Study Efficacy and Safety of INC280 in Patients With Advanced Hepatocellular Carcinoma.

TTP is defined as the time from the date of treatment start to the date of the first documented radiological confirmation of disease progression or death due to underlying cancer. Tumor response was based on investigator assessment per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. For RECIST v1.1, Progressive disease (PD) = At least a 20% increase in the sum of diameters of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition, the sum must also demonstrate an absolute increase of at least 5 mm. If a patient had not had the event at the date of analysis cut-off or when he/she received any further anti-neoplastic therapy, TTP was censored at the time of the last adequate assessment. TTP was estimated using the Kaplan-Meier method.

Time frame: Up to approximately 8 years and 2 months

Population: All patients who received at least one dose of INC280. Patients were analyzed according to the treatment group defined in the study protocol to which they were assigned at baseline: Dose-Determining part and Dose Expansion part. In alignment with the primary objective of the study, efficacy was analyzed in the dose expansion part based on the level of c-MET expression, independently of the formulation received, the capsule or the tablet that was introduced later to facilitate the dosing.

PK parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods. Accumulation ratio of drug exposure was calculated as AUC0-12h on Cycle 1 Day 15 divided by AUC0-12h on Cycle 1 Day 1.

Time frame: pre-dose, 30 minutes and 1, 2, 4, 6 and 8 hours after morning dose and 12 hours after evening dose on Cycle 1 Day 1 and Cycle 1 Day 15. The duration of one cycle was 21 days.

Population: Patients in the pharmacokinetic analysis set (PAS) with an available value for the outcome measure. PAS consists of all patients who provided an evaluable PK profile. A profile is considered evaluable if all the following conditions are satisfied: patient received at least one dose of the planned treatments, patient provided at least one primary PK parameter and patient did not vomit within 4 hours after the dosing of INC280. Full PK blood samples were not collected in the Dose-Expansion Part

PK parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods. Apparent drug clearance from the plasma was calculated as dose/AUCinf.

Time frame: pre-dose, 30 minutes and 1, 2, 4, 6 and 8 hours after morning dose and 12 hours after evening dose on Cycle 1 Day 1 and Cycle 1 Day 15. The duration of one cycle was 21 days.

Population: Patients in the pharmacokinetic analysis set (PAS) with an available value for the outcome measure. PAS consists of all patients who provided an evaluable PK profile. A profile is considered evaluable if all the following conditions are satisfied: patient received at least one dose of the planned treatments, patient provided at least one primary PK parameter and patient did not vomit within 4 hours after the dosing of INC280. Full PK blood samples were not collected in the Dose-Expansion Part

PK parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-12h calculation. A dosing interval was 12 hours for twice daily dosing.

Time frame: pre-dose, 30 minutes and 1, 2, 4, 6 and 8 hours after morning dose and 12 hours after evening dose on Cycle 1 Day 1 and Cycle 1 Day 15. The duration of one cycle was 21 days.

Population: Patients in the pharmacokinetic analysis set (PAS) with an available value for the outcome measure. PAS consists of all patients who provided an evaluable PK profile. A profile is considered evaluable if all the following conditions are satisfied: patient received at least one dose of the planned treatments, patient provided at least one primary PK parameter and patient did not vomit within 4 hours after the dosing of INC280. Full PK blood samples were not collected in the Dose-Expansion Part

Tumor response was based on local investigator assessment per RECIST v1.1. DCR is defined as the percentage of participants with a BOR of Complete Response (CR), Partial Response (PR) and 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 diameter 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: Up to approximately 8 years and 2 months

Population: All patients who received at least one dose of INC280. Patients were analyzed according to the treatment group defined in the protocol to which they were assigned at baseline: Dose-Determining part and Dose Expansion part. In alignment with the secondary efficacy objective of the study, efficacy was analyzed in the dose expansion part based on the level of c-MET expression, independently of the formulation received, the capsule or the tablet that was introduced later to facilitate the dosing.

Dose intensity of INC280 was calculated as actual cumulative dose in milligrams divided by duration of exposure in days.

Time frame: From first dose of study drug to last dose, up to approximately 8 years and 1 month

Population: Safety Set: All patients who received at least one dose of INC280. Patients were analyzed according to the treatment they actually received.

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, 30 minutes and 1, 2, 4, 6 and 8 hours after morning dose and 12 hours after evening dose on Cycle 1 Day 1 and Cycle 1 Day 15. The duration of one cycle was 21 days.

