Nasopharyngeal Carcinoma
Conditions
Keywords
PDR001, nasopharyngeal cancer, moderately differentiated/undifferentiated, locally advanced, recurrent or metastatic NPC, after first- line platinum-based therapy
Brief summary
The purpose of this randomized controlled Phase II study is to assess the efficacy of PDR001 versus investigator's choice of chemotherapy in patients with advanced nasopharyngeal carcinoma (NPC). By blocking the interaction between PD-1 and its ligands PD-L1 and PD-L2, PDR001 leads to the activation of a T-cell mediated antitumor immune response.
Detailed description
This was an open-label, multi-center, randomized, and controlled Phase II study to evaluate the efficacy and safety of spartalizumab versus investigator's choice of treatment in subjects with moderately differentiated/undifferentiated locally advanced recurrent or metastatic NPC who progressed on or after first-line treatment. Participants who met the inclusion/exclusion criteria were randomized in a 2:1 ratio to either investigational arm (spartalizumab) or control arm (commonly used chemotherapy as per investigator's choice). Participants treated with spartalizumab could continue treatment until confirmed progressive disease as per immune-related response criteria (irRC). Participants in the chemotherapy arm were allowed to crossover to spartalizumab if they had radiological progression as per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) documented by an independent central review and the Investigator believed this was the best treatment option for the patient.
Interventions
DRUGSpartalizumab
Spartalizumab was administered via intravenous infusion at a dose of 400 mg every 4 weeks (Q4W). Spartalizumab is a humanized anti-PD-1 IgG4 antibody which blocks the binding of PD1 to its ligands PD-L1 and PD-L2.
DRUGInvestigator choice of chemotherapy
Commonly used chemotherapy as per investigator's choice. The dose and route of administration was the one described in each drug's label.
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
* Histologically documented non-keratinizing locally advanced recurrent or metastatic NPC. * Must be resistant to platinum-based chemotherapy (defined as progression on or after platinum-based chemotherapy given in the recurrent/metastatic setting). * May have received at least 1 prior therapy for recurrent or metastatic disease, up to 2 prior systemic therapies. * An archival tumor specimen or newly obtained tumor sample may be submitted at screening/baseline (a fresh tumor sample is preferred), unless agreed differently between Novartis and the Investigator. * At least 1 measurable lesion (as per RECIST v1.1) progressing or new since last anti-tumor therapy. * Prior treated brain or meningeal metastases must be without MRI evidence of progression for at least 8 weeks and off systemic steroids for at least 2 weeks prior to screening/baseline. * Patient must be willing to undergo testing for human immunodeficiency virus (HIV) if not tested within the past 6 months. If HIV+ positive, patient will be eligible if: his/ her CD4+ count ≥ 300/μL; his/her viral load is undetectable; he/she is currently receiving highly active antiretroviral therapy (HAART).
