Study of Efficacy and Safety of Nivolumab in Combination With EGF816 and of Nivolumab in Combination With INC280 in Patients With Previously Treated Non-small Cell Lung Cancer

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.

Time frame: 6 months

Population: All patients who had received at least 1 dose of INC280, EGF816 or nivolumab.

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

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

Population: All patients who had extensive PK sampling and provided an EGF816 evaluable PK profile on Cycle 1 Day 15. The EGF816 PK profile was considered evaluable if all the following conditions were satisfied: patient had received planned doses and patient had provided at least 1 valid primary PK parameter (Cmax, Tmax, AUClast).

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

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

Population: All patients who had extensive PK sampling and provided an INC280 evaluable PK profile on Cycle 1 Day 15. The INC280 PK profile was considered evaluable if all the following conditions were satisfied: patient had received planned doses and patient had provided at least 1 valid primary PK parameter (Cmax, Tmax, AUClast). In the Group 2B, no patients provided an INC280 evaluable PK profile.

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.

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

Population: All patients who had received at least 1 dose of INC280, EGF816 or nivolumab.

Dose intensity (mg/day) of EGF816 and INC280 was calculated as actual cumulative dose in milligrams divided by duration of exposure in days.

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

Population: All patients who had received at least 1 dose of INC280, EGF816 or nivolumab and had at least 1 valid post-baseline safety assessment.

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).

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

Population: All patients who had received at least 1 dose of INC280, EGF816 or nivolumab and had at least 1 valid post-baseline safety assessment.

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.

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

Population: All patients who had extensive PK sampling and provided an EGF816 evaluable PK profile on Cycle 1 Day 15. The EGF816 PK profile was considered evaluable if all the following conditions were satisfied: patient had received planned doses and patient had provided at least 1 valid primary PK parameter (Cmax, Tmax, AUClast).

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.

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

Population: All patients who had extensive PK sampling and provided an INC280 evaluable PK profile on Cycle 1 Day 15. The INC280 PK profile was considered evaluable if all the following conditions were satisfied: patient had received planned doses and patient had provided at least 1 valid primary PK parameter (Cmax, Tmax, AUClast). In the Group 2B, no patients provided an INC280 evaluable PK profile.

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

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

Population: All patients who had received at least 1 dose of INC280, EGF816 or nivolumab.

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.

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

Population: All patients who had extensive PK sampling and provided an EGF816 evaluable PK profile on Cycle 1 Day 15. The EGF816 PK profile was considered evaluable if all the following conditions were satisfied: patient had received planned doses and patient had provided at least 1 valid primary PK parameter (Cmax, Tmax, AUClast).

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.

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

Population: All patients who had extensive PK sampling and provided an INC280 evaluable PK profile on Cycle 1 Day 15. The INC280 PK profile was considered evaluable if all the following conditions were satisfied: patient had received planned doses and patient had provided at least 1 valid primary PK parameter (Cmax, Tmax, AUClast). In the Group 2B, no patients provided an INC280 evaluable PK profile.

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.

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

Population: All patients who had received at least 1 dose of INC280, EGF816 or nivolumab and had at least 1 valid post-baseline safety assessment.

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.

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

Population: All patients who had received at least 1 dose of INC280, EGF816 or nivolumab and had at least 1 valid post-baseline safety assessment.

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.

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

Population: All patients who had received at least 1 dose of INC280, EGF816 or nivolumab.

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.

Time frame: 1 year

Population: All patients who had received at least 1 dose of INC280, EGF816 or nivolumab.

Nivolumab serum concentrations were assessed in samples taken at pre-dose. Pre-dose samples were collected before the next dose administration.

Time frame: 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.

Population: All patients who had provided at least 1 evaluable nivolumab PK concentration. For a nivolumab PK concentration to be evaluable in pre-dose samples, a patient was required to have the sample collected before the next dose administration. Samples were not collected in Group 1 on Cycle 1 Day 1.

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.

Time frame: 3 months

Population: All patients who had received at least 1 dose of INC280, EGF816 or nivolumab.

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.

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

Population: All patients who had extensive PK sampling and provided an EGF816 evaluable PK profile on Cycle 1 Day 15. The EGF816 PK profile was considered evaluable if all the following conditions were satisfied: patient had received planned doses and patient had provided at least 1 valid primary PK parameter (Cmax, Tmax, AUClast).

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.

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

Population: All patients who had extensive PK sampling and provided an INC280 evaluable PK profile on Cycle 1 Day 15. The INC280 PK profile was considered evaluable if all the following conditions were satisfied: patient had received planned doses and patient had provided at least 1 valid primary PK parameter (Cmax, Tmax, AUClast). In the Group 2B, no patients provided an INC280 evaluable PK profile.