Study of Capmatinib and Spartalizumab/Placebo in Advanced NSCLC Patients With MET Exon 14 Skipping Mutations

Run-in Part: Dose Intensity of Spartalizumab

Dose intensity of spartalizumab was calculated as actual cumulative dose in milligrams divided by duration of exposure in days and then multiplied by the duration of one cycle (28 days).

Time frame: From first dose of spartalizumab to last dose, up to 0.9 years

Run-in Part: Disease Control Rate (DCR) by Investigator Assessment as Per RECIST 1.1

DCR is defined as the percentage of participants with a best overall response of Complete Response (CR), Partial Response (PR), Stable Disease (SD), and non-CR/non-progressive disease (for subjects without target lesions). Tumor response was based on local investigator assessment per RECIST v1.1. 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 2 years and 4 months

Run-in Part: Progression-Free Survival (PFS) by Investigator Assessment as Per RECIST 1.1

PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. Tumor response was based on investigator assessment per RECIST v1.1. Progression is defined using RECIST v1.1 as at least 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. PFS was analyzed using Kaplan-Meier estimates.

Time frame: Up to approximately 2 years and 5 months

Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Capmatinib

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

Time frame: pre-dose and 1, 2, 4 and 8 hours after morning dose on Cycle 3 Day 1. The duration of one cycle was 28 days.

Run-in Part: Time to Reach Maximum Plasma Concentration (Tmax) of Capmatinib

PK parameters were calculated based on capmatinib 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 and 1, 2, 4 and 8 hours after morning dose on Cycle 3 Day 1. The duration of one cycle was 28 days.

Run-in Part: Area Under the Plasma Concentration-time Curve From Time Zero to the End of a Dosing Interval (AUCtau) of Capmatinib

PK parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUCtau calculation. A dosing interval (tau) is defined as 12 hours. The portion of area under the curve between 8 hours and 12 hours post-dose was calculated by extrapolation based on terminal elimination slop.

Time frame: pre-dose and 1, 2, 4 and 8 hours after morning dose on Cycle 3 Day 1. The duration of one cycle was 28 days.

Run-in Part: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib

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

Time frame: pre-dose and 1, 2, 4 and 8 hours after morning dose on Cycle 3 Day 1. The duration of one cycle was 28 days.

Run-in Part: Maximum Observed Serum Concentration (Cmax) of Spartalizumab

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

Time frame: pre-infusion and 1, 72, 168, 336 and 672 hours after completion of the spartalizumab infusion on Cycle 3 Day 1. The duration of the infusion was approximately 30 minutes. The duration of one cycle was 28 days.

Run-in Part: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab

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

Time frame: pre-infusion and 1, 72, 168, 336 and 672 hours after completion of the spartalizumab infusion on Cycle 3 Day 1. The duration of the infusion was approximately 30 minutes. The duration of one cycle was 28 days.

Run-in Part: Area Under the Serum Concentration-time Curve From Time Zero to the End of a Dosing Interval (AUCtau) of Spartalizumab

PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUCtau calculation. A dosing interval (tau) is defined as 28 days.

Time frame: pre-infusion and 1, 72, 168, 336 and 672 hours after completion of the spartalizumab infusion on Cycle 3 Day 1. The duration of the infusion was approximately 30 minutes. The duration of one cycle was 28 days.

Run-in Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab

PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.

Time frame: pre-infusion and 1, 72, 168, 336 and 672 hours after completion of the spartalizumab infusion on Cycle 3 Day 1. The duration of the infusion was approximately 30 minutes. The duration of one cycle was 28 days.

Randomized Part: Overall Survival (OS)

OS is defined as the time from date of start of treatment to date of death due to any cause.

Time frame: Up to 12 years

Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab

Number of participants with at least one dose reduction of capmatinib and spartalizumab and number of participants with at least one dose interruption of capmatinib and spartalizumab.

Time frame: Up to 6 years

Randomized Part: Dose Intensity of Capmatinib and Spartalizumab

Dose intensity is defined as the ratio of actual cumulative dose and duration of exposure.

Time frame: Up to 6 years

Randomized Part: Progression-Free Survival (PFS) by Investigator Assessment as Per RECIST 1.1

PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause. Tumor response based on investigator assessment per RECIST v1.1.

Time frame: Up to 6 years

Randomized Part: Disease Control Rate (DCR) by BIRC and Investigator Assessment as Per RECIST 1.1

DCR is defined as the percentage of participants with a best overall response of Complete Response (CR), Partial Response (PR), Stable Disease (SD), and non-CR/non-progressive disease (for subjects without target lesions). Tumor response based on BIRC and local investigator assessment per RECIST v1.1.

Time frame: Up to 6 years

Randomized Part: Overall Response Rate (ORR) by BIRC and Investigator Assessment as Per RECIST 1.1

ORR is defined as the percentage of participants with a best overall response of Complete Response (CR) and Partial Response (PR). Tumor response based on BIRC and local investigator assessment per RECIST v1.1.

Time frame: Up to 6 years

Randomized Part: Duration of Response (DOR) by BIRC and Investigator Assessment as Per RECIST 1.1

DOR is defined as the time from the date of first documented response (CR or PR) to the first documented progression per RECIST 1.1 or death due to any cause.