Exclusion criteria
* History of severe hypersensitivity reactions to other mAbs * Active autoimmune disease or a documented history of autoimmune disease, except vitiligo or resolved asthma/atopy that is treated with broncho-dilators. * Active HBV or HCV infections requiring therapy. * Prior PD-1- or PD-L1-directed therapy or any therapeutic cancer vaccine. * Patients receiving systemic treatment with any immunosuppressive medication. * Use of any vaccines against infectious diseases (e.g. varicella, pneumococcus) within 4 weeks of initiation of study treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment - Number of Participants With Progression or Death | From randomization up to maximum 3.3 years | PFS is the time from the date of randomization to the date of event defined as the first documented confirmed progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive disease is at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. Number of participants in each category (progression, death, censored) is reported in this record. |
| Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment - Median PFS | From randomization up to maximum 3.3 years | PFS is the time from the date of randomization to the date of event defined as the first documented confirmed progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive disease is at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) as Per RECIST v 1.1 | From randomization up to maximum 3.3 years | DOR only applies to subjects for whom best overall response is complete response (CR) or partial response (PR) based on central review of overall lesion response according to RECIST 1.1. DOR is defined as the time between the date of first documented response (confirmed CR or confirmed PR) and the date of first documented disease progression or death due to underlying cancer. If a patient not had an event, duration was censored at the date of last adequate tumor assessment. |
| Time to Progression (TTP) as Per RECIST v 1.1 | From randomization up to maximum 3.3 years | TTP is defined as time from date of randomization to the date of event defined as the first documented progression or death due to underlying cancer. If a subject did not had an event, TTP was censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was RECIST v1.1. Progressive disease is at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. |
| Immune-related Progression-free Survival (irPFS) as Per irRC | From randomization up to maximum 3.3 years | irPFS is the time from the date of randomization to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was immune-related Response Criteria (irRC). Immune-related progressive disease is at least a 20% increase in the sum of diameters of all measured target lesions including new measurable lesions. |
| Maximum Observed Serum Concentration (Cmax) of Spartalizumab | pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days. | Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose. |
| Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab | pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 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. |
| Area Under the Serum Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) of Spartalizumab | pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days. | Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC calculation. The duration of the dosing interval (tau) was 28 days. |
| Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf) of Spartalizumab | pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days. | Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC calculation. The extrapolation of AUC to infinity could be calculated if the percentage of area extrapolated was less than 20% and the regression analysis of the terminal serum elimination phase met a pre-defined criteria of goodness of fit. |
| Accumulation Ratio (Racc) of Spartalizumab | pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days. | Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Racc was calculated as the ratio between AUCtau Cycle 3 and AUCtau Cycle 1. |
| Overall Survival (OS) | From randomization up to maximum 4.8 years. | Overall survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a patient is not known to have died, survival is censored at the date of last known date the patient was alive. |
| Number of Participants With Anti-spartalizumab Antibodies | Baseline (pre-dose on Cycle 1 Day 1) and post-baseline (assessed throughout the treatment up to maximum 655 days). | Validated immunoassays were used for screening and confirmation of the presence of anti-spartalizumab antibodies (ADA, anti-drug antibodies) in serum. Number of participants with each ADA status is reported in this record. |
| PD-L1 Percent Positive Tumor | Baseline (screening), Cycle 3 Day 1. The duration of one cycle was 28 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. |
| Percent Marker Area for CD8 Expression in Tumor Samples | Baseline (screening), Cycle 3 Day 1. The duration of one cycle was 28 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. |
| TIL Count in Tumor Samples | Baseline (screening), Cycle 3 Day 1. The duration of one cycle was 28 days. | The count of tumor-infiltrating lymphocytes (TILs) was measured in baseline (screening) and post-baseline paired tumor samples by immunohistochemical methods. This record summarizes the TIL count in tumor samples. |
| Fold Change From Baseline in IFN-gamma Levels in Plasma | Baseline (pre-dose on Cycle 1 Day 1), Cycle 1 Day 15, Cycle 2 Day 15 and end of treatment (assessed up to maximum 4 years). The duration of one cycle was 28 days. | The levels of interferon-gamma (IFN-gamma) were measured in plasma samples by immunoassay methods. This record summarizes the fold change from baseline in IFN-gamma levels in plasma. |
| Fold Change From Baseline in IL-6 Levels in Plasma | Baseline (pre-dose on Cycle 1 Day 1), Cycle 1 Day 15, Cycle 2 Day 15 and end of treatment (assessed up to maximum 4 years). The duration of one cycle was 28 days. | The levels of interleukin-6 (IL-6) were measured in plasma samples by immunoassay methods. This record summarizes the fold change from baseline in IL-6 levels in plasma. |
| Fold Change From Baseline in TNF-alfa Levels in Plasma | Baseline (pre-dose on Cycle 1 Day 1), Cycle 1 Day 15, Cycle 2 Day 15 and end of treatment (assessed up to maximum 4 years). The duration of one cycle was 28 days. | The levels of tumor necrosis factor-alpha (TNF-alfa) were measured in plasma samples by immunoassay methods. This record summarizes the fold change from baseline in TNF-alfa levels in plasma. |
| Terminal Elimination Half-life (T1/2) of Spartalizumab | pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days. | Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Elimination half-life (T1/2) values were calculated as 0.693/terminal elimination rate constant. |
| Overall Response Rate (ORR) as Per RECIST v 1.1 | From randomization up to maximum 3.3 years | ORR is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR). Tumor response was based on central review of overall lesion response according to RECIST 1.1. For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
Countries
China, France, Hong Kong, Singapore, Taiwan, Thailand, United States
Participant flow
Recruitment details
Participants took part in 19 investigative sites in 7 countries.
