post INC280 dose on Cycle 1 Day 15. The duration of one cycle was 28 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: This endpoint is only applicable for Groups 2A and 2B.

End point values	Nivolumab and INC280, high cMet	Nivolumab and INC280, low cMet
Number of subjects analysed	5	0 ^[13]
Units: ng/mL
geometric mean (geometric coefficient of variation)	428 ( 105 )	( )

Notes
[13] - In the Group 2B, no patients provided an INC280 evaluable PK profile.

No statistical analyses for this end point

Secondary: Pre-dose serum concentration of nivolumab

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End point title

Pre-dose serum concentration of nivolumab

End point description

Nivolumab serum concentrations were assessed in samples taken at pre-dose. Pre-dose samples were collected before the next dose administration. Due to EudraCT system limitations, data fields cannot be blank if the number of subjects analyzed in the corresponding column is greater than 0. Therefore, not applicable values (eg. nivolumab concentration when n=0) are indicated as ‘999’. Additionally, in Cycle 1 Day 1, ‘0’ indicates that the values were below the lower limit of quantification (<0.20 ng/mL).

End point type

Secondary

End point timeframe

pre-dose on Cycle 1 Day 1 (groups 2A and 2B only) and pre-dose on Cycle 1 Day 15 and Cycle 2 Day 1 (all groups). The duration of one cycle was 28 days.

End point values	Nivolumab and EGF816	Nivolumab and INC280, high cMet	Nivolumab and INC280, low cMet
Number of subjects analysed	18	15	29
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1 (n=0, 7, 16)	999 ( 999 )	0 ( 0 )	0 ( 0 )
Cycle 1 Day 15 (n=17, 13, 23)	17.2 ( 28.6 )	18.6 ( 45.3 )	19.5 ( 35.6 )
Cycle 2 Day 1 (n=15, 10, 22)	21.3 ( 54.6 )	35.7 ( 26.6 )	26.4 ( 77.1 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study medication up to 100 days after last dose of study medication, with a maximum duration of 5 years.

