Non-small Cell Lung Cancer
Conditions
Keywords
ACZ885, canakinumab, pembrolizumab, NSCLC, non-small cell lung cancer, non small cell lung cancer, early stage NSCLC, squamous, non-squamous,, MPR, major pathological response, hs-CRP, PD-L1, hsCRP, surgery, neo-adjuvant, neo adjuvant, CD8, hs-IL-6, CANOPY
Brief summary
The purpose of this study was to evaluate the major pathological response (MPR) rate of canakinumab given as a neoadjuvant treatment, either as single agent or in combination with pembrolizumab, in addition to evaluate the MPR of pembrolizumab as a single agent and the dynamic of the tumor microenvironment changes on treatment.
Detailed description
This was a randomized, phase II, open-label study evaluating canakinumab, an anti-IL-1β monoclonal antibody, or pembrolizumab, a monoclonal antibody designed to block the PD-1 receptor, as monotherapy or in combination as neoadjuvant therapy. The study population included adult subjects with resectable non-small cell lung cancer (NSCLC) planned for surgery in approximately 4-6 weeks. Subjects were treated for a maximum duration of 6 weeks (2 cycles) until surgery, progression, unacceptable toxicity or discontinuation from the study treatment for any other reason. Subjects were randomized in a 2:2:1 ratio to one of the 3 treatment arms (canakinumab alone or canakinumab in combination with pembrolizumab or pembrolizumab alone). Surgery was performed between 4 to 6 weeks after the first dose of study treatment. All randomized subjects were followed for safety for up to 130 days following the last dose of study treatment (safety follow-up period).
Interventions
DRUGCanakinumab
200 mg of canakinumab administered via subcutaneous injections once every 3 weeks for a maximum duration of 6 weeks
DRUGPembrolizumab
200 mg of pembrolizumab administered via infusion once every 3 weeks for a maximum duration of 6 weeks
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
Key inclusion criteria: * Histologically confirmed NSCLC stage IB-IIIA (per AJCC 8th edition), deemed suitable for primary resection by treating surgeon, except for N2 and T4 tumors. * Subject must have been eligible for surgery and with a planned surgical resection in approximately 4-6 weeks (after the first dose of study treatment). * A mandatory newly obtained tissue biopsy from primary site was required for study enrollment. An archival biopsy was also acceptable if obtained up to 5 months before first day of study treatment and if the subject did not go through antineoplastic systemic therapies between biopsy collection date and beginning of study treatment. * Eastern Cooperative oncology group (ECOG) performance status of 0 or 1. Key
Exclusion criteria
* Subjects with unresectable or metastatic disease. * History of severe hypersensitivity reactions to monoclonal antibodies, which in the opinion of the investigator may pose an increased risk of serious infusion reaction * Subjects who received prior systemic therapy (including chemotherapy, other anti-cancer therapies and any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) in the past 3 years before screening * Active autoimmune disease that has required systemic treatment in the past 2 years prior to randomization. Control of the disorder with replacement therapy was permitted * Subject with suspected or proven immunocompromised state or infections
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Major Pathological Response (MPR) Rate at the Time of Surgery in Subjects Randomized to Canakinumab Monotherapy and in Combination With Pembrolizumab Based on Central Review | At time of surgery (up to 6 weeks after first dose of study treatment) | MPR was defined as the percentage of participants with major pathological response (defined as ≤10% residual viable tumor cells on surgical samples). Any participant who had \>10% residual viable cancer cells, or started new antineoplastic therapy prior to surgery, or did not have the surgery performed, or had the surgery performed but with unevaluable MPR result, was considered as a non-responder. MPR was assessed at the time of surgery in all subjects randomized to canakinumab monotherapy and in combination with pembrolizumab based on central review. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Canakinumab ADA Incidence | From baseline (Predose on Day 1 of Cycle 1) up to 130 days after last dose of study treatment (assessed up to 24.6 weeks). Cycle = 21 days | Canakinumab ADA incidence on treatment was calculated as the percentage of participants who were canakinumab treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and canakinumab treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer) |