Pre-assignment details
The screening period began once patients had signed the study informed consent. All screening evaluations were performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the study treatment. After screening, the treatment period started on Cycle 1 Day 1.
Participants by arm
| Arm | Count |
|---|---|
| Spartalizumab 400 mg Q4W anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab | 82 |
| Chemotherapy Commonly used chemotherapy as per investigator's choice | 40 |
| Total | 122 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 4 | 2 |
| Overall Study | Physician Decision | 10 | 1 |
| Overall Study | progressive disease | 66 | 35 |
| Overall Study | subject / guardian decision | 1 | 2 |
Baseline characteristics
| Characteristic | Spartalizumab 400 mg Q4W | Chemotherapy | Total |
|---|---|---|---|
| Age, Continuous | 51.1 years STANDARD_DEVIATION 11.54 | 50.5 years STANDARD_DEVIATION 12.32 | 50.9 years STANDARD_DEVIATION 11.75 |
| Race/Ethnicity, Customized Asian | 70 Participants | 37 Participants | 107 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 12 Participants | 2 Participants | 14 Participants |
| Sex: Female, Male Female | 14 Participants | 7 Participants | 21 Participants |
| Sex: Female, Male Male | 68 Participants | 33 Participants | 101 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 82 | 3 / 39 | 3 / 27 | 8 / 109 |
| other Total, other adverse events | 76 / 82 | 37 / 39 | 25 / 27 | 101 / 109 |
| serious Total, serious adverse events | 28 / 82 | 15 / 39 | 12 / 27 | 40 / 109 |
Outcome results
Primary
Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment - Median PFS
PFS is the time from the date of randomization to the date of event defined as the first documented confirmed progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive disease is at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline.
Time frame: From randomization up to maximum 3.3 years
Population: All participants to whom study treatment was assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Spartalizumab 400 mg Q4W | Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment - Median PFS | 1.9 months |
| Chemotherapy | Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment - Median PFS | 5.6 months |
Primary
Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment - Number of Participants With Progression or Death
PFS is the time from the date of randomization to the date of event defined as the first documented confirmed progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive disease is at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. Number of participants in each category (progression, death, censored) is reported in this record.
Time frame: From randomization up to maximum 3.3 years
Population: All participants to whom study treatment was assigned by randomization.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Spartalizumab 400 mg Q4W | Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment - Number of Participants With Progression or Death | number of progression | 62 Participants |
| Spartalizumab 400 mg Q4W | Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment - Number of Participants With Progression or Death | number of deaths | 3 Participants |
| Spartalizumab 400 mg Q4W | Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment - Number of Participants With Progression or Death | number of censored | 17 Participants |
| Chemotherapy | Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment - Number of Participants With Progression or Death | number of progression | 32 Participants |
| Chemotherapy | Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment - Number of Participants With Progression or Death | number of deaths | 1 Participants |
| Chemotherapy | Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment - Number of Participants With Progression or Death | number of censored | 7 Participants |
Secondary
Accumulation Ratio (Racc) of Spartalizumab
Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Racc was calculated as the ratio between AUCtau Cycle 3 and AUCtau Cycle 1.