Adverse event reporting additional description

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.1

Reporting group title

Nivolumab and EGF816

Reporting group description

Group 1: EGF816 150 mg QD + Nivolumab 3 mg/kg Q2W

Reporting group title

Nivolumab and INC280, high cMet

Reporting group description

Group 2A: INC280 400 mg BID, High cMET + Nivolumab 3 mg/kg Q2W

Reporting group title

Nivolumab and INC280, low cMet

Reporting group description

Group 2B: INC280 400 mg BID, Low cMet + Nivolumab 3 mg/kg Q2W

Reporting group title

Nivolumab and INC280, high+low cMet

Reporting group description

Group 2A+2B (low and high cMet): INC280 400 mg BID + Nivolumab 3 mg/kg Q2W

Serious adverse events	Nivolumab and EGF816	Nivolumab and INC280, high cMet	Nivolumab and INC280, low cMet	Nivolumab and INC280, high+low cMet
Total subjects affected by serious adverse events
subjects affected / exposed	14 / 18 (77.78%)	8 / 16 (50.00%)	18 / 30 (60.00%)	26 / 46 (56.52%)
number of deaths (all causes)	8	4	10	14
number of deaths resulting from adverse events	2	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to meninges
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Giant cell arteritis
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Condition aggravated
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	1 / 18 (5.56%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gait disturbance
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
Pyrexia
subjects affected / exposed	4 / 18 (22.22%)	1 / 16 (6.25%)	3 / 30 (10.00%)	4 / 46 (8.70%)
occurrences causally related to treatment / all	2 / 4	1 / 1	2 / 3	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Contrast media allergy
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Bronchospasm
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	2 / 18 (11.11%)	2 / 16 (12.50%)	2 / 30 (6.67%)	4 / 46 (8.70%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2
Interstitial lung disease
subjects affected / exposed	3 / 18 (16.67%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	2 / 18 (11.11%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	1 / 18 (5.56%)	1 / 16 (6.25%)	1 / 30 (3.33%)	2 / 46 (4.35%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 1	2 / 2
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Tachypnoea
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood creatinine increased
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinus tachycardia
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Ataxia
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	1 / 18 (5.56%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysaesthesia
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysarthria
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
Lethargy
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Somnolence
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Disseminated intravascular coagulation
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Diplopia
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	1 / 30 (3.33%)	2 / 46 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 18 (5.56%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 2	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	2 / 30 (6.67%)	3 / 46 (6.52%)
occurrences causally related to treatment / all	0 / 0	1 / 1	2 / 2	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic function abnormal
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rash macular
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stevens-Johnson syndrome
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myositis
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal wall abscess
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial infection
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
Pneumonia
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetic ketoacidosis
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperamylasaemia
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Nivolumab and EGF816	Nivolumab and INC280, high cMet	Nivolumab and INC280, low cMet	Nivolumab and INC280, high+low cMet
Total subjects affected by non serious adverse events
subjects affected / exposed	18 / 18 (100.00%)	16 / 16 (100.00%)	29 / 30 (96.67%)	45 / 46 (97.83%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Benign neoplasm
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Infected naevus
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Metastases to meninges
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Vascular disorders
Giant cell arteritis
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	2	0	2
Haematoma
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Hypertension
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences all number	1	0	1	1
Peripheral ischaemia
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	7 / 18 (38.89%)	6 / 16 (37.50%)	10 / 30 (33.33%)	16 / 46 (34.78%)
occurrences all number	11	10	15	25
Chest discomfort
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Catheter site swelling
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Chills
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Face oedema
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Fatigue
subjects affected / exposed	3 / 18 (16.67%)	5 / 16 (31.25%)	4 / 30 (13.33%)	9 / 46 (19.57%)
occurrences all number	3	6	4	10
Gait disturbance
subjects affected / exposed	2 / 18 (11.11%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	2	0	0	0
Influenza like illness
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 30 (6.67%)	2 / 46 (4.35%)
occurrences all number	0	0	4	4
Non-cardiac chest pain
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 30 (6.67%)	2 / 46 (4.35%)
occurrences all number	0	0	3	3
Oedema
