Advanced Hepatocellular Carcinoma
Conditions
Keywords
Phase Ib/II, INC280, PDR001, capmatinib, spartalizumab, checkpoint inhibitor, PD-1, Liver cancer
Brief summary
The purpose of this study of capmatinib (INC280) and spartalizumab (PDR001) was to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of spartalizumab administered intravenously (i.v.) as a single agent or in combination with capmatinib administered orally in adult patients with advanced hepatocellular carcinoma (HCC).
Detailed description
This was a Phase Ib/II, open label, multicenter study starting with a Phase Ib dose escalation part followed by a randomized Phase II part in patients with advanced hepatocellular carcinoma. Capmatinib was administered orally twice daily (BID) and spartalizumab was administered i.v. every 3 weeks (Q3W) until the occurrence of unacceptable toxicity, progressive disease as per irRC and/or treatment was discontinued at the discretion of the Investigator or the participant. A complete cycle of treatment was defined as 21 days. During the Phase Ib dose escalation part of the study, participants were treated with capmatinib in combination with a fixed dose of spartalizumab until the maximum tolerated dose (MTD) was reached or the recommended phase 2 dose (RP2D) was established. The capmatinib dose was increased and the spartalizumab dose remained constant. Once the MTD and/or RP2D were declared for capmatinib in combination with spartalizumab, additional participants were enrolled in the Phase II part in order to assess the anti-tumor activity of capmatinib in combination with spartalizumab and spartalizumab single agent. Participants were randomly assigned, in a 1:1 ratio, to treatment with either capmatinib in combination with spartalizumab or spartalizumab single agent.
Interventions
DRUGSpartalizumab
Spartalizumab administered via intravenous (i.v.) infusion once every 3 weeks (Q3W)
DRUGCapmatinib
Capmatinib administered orally as a tablet on a continuous twice daily (BID) dosing schedule
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically or cytologically documented locally advanced recurrent or metastatic HCC or for patients with cirrhosis according to the American Association for the Study of Liver Diseases (AASLD) and Asian Pacific Association for the study of the liver (APASL) criteria. Current cirrhotic status of Child Pugh Class A (5-6 points), with no encephalopathy and/or clinically significant ascites (defined as requiring the use of diuretics or paracentesis treatment). 2. Patients must have received prior systemic sorafenib treatment for HCC with documented progression during or after discontinuation of sorafenib treatment (for France only: patients must have received at least 8 weeks of prior sorafenib treatment), or are intolerant to sorafenib (defined as documented Grade 3 or 4 adverse events that led to sorafenib discontinuation),. 3. ECOG Performance Status ≤ 1. 4. Willing and able to swallow and retain oral medication.
Exclusion criteria
1. Use of any live vaccines within 4 weeks of initiation of study treatment. 2. History of severe hypersensitivity reactions to other monoclonal antibodies (mAbs). 3. Clinically significant pleural effusion that either required pleurocentesis or is associated with shortness of breath. 4. Active autoimmune disease or a documented history of autoimmune disease. 5. Clinically significant, uncontrolled heart diseases. 6. Patient having out of range laboratory values defined as: * Total bilirubin \> 2 mg/dL, except for patients with Gilbert's syndrome who are excluded if total bilirubin \> 3.0 x ULN or direct bilirubin \> 1.5 x ULN * Alanine aminotransferase (ALT) \> 5 x ULN * Aspartate aminotransferase (AST) \> 5 x ULN * Coagulation: Prothrombin Time (PT) \> 4 seconds more than the ULN or International Normalized Ratio (INR) \> 1.7 * Absolute neutrophil count (ANC) \< 1.5 x 109/L * Platelet count \< 75 x 109/L * Hemoglobin \< 9 g/dL * Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) \< 45 mL/min * Asymptomatic serum amylase grade \> 2 (1.5-2.0 x ULN). Patients with grade 1 or grade 2 serum amylase at the beginning of the study must be confirmed to have no signs or symptoms suggesting pancreatitis or pancreatic injury (e.g., elevated P-amylase, abnormal imaging findings of pancreas, etc.) * Serum lipase \> ULN * Potassium, Magnesium, Phosphorus, total Calcium (corrected for serum albumin) outside of normal limits (patients may be enrolled if corrected to within normal limits with supplements during screening)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | From first dose of study medication up to 30 days after last dose, with a maximum duration of 3.3 years | Number of participants with AEs and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. For CTCAE v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. The on-treatment period is defined from the day of first administration of study treatment up to 30 days after the date of its last administration. |
| Phase Ib: Number of Participants With Dose-Limiting Toxicities (DLTs) During the First 2 Cycles of Treatment | 42 days | A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 assessed as unrelated to disease, disease progression, inter-current illness or concomitant medications that occurs within the first 2 cycles of treatment with capmatinib in combination with spartalizumab during the dose escalation part of the study. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher. The duration of one treatment cycle is 21 days. |
| Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab | From first dose of study medication up to last dose, with a maximum duration of 3.2 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. No dose modifications (i.e. dose reduction) were allowed for spartalizumab. |
| Phase Ib: Dose Intensity of Capmatinib | From first dose of study medication up to last dose, with a maximum duration of 3.2 years | Dose intensity of capmatinib was calculated as actual cumulative dose in milligrams divided by duration of exposure in days. |
| Phase Ib: Dose Intensity of Spartalizumab | From first dose of study medication up to last dose, with a maximum duration of 3.2 years | Dose intensity of spartalizumab was calculated as actual cumulative dose in milligrams divided by duration of exposure in weeks and then multiplied by 3 weeks (3W). |
| Phase II: Overall Response Rate (ORR) Per RECIST v1.1 | From start of treatment until end of treatment, assessed up to 2.2 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase Ib and Phase II: Time to Response (TTR) Per RECIST v1.1 | From start of treatment until first documented response, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II | TTR is defined as the time from the date of start of treatment to the date of first documented response (CR or PR, which must be confirmed subsequently) for patients who achieved a confirmed CR or PR. Tumor response was based on local investigator assessment per RECIST v1.1. Patients who did not achieve a confirmed CR or PR were censored at the maximum follow-up time for patients who had a Progression-Free Survival (PFS) event (i.e. either progressed or died due to any cause), or at the date of last adequate tumor assessment before the start of a new anticancer therapy (if any) otherwise. According to the statistical analysis plan (SAP), summary estimates of TTR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving a confirmed CR or PR in each treatment group/arm. |
| Phase Ib and Phase II: Time to Response (TTR) Per irRC | From start of treatment until first documented response, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II | TTR is defined as the time from the date of start of treatment to the date of first documented response (irCR or irPR, which must be confirmed subsequently) for patients who achieved a confirmed irCR or irPR. Tumor response was based on local investigator assessment per irRC. Patients who did not achieve a confirmed irCR or irPR were censored at the maximum follow-up time for patients who had a Progression-Free Survival (PFS) event (i.e. either progressed or died due to any cause), or at the date of last adequate tumor assessment before the start of a new anticancer therapy (if any) otherwise. According to the statistical analysis plan (SAP), summary estimates of TTR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving a confirmed irCR or irPR in each treatment group/arm. |
| Phase Ib and Phase II: Progression-Free Survival (PFS) Per RECIST v1.1 | From start of treatment until first documented progression or death due to any cause, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II | PFS is defined as the time from the date of start of treatment to the date of the first documented progression per RECIST v1.1 or death due to any cause. If a patient did not experience an event or started a new anticancer therapy, PFS was censored at the date of the last adequate tumor evaluation before the start of a new anticancer therapy, if any. Tumor response was based on local investigator assessment per RECIST v1.1. PFS was estimated using the Kaplan-Meier Method. |
| Phase Ib: Maximum Observed Plasma Concentration (Cmax) of Capmatinib | pre-dose, 0.5, 1, 2, 4 and 8 hours post capmatinib dose on Cycle 2 Day 1 (C2D1). The duration of one cycle was 21 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. |