Time frame: pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.
Population: All participants who had at least one dose of spartalizumab and had at least one evaluable concentration measurement of spartalizumab. PK samples were only collected in participants to whom spartalizumab was assigned by randomization.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Spartalizumab 400 mg Q4W | Accumulation Ratio (Racc) of Spartalizumab | 1.61 ratio | Geometric Coefficient of Variation 19.6 |
Secondary
Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf) of Spartalizumab
Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC calculation. The extrapolation of AUC to infinity could be calculated if the percentage of area extrapolated was less than 20% and the regression analysis of the terminal serum elimination phase met a pre-defined criteria of goodness of fit.
Time frame: pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.
Population: All participants who had at least one dose of spartalizumab and the extrapolation of AUC to infinity could be calculated as described in the description of the endpoint. PK samples were only collected in participants to whom spartalizumab was assigned by randomization.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Spartalizumab 400 mg Q4W | Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf) of Spartalizumab | Cycle 1 | 1180 day*ug/mL | Geometric Coefficient of Variation 23.9 |
| Spartalizumab 400 mg Q4W | Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf) of Spartalizumab | Cycle 3 | 1090 day*ug/mL | Geometric Coefficient of Variation 84.8 |
Secondary
Area Under the Serum Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) of Spartalizumab
Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC calculation. The duration of the dosing interval (tau) was 28 days.
Time frame: pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.
Population: All participants who had at least one dose of spartalizumab and had at least one evaluable concentration measurement of spartalizumab. PK samples were only collected in participants to whom spartalizumab was assigned by randomization.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Spartalizumab 400 mg Q4W | Area Under the Serum Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) of Spartalizumab | Cycle 1 | 1340 day*ug/mL | Geometric Coefficient of Variation 25.8 |
| Spartalizumab 400 mg Q4W | Area Under the Serum Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) of Spartalizumab | Cycle 3 | 2260 day*ug/mL | Geometric Coefficient of Variation 30.6 |
Secondary
Duration of Response (DOR) as Per RECIST v 1.1
DOR only applies to subjects for whom best overall response is complete response (CR) or partial response (PR) based on central review of overall lesion response according to RECIST 1.1. DOR is defined as the time between the date of first documented response (confirmed CR or confirmed PR) and the date of first documented disease progression or death due to underlying cancer. If a patient not had an event, duration was censored at the date of last adequate tumor assessment.
Time frame: From randomization up to maximum 3.3 years
Population: All participants for whom best overall response is complete response (CR) or partial response (PR) as per RECIST 1.1 based on central review.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Spartalizumab 400 mg Q4W | Duration of Response (DOR) as Per RECIST v 1.1 | 10.2 months |
| Chemotherapy | Duration of Response (DOR) as Per RECIST v 1.1 | 5.7 months |
Secondary
Fold Change From Baseline in IFN-gamma Levels in Plasma
The levels of interferon-gamma (IFN-gamma) were measured in plasma samples by immunoassay methods. This record summarizes the fold change from baseline in IFN-gamma levels in plasma.
Time frame: Baseline (pre-dose on Cycle 1 Day 1), Cycle 1 Day 15, Cycle 2 Day 15 and end of treatment (assessed up to maximum 4 years). The duration of one cycle was 28 days.
Population: All participants to whom study treatment was assigned by randomization to spartalizumab. Biomarker samples were not collected in participants randomized to chemotherapy.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Spartalizumab 400 mg Q4W | Fold Change From Baseline in IFN-gamma Levels in Plasma | Cycle 1 Day 15 | 1.53 fold change |
| Spartalizumab 400 mg Q4W | Fold Change From Baseline in IFN-gamma Levels in Plasma | Cycle 2 Day 15 | 1.31 fold change |
| Spartalizumab 400 mg Q4W | Fold Change From Baseline in IFN-gamma Levels in Plasma | End of treatment | 1.11 fold change |
Secondary
Fold Change From Baseline in IL-6 Levels in Plasma
The levels of interleukin-6 (IL-6) were measured in plasma samples by immunoassay methods. This record summarizes the fold change from baseline in IL-6 levels in plasma.