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	1 / 30 (3.33%)	2 / 46 (4.35%)
occurrences all number	0	1	1	2
Oedema peripheral
subjects affected / exposed	1 / 18 (5.56%)	8 / 16 (50.00%)	8 / 30 (26.67%)	16 / 46 (34.78%)
occurrences all number	1	14	16	30
Pain
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Peripheral swelling
subjects affected / exposed	1 / 18 (5.56%)	2 / 16 (12.50%)	0 / 30 (0.00%)	2 / 46 (4.35%)
occurrences all number	2	2	0	2
Pyrexia
subjects affected / exposed	10 / 18 (55.56%)	6 / 16 (37.50%)	3 / 30 (10.00%)	9 / 46 (19.57%)
occurrences all number	18	6	6	12
Reproductive system and breast disorders
Breast haematoma
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Cystocele
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Genital ulceration
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Pelvic pain
subjects affected / exposed	2 / 18 (11.11%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	2	0	0	0
Perineal fistula
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Vulvovaginal pruritus
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Vulvovaginal discomfort
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	4 / 18 (22.22%)	3 / 16 (18.75%)	4 / 30 (13.33%)	7 / 46 (15.22%)
occurrences all number	7	3	4	7
Dysphonia
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Dyspnoea
subjects affected / exposed	4 / 18 (22.22%)	2 / 16 (12.50%)	7 / 30 (23.33%)	9 / 46 (19.57%)
occurrences all number	7	2	10	12
Dyspnoea exertional
subjects affected / exposed	1 / 18 (5.56%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	2	1	0	1
Haemoptysis
subjects affected / exposed	1 / 18 (5.56%)	1 / 16 (6.25%)	1 / 30 (3.33%)	2 / 46 (4.35%)
occurrences all number	1	2	1	3
Epistaxis
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Nasal dryness
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Pleural effusion
subjects affected / exposed	0 / 18 (0.00%)	2 / 16 (12.50%)	2 / 30 (6.67%)	4 / 46 (8.70%)
occurrences all number	0	2	2	4
Pneumonitis
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	1 / 30 (3.33%)	2 / 46 (4.35%)
occurrences all number	0	1	1	2
Sleep apnoea syndrome
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	1 / 30 (3.33%)	2 / 46 (4.35%)
occurrences all number	0	1	1	2
Insomnia
subjects affected / exposed	2 / 18 (11.11%)	2 / 16 (12.50%)	1 / 30 (3.33%)	3 / 46 (6.52%)
occurrences all number	2	2	1	3
Suicidal ideation
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Product issues
Device occlusion
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Thrombosis in device
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 18 (0.00%)	2 / 16 (12.50%)	5 / 30 (16.67%)	7 / 46 (15.22%)
occurrences all number	0	2	7	9
Amylase increased
subjects affected / exposed	6 / 18 (33.33%)	9 / 16 (56.25%)	6 / 30 (20.00%)	15 / 46 (32.61%)
occurrences all number	11	20	14	34
Aspartate aminotransferase increased
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	5 / 30 (16.67%)	6 / 46 (13.04%)
occurrences all number	0	1	9	10
Bilirubin conjugated increased
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Blood albumin decreased
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Blood bilirubin increased
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 30 (6.67%)	2 / 46 (4.35%)
occurrences all number	0	0	2	2
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	1 / 30 (3.33%)	2 / 46 (4.35%)
occurrences all number	0	1	1	2
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	6 / 30 (20.00%)	6 / 46 (13.04%)
occurrences all number	0	0	8	8
Blood creatinine increased
subjects affected / exposed	0 / 18 (0.00%)	6 / 16 (37.50%)	9 / 30 (30.00%)	15 / 46 (32.61%)
occurrences all number	0	12	13	25
Blood glucose increased
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	3	0	3
Blood triglycerides increased
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 18 (0.00%)	3 / 16 (18.75%)	0 / 30 (0.00%)	3 / 46 (6.52%)
occurrences all number	0	5	0	5
C-reactive protein increased
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	1 / 30 (3.33%)	2 / 46 (4.35%)
occurrences all number	0	1	1	2
Lipase increased
subjects affected / exposed	4 / 18 (22.22%)	7 / 16 (43.75%)	6 / 30 (20.00%)	13 / 46 (28.26%)
occurrences all number	5	14	6	20
Lymphocyte count decreased
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 30 (6.67%)	2 / 46 (4.35%)
occurrences all number	0	0	3	3
Platelet count decreased
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 30 (6.67%)	2 / 46 (4.35%)
occurrences all number	0	0	3	3
Transaminases increased
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	2 / 30 (6.67%)	3 / 46 (6.52%)
occurrences all number	0	1	2	3
Weight decreased
subjects affected / exposed	3 / 18 (16.67%)	2 / 16 (12.50%)	2 / 30 (6.67%)	4 / 46 (8.70%)
occurrences all number	3	2	2	4
White blood cell count decreased
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 30 (6.67%)	2 / 46 (4.35%)
occurrences all number	0	0	2	2
Injury, poisoning and procedural complications
Femur fracture
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Limb injury
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Lumbar vertebral fracture
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Muscle injury
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Procedural pain
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	2	0	0	0
Cardiac disorders
Extrasystoles
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Tachycardia
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 30 (6.67%)	2 / 46 (4.35%)
occurrences all number	0	0	2	2
Nervous system disorders
Balance disorder
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Cerebral ischaemia
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Dysaesthesia
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	2	0	0	0
Dizziness
