Carcinoma, Non-Small-Cell Lung
Conditions
Keywords
capmatinib, spartalizumab, MET mutation, EGFR wild-type, ALK negative mutation
Brief summary
A double-blind, placebo controlled, randomized, phase II study evaluating the efficacy and safety of capmatinib (INC280) and spartalizumab (PDR001) combination therapy versus capmatinib and placebo as first line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC) patients with MET exon 14 skipping (METΔex14) mutations
Detailed description
The purpose of this study was to evaluate the efficacy and safety of capmatinib in combination with spartalizumab in treatment naive patients with EGFR wild-type, ALK rearrangement negative advanced NSCLC, harboring METΔex14 mutations. A run-in part (Part 1) was conducted to determine the anti-tumor activity and safety of capmatinib in combination with spartalizumab. Upon review of safety data and confirmation of anti-tumor activity in Part 1, the randomized part (Part 2) was planned to be initiated to compare the efficacy and safety of capmatinib plus spartalizumab to capmatinib plus placebo. Combined treatment of METΔex14 mutated NSCLC with capmatinib and spartalizumab was expected to result in improved efficacy compared to each single agent due to direct targeting of an oncogenic driver (MET) as well as more efficient stimulation of an anti-tumor immune response than with PD-1 blockade alone. The study enrollment was halted on 28-Jul-2021 per sponsor's decision. The enrollment halt decision was based on lack of tolerability observed in capmatinib and spartalizumab combination treatment in the run-in part (Part 1) of the trial. Following the study enrollment halt during Part 1 (Run in Part), Part 2 was not initiated. Immediately following the enrollment halt: * All ongoing subjects were discontinued from spartalizumab treatment and continue to receive single agent capmatinib * Enrolled subjects who had not started study treatment were to receive capmatinib single agent treatment from the start
Interventions
DRUGSpartalizumab
Concentrate for solution for infusion
DRUGCapmatinib
Film-coated tablet
DRUGspartalizumab placebo
dextrose 5% in water (D5W) for infusion
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Run-in part: single arm, open-label. Randomized part: two-arms parallel assignment, double-blinded, placebo control
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Histologically confirmed locally advanced or metastatic NSCLC which is EGFR wild-type, ALK rearrangement negative and METΔex14 mutated * No prior systemic therapy for advanced/metastatic disease (neo-adjuvant/adjuvant treatment completed \> 12 months before relapse are permitted) * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 * Measurable disease as per RECIST 1.1 * Known PD-L1 tumor expression status (applicable to Randomized part 2 only) Key
Exclusion criteria
* Prior treatment with a PD-1/PD-L1 inhibitor, MET inhibitor or HGF inhibitor * Presence of symptomatic CNS metastases or requiring local CNS-directed therapy (radiotherapy or surgery), or increasing doses of corticosteroids 2 weeks prior to study entry * Impaired cardiac function or clinically significant cardiac disease * Presence or history of interstitial lung disease, non-infectious pneumonitis or interstitial pneumonitis, including clinically significant radiation pneumonitis * History of allogenic bone marrow or solid organ transplant * Radiotherapy to lung fields ≤ 4 weeks or to any other anatomic site ≤ 2 weeks prior to start of study treatment (palliative radiotherapy for bone lesions is allowed)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Run-in Part: Overall Response Rate (ORR) by Investigator Assessment as Per RECIST 1.1 | Up to approximately 2 years and 4 months | Tumor response was based on local investigator assessment as per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. ORR per RECIST v1.1 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. |
| Randomized Part: Progression-Free Survival (PFS) by BIRC as Per RECIST 1.1 | Up to 6 years | 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 blinded independent review committee (BIRC) assessment per RECIST v1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Run-in Part: Dose Intensity of Capmatinib | From first dose of capmatinib to last dose, up to 2.4 years | Dose intensity of capmatinib was calculated as actual cumulative dose in milligrams divided by duration of exposure in days. |
| Run-in Part: Dose Intensity of Spartalizumab | From first dose of spartalizumab to last dose, up to 0.9 years | 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). |
| Run-in Part: Disease Control Rate (DCR) by Investigator Assessment as Per RECIST 1.1 | Up to approximately 2 years and 4 months | 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). |
| Run-in Part: Progression-Free Survival (PFS) by Investigator Assessment as Per RECIST 1.1 | Up to approximately 2 years and 5 months | 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. |
| Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Capmatinib | 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. | 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. |
| Run-in Part: Time to Reach Maximum Plasma Concentration (Tmax) of Capmatinib | 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. | 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. |
| Run-in Part: Area Under the Plasma Concentration-time Curve From Time Zero to the End of a Dosing Interval (AUCtau) of Capmatinib | 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. | 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. |