Time frame: Baseline (pre-dose on Cycle 1 Day 1), Cycle 1 Day 15, Cycle 2 Day 15 and end of treatment (assessed up to maximum 4 years). The duration of one cycle was 28 days.
Population: All participants to whom study treatment was assigned by randomization to spartalizumab. Biomarker samples were not collected in participants randomized to chemotherapy.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Spartalizumab 400 mg Q4W | Fold Change From Baseline in IL-6 Levels in Plasma | Cycle 1 Day 15 | 1.10 fold change |
| Spartalizumab 400 mg Q4W | Fold Change From Baseline in IL-6 Levels in Plasma | Cycle 2 Day 15 | 1.35 fold change |
| Spartalizumab 400 mg Q4W | Fold Change From Baseline in IL-6 Levels in Plasma | End of treatment | 1.41 fold change |
Secondary
Fold Change From Baseline in TNF-alfa Levels in Plasma
The levels of tumor necrosis factor-alpha (TNF-alfa) were measured in plasma samples by immunoassay methods. This record summarizes the fold change from baseline in TNF-alfa levels in plasma.
Time frame: Baseline (pre-dose on Cycle 1 Day 1), Cycle 1 Day 15, Cycle 2 Day 15 and end of treatment (assessed up to maximum 4 years). The duration of one cycle was 28 days.
Population: All participants to whom study treatment was assigned by randomization to spartalizumab. Biomarker samples were not collected in participants randomized to chemotherapy.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Spartalizumab 400 mg Q4W | Fold Change From Baseline in TNF-alfa Levels in Plasma | Cycle 2 Day 15 | 1.39 fold change |
| Spartalizumab 400 mg Q4W | Fold Change From Baseline in TNF-alfa Levels in Plasma | End of treatment | 1.67 fold change |
| Spartalizumab 400 mg Q4W | Fold Change From Baseline in TNF-alfa Levels in Plasma | Cycle 1 Day 15 | 1.32 fold change |
Secondary
Immune-related Progression-free Survival (irPFS) as Per irRC
irPFS is the time from the date of randomization to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was immune-related Response Criteria (irRC). Immune-related progressive disease is at least a 20% increase in the sum of diameters of all measured target lesions including new measurable lesions.
Time frame: From randomization up to maximum 3.3 years
Population: All participants to whom study treatment was assigned by randomization to spartalizumab. For the chemotherapy arm, tumor scans for efficacy assessment as per irRC were not planned.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Spartalizumab 400 mg Q4W | Immune-related Progression-free Survival (irPFS) as Per irRC | 1.9 months |
Secondary
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, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.
Population: All participants who had at least one dose of spartalizumab and had at least one evaluable concentration measurement of spartalizumab. PK samples were only collected in participants to whom spartalizumab was assigned by randomization.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Spartalizumab 400 mg Q4W | Maximum Observed Serum Concentration (Cmax) of Spartalizumab | Cycle 1 | 116 ug/mL | Geometric Coefficient of Variation 21.9 |
| Spartalizumab 400 mg Q4W | Maximum Observed Serum Concentration (Cmax) of Spartalizumab | Cycle 3 | 149 ug/mL | Geometric Coefficient of Variation 25.8 |
Secondary
Number of Participants With Anti-spartalizumab Antibodies
Validated immunoassays were used for screening and confirmation of the presence of anti-spartalizumab antibodies (ADA, anti-drug antibodies) in serum. Number of participants with each ADA status is reported in this record.
Time frame: Baseline (pre-dose on Cycle 1 Day 1) and post-baseline (assessed throughout the treatment up to maximum 655 days).