subjects affected / exposed	3 / 18 (16.67%)	1 / 16 (6.25%)	3 / 30 (10.00%)	4 / 46 (8.70%)
occurrences all number	3	1	5	6
Dysgeusia
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Essential tremor
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Headache
subjects affected / exposed	4 / 18 (22.22%)	5 / 16 (31.25%)	0 / 30 (0.00%)	5 / 46 (10.87%)
occurrences all number	5	6	0	6
Hydrocephalus
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Lethargy
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 30 (6.67%)	2 / 46 (4.35%)
occurrences all number	0	0	2	2
Nervous system disorder
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	2	0	2
Paraesthesia
subjects affected / exposed	2 / 18 (11.11%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	3	1	0	1
Peripheral sensory neuropathy
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Presyncope
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Sciatica
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Somnolence
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	2	0	2
Seizure
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences all number	1	0	1	1
Speech disorder
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Tremor
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Spinal cord compression
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	4 / 18 (22.22%)	4 / 16 (25.00%)	7 / 30 (23.33%)	11 / 46 (23.91%)
occurrences all number	4	5	11	16
Leukopenia
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	2	0	0	0
Neutropenia
subjects affected / exposed	1 / 18 (5.56%)	1 / 16 (6.25%)	2 / 30 (6.67%)	3 / 46 (6.52%)
occurrences all number	1	1	2	3
Thrombocytopenia
subjects affected / exposed	2 / 18 (11.11%)	0 / 16 (0.00%)	2 / 30 (6.67%)	2 / 46 (4.35%)
occurrences all number	2	0	2	2
Ear and labyrinth disorders
Deafness
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Tinnitus
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Eye disorders
Dry eye
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Uveitis
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Vision blurred
subjects affected / exposed	1 / 18 (5.56%)	2 / 16 (12.50%)	0 / 30 (0.00%)	2 / 46 (4.35%)
occurrences all number	1	2	0	2
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 18 (11.11%)	0 / 16 (0.00%)	2 / 30 (6.67%)	2 / 46 (4.35%)
occurrences all number	3	0	2	2
Abdominal pain upper
subjects affected / exposed	2 / 18 (11.11%)	1 / 16 (6.25%)	3 / 30 (10.00%)	4 / 46 (8.70%)
occurrences all number	2	3	3	6
Anal haemorrhage
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Aphthous ulcer
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Ascites
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Constipation
subjects affected / exposed	3 / 18 (16.67%)	5 / 16 (31.25%)	2 / 30 (6.67%)	7 / 46 (15.22%)
occurrences all number	5	9	2	11
Diarrhoea
subjects affected / exposed	9 / 18 (50.00%)	5 / 16 (31.25%)	6 / 30 (20.00%)	11 / 46 (23.91%)
occurrences all number	17	10	18	28
Dry mouth
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Dysphagia
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences all number	1	0	1	1
Faeces discoloured
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 18 (0.00%)	2 / 16 (12.50%)	1 / 30 (3.33%)	3 / 46 (6.52%)
occurrences all number	0	2	1	3
Oesophageal pain
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Nausea
subjects affected / exposed	5 / 18 (27.78%)	13 / 16 (81.25%)	12 / 30 (40.00%)	25 / 46 (54.35%)
occurrences all number	7	20	22	42
Stomatitis
subjects affected / exposed	3 / 18 (16.67%)	1 / 16 (6.25%)	2 / 30 (6.67%)	3 / 46 (6.52%)
occurrences all number	6	1	2	3
Toothache
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Vomiting
subjects affected / exposed	5 / 18 (27.78%)	9 / 16 (56.25%)	7 / 30 (23.33%)	16 / 46 (34.78%)
occurrences all number	5	11	9	20
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Hepatic pain
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	2	0	0	0
Skin and subcutaneous tissue disorders
Actinic keratosis
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Alopecia
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Dermatitis acneiform
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Dry skin
subjects affected / exposed	4 / 18 (22.22%)	2 / 16 (12.50%)	2 / 30 (6.67%)	4 / 46 (8.70%)
occurrences all number	4	2	2	4
Dermatitis exfoliative
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Ecchymosis
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Erythema
subjects affected / exposed	2 / 18 (11.11%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	2	1	0	1
Eczema
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Hyperhidrosis
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Nail disorder
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	2	0	0	0
Lichenoid keratosis
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Nail dystrophy
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Onychoclasis
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Pain of skin
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Palmar erythema
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Pruritus
subjects affected / exposed	6 / 18 (33.33%)	2 / 16 (12.50%)	4 / 30 (13.33%)	6 / 46 (13.04%)
occurrences all number	14	3	4	7
Rash
subjects affected / exposed	12 / 18 (66.67%)	3 / 16 (18.75%)	4 / 30 (13.33%)	7 / 46 (15.22%)
occurrences all number	20	4	5	9
Rash erythematous
subjects affected / exposed	2 / 18 (11.11%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	3	0	0	0
Rash maculo-papular
subjects affected / exposed	3 / 18 (16.67%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	15	1	0	1
Rash pruritic
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Skin exfoliation
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Skin fissures
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	2	0	0	0