| Run-in Part: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib | 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. | PK parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation. |
| Run-in Part: Maximum Observed Serum Concentration (Cmax) of Spartalizumab | 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. | 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. |
| Run-in Part: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab | 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. | 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. |
| Run-in Part: Area Under the Serum Concentration-time Curve From Time Zero to the End of a Dosing Interval (AUCtau) of Spartalizumab | 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. | 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. |
| Run-in Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab | 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. | PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation. |
| Randomized Part: Overall Survival (OS) | Up to 12 years | OS is defined as the time from date of start of treatment to date of death due to any cause. |
| Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab | Up to 6 years | 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. |
| Randomized Part: Dose Intensity of Capmatinib and Spartalizumab | Up to 6 years | Dose intensity is defined as the ratio of actual cumulative dose and duration of exposure. |
| Run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib | From first dose of capmatinib to last dose, up to 2.4 years | Number of participants with at least one dose reduction of capmatinib and number of participants with at least one dose interruption of capmatinib. |
| Randomized Part: Disease Control Rate (DCR) by BIRC and Investigator Assessment as Per RECIST 1.1 | Up to 6 years | 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. |
| Randomized Part: Overall Response Rate (ORR) by BIRC and Investigator Assessment as Per RECIST 1.1 | Up to 6 years | 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. |
| Randomized Part: Duration of Response (DOR) by BIRC and Investigator Assessment as Per RECIST 1.1 | Up to 6 years | 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. |
| Randomized Part: Time to Response (TTR) by BIRC and Investigator Assessment as Per RECIST 1.1 | Up to 6 years | 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. |
| Randomized Part: Change From Baseline in EORTC QLQ-C30 | Up to 6 years | 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. |
| Randomized Part: Change From Baseline in EORTC QLQ-LC13 | Up to 6 years | 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. |
| Randomized Part: Change From Baseline in EQ-5D-5L | Up to 6 years | 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. |
| Randomized Part: Time to Definitive 10 Points Deterioration Symptom Scores for Pain in Chest, Coughing and Dyspnea Per QLQ-LC13 Questionnaire | Up to 6 years | 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. |
| Randomized Part: Time to Definitive Deterioration in Global Health Status/QoL, Shortness of Breath and Pain Per EORTC QLQ-C30 | Up to 6 years | 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. |
| Randomized Part: Maximum Observed Concentration (Cmax) of Capmatinib and Spartalizumab | Up to 6 years | 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. |
| Randomized Part: Time to Reach Maximum Concentration (Tmax) of Capmatinib and Spartalizumab | Up to 6 years | 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. |
| Randomized Part: Area Under the Concentration-time Curve From Time Zero to the End of a Dosing Interval (AUCtau) of Capmatinib and Spartalizumab | Up to 6 years | Pharmacokinetic (PK) parameters calculated based on capmatinib and spartalizumab concentrations in plasma and serum, respectively, by using non-compartmental methods. |
| Randomized Part: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib and Spartalizumab | Up to 6 years | Pharmacokinetic (PK) parameters calculated based on capmatinib and spartalizumab concentrations in plasma and serum, respectively, by using non-compartmental methods. |
| Randomized Part: Number of Participants With Anti-spartalizumab Antibodies | Baseline (pre-dose), up to 6 years | Immunogenicity (IG) evaluated in serum samples. The assay to quantify and assess the IG was a validated homogeneous enzyme-linked immunosorbent assay (ELISA). |
| Randomized Part: Progression-Free Survival (PFS) by Investigator Assessment as Per RECIST 1.1 | Up to 6 years | 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. |
| Run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of Spartalizumab | From first dose of spartalizumab to last dose, up to 0.9 years | Number of participants with at least one dose reduction of spartalizumab and number of participants with at least one dose interruption of spartalizumab. Dose reductions were not allowed for spartalizumab. |
Countries
Belgium, Canada, France, Germany, Italy, Japan, South Korea, Spain, United States
Participant flow
Recruitment details
Participants took part in 15 investigative sites in 9 countries.
Pre-assignment details
The screening period began once patients had signed the study informed consent. Screening evaluations were performed within 28 days prior to the first dose of study treatment. After screening, the treatment period started on Cycle 1 Day 1. The study enrollment was halted during the Run-in part per sponsor's decision. Following the study enrollment halt, spartalizumab treatment was discontinued and Part 2 was not initiated.