Population: All participants who had at least one dose of spartalizumab and had a determinant baseline immunogenicity (IG) sample and at least one determinant post-baseline IG sample. A determinant IG sample is neither ADA-inconclusive nor unevaluable. IG samples were only collected in participants to whom spartalizumab was assigned by randomization.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Spartalizumab 400 mg Q4W | Number of Participants With Anti-spartalizumab Antibodies | ADA-negative at baseline | 66 Participants |
| Spartalizumab 400 mg Q4W | Number of Participants With Anti-spartalizumab Antibodies | ADA-positive at baseline | 6 Participants |
| Spartalizumab 400 mg Q4W | Number of Participants With Anti-spartalizumab Antibodies | ADA-negative at post-baseline | 59 Participants |
| Spartalizumab 400 mg Q4W | Number of Participants With Anti-spartalizumab Antibodies | ADA-positive at post-baseline (i.e. ADA incidence) | 9 Participants |
Secondary
Overall Response Rate (ORR) as Per RECIST v 1.1
ORR is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR). Tumor response was based on central review of overall lesion response according to RECIST 1.1. For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: From randomization up to maximum 3.3 years
Population: All participants to whom study treatment was assigned by randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Spartalizumab 400 mg Q4W | Overall Response Rate (ORR) as Per RECIST v 1.1 | 15 Participants |
| Chemotherapy | Overall Response Rate (ORR) as Per RECIST v 1.1 | 13 Participants |
Secondary
Overall Survival (OS)
Overall survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a patient is not known to have died, survival is censored at the date of last known date the patient was alive.
Time frame: From randomization up to maximum 4.8 years.
Population: All participants to whom study treatment was assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Spartalizumab 400 mg Q4W | Overall Survival (OS) | 20.1 months |
| Chemotherapy | Overall Survival (OS) | 16.0 months |
Secondary
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), Cycle 3 Day 1. The duration of one cycle was 28 days.
Population: All participants to whom study treatment was assigned by randomization to spartalizumab and had a valid assessment for the outcome measure. Biomarker samples were not collected in participants randomized to chemotherapy.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Spartalizumab 400 mg Q4W | PD-L1 Percent Positive Tumor | Cycle 3 Day 1 | 90.00 PD-L1 positivity percentage |
| Spartalizumab 400 mg Q4W | PD-L1 Percent Positive Tumor | Baseline | 20.00 PD-L1 positivity percentage |
Secondary
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), Cycle 3 Day 1. The duration of one cycle was 28 days.
Population: All participants to whom study treatment was assigned by randomization to spartalizumab and had a valid assessment for the outcome measure. Biomarker samples were not collected in participants randomized to chemotherapy.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Spartalizumab 400 mg Q4W | Percent Marker Area for CD8 Expression in Tumor Samples | Baseline | 4.23 CD8 percent marker area |
| Spartalizumab 400 mg Q4W | Percent Marker Area for CD8 Expression in Tumor Samples | Cycle 3 Day 1 | 2.22 CD8 percent marker area |
Secondary
Terminal Elimination Half-life (T1/2) of Spartalizumab
Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Elimination half-life (T1/2) values were calculated as 0.693/terminal elimination rate constant.
Time frame: pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.
Population: All participants who had at least one dose of spartalizumab and had at least one evaluable concentration measurement of spartalizumab. PK samples were only collected in participants to whom spartalizumab was assigned by randomization.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Spartalizumab 400 mg Q4W | Terminal Elimination Half-life (T1/2) of Spartalizumab | Cycle 1 | 20.1 days |
| Spartalizumab 400 mg Q4W | Terminal Elimination Half-life (T1/2) of Spartalizumab | Cycle 3 | 22.7 days |
Secondary
TIL Count in Tumor Samples
The count of tumor-infiltrating lymphocytes (TILs) was measured in baseline (screening) and post-baseline paired tumor samples by immunohistochemical methods. This record summarizes the TIL count in tumor samples.
Time frame: Baseline (screening), Cycle 3 Day 1. The duration of one cycle was 28 days.
