Carcinoma, Non-Small-Cell Lung
Conditions
Keywords
Non-small-cell lung carcinoma, Non-small-cell lung cancer, NSCLC, epidermal growth factor receptor wild type, EGFRwt, Anaplastic lymphoma kinase negative, ALK-, INC280, capmatinib and spartalizumab, combination therapy, docetaxel
Brief summary
The purpose of this trial was to evaluate the safety and efficacy of capmatinib in combination with spartalizumab in adult participants with epidermal growth factor receptor (EGFR) wild type (for exon 19 deletions and exon 21 L858R substitution mutations), anaplastic lymphoma kinase (ALK) rearrangement negative in locally advanced (stage IIIB, not eligible for definitive chemo-radiation) or metastatic (stage IV) Non-small cell lung cancer (NSCLC) after failure of platinum doublet and checkpoint inhibitor treatment.
Detailed description
This was a two-part prospectively designed, multicenter, open-label, randomized phase II study. Part 1: Run-in. Prior to the randomized part of the study, a run-in to assess the safety and tolerability as well as preliminary efficacy of the capmatinib and spartalizumab combination was conducted. Participants were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days. A review was planned to take place after all participants had at least 24 weeks of follow-up. The decision to expand the study to the randomized part was to be based on the safety, tolerability, and preliminary efficacy of the capmatinib and spartalizumab combination. Part 2: Randomized. Subjects were planned to be randomized to one of the following arms in a 2:1 ratio: 1) combination of capmatinib 400 mg BID and spartalizumab 400 mg i.v. once every 28 days; 2) docetaxel 75 mg/m2 i.v. following local guidelines as per standard of care and product labels. Based on the results obtained in the run-in part of the study, the randomized part was not opened. For the run-in part of the study, the treatment period began on Cycle 1 Day 1 and continued in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of informed consent, pregnancy, lost to follow-up, or death irrespective of start of new anti-neoplastic therapy. After treatment discontinuation, all subjects were followed for safety evaluations during the safety follow-up period, and the subject's status was collected every 8 weeks as part of the survival follow-up
Interventions
DRUGCapmatinib
Capmatinib 400 mg (tablets) orally taken twice daily
DRUGSpartalizumab
Spartalizumab 400 mg via intravenous infusion once every 28 days
DRUGDocetaxel
Docetaxel 75mg/m2 i.v. following local guidelines as per standard of care and product labels once every 21 days
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Run-in part was single group. Randomized part (parallel design) was not opened.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed locally advanced/metastatic (stage IIIB/IV), EGFR wild-type, ALK rearrangement negative, non-small cell lung cancer * Subject had demonstrated progression following one prior platinum doublet and one prior PD-(L)1 checkpoint inhibitor (either alone or in combination, the most recent treatment regimen must have contained a PD-(L)1 checkpoint inhibitor) * Subjects must be candidates for single agent docetaxel * Subjects must have at least one lesion evaluable by RECIST 1.1
Exclusion criteria
* Prior treatment with a MET inhibitor or HGF (Hepatocyte growth factor) targeting therapy * Any untreated central nervous system (CNS) lesion * Use of any live vaccines against infectious diseases within 12 weeks of initiation of study treatment. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Run-in Part: Percentage of Participants With Dose Limiting Toxicities (DLTs) | From the day of the first dose of study medication up to 56 days | A DLT was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol. |
| Run-in Part: Percentage of Participants With Adverse Events (AEs) | From the day of the first dose of study medication to 150 days after the last dose of spartalizumab, or 30 days after the last dose of capmatinib (whichever is later) up to maximum duration of approximately 1.7 years | Percentage of participants with AEs, including changes from baseline in vital signs and laboratory results qualifying and reported as AEs. AEs were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0: Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: Death |
| Run-in Part: Percentage of Participants With at Least One Dose Reduction. | From the day of the first dose of study medication to end of treatment, assessed up to maximum duration of 68 weeks | Percentage of participants with at least one dose reduction. Dose reductions were only allowed for capmatinib |
| Run-in Part: Percentage of Participants With at Least One Dose Interruption | From the day of the first dose of study medication to end of treatment, assessed up to maximum duration of 68 weeks | Percentage of participants with at least one dose interruption. Dose interruptions were allowed for capmatinib and spartalizumab. |
| Run-in Part: Relative Dose Intensity Received by Participants | From the day of the first dose of study medication to end of treatment, assessed up to maximum duration of 68 weeks | The relative dose intensity of capmatinib and spartalizumab is computed as the ratio of dose intensity and planned dose intensity, multiplied by 100. |
| Randomized Part: Overall Survival (OS) | From start of treatment to death due to any cause, assessed until the end of the study (up to a planned duration of 18 months) | OS is defined as the time from date of start of treatment to date of death due to any cause. If a participant was not known to have died, survival was censored at the date of last known date patient alive. Results are not available because randomized part never started. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Based on RECIST 1.1 and as Per Investigator Assessment | From start of treatment until end of treatment, assessed up to 68 weeks (run-in part) | ORR is defined as the percentage of subjects with best overall response (BOR) of complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and as per investigator assessment. 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. ORR results for randomized part are not available because randomized part never started. |