Urticaria
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	2 / 18 (11.11%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	2	0	0	0
Pollakiuria
subjects affected / exposed	3 / 18 (16.67%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	3	0	0	0
Renal impairment
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Renal failure
subjects affected / exposed	1 / 18 (5.56%)	1 / 16 (6.25%)	1 / 30 (3.33%)	2 / 46 (4.35%)
occurrences all number	1	2	1	3
Urinary incontinence
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	0 / 18 (0.00%)	2 / 16 (12.50%)	0 / 30 (0.00%)	2 / 46 (4.35%)
occurrences all number	0	2	0	2
Hypophysitis
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Hypothyroidism
subjects affected / exposed	1 / 18 (5.56%)	1 / 16 (6.25%)	1 / 30 (3.33%)	2 / 46 (4.35%)
occurrences all number	1	1	1	2
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 30 (6.67%)	2 / 46 (4.35%)
occurrences all number	0	0	3	3
Arthralgia
subjects affected / exposed	4 / 18 (22.22%)	5 / 16 (31.25%)	4 / 30 (13.33%)	9 / 46 (19.57%)
occurrences all number	4	8	7	15
Back pain
subjects affected / exposed	1 / 18 (5.56%)	3 / 16 (18.75%)	3 / 30 (10.00%)	6 / 46 (13.04%)
occurrences all number	2	3	4	7
Bone pain
subjects affected / exposed	1 / 18 (5.56%)	1 / 16 (6.25%)	2 / 30 (6.67%)	3 / 46 (6.52%)
occurrences all number	1	1	3	4
Muscle contracture
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Muscle spasms
subjects affected / exposed	2 / 18 (11.11%)	2 / 16 (12.50%)	1 / 30 (3.33%)	3 / 46 (6.52%)
occurrences all number	2	3	1	4
Muscular weakness
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Musculoskeletal pain
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences all number	1	0	1	1
Musculoskeletal stiffness
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Myalgia
subjects affected / exposed	0 / 18 (0.00%)	3 / 16 (18.75%)	3 / 30 (10.00%)	6 / 46 (13.04%)
occurrences all number	0	3	3	6
Pain in extremity
subjects affected / exposed	1 / 18 (5.56%)	1 / 16 (6.25%)	3 / 30 (10.00%)	4 / 46 (8.70%)
occurrences all number	2	1	3	4
Spinal pain
subjects affected / exposed	1 / 18 (5.56%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	1	1	0	1
Infections and infestations
Abdominal wall abscess
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Candida infection
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Bronchitis
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Cellulitis
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Conjunctivitis
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Cystitis bacterial
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Dermatitis infected
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Herpes zoster
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	1 / 30 (3.33%)	2 / 46 (4.35%)
occurrences all number	0	1	1	2
Herpes simplex
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Influenza
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	2	0	0	0
Lower respiratory tract infection
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	2	0	2
Nasopharyngitis
subjects affected / exposed	1 / 18 (5.56%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	1	1	0	1
Oesophageal candidiasis
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Oral candidiasis
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Paronychia
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Pneumonia
subjects affected / exposed	2 / 18 (11.11%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences all number	2	0	1	1
Pulpitis dental
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Respiratory tract infection viral
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Sinusitis
subjects affected / exposed	0 / 18 (0.00%)	2 / 16 (12.50%)	0 / 30 (0.00%)	2 / 46 (4.35%)
occurrences all number	0	2	0	2
Upper respiratory tract infection
subjects affected / exposed	2 / 18 (11.11%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 46 (2.17%)
occurrences all number	4	0	1	1
Urinary tract infection
subjects affected / exposed	1 / 18 (5.56%)	2 / 16 (12.50%)	1 / 30 (3.33%)	3 / 46 (6.52%)
occurrences all number	1	2	1	3
Metabolism and nutrition disorders
Cell death
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Decreased appetite
subjects affected / exposed	6 / 18 (33.33%)	2 / 16 (12.50%)	9 / 30 (30.00%)	11 / 46 (23.91%)
occurrences all number	6	3	9	12
Hypercalcaemia
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	1	0	1
Hyperkalaemia
subjects affected / exposed	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 46 (2.17%)
occurrences all number	0	2	0	2
Hyperuricaemia
subjects affected / exposed	2 / 18 (11.11%)	0 / 16 (0.00%)	2 / 30 (6.67%)	2 / 46 (4.35%)
occurrences all number	4	0	3	3
Hypoalbuminaemia
subjects affected / exposed	0 / 18 (0.00%)	2 / 16 (12.50%)	9 / 30 (30.00%)	11 / 46 (23.91%)
occurrences all number	0	3	10	13
Hypocalcaemia
subjects affected / exposed	2 / 18 (11.11%)	0 / 16 (0.00%)	2 / 30 (6.67%)	2 / 46 (4.35%)
occurrences all number	2	0	3	3
Hypokalaemia
subjects affected / exposed	3 / 18 (16.67%)	2 / 16 (12.50%)	7 / 30 (23.33%)	9 / 46 (19.57%)
occurrences all number	4	2	16	18
Hypochloraemia
subjects affected / exposed	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 46 (0.00%)
occurrences all number	1	0	0	0
Hypomagnesaemia
subjects affected / exposed	1 / 18 (5.56%)	2 / 16 (12.50%)	3 / 30 (10.00%)	5 / 46 (10.87%)
occurrences all number	1	2	3	5
Hyponatraemia
subjects affected / exposed	1 / 18 (5.56%)	1 / 16 (6.25%)	1 / 30 (3.33%)	2 / 46 (4.35%)
occurrences all number	1	1	2	3
Hypophosphataemia
subjects affected / exposed	0 / 18 (0.00%)	2 / 16 (12.50%)	0 / 30 (0.00%)	2 / 46 (4.35%)
occurrences all number	0	3	0	3
Hypoproteinaemia
subjects affected / exposed	0 / 18 (0.00%)	2 / 16 (12.50%)	0 / 30 (0.00%)	2 / 46 (4.35%)
occurrences all number	0	3	0	3