| Phase Ib and Phase II: Progression-Free Survival (PFS) Per irRC | From start of treatment until first documented progression or death due to any cause, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II | PFS is defined as the time from the date of start of treatment to the date of the first documented and confirmed progression per irRC or death due to any cause. If a patient did not experience an event or started a new anticancer therapy, PFS was censored at the date of the last adequate tumor evaluation before the start of a new anticancer therapy, if any. Tumor response was based on local investigator assessment per irRC. PFS was estimated using the Kaplan-Meier Method. |
| Phase Ib and Phase II: Time to Progression (TTP) Per RECIST v1.1 | From start of treatment until first documented progression or death due to underlying cancer, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II | TTP is defined as the time from the date of start of treatment to the date of the first documented progression per RECIST v1.1 or death due to underlying cancer. If a patient did not experience an event or started a new anticancer therapy, TTP was censored at the date of the last adequate tumor evaluation before the start of a new anticancer therapy, if any. Tumor response was based on local investigator assessment per RECIST v1.1. TTP was estimated using the Kaplan-Meier Method. |
| Phase Ib and Phase II: Time to Progression (TTP) Per irRC | From start of treatment until first documented progression or death due to underlying cancer, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II | TTP is defined as the time from the date of start of treatment to the date of the first documented and confirmed progression per irRC or death due to underlying cancer. If a patient did not experience an event or started a new anticancer therapy, TTP was censored at the date of the last adequate tumor evaluation before the start of a new anticancer therapy, if any. Tumor response was based on local investigator assessment per irRC. |
| Phase Ib and Phase II: Overall Survival (OS) | From start of treatment until death due to any cause, assessed up to 3.6 years in Phase Ib and up to 2.9 years in Phase II | OS is defined as the time from date of start of treatment to date of death due to any cause. If a patient was not known to have died, OS time was censored at the date of last contact. OS was estimated using the Kaplan-Meier Method. |
| Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | From first dose of study medication up to 30 days after last dose, with a maximum duration of 2.3 years | Number of participants with AEs and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. For CTCAE v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. The on-treatment period is defined from the day of first administration of study treatment up to 30 days after the date of its last administration. |
| Phase II: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab | From first dose of study medication up to last dose, with a maximum duration of 2.2 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. No dose modifications (i.e. dose reduction) were allowed for spartalizumab. |
| Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | From start of treatment until end of treatment, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II | BOR is defined as the best response recorded from the start of the study treatment until disease progression/recurrence, based on local investigator assessment per RECIST v1.1. For RECIST v1.1, R=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters; PD= At least a 20% increase in the sum of diameters of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition, the sum must also demonstrate an absolute increase of at least 5 mm; SD= Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression). The number of participants in each response category is reported in the table. |
| Phase II: Dose Intensity of Spartalizumab | From first dose of study medication up to last dose, with a maximum duration of 2.2 years | Dose intensity of spartalizumab was calculated as actual cumulative dose in milligrams divided by duration of exposure in weeks and then multiplied by 3 weeks (3W). |
| Phase Ib: Time to Reach Maximum Plasma Concentration (Tmax) of Capmatinib | pre-dose, 0.5, 1, 2, 4 and 8 hours post capmatinib dose on Cycle 2 Day 1 (C2D1). The duration of one cycle was 21 days. | Pharmacokinetic (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. |
| Phase Ib: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib | pre-dose, 0.5, 1, 2, 4 and 8 hours post capmatinib dose on Cycle 2 Day 1 (C2D1). The duration of one cycle was 21 days. | Pharmacokinetic (PK) parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation. |
| Phase II: Pre-dose Plasma Concentration of Capmatinib | Pre-dose of capmatinib on Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1 and Cycle 6 Day 1. The duration of one cycle was 21 days. | Capmatinib plasma concentration was assessed in samples taken at pre-dose. Pre-dose samples were collected before the next dose administration. |
| Phase Ib and Phase II: Maximum Observed Serum Concentration (Cmax) of Spartalizumab | pre-dose, 1, 24, 48, 72, 168, 240, 336 and 504 hours after completion of spartalizumab infusion on Cycle 1 and Cycle 3. The duration of one cycle was 21 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. |
| Phase Ib and Phase II: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab | pre-dose, 1, 24, 48, 72, 168, 240, 336 and 504 hours after completion of spartalizumab infusion on Cycle 1 and Cycle 3. The duration of one cycle was 21 days. | Pharmacokinetic (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. |
| Phase Ib and Phase II: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab | pre-dose, 1, 24, 48, 72, 168, 240, 336 and 504 hours after completion of spartalizumab infusion on Cycle 1 and Cycle 3. The duration of one cycle was 21 days. | Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation. |
| Phase Ib and Phase II: Percent Marker Area for CD8 Expression in Tumor Samples | Baseline (screening) and post-baseline (assessed throughout the treatment up to maximum 115 days). | The expression of CD8 was measured in tumor samples by immunohistochemical methods. This record summarizes the percent marker area for CD8 expression in tumor samples. |
| Phase Ib and Phase II: PD-L1 Percent Positive Tumor | Baseline (screening) and post-baseline (assessed throughout the treatment up to maximum 115 days). | The expression of programmed cell death-ligand 1 (PD-L1) was measured in tumor samples by immunohistochemical methods. This record summarizes the PD-L1 positivity percentage in tumor samples. |
| Phase II: Dose Intensity of Capmatinib | From first dose of study medication up to last dose, with a maximum duration of 2.2 years | Dose intensity of capmatinib was calculated as actual cumulative dose in milligrams divided by duration of exposure in days. |
| Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | From start of treatment until end of treatment, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II | BOR is defined as the best response recorded from the start of the study treatment until disease progression/recurrence, based on local investigator assessment per Immune-related Response Criteria (irRC). For irRC, irCR=Disappearance of all non-nodal target lesions and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; irPR= At least a 30% decrease in the sum of diameters of all target lesions including new measurable lesions, taking as reference the baseline sum of diameters; irPD= At least a 20% increase in the sum of diameters of all measured target lesions including new measurable 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; irSD= Neither sufficient shrinkage to qualify for irPR or irCR nor an increase in lesions which would qualify for irPD). |
| Phase Ib: Overall Response Rate (ORR) Per RECIST v1.1 | From start of treatment until end of treatment, assessed up to 3.2 years | Tumor response was based on local investigator assessment as per 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. |
| Phase Ib and Phase II: Overall Response Rate (ORR) Per irRC | From start of treatment until end of treatment, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II | Tumor response was based on local investigator assessment as per irRC. ORR per irRC is defined as the percentage of participants with a best overall response of immune related Complete Response (irCR) or immune related Partial Response (irPR). For irRC, irCR=Disappearance of all non-nodal target lesions and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; irPR= At least a 30% decrease in the sum of diameters of all target lesions including new measurable lesions, taking as reference the baseline sum of diameters. |
| Phase Ib and Phase II: Duration of Response (DOR) Per RECIST v1.1 | From first documented response to first documented disease progression or death due to any cause, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II | DOR only applies to patients for whom best overall response is complete response (CR) or partial response (PR) based on local investigator assessment of overall lesion response according to RECIST v1.1. DOR is defined as the time from the date of first documented response (confirmed CR or confirmed PR) to the date of first documented disease progression or death due to any cause. If a patient not had an event, duration was censored at the date of last adequate tumor assessment before the start of a new anticancer therapy, if any. According to the statistical analysis plan (SAP), summary estimates of DOR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving a confirmed CR or PR in each treatment group/arm. |