| Disease Control Rate (DCR) Based on RECIST 1.1 and as Per Investigator Assessment | From start of treatment until end of treatment, assessed up to 68 weeks (run-in part) | DCR is defined as the percentage of subjects with best overall response of CR or PR or stable disease based on RECIST 1.1 and as per investigator assessment. 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. Stable disease: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression. DCR results for randomized part are not available because randomized part never started. |
| Progression Free Survival (PFS) | From start of treatment until the first documented radiological progression or death, whichever comes first, assessed up to 68 weeks (run-in part) | PFS is defined as the time from the date of start of treatment to the date of the first documented radiological progression or death due to any cause. For participants who had not progressed or died at the analysis cut-off date, PFS was censored at the date of the last adequate tumor evaluation date. An adequate tumour assessment is a tumour assessment with an overall response other than unknown. Progression is defined using RECIST 1.1 and as per investigator assessment as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PFS results for randomized part are not available because randomized part never started. |
| Time to Response (TTR) Based on RECIST 1.1 and as Per Investigator Assessment | From start of treatment to the first documented response of either complete response or partial response, assessed up to 68 weeks (run-in part) | 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. TTR was evaluated according to RECIST 1.1 and as per investigator assessment. 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. For run-in part, TTR results are not available because there were no participants achieving response (CR or PR) For randomized part , TTR results are not available because randomized part never started. |
| Duration of Response (DOR) Based on RECIST 1.1 and as Per Investigator Assessment | From first documented response (CR or PR) to first documented progression or death, whichever came first, assessed up to 68 weeks (run-in part) | DOR is the time between the date of first documented response(CR or PR) and the date of first documented progression or death due to underlying cancer based on RECIST1.1 and as per investigator assessment. If progression or death has not occurred, the subject is censored at the date of last adequate tumor assessment. CR: Disappearance of all non-nodal target lesions and 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. Progression: at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. The sum must also demonstrate an absolute increase of at least 5 mm. Results are not available because there were no participants achieving response in the run-in part and randomized part never started |
| AUClast of Capmatinib | Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days | AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration. AUClast was calculated using non-compartmental methods. |
| AUCtau of Capmatinib | Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days | AUCtau is the area under the plasma concentration-time curve from time zero to the end of the dosing interval Tau. AUCtau was calculated using non-compartmental methods. |
| Maximum Plasma Concentration (Cmax) of Capmatinib | Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days | The maximum (peak) observed plasma concentration after single dose administration. Cmax was calculated using non-compartmental methods. |
| Time to Reach Maximum (Tmax) Plasma Concentration of Capmatinib | Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days | Tmax is the time to reach maximum (peak) plasma concentration of capmatinib after single dose administration (time). Tmax was calculated using non-compartmental methods. |
| AUClast of Spartlizumab | CCycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days | AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration. AUClast was calculated using non-compartmental methods. |
| AUCtau of Spartlizumab | Cycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days | AUCtau is the area under the plasma concentration-time curve from time zero to the end of the dosing interval Tau. AUCtau was calculated using non-compartmental methods. |
| Maximum Plasma Concentration (Cmax) of Spartlizumab | Cycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days | The maximum (peak) observed plasma concentration after single dose administration. Cmax was calculated using non-compartmental methods. |
| Time to Reach Maximum (Tmax) Plasma Concentration of Spartlizumab | Cycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days | Tmax is the time to reach maximum (peak) plasma concentration of spartlizumab after single dose administration (time). Tmax was calculated using non-compartmental methods. |
| Spartalizumab Antidrug Antibodies (ADA) Prevalence at Baseline | Cycle 1 Day 1 at predose. Each Cycle is 28 days | ADA prevalence at baseline was calculated as the proportion of participants who had an ADA positive result at baseline |
| Spartalizumab ADA Incidence On-treatment | Predose at Cycle (C)1 Day (D)1, C2D1, C3D1, C4D1, C6D1, C8D1, C10D1, C12D1, thereafter every 6 cycles until discontinuation, and end of treatment (EOT), 30-day and 150-day after EOT | ADA incidence on treatment was calculated as the proportion of participants who were treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer) |
Countries
Belgium, France, Germany, Israel, Spain, United States
Participant flow
Pre-assignment details
Based on preliminary results of run-in part, the decision was not to open randomized part of the study. Therefore, no participants were enrolled in randomized part.