Participants by arm
| Arm | Count |
|---|---|
| Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W Capmatinib 400 mg orally twice daily (BID) in combination with spartalizumab 400 mg intravenously every 28 days (Q4W) in the run-in part. | 31 |
| Randomized Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W Capmatinib 400 mg orally twice daily (BID) in combination with spartalizumab 400 mg intravenously every 28 days (Q4W) in the randomized part. | 0 |
| Randomized Part: Capmatinib 400 mg BID + Placebo Capmatinib 400 mg orally twice daily (BID) in combination with spartalizumab matching placebo intravenously every 28 days (Q4W) in the randomized part. | 0 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 0 | 0 |
| Overall Study | Death | 1 | 0 | 0 |
| Overall Study | Physician Decision | 2 | 0 | 0 |
| Overall Study | Progressive disease | 10 | 0 | 0 |
| Overall Study | Subject decision | 3 | 0 | 0 |
| Overall Study | Transfer to another clinical study or to other alternative treatment option | 8 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W | Randomized Part: Capmatinib 400 mg BID + Placebo | Randomized Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W |
|---|---|---|---|---|
| Age, Continuous | 71.6 years STANDARD_DEVIATION 9.5 | 71.6 years STANDARD_DEVIATION 9.5 | — | — |
| Race/Ethnicity, Customized Asian | 6 Participants | 6 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 23 Participants | 23 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 16 Participants | 16 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 15 Participants | 15 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 28 | 0 / 28 | 0 / 3 |
| other Total, other adverse events | 25 / 28 | 18 / 28 | 3 / 3 |
| serious Total, serious adverse events | 11 / 28 | 8 / 28 | 1 / 3 |
Outcome results
Primary
Randomized Part: Progression-Free Survival (PFS) by BIRC 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 blinded independent review committee (BIRC) assessment per RECIST v1.1.
Time frame: Up to 6 years
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment in the randomized part. The randomized part of the study was not initiated and data was not collected.
Primary
Run-in Part: Overall Response Rate (ORR) by Investigator Assessment as Per RECIST 1.1
Tumor response was based on local investigator assessment as per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. ORR per RECIST v1.1 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: Up to approximately 2 years and 4 months
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment (i.e. at least one dose of any component of the study treatment that is capmatinib or spartalizumab) in the single arm run-in part. Patients were analyzed according to the treatment they were assigned to.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W | Run-in Part: Overall Response Rate (ORR) by Investigator Assessment as Per RECIST 1.1 | 35.5 percentage of participants |
Secondary
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
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment in the randomized part. The randomized part of the study was not initiated and data was not collected.
Secondary
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
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment in the randomized part. The randomized part of the study was not initiated and data was not collected.
Secondary
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
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment in the randomized part. The randomized part of the study was not initiated and data was not collected.
Secondary
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
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment in the randomized part. The randomized part of the study was not initiated and data was not collected.
Secondary
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
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment in the randomized part. The randomized part of the study was not initiated and data was not collected.
Secondary
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
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment in the randomized part. The randomized part of the study was not initiated and data was not collected.
Secondary
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
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment in the randomized part. The randomized part of the study was not initiated and data was not collected.
Secondary
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
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment in the randomized part. The randomized part of the study was not initiated and data was not collected.
Secondary
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
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment in the randomized part. The randomized part of the study was not initiated and data was not collected.
Secondary
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
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment in the randomized part. The randomized part of the study was not initiated and data was not collected.
Secondary
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
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment in the randomized part. The randomized part of the study was not initiated and data was not collected.
Secondary
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
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment in the randomized part. The randomized part of the study was not initiated and data was not collected.
Secondary
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
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment in the randomized part. The randomized part of the study was not initiated and data was not collected.
Secondary
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
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment in the randomized part. The randomized part of the study was not initiated and data was not collected.
Secondary
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
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment in the randomized part. The randomized part of the study was not initiated and data was not collected.
Secondary
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
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment in the randomized part. The randomized part of the study was not initiated and data was not collected.
Secondary
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
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment in the randomized part. The randomized part of the study was not initiated and data was not collected.
Secondary
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
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment in the randomized part. The randomized part of the study was not initiated and data was not collected.
Secondary
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.
Population: Patients in the capmatinib full pharmacokinetic analysis set (INC-FPAS) with an available value for the outcome measure. INC-FPAS consists of all patients who had an extensive PK sampling and provided a capmatinib evaluable PK profile on Cycle 3 Day 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W | Run-in Part: Area Under the Plasma Concentration-time Curve From Time Zero to the End of a Dosing Interval (AUCtau) of Capmatinib | 12900 hr*ng/mL | Geometric Coefficient of Variation 96.1 |
Secondary
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.
Population: Patients in the capmatinib full pharmacokinetic analysis set (INC-FPAS) with an available value for the outcome measure. INC-FPAS consists of all patients who had an extensive PK sampling and provided a capmatinib evaluable PK profile on Cycle 3 Day 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W | Run-in Part: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib | 10000 hr*ng/mL | Geometric Coefficient of Variation 61.8 |
Secondary
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.
Population: Patients in the spartalizumab full pharmacokinetic analysis set (PDR-FPAS) with an available value for the outcome measure. PDR-FPAS consists of all patients who had an extensive PK sampling and provided a spartalizumab evaluable PK profile on Cycle 3.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W | Run-in Part: Area Under the Serum Concentration-time Curve From Time Zero to the End of a Dosing Interval (AUCtau) of Spartalizumab | 49700 hr*µg/mL | Geometric Coefficient of Variation 47.8 |
Secondary
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.