| Phase Ib and Phase II: Duration of Response (DOR) Per irRC | From first documented response to first documented disease progression or death due to any cause, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II | DOR only applies to patients for whom best overall response is immune-related complete response (irCR) or immune-related partial response (irPR) based on local investigator assessment of overall lesion response according to irRC. DOR is defined as the time from the date of first documented response (confirmed irCR or confirmed irPR) to the date of first documented disease progression or death due to any cause. If a patient not had an event, duration was censored at the date of last adequate tumor assessment before the start of a new anticancer therapy, if any. According to the statistical analysis plan (SAP), summary estimates of DOR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving a confirmed irCR or irPR in each treatment group/arm. |
Countries
Canada, China, France, Germany, Hong Kong, Italy, South Korea, Taiwan
Participant flow
Recruitment details
Participants took part in 18 investigative sites in 8 countries.
Pre-assignment details
The screening period began once patients had signed the study informed consent. Screening evaluations were performed within 21 days prior to the first dose of study medication. After screening, the treatment period started on Cycle 1 Day 1.
Participants by arm
| Arm | Count |
|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W Capmatinib 200 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib | 6 |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W Capmatinib 300 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib | 10 |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Capmatinib 400 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib | 11 |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W Capmatinib 400 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase II | 32 |
| Phase II: Spartalizumab 300 mg Q3W Spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase II | 30 |
| Total | 89 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 | 1 | 2 | 1 |
| Overall Study | Death | 1 | 0 | 1 | 2 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 2 | 1 | 5 |
| Overall Study | Progressive disease | 3 | 7 | 6 | 26 | 20 |
| Overall Study | Subject/guardian decision | 1 | 1 | 1 | 1 | 3 |
Baseline characteristics
| Characteristic | Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase II: Spartalizumab 300 mg Q3W | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 68.5 years STANDARD_DEVIATION 7.42 | 63.2 years STANDARD_DEVIATION 10.24 | 64.6 years STANDARD_DEVIATION 8.99 | 64.8 years STANDARD_DEVIATION 10.02 | 63.4 years STANDARD_DEVIATION 9.97 | 64.4 years STANDARD_DEVIATION 9.64 |
| Race/Ethnicity, Customized Asian | 3 Participants | 3 Participants | 4 Participants | 12 Participants | 12 Participants | 34 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 1 Participants | 10 Participants | 8 Participants | 19 Participants |
| Race/Ethnicity, Customized White | 3 Participants | 7 Participants | 6 Participants | 10 Participants | 10 Participants | 36 Participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants | 3 Participants | 5 Participants | 12 Participants |
| Sex: Female, Male Male | 6 Participants | 8 Participants | 9 Participants | 29 Participants | 25 Participants | 77 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 6 | 3 / 10 | 4 / 11 | 8 / 32 | 13 / 30 | 3 / 3 | 5 / 7 | 4 / 7 | 15 / 24 | 10 / 17 |
| other Total, other adverse events | 6 / 6 | 10 / 10 | 10 / 11 | 32 / 32 | 30 / 30 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 1 / 6 | 1 / 10 | 6 / 11 | 14 / 32 | 12 / 30 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Phase Ib: 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 study medication up to last dose, with a maximum duration of 3.2 years
Population: All patients who had received at least one dose of spartalizumab or capmatinib in the Phase Ib part
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Dose Intensity of Capmatinib | 391.2 mg/day |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Dose Intensity of Capmatinib | 580.0 mg/day |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Dose Intensity of Capmatinib | 755.6 mg/day |
Primary
Phase Ib: Dose Intensity of Spartalizumab
Dose intensity of spartalizumab was calculated as actual cumulative dose in milligrams divided by duration of exposure in weeks and then multiplied by 3 weeks (3W).
Time frame: From first dose of study medication up to last dose, with a maximum duration of 3.2 years
Population: All patients who had received at least one dose of spartalizumab or capmatinib in the Phase Ib part
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Dose Intensity of Spartalizumab | 293.18 mg/3W |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Dose Intensity of Spartalizumab | 300.00 mg/3W |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Dose Intensity of Spartalizumab | 300.00 mg/3W |
Primary
Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period
Number of participants with AEs and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. For CTCAE v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. The on-treatment period is defined from the day of first administration of study treatment up to 30 days after the date of its last administration.
Time frame: From first dose of study medication up to 30 days after last dose, with a maximum duration of 3.3 years
Population: All patients who had received at least one dose of spartalizumab or capmatinib in the Phase Ib part
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs requiring additional therapy | 6 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs leading to discontinuation | 3 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related SAEs | 0 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs with grade ≥ 3 | 6 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related fatal SAEs | 0 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Fatal SAEs | 1 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs | 6 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related AEs | 5 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs leading to dose adjustment/interruption | 3 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related AEs with grade ≥ 3 | 4 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AE due to infusion reaction | 0 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related AEs leading to discontinuation | 2 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | SAEs | 1 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Fatal SAEs | 0 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs | 10 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related AEs | 7 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs with grade ≥ 3 | 7 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related AEs with grade ≥ 3 | 4 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | SAEs | 1 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related SAEs | 0 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related fatal SAEs | 0 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs leading to discontinuation | 4 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related AEs leading to discontinuation | 1 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs leading to dose adjustment/interruption | 6 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs requiring additional therapy | 9 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AE due to infusion reaction | 0 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs leading to discontinuation | 4 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related AEs with grade ≥ 3 | 6 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs requiring additional therapy | 10 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related AEs leading to discontinuation | 4 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs with grade ≥ 3 | 7 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs | 10 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs leading to dose adjustment/interruption | 7 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Fatal SAEs | 1 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related SAEs | 5 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related AEs | 10 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related fatal SAEs | 1 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | SAEs | 6 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AE due to infusion reaction | 1 Participants |
Primary
Phase Ib: Number of Participants With Dose-Limiting Toxicities (DLTs) During the First 2 Cycles of Treatment
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 assessed as unrelated to disease, disease progression, inter-current illness or concomitant medications that occurs within the first 2 cycles of treatment with capmatinib in combination with spartalizumab during the dose escalation part of the study. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher. The duration of one treatment cycle is 21 days.