Participants by arm
| Arm | Count |
|---|---|
| Run-in Part: Capmatinib + Spartalizumab Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days | 18 |
| Randomized Part: Capmatinib + Spartalizumab Participants (enrolled in the randomized part) treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days | 0 |
| Randomized Part: Docetaxel Participants (enrolled in the randomized part) treated with docetaxel 75mg/m2 i.v. following local guidelines as per standard of care and product labels once every 21 days | 0 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 0 | 0 |
| Overall Study | Clinical progression | 2 | 0 | 0 |
| Overall Study | Participant refused to take investigational product | 1 | 0 | 0 |
| Overall Study | Progressive disease | 10 | 0 | 0 |
Baseline characteristics
| Characteristic | Run-in Part: Capmatinib + Spartalizumab | Total | Randomized Part: Capmatinib + Spartalizumab | Randomized Part: Docetaxel |
|---|---|---|---|---|
| Age, Continuous | 61.2 Years STANDARD_DEVIATION 10.52 | 61.2 Years STANDARD_DEVIATION 10.52 | — | — |
| Race/Ethnicity, Customized Missing | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 17 Participants | 17 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 7 Participants | 7 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 11 Participants | 11 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 5 / 18 |
| other Total, other adverse events | 18 / 18 |
| serious Total, serious adverse events | 10 / 18 |
Outcome results
Primary
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. If a participant was not known to have died, survival was censored at the date of last known date patient alive. Results are not available because randomized part never started.
Time frame: From start of treatment to death due to any cause, assessed until the end of the study (up to a planned duration of 18 months)
Population: Data was not collected as no participants were enrolled in randomized part.
Primary
Run-in Part: Percentage of Participants With Adverse Events (AEs)
Percentage of participants with AEs, including changes from baseline in vital signs and laboratory results qualifying and reported as AEs. AEs were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0: Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: Death
Time frame: From the day of the first dose of study medication to 150 days after the last dose of spartalizumab, or 30 days after the last dose of capmatinib (whichever is later) up to maximum duration of approximately 1.7 years
Population: All participants in the run-in who received at least one dose of study treatment (i.e. at least one dose of spartalizumab \[including incomplete infusion\] or of capmatinib).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With Adverse Events (AEs) | AEs- All grades | 18 Participants |
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With Adverse Events (AEs) | AEs- Grade ≥3 | 11 Participants |
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With Adverse Events (AEs) | Treatment-related AEs- All grades | 14 Participants |
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With Adverse Events (AEs) | Treatment related AEs- Grade ≥3 | 1 Participants |
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With Adverse Events (AEs) | Serious AEs (SAEs)- All grades | 10 Participants |
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With Adverse Events (AEs) | Treatment-related SAEs- Grade ≥3 | 0 Participants |
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With Adverse Events (AEs) | Fatal SAEs- All grades | 1 Participants |
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With Adverse Events (AEs) | Fatal SAEs- Grade ≥3 | 1 Participants |
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With Adverse Events (AEs) | AEs leading to dose adjustment/interruption- All grades | 9 Participants |
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With Adverse Events (AEs) | AEs leading to dose adjustment/interruption- Grade ≥3 | 5 Participants |
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With Adverse Events (AEs) | AEs requiring additional therapy- All grades | 16 Participants |
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With Adverse Events (AEs) | AEs requiring additional therapy- Grade ≥3 | 8 Participants |
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With Adverse Events (AEs) | SAEs- Grade ≥3 | 7 Participants |
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With Adverse Events (AEs) | Treatment-related SAEs- All grades | 3 Participants |
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With Adverse Events (AEs) | AEs leading to discontinuation- All grades | 5 Participants |
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With Adverse Events (AEs) | AEs leading to discontinuation- Grade ≥3 | 3 Participants |
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With Adverse Events (AEs) | Treatment-related AEs leading to discontinuation- All grades | 3 Participants |
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With Adverse Events (AEs) | Treatment-related AEs leading to discontinuation- Grade ≥3 | 1 Participants |
Primary
Run-in Part: Percentage of Participants With at Least One Dose Interruption
Percentage of participants with at least one dose interruption. Dose interruptions were allowed for capmatinib and spartalizumab.