More information

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Were there any global substantial amendments to the protocol? Yes

22 Jul 2015

Provided additional guidelines for hepatic AE management for EGF816 and INC280; update contraception guidance following nivolumab treatment and prohibited concomitant medications and updated exclusion criteria; and implemented HIV testing at screening for patients in Germany.

16 Oct 2015

Clarified the definition of toxicity as independent of study drug; modified guideline for hepatotoxicity for cases meeting Hy’s law criteria; and provided guidelines for dose modification or discontinuation for EGF816-related interstitial lung disease.

15 Feb 2016

Implemented changes that were introduced with 2 Urgent Safety Measures, including enrollment halt into Group 1 (EGF816 + nivolumab), nivolumab permanent discontinuation for all ongoing patients in Group 1, and dose escalation guidelines update for EGF816 and INC280 and skin-toxicity management guidelines.

19 May 2016

Expanded the eligibility of Group 2 patients (INC280 plus nivolumab) to include patients with NSCLC without high cMet levels (i.e., any level of cMet was permitted); allowed the exploration of the immunomodulatory activity of INC280 in patients with NSCLC by introducing new biomarker tests; added the provision for study treatment to be temporarily interrupted for palliative treatment of symptomatic CNS or bone lesions with non-invasive therapy; decreased the frequency of radiological efficacy assessments after Cycle 24; provided additional guidance for management to liver toxicities; and updated eligibility criteria and dose modification guidelines for amylase and lipase, and permitted and prohibited concomitant medications for INC280.