Time frame: 42 days
Population: Patients in Phase Ib who either met the minimum exposure criterion and had sufficient safety evaluations, or had experienced a DLT during Cycles 1 and 2. A patient was considered to have met the minimum exposure criterion if received at least 2 doses of spartalizumab and 28 days of capmatinib during Cycles 1 and 2. Patients who did not experience a DLT during the first 2 cycles were considered to have sufficient safety evaluations if they had been observed for at least 42 days after first dose.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Dose-Limiting Toxicities (DLTs) During the First 2 Cycles of Treatment | 0 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Dose-Limiting Toxicities (DLTs) During the First 2 Cycles of Treatment | 0 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Dose-Limiting Toxicities (DLTs) During the First 2 Cycles of Treatment | 1 Participants |
Primary
Phase Ib: 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. No dose modifications (i.e. dose reduction) were allowed for spartalizumab.
Time frame: From first dose of study medication up to last dose, with a maximum duration of 3.2 years
Population: All patients who had received at least one dose of spartalizumab or capmatinib in the Phase Ib part
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab | Capmatinib dose reduction | 2 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab | Capmatinib dose interruption | 4 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab | Spartalizumab dose reduction | 0 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab | Spartalizumab dose interruption | 4 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab | Spartalizumab dose interruption | 4 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab | Capmatinib dose reduction | 4 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab | Spartalizumab dose reduction | 0 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab | Capmatinib dose interruption | 6 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab | Spartalizumab dose interruption | 7 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab | Capmatinib dose interruption | 8 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab | Spartalizumab dose reduction | 0 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab | Capmatinib dose reduction | 8 Participants |
Primary
Phase II: Overall Response Rate (ORR) Per RECIST v1.1
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: From start of treatment until end of treatment, assessed up to 2.2 years
Population: All patients to whom study treatment was assigned by randomization in the Phase II part
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Overall Response Rate (ORR) Per RECIST v1.1 | 9.4 percentage of participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase II: Overall Response Rate (ORR) Per RECIST v1.1 | 10.0 percentage of participants |
Bayesian Logistic Regression Model
Secondary
Phase Ib and Phase II: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab
Pharmacokinetic (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-dose, 1, 24, 48, 72, 168, 240, 336 and 504 hours after completion of spartalizumab infusion on Cycle 1 and Cycle 3. The duration of one cycle was 21 days.
Population: All patients in Phase Ib and Phase II who provided an evaluable PK profile of spartalizumab on Cycle 1 Day 1 and Cycle 3 Day 1. The spartalizumab PK profile was considered evaluable if all the following conditions were satisfied: patient received the planned treatment with spartalizumab and patient provided at least 1 primary PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab | Cycle 1 | 739 day*µg/mL | Geometric Coefficient of Variation 24.7 |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab | Cycle 3 | 1280 day*µg/mL | Geometric Coefficient of Variation 39.2 |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab | Cycle 1 | 726 day*µg/mL | Geometric Coefficient of Variation 20.9 |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab | Cycle 3 | 1220 day*µg/mL | Geometric Coefficient of Variation 25.5 |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab | Cycle 1 | 813 day*µg/mL | Geometric Coefficient of Variation 19.4 |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab | Cycle 3 | 1630 day*µg/mL | Geometric Coefficient of Variation 23.2 |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab | Cycle 3 | 1330 day*µg/mL | Geometric Coefficient of Variation 41.6 |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab | Cycle 1 | 805 day*µg/mL | Geometric Coefficient of Variation 33.4 |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab | Cycle 1 | 693 day*µg/mL | Geometric Coefficient of Variation 35.3 |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab | Cycle 3 | 883 day*µg/mL | Geometric Coefficient of Variation 79.1 |
Secondary
Phase Ib and Phase II: Best Overall Response (BOR) Per irRC
BOR is defined as the best response recorded from the start of the study treatment until disease progression/recurrence, based on local investigator assessment per Immune-related Response Criteria (irRC). For irRC, irCR=Disappearance of all non-nodal target lesions and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; irPR= At least a 30% decrease in the sum of diameters of all target lesions including new measurable lesions, taking as reference the baseline sum of diameters; irPD= At least a 20% increase in the sum of diameters of all measured target lesions including new measurable 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; irSD= Neither sufficient shrinkage to qualify for irPR or irCR nor an increase in lesions which would qualify for irPD).
Time frame: From start of treatment until end of treatment, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Population: All patients who received at least one dose of study treatment in the Phase Ib part, and all patients to whom study treatment was assigned by randomization in the Phase II part.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Immune-related Partial Response (irPR) | 2 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Unknown | 0 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Immune-related Stable Disease (irSD) | 1 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Immune-related Progressive Disease (irPD) | 3 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Immune-related Complete Response (irCR) | 0 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Immune-related Stable Disease (irSD) | 7 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Immune-related Complete Response (irCR) | 0 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Immune-related Partial Response (irPR) | 0 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Immune-related Progressive Disease (irPD) | 2 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Unknown | 1 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Immune-related Complete Response (irCR) | 0 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Unknown | 0 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Immune-related Stable Disease (irSD) | 3 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Immune-related Progressive Disease (irPD) | 5 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Immune-related Partial Response (irPR) | 3 Participants |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Immune-related Progressive Disease (irPD) | 10 Participants |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Immune-related Stable Disease (irSD) | 15 Participants |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Immune-related Complete Response (irCR) | 0 Participants |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Unknown | 3 Participants |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Immune-related Partial Response (irPR) | 4 Participants |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Immune-related Stable Disease (irSD) | 9 Participants |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Unknown | 4 Participants |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Immune-related Complete Response (irCR) | 0 Participants |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Immune-related Partial Response (irPR) | 3 Participants |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per irRC | Immune-related Progressive Disease (irPD) | 14 Participants |
Secondary
Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1
BOR is defined as the best response recorded from the start of the study treatment until disease progression/recurrence, based on local investigator assessment per RECIST v1.1. For RECIST v1.1, R=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters; PD= At least a 20% increase in the sum of diameters of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition, the sum must also demonstrate an absolute increase of at least 5 mm; SD= Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression). The number of participants in each response category is reported in the table.