| Pembrolizumab ADA Prevalence | Predose (0 hour) on Day 1 of Cycle 1 (Cycle = 21 days) | Pembrolizumab ADA prevalence at baseline was calculated as the percentage of participants who had a pembrolizumab ADA positive result at baseline |
| Pembrolizumab ADA Incidence | From baseline (Predose on Day 1 of Cycle 1) up to 26 days after last dose of study treatment (assessed up to 10.7 weeks). Cycle = 21 days | Pembrolizumab ADA incidence on treatment was calculated as the percentage of participants who were pembrolizumab treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and pembrolizumab treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer) |
| Overall Response Rate (ORR) Based on Local Investigator Assessment Using RECIST v1.1 | From date of randomization to date of surgery, assessed up to 6 weeks | ORR is defined as the percentage of subjects with confirmed best overall response of complete response (CR) or partial response (PR), as per local investigator's assessment by RECIST 1.1. 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 |
| Serum Canakinumab Concentration | Predose (0 hour) on Day 1 of Cycles 1 and 2 (Cycle =21 days) | Canakinumab serum concentrations were determined at the specified time points. |
| Canakinumab Antidrug Antibodies (ADA) Prevalence | Predose (0 hour) on Day 1 of Cycle 1 (Cycle=21 days) | Canakinumab ADA prevalence at baseline was calculated as the percentage of participants who had a canakinumab ADA positive result at baseline |
| Surgical Feasibility Rate | Up to 6 weeks after first dose | Surgical feasibility rate was defined as the percentage of subjects who underwent surgery following study treatment. |
| Major Pathological Response (MPR) Rate at the Time of Surgery in Subjects Randomized to Pembrolizumab Monotherapy Based on Central Review | At time of surgery (up to 6 weeks after first dose) | MPR was defined as the percentage of participants with major pathological response (defined as ≤10% residual viable tumor cells on surgical samples). Any participant who had \>10% residual viable cancer cells, or started new antineoplastic therapy prior to surgery, or did not have the surgery performed, or had the surgery performed but with unevaluable MPR result, was considered as a non-responder. MPR was assessed at the time of surgery in all subjects randomized to pembrolizumab monotherapy arm based on central review. |
| Difference in Major Pathological Response (MPR) Rate Between the Canakinumab Plus Pembrolizumab Arm and the Pembrolizumab Arm Based on Central Review | At time of surgery (up to 6 weeks after first dose of study treatment) | MPR was defined as the percentage of participants with ≤10% residual viable tumor cells on surgical samples. MPR was assessed at the time of surgery based on central review. The difference in MPR rate between the canakinumab plus pembrolizumab arm and the pembrolizumab arm based on central review along with the Chang and Zhang confidence interval was assessed. |
| Major Pathological Response (MPR) Rate at the Time of Surgery in All Subjects Based on Local Review | At time of surgery (up to 6 weeks after first dose) | MPR was defined as the percentage of participants with major pathological response (defined as ≤10% residual viable tumor cells on surgical samples). Any participant who had \>10% residual viable cancer cells, or started new antineoplastic therapy prior to surgery, or did not have the surgery performed, or had the surgery performed but with unevaluable MPR result, was considered as a non-responder. MPR was assessed at the time of surgery in all subjects based on local review. |
| Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | From date of randomization up to 6 weeks after first dose | MPR was defined as the percentage of participants with major pathological response (defined as ≤10% residual viable tumor cells on surgical samples). Any participant who had \>10% residual viable cancer cells, or started new antineoplastic therapy prior to surgery, or did not have the surgery performed, or had the surgery performed but with unevaluable MPR result, was considered as a non-responder. MPR rate was analyzed by the biomarker subgroups at baseline. Biomarkers included PD-L1, CD8, hs-CRP and hs-IL-6. |
| Serum Pembrolizumab Concentration | Predose (0 hour) and 0.5 hours post dose on Day 1 of Cycle 1 and predose on Cycle 2 (Cycle =21 days) | Pembrolizumab serum concentrations were determined at the specified time points. |
Countries
Belgium, Canada, France, Germany, Greece, Japan, Netherlands, Russia, Spain, Taiwan, Turkey (Türkiye), United States
Participant flow
Recruitment details
The study was conducted in 29 centers across 12 countries.