Population: Patients in the spartalizumab full pharmacokinetic analysis set (PDR-FPAS) with an available value for the outcome measure. PDR-FPAS consists of all patients who had an extensive PK sampling and provided a spartalizumab evaluable PK profile on Cycle 3.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W | Run-in Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab | 52900 hr*µg/mL | Geometric Coefficient of Variation 64.6 |
Secondary
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
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment (i.e. at least one dose of any component of the study treatment that is capmatinib or spartalizumab) in the single arm run-in part. Patients were analyzed according to the treatment they were assigned to.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W | Run-in Part: Disease Control Rate (DCR) by Investigator Assessment as Per RECIST 1.1 | 77.4 percentage of participants |
Secondary
Run-in Part: Dose Intensity of Capmatinib
Dose intensity of capmatinib was calculated as actual cumulative dose in milligrams divided by duration of exposure in days.
Time frame: From first dose of capmatinib to last dose, up to 2.4 years
Population: All patients to whom study treatment had been assigned and who received at least one dose of capmatinib in the single arm run-in part. Patients were analyzed according to the treatment they were assigned to.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W | Run-in Part: Dose Intensity of Capmatinib | 595.9 mg/day | Standard Deviation 173.6 |
Secondary
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
Population: All patients to whom study treatment had been assigned and who received at least one dose of spartalizumab in the single arm run-in part. Patients were analyzed according to the treatment they were assigned to.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W | Run-in Part: Dose Intensity of Spartalizumab | 365.6 mg/cycle | Standard Deviation 51.5 |
Secondary
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.
Population: Patients in the capmatinib full pharmacokinetic analysis set (INC-FPAS) with an available value for the outcome measure. INC-FPAS consists of all patients who had an extensive PK sampling and provided a capmatinib evaluable PK profile on Cycle 3 Day 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W | Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Capmatinib | 2730 ng/mL | Geometric Coefficient of Variation 74.3 |
Secondary
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.
Population: Patients in the spartalizumab full pharmacokinetic analysis set (PDR-FPAS) with an available value for the outcome measure. PDR-FPAS consists of all patients who had an extensive PK sampling and provided a spartalizumab evaluable PK profile on Cycle 3.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W | Run-in Part: Maximum Observed Serum Concentration (Cmax) of Spartalizumab | 135 µg/mL | Geometric Coefficient of Variation 28.4 |
Secondary
Run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib
Number of participants with at least one dose reduction of capmatinib and number of participants with at least one dose interruption of capmatinib.
Time frame: From first dose of capmatinib to last dose, up to 2.4 years
Population: All patients to whom study treatment had been assigned and who received at least one dose of capmatinib in the single arm run-in part. Patients were analyzed according to the treatment they were assigned to.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W | Run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib | At least one dose reduction | 19 Participants |
| Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W | Run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib | At least one dose interruption | 20 Participants |
Secondary
Run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of Spartalizumab
Number of participants with at least one dose reduction of spartalizumab and number of participants with at least one dose interruption of spartalizumab. Dose reductions were not allowed for spartalizumab.
Time frame: From first dose of spartalizumab to last dose, up to 0.9 years
Population: All patients to whom study treatment had been assigned and who received at least one dose of spartalizumab in the single arm run-in part. Patients were analyzed according to the treatment they were assigned to.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W | Run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of Spartalizumab | At least one dose reduction | 0 Participants |
| Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W | Run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of Spartalizumab | At least one dose interruption | 7 Participants |
Secondary
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
Population: All patients to whom study treatment had been assigned and who received at least one dose of study treatment (i.e. at least one dose of any component of the study treatment that is capmatinib or spartalizumab) in the single arm run-in part. Patients were analyzed according to the treatment they were assigned to.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W | Run-in Part: Progression-Free Survival (PFS) by Investigator Assessment as Per RECIST 1.1 | 16.5 months |
Secondary
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.
Population: Patients in the capmatinib full pharmacokinetic analysis set (INC-FPAS) with an available value for the outcome measure. INC-FPAS consists of all patients who had an extensive PK sampling and provided a capmatinib evaluable PK profile on Cycle 3 Day 1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W | Run-in Part: Time to Reach Maximum Plasma Concentration (Tmax) of Capmatinib | 1.75 hours |
Secondary
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.
Population: Patients in the spartalizumab full pharmacokinetic analysis set (PDR-FPAS) with an available value for the outcome measure. PDR-FPAS consists of all patients who had an extensive PK sampling and provided a spartalizumab evaluable PK profile on Cycle 3.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W | Run-in Part: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab | 1.67 hours |