Time frame: From start of treatment until end of treatment, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Population: All patients who received at least one dose of study treatment in the Phase Ib part, and all patients to whom study treatment was assigned by randomization in the Phase II part.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Progressive Disease (PD) | 3 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Complete Response (CR) | 0 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Unknown | 0 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Partial Response (PR) | 2 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Stable Disease (SD) | 1 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Progressive Disease (PD) | 2 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Stable Disease (SD) | 7 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Partial Response (PR) | 0 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Unknown | 1 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Complete Response (CR) | 0 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Stable Disease (SD) | 2 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Complete Response (CR) | 0 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Partial Response (PR) | 2 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Progressive Disease (PD) | 7 Participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Unknown | 0 Participants |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Unknown | 4 Participants |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Complete Response (CR) | 0 Participants |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Progressive Disease (PD) | 13 Participants |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Stable Disease (SD) | 12 Participants |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Partial Response (PR) | 3 Participants |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Stable Disease (SD) | 9 Participants |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Progressive Disease (PD) | 15 Participants |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Complete Response (CR) | 0 Participants |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Unknown | 3 Participants |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1 | Partial Response (PR) | 3 Participants |
Secondary
Phase Ib and Phase II: Duration of Response (DOR) Per irRC
DOR only applies to patients for whom best overall response is immune-related complete response (irCR) or immune-related partial response (irPR) based on local investigator assessment of overall lesion response according to irRC. DOR is defined as the time from the date of first documented response (confirmed irCR or confirmed irPR) to the date of first documented disease progression or death due to any cause. If a patient not had an event, duration was censored at the date of last adequate tumor assessment before the start of a new anticancer therapy, if any. According to the statistical analysis plan (SAP), summary estimates of DOR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving a confirmed irCR or irPR in each treatment group/arm.
Time frame: From first documented response to first documented disease progression or death due to any cause, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Population: All participants in Phase Ib and II for whom best overall response is immune-related complete response (irCR) or immune-related partial response (irPR) as per irRC based on local investigator assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Duration of Response (DOR) Per irRC | NA months |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Duration of Response (DOR) Per irRC | NA months |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Duration of Response (DOR) Per irRC | NA months |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Duration of Response (DOR) Per irRC | NA months |
Secondary
Phase Ib and Phase II: Duration of Response (DOR) Per RECIST v1.1
DOR only applies to patients for whom best overall response is complete response (CR) or partial response (PR) based on local investigator assessment of overall lesion response according to RECIST v1.1. DOR is defined as the time from the date of first documented response (confirmed CR or confirmed PR) to the date of first documented disease progression or death due to any cause. If a patient not had an event, duration was censored at the date of last adequate tumor assessment before the start of a new anticancer therapy, if any. According to the statistical analysis plan (SAP), summary estimates of DOR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving a confirmed CR or PR in each treatment group/arm.
Time frame: From first documented response to first documented disease progression or death due to any cause, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Population: All participants in Phase Ib and II for whom best overall response is complete response (CR) or partial response (PR) as per RECIST v1.1 based on local investigator assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Duration of Response (DOR) Per RECIST v1.1 | NA months |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Duration of Response (DOR) Per RECIST v1.1 | NA months |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Duration of Response (DOR) Per RECIST v1.1 | NA months |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Duration of Response (DOR) Per RECIST v1.1 | NA months |
Secondary
Phase Ib and Phase II: 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-dose, 1, 24, 48, 72, 168, 240, 336 and 504 hours after completion of spartalizumab infusion on Cycle 1 and Cycle 3. The duration of one cycle was 21 days.
Population: All patients in Phase Ib and Phase II who provided an evaluable PK profile of spartalizumab on Cycle 1 and Cycle 3. The spartalizumab PK profile was considered evaluable if all the following conditions were satisfied: patient received the planned treatment with spartalizumab and patient provided at least 1 primary PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Maximum Observed Serum Concentration (Cmax) of Spartalizumab | Cycle 1 | 75.7 µg/mL | Geometric Coefficient of Variation 22.6 |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Maximum Observed Serum Concentration (Cmax) of Spartalizumab | Cycle 3 | 105 µg/mL | Geometric Coefficient of Variation 35.8 |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Maximum Observed Serum Concentration (Cmax) of Spartalizumab | Cycle 1 | 77.2 µg/mL | Geometric Coefficient of Variation 20.9 |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Maximum Observed Serum Concentration (Cmax) of Spartalizumab | Cycle 3 | 101 µg/mL | Geometric Coefficient of Variation 22.3 |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Maximum Observed Serum Concentration (Cmax) of Spartalizumab | Cycle 1 | 84.7 µg/mL | Geometric Coefficient of Variation 23.3 |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Maximum Observed Serum Concentration (Cmax) of Spartalizumab | Cycle 3 | 128 µg/mL | Geometric Coefficient of Variation 20.9 |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Maximum Observed Serum Concentration (Cmax) of Spartalizumab | Cycle 3 | 115 µg/mL | Geometric Coefficient of Variation 30.2 |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Maximum Observed Serum Concentration (Cmax) of Spartalizumab | Cycle 1 | 81.7 µg/mL | Geometric Coefficient of Variation 30.1 |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Maximum Observed Serum Concentration (Cmax) of Spartalizumab | Cycle 1 | 72.8 µg/mL | Geometric Coefficient of Variation 30.9 |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Maximum Observed Serum Concentration (Cmax) of Spartalizumab | Cycle 3 | 101 µg/mL | Geometric Coefficient of Variation 42.2 |
Secondary
Phase Ib and Phase II: Overall Response Rate (ORR) Per irRC
Tumor response was based on local investigator assessment as per irRC. ORR per irRC is defined as the percentage of participants with a best overall response of immune related Complete Response (irCR) or immune related Partial Response (irPR). For irRC, irCR=Disappearance of all non-nodal target lesions and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; irPR= At least a 30% decrease in the sum of diameters of all target lesions including new measurable lesions, taking as reference the baseline sum of diameters.
Time frame: From start of treatment until end of treatment, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Population: All patients who received at least one dose of study treatment in the Phase Ib part, and all patients to whom study treatment was assigned by randomization in the Phase II part.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Overall Response Rate (ORR) Per irRC | 33.3 percentage of participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Overall Response Rate (ORR) Per irRC | 0 percentage of participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Overall Response Rate (ORR) Per irRC | 27.3 percentage of participants |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Overall Response Rate (ORR) Per irRC | 12.5 percentage of participants |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Overall Response Rate (ORR) Per irRC | 10.0 percentage of participants |
Secondary
Phase Ib and Phase II: 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 patient was not known to have died, OS time was censored at the date of last contact. OS was estimated using the Kaplan-Meier Method.