13 Apr 2017

Introduced the INC280 dose strength of 150 mg; made updates based on the new edition of INC280 investigator brochure; and updated exclusion criteria and requirement for pregnancy tests.

29 Jan 2018

Added recommendations for management of myotoxicity of nivolumab and pneumonitis/intestinal lung disease as a potential risk of INC280; updated administration instruction of INC280 and prohibited and permitted concomitant medications for Group 2; and clarified recommendations for discontinuing patients from study treatment versus from only one study drug in the setting of specific AEs.

21 Jun 2018

Updated guidelines for EGF816/INC280 dose modification/discontinuation in the context of non-infectious pneumonitis/interstitial lung disease.

12 Mar 2020

Introduced the timing for primary CSR; modified the duration of disease progression follow-up; streamlined study assessment to reduce the assessment burden of patients; refined the definition of end of study; updated the dose modification algorithm and AE management; and implemented a maximum duration of 2 years for nivolumab treatment

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.

Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com for complete trial results.

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Clinical trials

Clinical Trial Results: A phase II, multicenter, open-label study of EGF816 in combination with Nivolumab in adult patients with EGFR mutated non-small cell lung cancer and of INC280 in combination with Nivolumab in adult patients with cMet positive non-small cell lung cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression-Free Survival (PFS) rate at 6 months per RECIST v1.1

Primary: Progression-Free Survival (PFS) rate at 6 months per RECIST v1.1

Secondary: Overall Response Rate (ORR) per RECIST v1.1

Secondary: Overall Response Rate (ORR) per RECIST v1.1

Secondary: Disease Control Rate (DCR) per RECIST v1.1

Secondary: Disease Control Rate (DCR) per RECIST v1.1

Secondary: Median Progression-Free Survival (PFS) per RECIST v1.1

Secondary: Median Progression-Free Survival (PFS) per RECIST v1.1

Secondary: Progression-Free Survival (PFS) rate at 3 months per RECIST v1.1

Secondary: Progression-Free Survival (PFS) rate at 3 months per RECIST v1.1

Secondary: Overall Survival (OS) at 1 year

Secondary: Overall Survival (OS) at 1 year

Secondary: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Number of participants with dose reductions and dose interruptions of EGF816, INC280 and nivolumab

Secondary: Number of participants with dose reductions and dose interruptions of EGF816, INC280 and nivolumab

Secondary: Dose intensity of EGF816 and INC280

Secondary: Dose intensity of EGF816 and INC280

Secondary: Dose intensity of nivolumab

Secondary: Dose intensity of nivolumab

Secondary: Maximum observed plasma concentration (Cmax) of EGF816

Secondary: Maximum observed plasma concentration (Cmax) of EGF816

Secondary: Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of EGF816

Secondary: Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of EGF816

Secondary: Time to reach maximum plasma concentration (Tmax) of EGF816

Secondary: Time to reach maximum plasma concentration (Tmax) of EGF816

Secondary: Maximum observed plasma concentration (Cmax) of INC280

Secondary: Maximum observed plasma concentration (Cmax) of INC280

Secondary: Minimum observed plasma concentration (Cmin) of EGF816

Secondary: Minimum observed plasma concentration (Cmin) of EGF816

Secondary: Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of INC280

Secondary: Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of INC280

Secondary: Time to reach maximum plasma concentration (Tmax) of INC280

Secondary: Time to reach maximum plasma concentration (Tmax) of INC280

Secondary: Minimum observed plasma concentration (Cmin) of INC280

Secondary: Minimum observed plasma concentration (Cmin) of INC280

Secondary: Pre-dose serum concentration of nivolumab

Secondary: Pre-dose serum concentration of nivolumab

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A phase II, multicenter, open-label study of EGF816 in combination with Nivolumab in adult patients with EGFR mutated non-small cell lung cancer and of INC280 in combination with Nivolumab in adult patients with cMet positive non-small cell lung cancer