Time frame: From the day of the first dose of study medication to end of treatment, assessed up to maximum duration of 68 weeks
Population: All participants in the run-in who received at least one dose of study treatment (i.e. at least one dose of spartalizumab \[including incomplete infusion\] or of capmatinib).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With at Least One Dose Interruption | Capmatinib | 8 Participants |
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With at Least One Dose Interruption | Spartalizumab | 3 Participants |
Primary
Run-in Part: Percentage of Participants With at Least One Dose Reduction.
Percentage of participants with at least one dose reduction. Dose reductions were only allowed for capmatinib
Time frame: From the day of the first dose of study medication to end of treatment, assessed up to maximum duration of 68 weeks
Population: All participants in the run-in who received at least one dose of study treatment (i.e. at least one dose of spartalizumab \[including incomplete infusion\] or of capmatinib).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With at Least One Dose Reduction. | 6 Participants |
Primary
Run-in Part: Percentage of Participants With Dose Limiting Toxicities (DLTs)
A DLT was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol.
Time frame: From the day of the first dose of study medication up to 56 days
Population: All participants from the Safety Set in the run-in who experienced DLT during the first 8 weeks of dosing or met the minimum exposure criterion (subject received at least 1 infusion of spartalizumab and took at least 50% of the planned dose of capmatinib within the first 8 weeks of treatment) and had sufficient safety evaluations (subjects were observed for ≥56 days following the first dose, and are considered to have enough safety data to conclude that a DLT did not occur).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Percentage of Participants With Dose Limiting Toxicities (DLTs) | 1 Participants |
Primary
Run-in Part: Relative Dose Intensity Received by Participants
The relative dose intensity of capmatinib and spartalizumab is computed as the ratio of dose intensity and planned dose intensity, multiplied by 100.
Time frame: From the day of the first dose of study medication to end of treatment, assessed up to maximum duration of 68 weeks
Population: All participants in the run-in who received at least one dose of study treatment (i.e. at least one dose of spartalizumab \[including incomplete infusion\] or of capmatinib).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Relative Dose Intensity Received by Participants | Capmatinib | 99.6 Percentage of dose received |
| Run-in Part: Capmatinib + Spartalizumab | Run-in Part: Relative Dose Intensity Received by Participants | Spartalizumab | 100.0 Percentage of dose received |
Secondary
AUClast of Capmatinib
AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration. AUClast was calculated using non-compartmental methods.
Time frame: Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days
Population: The capmatinib pharmacokinetic (PK) analysis set included all participants in the run-in phase who provided at least one evaluable capmatinib PK concentration. Only those participants with data available for this endpoint at specified data points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Run-in Part: Capmatinib + Spartalizumab | AUClast of Capmatinib | 11500 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 47.3 |
Secondary
AUClast of Spartlizumab
AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration. AUClast was calculated using non-compartmental methods.
Time frame: CCycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days
Population: The spartlizumab pharmacokinetic (PK) analysis set included all participants in the run-in phase who provided at least one evaluable spartlizumab PK concentration. Only those participants with data available for this endpoint at specified data points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Run-in Part: Capmatinib + Spartalizumab | AUClast of Spartlizumab | 1720 microgram*day/milliliter (μg*day/mL) | Geometric Coefficient of Variation 64.5 |
Secondary
AUCtau of Capmatinib
AUCtau is the area under the plasma concentration-time curve from time zero to the end of the dosing interval Tau. AUCtau was calculated using non-compartmental methods.