Time frame: From start of treatment until death due to any cause, assessed up to 3.6 years in Phase Ib and up to 2.9 years in Phase II
Population: All patients who received at least one dose of study treatment in the Phase Ib part, and all patients to whom study treatment was assigned by randomization in the Phase II part.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Overall Survival (OS) | 14.98 months |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Overall Survival (OS) | 12.11 months |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Overall Survival (OS) | 16.53 months |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Overall Survival (OS) | 14.88 months |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Overall Survival (OS) | 9.78 months |
Secondary
Phase Ib and Phase II: PD-L1 Percent Positive Tumor
The expression of programmed cell death-ligand 1 (PD-L1) was measured in tumor samples by immunohistochemical methods. This record summarizes the PD-L1 positivity percentage in tumor samples.
Time frame: Baseline (screening) and post-baseline (assessed throughout the treatment up to maximum 115 days).
Population: All patients who received at least one dose of study treatment in the Phase Ib part and had a valid assessment for the outcome measure, and all patients to whom study treatment was assigned by randomization in the Phase II part and had a valid assessment for the outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: PD-L1 Percent Positive Tumor | Post-baseline | 12.5 PD-L1 positivity percentage |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: PD-L1 Percent Positive Tumor | Baseline | 0.0 PD-L1 positivity percentage |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: PD-L1 Percent Positive Tumor | Baseline | 0.0 PD-L1 positivity percentage |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: PD-L1 Percent Positive Tumor | Post-baseline | 0.0 PD-L1 positivity percentage |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: PD-L1 Percent Positive Tumor | Post-baseline | 0.0 PD-L1 positivity percentage |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: PD-L1 Percent Positive Tumor | Baseline | 0.0 PD-L1 positivity percentage |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: PD-L1 Percent Positive Tumor | Baseline | 0.0 PD-L1 positivity percentage |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: PD-L1 Percent Positive Tumor | Post-baseline | 0.0 PD-L1 positivity percentage |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: PD-L1 Percent Positive Tumor | Baseline | 0.0 PD-L1 positivity percentage |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: PD-L1 Percent Positive Tumor | Post-baseline | 0.0 PD-L1 positivity percentage |
Secondary
Phase Ib and Phase II: Percent Marker Area for CD8 Expression in Tumor Samples
The expression of CD8 was measured in tumor samples by immunohistochemical methods. This record summarizes the percent marker area for CD8 expression in tumor samples.
Time frame: Baseline (screening) and post-baseline (assessed throughout the treatment up to maximum 115 days).
Population: All patients who received at least one dose of study treatment in the Phase Ib part and had a valid assessment for the outcome measure, and all patients to whom study treatment was assigned by randomization in the Phase II part and had a valid assessment for the outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Percent Marker Area for CD8 Expression in Tumor Samples | Baseline | 0.6 CD8 percent marker area |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Percent Marker Area for CD8 Expression in Tumor Samples | Post-baseline | 3.0 CD8 percent marker area |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Percent Marker Area for CD8 Expression in Tumor Samples | Baseline | 0.9 CD8 percent marker area |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Percent Marker Area for CD8 Expression in Tumor Samples | Post-baseline | 2.6 CD8 percent marker area |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Percent Marker Area for CD8 Expression in Tumor Samples | Baseline | 0.4 CD8 percent marker area |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Percent Marker Area for CD8 Expression in Tumor Samples | Post-baseline | 1.0 CD8 percent marker area |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Percent Marker Area for CD8 Expression in Tumor Samples | Post-baseline | 1.3 CD8 percent marker area |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Percent Marker Area for CD8 Expression in Tumor Samples | Baseline | 0.5 CD8 percent marker area |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Percent Marker Area for CD8 Expression in Tumor Samples | Baseline | 0.3 CD8 percent marker area |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Percent Marker Area for CD8 Expression in Tumor Samples | Post-baseline | 0.9 CD8 percent marker area |
Secondary
Phase Ib and Phase II: Progression-Free Survival (PFS) Per irRC
PFS is defined as the time from the date of start of treatment to the date of the first documented and confirmed progression per irRC or death due to any cause. If a patient did not experience an event or started a new anticancer therapy, PFS was censored at the date of the last adequate tumor evaluation before the start of a new anticancer therapy, if any. Tumor response was based on local investigator assessment per irRC. PFS was estimated using the Kaplan-Meier Method.
Time frame: From start of treatment until first documented progression or death due to any cause, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Population: All patients who received at least one dose of study treatment in the Phase Ib part, and all patients to whom study treatment was assigned by randomization in the Phase II part.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Progression-Free Survival (PFS) Per irRC | 3.42 months |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Progression-Free Survival (PFS) Per irRC | 4.44 months |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Progression-Free Survival (PFS) Per irRC | 5.55 months |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Progression-Free Survival (PFS) Per irRC | 3.06 months |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Progression-Free Survival (PFS) Per irRC | 2.79 months |
Secondary
Phase Ib and Phase II: Progression-Free Survival (PFS) Per RECIST v1.1
PFS is defined as the time from the date of start of treatment to the date of the first documented progression per RECIST v1.1 or death due to any cause. If a patient did not experience an event or started a new anticancer therapy, PFS was censored at the date of the last adequate tumor evaluation before the start of a new anticancer therapy, if any. Tumor response was based on local investigator assessment per RECIST v1.1. PFS was estimated using the Kaplan-Meier Method.
Time frame: From start of treatment until first documented progression or death due to any cause, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Population: All patients who received at least one dose of study treatment in the Phase Ib part, and all patientss to whom study treatment was assigned by randomization in the Phase II part.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Progression-Free Survival (PFS) Per RECIST v1.1 | 3.42 months |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Progression-Free Survival (PFS) Per RECIST v1.1 | 4.44 months |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Progression-Free Survival (PFS) Per RECIST v1.1 | 1.35 months |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Progression-Free Survival (PFS) Per RECIST v1.1 | 2.79 months |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Progression-Free Survival (PFS) Per RECIST v1.1 | 2.79 months |
Secondary
Phase Ib and Phase II: Time to Progression (TTP) Per irRC
TTP is defined as the time from the date of start of treatment to the date of the first documented and confirmed progression per irRC or death due to underlying cancer. If a patient did not experience an event or started a new anticancer therapy, TTP was censored at the date of the last adequate tumor evaluation before the start of a new anticancer therapy, if any. Tumor response was based on local investigator assessment per irRC.
Time frame: From start of treatment until first documented progression or death due to underlying cancer, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Population: All patients who received at least one dose of study treatment in the Phase Ib part, and all patients to whom study treatment was assigned by randomization in the Phase II part.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Progression (TTP) Per irRC | 3.42 months |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Progression (TTP) Per irRC | 4.44 months |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Progression (TTP) Per irRC | 5.55 months |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Progression (TTP) Per irRC | 3.06 months |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Progression (TTP) Per irRC | 2.79 months |
Secondary
Phase Ib and Phase II: Time to Progression (TTP) Per RECIST v1.1
TTP is defined as the time from the date of start of treatment to the date of the first documented progression per RECIST v1.1 or death due to underlying cancer. If a patient did not experience an event or started a new anticancer therapy, TTP was censored at the date of the last adequate tumor evaluation before the start of a new anticancer therapy, if any. Tumor response was based on local investigator assessment per RECIST v1.1. TTP was estimated using the Kaplan-Meier Method.