Population: Patients in the pharmacokinetic analysis set (PAS) with an available value for the outcome measure. PAS consists of all patients who provided an evaluable PK profile. A profile is considered evaluable if all the following conditions are satisfied: patient received at least one dose of the planned treatments, patient provided at least one primary PK parameter and patient did not vomit within 4 hours after the dosing of INC280. Full PK blood samples were not collected in the Dose-Expansion Part

Number of participants with AEs (any AE regardless of seriousness) and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs.

Time frame: From first dose of study drug to 30 days after last dose, up to approximately 8 years and 2 months

Population: Safety Set: All patients who received at least one dose of INC280. Patients were analyzed according to the treatment they actually received.

For patients who did not tolerate the protocol-specified dosing scheme, dose adjustments and interruptions were permitted. Number of participants with dose reductions and dose interruptions of CINC280 is reported in this table.

Time frame: From first dose of study drug to last dose, up to approximately 8 years and 1 month

Population: Safety Set: All patients who received at least one dose of INC280. Patients were analyzed according to the treatment they actually received.

Tumor response was based on local investigator assessment per RECIST v1.1. ORR per RECIST v1.1 is defined as the percentage of participants with a best overall response (BOR) 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: Up to approximately 8 years and 2 months

Population: All patients who received at least one dose of INC280. Patients were analyzed according to the treatment group defined in the protocol to which they were assigned at baseline: Dose-Determining part and Dose Expansion part. In alignment with the secondary efficacy objective of the study, efficacy was analyzed in the dose expansion part based on the level of c-MET expression, independently of the formulation received, the capsule or the tablet that was introduced later to facilitate the dosing.

OS is defined as the time from date of first study treatment intake to date of death due to any cause. If a patient was not known to have died, survival was censored at the date of last contact. OS was analyzed using the Kaplan-Meier method.

Time frame: Up to approximately 8 years and 2 months

Population: All patients who received at least one dose of INC280. Patients were analyzed according to the treatment group defined in the protocol to which they were assigned at baseline: Dose-Determining part and Dose Expansion part. In alignment with the secondary efficacy objective of the study, efficacy was analyzed in the dose expansion part based on the level of c-MET expression, independently of the formulation received, the capsule or the tablet that was introduced later to facilitate the dosing.

PFS is defined as the time from date of first study treatment intake to the date of the first radiologically documented progression or death due to any cause or initiation of new antineoplastic therapy. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. PFS was analyzed using Kaplan-Meier estimates.

Time frame: Up to approximately 8 years and 2 months

Population: All patients who received at least one dose of INC280. Patients were analyzed according to the treatment group defined in the protocol to which they were assigned at baseline: Dose-Determining part and Dose Expansion part. In alignment with the secondary efficacy objective of the study, efficacy was analyzed in the dose expansion part based on the level of c-MET expression, independently of the formulation received, the capsule or the tablet that was introduced later to facilitate the dosing.

PK parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods. Elimination half-life (T1/2) values were calculated as natural logarithm (ln) 2/terminal elimination rate constant.

Time frame: pre-dose, 30 minutes and 1, 2, 4, 6 and 8 hours after morning dose and 12 hours after evening dose on Cycle 1 Day 1 and Cycle 1 Day 15. The duration of one cycle was 21 days.

Population: Patients in the pharmacokinetic analysis set (PAS) with an available value for the outcome measure. PAS consists of all patients who provided an evaluable PK profile. A profile is considered evaluable if all the following conditions are satisfied: patient received at least one dose of the planned treatments, patient provided at least one primary PK parameter and patient did not vomit within 4 hours after the dosing of INC280. Full PK blood samples were not collected in the Dose-Expansion Part

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, 30 minutes and 1, 2, 4, 6 and 8 hours after morning dose and 12 hours after evening dose on Cycle 1 Day 1 and Cycle 1 Day 15. The duration of one cycle was 21 days.

Population: Patients in the pharmacokinetic analysis set (PAS) with an available value for the outcome measure. PAS consists of all patients who provided an evaluable PK profile. A profile is considered evaluable if all the following conditions are satisfied: patient received at least one dose of the planned treatments, patient provided at least one primary PK parameter and patient did not vomit within 4 hours after the dosing of INC280. Full PK blood samples were not collected in the Dose-Expansion Part

On-treatment deaths were collected from start of treatment to 30 days after last dose. Survival follow-up deaths were collected from day 31 after last dose of study treatment until end of study. All deaths refer to the sum of on-treatment deaths plus survival follow-up deaths.

Time frame: On-treatment: Up to approximately 8 years and 2 months. Survival follow-up: Up to approximately 8 years and 2 months.

Population: Safety Set: All patients who received at least one dose of INC280. Patients were analyzed according to the treatment they actually received.