Time frame: Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days
Population: The capmatinib pharmacokinetic (PK) analysis set included all participants in the run-in phase who provided at least one evaluable capmatinib PK concentration. Only those participants with data available for this endpoint at specified data points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Run-in Part: Capmatinib + Spartalizumab | AUCtau of Capmatinib | 12800 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 48.5 |
Secondary
AUCtau of Spartlizumab
AUCtau is the area under the plasma concentration-time curve from time zero to the end of the dosing interval Tau. AUCtau was calculated using non-compartmental methods.
Time frame: Cycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days
Population: The spartlizumab pharmacokinetic (PK) analysis set included all participants in the run-in phase who provided at least one evaluable spartlizumab PK concentration. Only those participants with data available for this endpoint at specified data points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Run-in Part: Capmatinib + Spartalizumab | AUCtau of Spartlizumab | 2110 microgram*day/milliliter (μg*day/mL) | Geometric Coefficient of Variation 35.1 |
Secondary
Disease Control Rate (DCR) Based on RECIST 1.1 and as Per Investigator Assessment
DCR is defined as the percentage of subjects with best overall response of CR or PR or stable disease based on RECIST 1.1 and as per investigator assessment. 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. Stable disease: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression. DCR results for randomized part are not available because randomized part never started.
Time frame: From start of treatment until end of treatment, assessed up to 68 weeks (run-in part)
Population: All participants in the run-in who received at least one dose of any component of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Run-in Part: Capmatinib + Spartalizumab | Disease Control Rate (DCR) Based on RECIST 1.1 and as Per Investigator Assessment | 27.8 Percentage of participants |
Secondary
Duration of Response (DOR) Based on RECIST 1.1 and as Per Investigator Assessment
DOR is the time between the date of first documented response(CR or PR) and the date of first documented progression or death due to underlying cancer based on RECIST1.1 and as per investigator assessment. If progression or death has not occurred, the subject is censored at the date of last adequate tumor assessment. CR: Disappearance of all non-nodal target lesions and 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. Progression: at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. The sum must also demonstrate an absolute increase of at least 5 mm. Results are not available because there were no participants achieving response in the run-in part and randomized part never started
Time frame: From first documented response (CR or PR) to first documented progression or death, whichever came first, assessed up to 68 weeks (run-in part)
Population: No data available as no participants had event
Secondary
Maximum Plasma Concentration (Cmax) of Capmatinib
The maximum (peak) observed plasma concentration after single dose administration. Cmax was calculated using non-compartmental methods.
Time frame: Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days
Population: The capmatinib pharmacokinetic (PK) analysis set included all participants in the run-in phase who provided at least one evaluable capmatinib PK concentration. Only those participants with data available for this endpoint at specified data points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Run-in Part: Capmatinib + Spartalizumab | Maximum Plasma Concentration (Cmax) of Capmatinib | 3260 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 44.6 |
Secondary
Maximum Plasma Concentration (Cmax) of Spartlizumab
The maximum (peak) observed plasma concentration after single dose administration. Cmax was calculated using non-compartmental methods.
Time frame: Cycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days
Population: The spartlizumab pharmacokinetic (PK) analysis set included all participants in the run-in phase who provided at least one evaluable spartlizumab PK concentration. Only those participants with data available for this endpoint at specified data points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Run-in Part: Capmatinib + Spartalizumab | Maximum Plasma Concentration (Cmax) of Spartlizumab | 138 microgram/milliliter (μg/mL) | Geometric Coefficient of Variation 23.2 |
Secondary
Objective Response Rate (ORR) Based on RECIST 1.1 and as Per Investigator Assessment
ORR is defined as the percentage of subjects with best overall response (BOR) of complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and as per investigator assessment. 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. ORR results for randomized part are not available because randomized part never started.
Time frame: From start of treatment until end of treatment, assessed up to 68 weeks (run-in part)
Population: All participants in the run-in who received at least one dose of any component of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Run-in Part: Capmatinib + Spartalizumab | Objective Response Rate (ORR) Based on RECIST 1.1 and as Per Investigator Assessment | 0 Percentage of participants |
Secondary
Progression Free Survival (PFS)
PFS is defined as the time from the date of start of treatment to the date of the first documented radiological progression or death due to any cause. For participants who had not progressed or died at the analysis cut-off date, PFS was censored at the date of the last adequate tumor evaluation date. An adequate tumour assessment is a tumour assessment with an overall response other than unknown. Progression is defined using RECIST 1.1 and as per investigator assessment as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PFS results for randomized part are not available because randomized part never started.