Time frame: From start of treatment until first documented progression or death due to underlying cancer, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Population: All patients who received at least one dose of study treatment in the Phase Ib part, and all patients to whom study treatment was assigned by randomization in the Phase II part.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Progression (TTP) Per RECIST v1.1 | 3.42 months |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Progression (TTP) Per RECIST v1.1 | 4.44 months |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Progression (TTP) Per RECIST v1.1 | 1.35 months |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Progression (TTP) Per RECIST v1.1 | 2.79 months |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Progression (TTP) Per RECIST v1.1 | 2.79 months |
Secondary
Phase Ib and Phase II: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab
Pharmacokinetic (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-dose, 1, 24, 48, 72, 168, 240, 336 and 504 hours after completion of spartalizumab infusion on Cycle 1 and Cycle 3. The duration of one cycle was 21 days.
Population: All patients in Phase Ib and Phase II who provided an evaluable PK profile of spartalizumab on Cycle 1 Day 1 and Cycle 3 Day 1. The spartalizumab PK profile was considered evaluable if all the following conditions were satisfied: patient received the planned treatment with spartalizumab and patient provided at least 1 primary PK parameter.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab | Cycle 1 | 1.51 hours |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab | Cycle 3 | 1.53 hours |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab | Cycle 1 | 1.50 hours |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab | Cycle 3 | 1.47 hours |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab | Cycle 1 | 1.50 hours |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab | Cycle 3 | 1.52 hours |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab | Cycle 3 | 1.75 hours |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab | Cycle 1 | 1.64 hours |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab | Cycle 1 | 1.59 hours |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab | Cycle 3 | 1.58 hours |
Secondary
Phase Ib and Phase II: Time to Response (TTR) Per irRC
TTR is defined as the time from the date of start of treatment to the date of first documented response (irCR or irPR, which must be confirmed subsequently) for patients who achieved a confirmed irCR or irPR. Tumor response was based on local investigator assessment per irRC. Patients who did not achieve a confirmed irCR or irPR were censored at the maximum follow-up time for patients who had a Progression-Free Survival (PFS) event (i.e. either progressed or died due to any cause), or at the date of last adequate tumor assessment before the start of a new anticancer therapy (if any) otherwise. According to the statistical analysis plan (SAP), summary estimates of TTR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving a confirmed irCR or irPR in each treatment group/arm.
Time frame: From start of treatment until first documented response, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Population: All patients who received at least one dose of study treatment in the Phase Ib part, and all patients to whom study treatment was assigned by randomization in the Phase II part.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Response (TTR) Per irRC | NA months |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Response (TTR) Per irRC | NA months |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Response (TTR) Per irRC | NA months |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Response (TTR) Per irRC | NA months |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Response (TTR) Per irRC | NA months |
Secondary
Phase Ib and Phase II: Time to Response (TTR) Per RECIST v1.1
TTR is defined as the time from the date of start of treatment to the date of first documented response (CR or PR, which must be confirmed subsequently) for patients who achieved a confirmed CR or PR. Tumor response was based on local investigator assessment per RECIST v1.1. Patients who did not achieve a confirmed CR or PR were censored at the maximum follow-up time for patients who had a Progression-Free Survival (PFS) event (i.e. either progressed or died due to any cause), or at the date of last adequate tumor assessment before the start of a new anticancer therapy (if any) otherwise. According to the statistical analysis plan (SAP), summary estimates of TTR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving a confirmed CR or PR in each treatment group/arm.
Time frame: From start of treatment until first documented response, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Population: All patients who received at least one dose of study treatment in the Phase Ib part, and all patients to whom study treatment was assigned by randomization in the Phase II part.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Response (TTR) Per RECIST v1.1 | NA months |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Response (TTR) Per RECIST v1.1 | NA months |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Response (TTR) Per RECIST v1.1 | NA months |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Response (TTR) Per RECIST v1.1 | NA months |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: Time to Response (TTR) Per RECIST v1.1 | NA months |
Secondary
Phase Ib: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib
Pharmacokinetic (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, 0.5, 1, 2, 4 and 8 hours post capmatinib dose on Cycle 2 Day 1 (C2D1). The duration of one cycle was 21 days.
Population: All patients in Phase Ib who provided an evaluable capmatinib PK profile on C2D1. Capmatinib PK profile was considered evaluable if all the following conditions were satisfied: patient took the same dose of capmatinib for at least 3 consecutive days prior to sampling, patient had the pre-dose sample collected before next dose administration and at least 9 hours after last dose administration, patient did not vomit within 4 hours after dosing and patient provided at least 1 primary PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib | 5740 hours*ng/mL | Geometric Coefficient of Variation 51.6 |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib | 8570 hours*ng/mL | Geometric Coefficient of Variation 60.7 |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib | 16000 hours*ng/mL | Geometric Coefficient of Variation 30.6 |
Secondary
Phase Ib: 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, 0.5, 1, 2, 4 and 8 hours post capmatinib dose on Cycle 2 Day 1 (C2D1). The duration of one cycle was 21 days.
Population: All patients in Phase Ib who provided an evaluable capmatinib PK profile on C2D1. Capmatinib PK profile was considered evaluable if all the following conditions were satisfied: patient took the same dose of capmatinib for at least 3 consecutive days prior to sampling, patient had the pre-dose sample collected before next dose administration and at least 9 hours after last dose administration, patient did not vomit within 4 hours after dosing and patient provided at least 1 primary PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Maximum Observed Plasma Concentration (Cmax) of Capmatinib | 1680 ng/mL | Geometric Coefficient of Variation 64 |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Maximum Observed Plasma Concentration (Cmax) of Capmatinib | 3110 ng/mL | Geometric Coefficient of Variation 61.2 |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Maximum Observed Plasma Concentration (Cmax) of Capmatinib | 4980 ng/mL | Geometric Coefficient of Variation 23 |
Secondary
Phase Ib: Overall Response Rate (ORR) Per RECIST v1.1
Tumor response was based on local investigator assessment as per 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: From start of treatment until end of treatment, assessed up to 3.2 years
Population: All patients who had received at least one dose of spartalizumab or capmatinib capmatinib in the Phase Ib part
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Overall Response Rate (ORR) Per RECIST v1.1 | 33.3 percentage of participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Overall Response Rate (ORR) Per RECIST v1.1 | 0 percentage of participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Overall Response Rate (ORR) Per RECIST v1.1 | 18.2 percentage of participants |
Secondary
Phase Ib: Time to Reach Maximum Plasma Concentration (Tmax) of Capmatinib
Pharmacokinetic (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, 0.5, 1, 2, 4 and 8 hours post capmatinib dose on Cycle 2 Day 1 (C2D1). The duration of one cycle was 21 days.