Population: All participants to whom study treatment was assigned by randomization to spartalizumab and had paired tumor biopsies. Biomarker samples were not collected in participants randomized to chemotherapy.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Spartalizumab 400 mg Q4W | TIL Count in Tumor Samples | Baseline | 10 TILs |
| Spartalizumab 400 mg Q4W | TIL Count in Tumor Samples | Cycle 3 Day 1 | 15 TILs |
Secondary
Time to Progression (TTP) as Per RECIST v 1.1
TTP is defined as time from date of randomization to the date of event defined as the first documented progression or death due to underlying cancer. If a subject did not had an event, TTP was censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was RECIST v1.1. Progressive disease is at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline.
Time frame: From randomization up to maximum 3.3 years
Population: All participants to whom study treatment was assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Spartalizumab 400 mg Q4W | Time to Progression (TTP) as Per RECIST v 1.1 | 1.9 months |
| Chemotherapy | Time to Progression (TTP) as Per RECIST v 1.1 | 5.6 months |
Secondary
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, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.
Population: All participants who had at least one dose of spartalizumab and had at least one evaluable concentration measurement of spartalizumab. PK samples were only collected in participants to whom spartalizumab was assigned by randomization.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Spartalizumab 400 mg Q4W | Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab | Cycle 1 | 1.57 hours |
| Spartalizumab 400 mg Q4W | Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab | Cycle 3 | 1.57 hours |
Post Hoc
All Collected Deaths
On-treatment deaths were collected from the start of treatment up to 30 days after study drug discontinuation, for a maximum duration of 4.0 years. Post-treatment deaths were collected after the on-treatment period (starting at day 31 after last dose of study treatment), up to 4.8 years. For the crossover patients, the deaths collected before crossing over are summarized in the chemotherapy arm and the deaths collected after the crossover are summarized in the crossover arm.
Time frame: Up to 4.0 years (on-treatment deaths) and 4.8 years (all deaths).
Population: All participants to whom study treatment was assigned by randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Spartalizumab 400 mg Q4W | All Collected Deaths | Total Deaths | 48 participants |
| Spartalizumab 400 mg Q4W | All Collected Deaths | Deaths on-treatment | 5 participants |
| Chemotherapy | All Collected Deaths | Total Deaths | 9 participants |
| Chemotherapy | All Collected Deaths | Deaths on-treatment | 3 participants |
| Crossover to Spartalizumab | All Collected Deaths | Total Deaths | 19 participants |
| Crossover to Spartalizumab | All Collected Deaths | Deaths on-treatment | 3 participants |
Post Hoc
Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment in Participants Who Crossed Over - Median PFS
PFS is the time from the date of first dose of spartalizumab to the date of event defined as the first documented confirmed progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive disease is at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline.
Time frame: From first dose of spartalizumab up to maximum 0.6 years
Population: All participants who crossed over from chemotherapy to spartalizumab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Spartalizumab 400 mg Q4W | Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment in Participants Who Crossed Over - Median PFS | 1.7 months |
Post Hoc
Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment in Participants Who Crossed Over - Number of Participants With Progression or Death
PFS is the time from the date of first dose of spartalizumab to the date of event defined as the first documented confirmed progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive disease is at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. Number of participants in each category (progression, death, censored) is reported in this record.
Time frame: From first dose of spartalizumab up to maximum 0.6 years
Population: All participants who crossed over from chemotherapy to spartalizumab.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Spartalizumab 400 mg Q4W | Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment in Participants Who Crossed Over - Number of Participants With Progression or Death | number of progression | 20 Participants |
| Spartalizumab 400 mg Q4W | Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment in Participants Who Crossed Over - Number of Participants With Progression or Death | number of deaths | 5 Participants |
| Spartalizumab 400 mg Q4W | Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment in Participants Who Crossed Over - Number of Participants With Progression or Death | number of censored | 2 Participants |