Pre-assignment details
Screening assessments were done within 28 days prior to randomization. A total of 163 participants were screened. Of them, 88 participants were randomized. After treatment completion or discontinuation, all subjects were followed for safety for up to 130 days following the last dose of study treatment (safety follow-up period).
Participants by arm
| Arm | Count |
|---|---|
| Canakinumab Monotherapy Participants received 200 mg of canakinumab once every 3 weeks for a maximum duration of 6 weeks prior to surgery | 35 |
| Canakinumab + Pembrolizumab Participants received 200 mg of canakinumab in combination with 200 mg of pembrolizumab once every 3 weeks for a maximum duration of 6 weeks prior to surgery | 35 |
| Pembrolizumab Monotherapy Participants received 200 mg of pembrolizumab every 3 weeks for a maximum duration of 6 weeks prior to surgery | 18 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Safety Follow-up Period | Death | 3 | 2 | 1 |
| Safety Follow-up Period | Subject Decision | 2 | 1 | 0 |
| Treatment Period | Adverse Event | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Canakinumab Monotherapy | Canakinumab + Pembrolizumab | Pembrolizumab Monotherapy | Total |
|---|---|---|---|---|
| Age, Continuous | 65.5 Years STANDARD_DEVIATION 9.88 | 67.1 Years STANDARD_DEVIATION 6.98 | 66.1 Years STANDARD_DEVIATION 5.61 | 66.2 Years STANDARD_DEVIATION 7.99 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 7 Participants | 3 Participants | 2 Participants | 12 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Unknown | 7 Participants | 5 Participants | 4 Participants | 16 Participants |
| Race/Ethnicity, Customized White | 20 Participants | 25 Participants | 12 Participants | 57 Participants |
| Sex: Female, Male Female | 13 Participants | 14 Participants | 9 Participants | 36 Participants |
| Sex: Female, Male Male | 22 Participants | 21 Participants | 9 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 35 | 2 / 35 | 1 / 18 |
| other Total, other adverse events | 28 / 35 | 27 / 35 | 14 / 18 |
| serious Total, serious adverse events | 10 / 35 | 9 / 35 | 4 / 18 |
Outcome results
Primary
Major Pathological Response (MPR) Rate at the Time of Surgery in Subjects Randomized to Canakinumab Monotherapy and in Combination With Pembrolizumab Based on Central Review
MPR was defined as the percentage of participants with major pathological response (defined as ≤10% residual viable tumor cells on surgical samples). Any participant who had \>10% residual viable cancer cells, or started new antineoplastic therapy prior to surgery, or did not have the surgery performed, or had the surgery performed but with unevaluable MPR result, was considered as a non-responder. MPR was assessed at the time of surgery in all subjects randomized to canakinumab monotherapy and in combination with pembrolizumab based on central review.