Time frame: From start of treatment until the first documented radiological progression or death, whichever comes first, assessed up to 68 weeks (run-in part)
Population: All participants in the run-in who received at least one dose of any component of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Run-in Part: Capmatinib + Spartalizumab | Progression Free Survival (PFS) | 1.9 Months |
Secondary
Spartalizumab ADA Incidence On-treatment
ADA incidence on treatment was calculated as the proportion of participants who were treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)
Time frame: Predose at Cycle (C)1 Day (D)1, C2D1, C3D1, C4D1, C6D1, C8D1, C10D1, C12D1, thereafter every 6 cycles until discontinuation, and end of treatment (EOT), 30-day and 150-day after EOT
Population: The IG incidence set includes all subjects in the IG prevalence set with a determinant baseline IG sample and at least one determinant post-baseline IG sample.~Determinant sample: sample that is neither ADA-inconclusive nor unevaluable.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Run-in Part: Capmatinib + Spartalizumab | Spartalizumab ADA Incidence On-treatment | 3 Participants |
Secondary
Spartalizumab Antidrug Antibodies (ADA) Prevalence at Baseline
ADA prevalence at baseline was calculated as the proportion of participants who had an ADA positive result at baseline
Time frame: Cycle 1 Day 1 at predose. Each Cycle is 28 days
Population: immunogenicity (IG) prevalence set includes all subjects in the Full analysis set with a determinant baseline IG sample or at least one determinant post-baseline sample.~Determinant sample: sample that is neither ADA-inconclusive nor unevaluable
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Run-in Part: Capmatinib + Spartalizumab | Spartalizumab Antidrug Antibodies (ADA) Prevalence at Baseline | 3 Participants |
Secondary
Time to Reach Maximum (Tmax) Plasma Concentration of Capmatinib
Tmax is the time to reach maximum (peak) plasma concentration of capmatinib after single dose administration (time). Tmax was calculated using non-compartmental methods.
Time frame: Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days
Population: The capmatinib pharmacokinetic (PK) analysis set included all participants in the run-in phase who provided at least one evaluable capmatinib PK concentration. Only those participants with data available for this endpoint at specified data points were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Run-in Part: Capmatinib + Spartalizumab | Time to Reach Maximum (Tmax) Plasma Concentration of Capmatinib | 1.42 hour (h) |
Secondary
Time to Reach Maximum (Tmax) Plasma Concentration of Spartlizumab
Tmax is the time to reach maximum (peak) plasma concentration of spartlizumab after single dose administration (time). Tmax was calculated using non-compartmental methods.
Time frame: Cycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days
Population: The spartlizumab pharmacokinetic (PK) analysis set included all participants in the run-in phase who provided at least one evaluable spartlizumab PK concentration. Only those participants with data available for this endpoint at specified data points were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Run-in Part: Capmatinib + Spartalizumab | Time to Reach Maximum (Tmax) Plasma Concentration of Spartlizumab | 1.13 hour (h) |
Secondary
Time to Response (TTR) Based on RECIST 1.1 and as Per Investigator Assessment
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. TTR was evaluated according to RECIST 1.1 and as per investigator assessment. 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. For run-in part, TTR results are not available because there were no participants achieving response (CR or PR) For randomized part , TTR results are not available because randomized part never started.
Time frame: From start of treatment to the first documented response of either complete response or partial response, assessed up to 68 weeks (run-in part)
Population: No data available as no participants had event
Post Hoc
All Collected Deaths
On-treatment deaths due to any cause were collected from first dose of study medication to 150 days after the last dose of spartalizumab, or 30 days after the last dose of capmatinib, whichever is later, up to a maximum duration of approximately 1.7 years. Total deaths were collected from first dose of study treatment until end of post-treatment efficacy or survival follow, up to maximum duration of approximately 1.7 years
Time frame: On-treatment deaths: up to approximately 1.7 years. All deaths: up to approximately 1.7 years
Population: Safety Set consisted of all participants who received at least one dose of study treatment, i.e. at least one dose of spartalizumab \[including incomplete infusion\] or of capmatinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Run-in Part: Capmatinib + Spartalizumab | All Collected Deaths | Total Deaths | 12 Participants |
| Run-in Part: Capmatinib + Spartalizumab | All Collected Deaths | Deaths on-treatment | 5 Participants |