Time frame: Up to 6 years

Randomized Part: Time to Response (TTR) by BIRC and Investigator Assessment as Per RECIST 1.1

TTR is defined as the time from the date of start of treatment to the first documented response of either CR or PR, which must be subsequently confirmed, according to RECIST 1.1.

Time frame: Up to 6 years

Randomized Part: Change From Baseline in EORTC QLQ-C30

The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items and is composed of both multi-item scales and single-item measures. These include 5 functional scales (physical, role, emotional, cognitive, and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial impact) and a global health status/QoL scale. All scales and single-item measures range in score from 0 to 100. For the functional and the global QoL scales, a higher score indicates better health. For the symptom scales, a higher score indicates more symptom burden. The QLQ-C30 summary score (0-100) is calculated as the mean of 13 of the 15 QLQ-C30 scale and item scores (excluding global QoL and financial impact), with a higher score indicating a better health-related QoL.

Time frame: Up to 6 years

Randomized Part: Change From Baseline in EORTC QLQ-LC13

EORTC QLQ-LC13 is used in conjunction with the EORTC QLQ-C30 and provides information on an additional 13 items specifically related to lung cancer. The five domains of the LC13 include pain, dyspnea, coughing and hemoptysis, and are based on their presence over the past week. All but the pain domain are scored on a 4 point Likert scale ranging from "not at all" to "very much". Pain score is based on its presence, hence yes or no. Scores are averaged and transformed to 0 to 100. A higher score indicates a higher presence of symptoms.

Time frame: Up to 6 years

Randomized Part: Change From Baseline in EQ-5D-5L

The EQ-5D-5L is a standardized measure of health utility that provides a single index value for one's health status. The EQ-5D-5L contains one item for each of five dimensions of health-related quality of life (HRQOL) (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Response options for each item vary from having no problems to extreme problems. Subject responses to the five dimensions of HRQOL reflect a specific health state that corresponds to a population preference weight for that state on a continuous scale of 0 (death) to 1 (perfect health). A visual analog scale (ranging from 0 to 100) is also included to capture subject's rating of their overall health status. Higher scores of the EQ-5D-5L represent better health states.

Time frame: Up to 6 years

Randomized Part: Time to Definitive 10 Points Deterioration Symptom Scores for Pain in Chest, Coughing and Dyspnea Per QLQ-LC13 Questionnaire

EORTC QLQ-LC13 is used in conjunction with the EORTC QLQ-C30 and provides information on an additional 13 items specifically related to lung cancer. The five domains of the LC13 include pain in chest, dyspnea, coughing and hemoptysis, and are based on their presence over the past week. All but the pain domain are scored on a 4 point Likert scale ranging from "not at all" to "very much". Pain score is based on its presence, hence yes or no. Scores are averaged and transformed to 0 to 100. A higher score indicates a higher presence of symptoms. The time to definitive 10 points deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10 points relative to baseline worsening of the corresponding scale score or death due to any cause.

Time frame: Up to 6 years

Randomized Part: Time to Definitive Deterioration in Global Health Status/QoL, Shortness of Breath and Pain Per EORTC QLQ-C30

The EORTC QLQ-C30 contains 30 items and is composed of both multi-item scales and single-item measures. These include 5 functional scales (physical, role, emotional, cognitive, and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial impact) and a global health status/QoL scale. All scales and single-item measures range in score from 0 to 100. For the functional and the global QoL scales, a higher score indicates better health. For the symptom scales, a higher score indicates more symptom burden. The time to definitive 10 points deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10 points relative to baseline worsening of the corresponding scale score or death due to any cause.

Time frame: Up to 6 years

Randomized Part: Maximum Observed Concentration (Cmax) of Capmatinib and Spartalizumab

Pharmacokinetic (PK) parameters calculated based on capmatinib and spartalizumab concentrations in plasma and serum, respectively, by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.

Time frame: Up to 6 years

Randomized Part: Time to Reach Maximum Concentration (Tmax) of Capmatinib and Spartalizumab

Pharmacokinetic (PK) parameters calculated based on capmatinib and spartalizumab concentrations in plasma and serum, respectively, by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) concentration following a dose.

Time frame: Up to 6 years

Randomized Part: Area Under the Concentration-time Curve From Time Zero to the End of a Dosing Interval (AUCtau) of Capmatinib and Spartalizumab

Pharmacokinetic (PK) parameters calculated based on capmatinib and spartalizumab concentrations in plasma and serum, respectively, by using non-compartmental methods.

Time frame: Up to 6 years

Randomized Part: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib and Spartalizumab

Pharmacokinetic (PK) parameters calculated based on capmatinib and spartalizumab concentrations in plasma and serum, respectively, by using non-compartmental methods.

Time frame: Up to 6 years

Randomized Part: Number of Participants With Anti-spartalizumab Antibodies

Immunogenicity (IG) evaluated in serum samples. The assay to quantify and assess the IG was a validated homogeneous enzyme-linked immunosorbent assay (ELISA).

Time frame: Baseline (pre-dose), up to 6 years