Time frame: At time of surgery (up to 6 weeks after first dose of study treatment)
Population: All subjects who were randomized to canakinumab monotherapy or canakinumab in combination with pembrolizumab
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Canakinumab Monotherapy | Major Pathological Response (MPR) Rate at the Time of Surgery in Subjects Randomized to Canakinumab Monotherapy and in Combination With Pembrolizumab Based on Central Review | 2.9 Percentage of participants |
| Canakinumab + Pembrolizumab | Major Pathological Response (MPR) Rate at the Time of Surgery in Subjects Randomized to Canakinumab Monotherapy and in Combination With Pembrolizumab Based on Central Review | 17.1 Percentage of participants |
Secondary
Canakinumab ADA Incidence
Canakinumab ADA incidence on treatment was calculated as the percentage of participants who were canakinumab treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and canakinumab treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)
Time frame: From baseline (Predose on Day 1 of Cycle 1) up to 130 days after last dose of study treatment (assessed up to 24.6 weeks). Cycle = 21 days
Population: All subjects randomized to canakinumab monotherapy or canakinumab in combination with pembrolizumab who received at least one dose of canakinumab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Canakinumab Monotherapy | Canakinumab ADA Incidence | 1 Participants |
| Canakinumab + Pembrolizumab | Canakinumab ADA Incidence | 0 Participants |
Secondary
Canakinumab Antidrug Antibodies (ADA) Prevalence
Canakinumab ADA prevalence at baseline was calculated as the percentage of participants who had a canakinumab ADA positive result at baseline
Time frame: Predose (0 hour) on Day 1 of Cycle 1 (Cycle=21 days)
Population: All subjects randomized to canakinumab monotherapy or canakinumab in combination with pembrolizumab who received at least one dose of canakinumab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Canakinumab Monotherapy | Canakinumab Antidrug Antibodies (ADA) Prevalence | 0 Participants |
| Canakinumab + Pembrolizumab | Canakinumab Antidrug Antibodies (ADA) Prevalence | 0 Participants |
Secondary
Difference in Major Pathological Response (MPR) Rate Between the Canakinumab Plus Pembrolizumab Arm and the Pembrolizumab Arm Based on Central Review
MPR was defined as the percentage of participants with ≤10% residual viable tumor cells on surgical samples. MPR was assessed at the time of surgery based on central review. The difference in MPR rate between the canakinumab plus pembrolizumab arm and the pembrolizumab arm based on central review along with the Chang and Zhang confidence interval was assessed.
Time frame: At time of surgery (up to 6 weeks after first dose of study treatment)
Population: All subjects who were randomized to canakinumab in combination with pembrolizumab or pembrolizumab monotherapy arms
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Canakinumab Monotherapy | Difference in Major Pathological Response (MPR) Rate Between the Canakinumab Plus Pembrolizumab Arm and the Pembrolizumab Arm Based on Central Review | 17.1 Percentage of participants |
| Canakinumab + Pembrolizumab | Difference in Major Pathological Response (MPR) Rate Between the Canakinumab Plus Pembrolizumab Arm and the Pembrolizumab Arm Based on Central Review | 16.7 Percentage of participants |
Comparison: Difference in MPR rate95% CI: [-25.56, 21.23]
Secondary
Major Pathological Response (MPR) Rate at the Time of Surgery in All Subjects Based on Local Review
MPR was defined as the percentage of participants with major pathological response (defined as ≤10% residual viable tumor cells on surgical samples). Any participant who had \>10% residual viable cancer cells, or started new antineoplastic therapy prior to surgery, or did not have the surgery performed, or had the surgery performed but with unevaluable MPR result, was considered as a non-responder. MPR was assessed at the time of surgery in all subjects based on local review.
Time frame: At time of surgery (up to 6 weeks after first dose)
Population: FAS including all subjects to whom study treatment was assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Canakinumab Monotherapy | Major Pathological Response (MPR) Rate at the Time of Surgery in All Subjects Based on Local Review | 0 Percentage of participants |
| Canakinumab + Pembrolizumab | Major Pathological Response (MPR) Rate at the Time of Surgery in All Subjects Based on Local Review | 20.0 Percentage of participants |
| Pembrolizumab Monotherapy | Major Pathological Response (MPR) Rate at the Time of Surgery in All Subjects Based on Local Review | 22.2 Percentage of participants |
Secondary
Major Pathological Response (MPR) Rate at the Time of Surgery in Subjects Randomized to Pembrolizumab Monotherapy Based on Central Review
MPR was defined as the percentage of participants with major pathological response (defined as ≤10% residual viable tumor cells on surgical samples). Any participant who had \>10% residual viable cancer cells, or started new antineoplastic therapy prior to surgery, or did not have the surgery performed, or had the surgery performed but with unevaluable MPR result, was considered as a non-responder. MPR was assessed at the time of surgery in all subjects randomized to pembrolizumab monotherapy arm based on central review.