Population: All patients in Phase Ib who provided an evaluable capmatinib PK profile on C2D1. Capmatinib PK profile was considered evaluable if all the following conditions were satisfied: patient took the same dose of capmatinib for at least 3 consecutive days prior to sampling, patient had the pre-dose sample collected before next dose administration and at least 9 hours after last dose administration, patient did not vomit within 4 hours after dosing and patient provided at least 1 primary PK parameter.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Time to Reach Maximum Plasma Concentration (Tmax) of Capmatinib | 0.959 hours |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Time to Reach Maximum Plasma Concentration (Tmax) of Capmatinib | 1.00 hours |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib: Time to Reach Maximum Plasma Concentration (Tmax) of Capmatinib | 1.00 hours |
Secondary
Phase II: 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 study medication up to last dose, with a maximum duration of 2.2 years
Population: All patients assigned by randomization to capmatinib in combination with spartalizumab in the Phase II part
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Dose Intensity of Capmatinib | 696.4 mg/day |
Secondary
Phase II: Dose Intensity of Spartalizumab
Dose intensity of spartalizumab was calculated as actual cumulative dose in milligrams divided by duration of exposure in weeks and then multiplied by 3 weeks (3W).
Time frame: From first dose of study medication up to last dose, with a maximum duration of 2.2 years
Population: All patients to whom study treatment was assigned by randomization in the Phase II part
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Dose Intensity of Spartalizumab | 300.00 mg/3W |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase II: Dose Intensity of Spartalizumab | 300.00 mg/3W |
Secondary
Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period
Number of participants with AEs and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. For CTCAE v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. The on-treatment period is defined from the day of first administration of study treatment up to 30 days after the date of its last administration.
Time frame: From first dose of study medication up to 30 days after last dose, with a maximum duration of 2.3 years
Population: All patients to whom study treatment was assigned by randomization in the Phase II part
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs | 32 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related AEs | 30 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs with grade ≥ 3 | 25 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related AEs with grade ≥ 3 | 18 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | SAEs | 14 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related SAEs | 7 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Fatal SAEs | 1 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs leading to discontinuation | 10 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related AEs leading to discontinuation | 7 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs leading to dose adjustment/interruption | 22 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs requiring additional therapy | 30 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AE due to infusion reaction | 1 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs requiring additional therapy | 29 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs | 30 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Fatal SAEs | 1 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related AEs | 18 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs leading to dose adjustment/interruption | 11 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs with grade ≥ 3 | 15 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AEs leading to discontinuation | 1 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related AEs with grade ≥ 3 | 3 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | AE due to infusion reaction | 0 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | SAEs | 10 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related AEs leading to discontinuation | 0 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period | Treatment-related SAEs | 1 Participants |
Secondary
Phase II: 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. No dose modifications (i.e. dose reduction) were allowed for spartalizumab.
Time frame: From first dose of study medication up to last dose, with a maximum duration of 2.2 years
Population: All patients to whom study treatment was assigned by randomization in the Phase II part
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab | Capmatinib dose reduction | 18 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab | Capmatinib dose interruption | 22 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab | Spartalizumab dose reduction | 0 Participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab | Spartalizumab dose interruption | 12 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab | Spartalizumab dose reduction | 0 Participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase II: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab | Spartalizumab dose interruption | 13 Participants |
Secondary
Phase II: Pre-dose Plasma Concentration of Capmatinib
Capmatinib plasma concentration was assessed in samples taken at pre-dose. Pre-dose samples were collected before the next dose administration.
Time frame: Pre-dose of capmatinib on Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1 and Cycle 6 Day 1. The duration of one cycle was 21 days.
Population: All patients in Phase II part who provided an evaluable capmatinib concentration at the specified timepoints. Capmatinib concentration was considered evaluable if all the following conditions were satisfied: patient took the same dose of capmatinib for at least 3 consecutive days prior to sampling, patient had the pre-dose sample collected before next dose administration and at least 9 hours after last dose administration, patient did not vomit within 4 hours after the dosing prior to sampling.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Pre-dose Plasma Concentration of Capmatinib | Cycle 2 Day 1 | 607 ng/mL | Geometric Coefficient of Variation 99.4 |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Pre-dose Plasma Concentration of Capmatinib | Cycle 3 Day 1 | 345 ng/mL | Geometric Coefficient of Variation 110 |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Pre-dose Plasma Concentration of Capmatinib | Cycle 4 Day 1 | 410 ng/mL | Geometric Coefficient of Variation 132 |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Pre-dose Plasma Concentration of Capmatinib | Cycle 5 Day 1 | 363 ng/mL | Geometric Coefficient of Variation 68.6 |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase II: Pre-dose Plasma Concentration of Capmatinib | Cycle 6 Day 1 | 275 ng/mL | Geometric Coefficient of Variation 102 |
Post Hoc
Phase Ib and Phase II: All-Collected Deaths
On-treatment and post-treatment safety follow-up deaths were collected from first dose of study medication to 150 days after the last dose of study medication. Post-treatment survival follow-up deaths were collected from day 151 after last dose of study medication to end of study. All deaths refer to the sum of on-treatment and post-treatment safety follow-up deaths plus post-treatment survival follow-up deaths.
Time frame: On-treatment and post-treatment safety follow-up deaths: up to 3.6 years in Phase Ib and 2.6 years in Phase II. Post treatment survival follow-up deaths: up to 3.6 years in Phase Ib and 2.9 years in Phase II.
Population: All patients who received at least one dose of study treatment in the Phase Ib part, and all patients to whom study treatment was assigned by randomization in the Phase II part.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: All-Collected Deaths | Post-treatment survival follow-up deaths | 3 participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: All-Collected Deaths | On-treatment and post-treatment safety follow-up deaths | 3 participants |
| Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: All-Collected Deaths | All deaths | 6 participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: All-Collected Deaths | On-treatment and post-treatment safety follow-up deaths | 3 participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: All-Collected Deaths | All deaths | 8 participants |
| Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: All-Collected Deaths | Post-treatment survival follow-up deaths | 5 participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: All-Collected Deaths | On-treatment and post-treatment safety follow-up deaths | 4 participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: All-Collected Deaths | Post-treatment survival follow-up deaths | 4 participants |
| Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: All-Collected Deaths | All deaths | 8 participants |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: All-Collected Deaths | All deaths | 23 participants |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: All-Collected Deaths | On-treatment and post-treatment safety follow-up deaths | 8 participants |
| Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W | Phase Ib and Phase II: All-Collected Deaths | Post-treatment survival follow-up deaths | 15 participants |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: All-Collected Deaths | Post-treatment survival follow-up deaths | 10 participants |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: All-Collected Deaths | On-treatment and post-treatment safety follow-up deaths | 13 participants |
| Phase II: Spartalizumab 300 mg Q3W | Phase Ib and Phase II: All-Collected Deaths | All deaths | 23 participants |