Time frame: At time of surgery (up to 6 weeks after first dose)
Population: All subjects who were randomized to pembrolizumab monotherapy arm
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Canakinumab Monotherapy | Major Pathological Response (MPR) Rate at the Time of Surgery in Subjects Randomized to Pembrolizumab Monotherapy Based on Central Review | 16.7 Percentage of participants |
Secondary
Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers
MPR was defined as the percentage of participants with major pathological response (defined as ≤10% residual viable tumor cells on surgical samples). Any participant who had \>10% residual viable cancer cells, or started new antineoplastic therapy prior to surgery, or did not have the surgery performed, or had the surgery performed but with unevaluable MPR result, was considered as a non-responder. MPR rate was analyzed by the biomarker subgroups at baseline. Biomarkers included PD-L1, CD8, hs-CRP and hs-IL-6.
Time frame: From date of randomization up to 6 weeks after first dose
Population: All subjects to whom study treatment was assigned by randomization. Number analyzed is the number of participants with data available for analysis for each category
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Canakinumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | hs-IL-6: >=Q2 (5.36 pg/mL) to <Q3 (12.03 pg/mL) | 0 Percentage of participants |
| Canakinumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | hs-CRP: >=2mg/L | 0 Percentage of participants |
| Canakinumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | CD8: <3% | 0 Percentage of participants |
| Canakinumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | hs-IL-6: >=Q1 (2.52 pg/mL) to <Q2 (5.36 pg/mL) | 0 Percentage of participants |
| Canakinumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | hs-IL-6: <Q1 (2.52 mg/L) | 16.7 Percentage of participants |
| Canakinumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | PD-L1: <1% | 0 Percentage of participants |
| Canakinumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | PD-L1: >=50% | 0 Percentage of participants |
| Canakinumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | PD-L1: 1-49% | 6.7 Percentage of participants |
| Canakinumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | hs-IL-6: >=Q3 (12.03 pg/mL) | 0 Percentage of participants |
| Canakinumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | hs-CRP: <2mg/L | 12.5 Percentage of participants |
| Canakinumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | CD8: >=3% | 0 Percentage of participants |
| Canakinumab + Pembrolizumab | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | hs-IL-6: <Q1 (2.52 mg/L) | 12.5 Percentage of participants |
| Canakinumab + Pembrolizumab | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | PD-L1: <1% | 7.1 Percentage of participants |
| Canakinumab + Pembrolizumab | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | PD-L1: 1-49% | 15.4 Percentage of participants |
| Canakinumab + Pembrolizumab | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | PD-L1: >=50% | 42.9 Percentage of participants |
| Canakinumab + Pembrolizumab | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | hs-CRP: <2mg/L | 7.7 Percentage of participants |
| Canakinumab + Pembrolizumab | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | hs-CRP: >=2mg/L | 22.7 Percentage of participants |
| Canakinumab + Pembrolizumab | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | hs-IL-6: >=Q1 (2.52 pg/mL) to <Q2 (5.36 pg/mL) | 10 Percentage of participants |
| Canakinumab + Pembrolizumab | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | hs-IL-6: >=Q2 (5.36 pg/mL) to <Q3 (12.03 pg/mL) | 28.6 Percentage of participants |
| Canakinumab + Pembrolizumab | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | hs-IL-6: >=Q3 (12.03 pg/mL) | 20.0 Percentage of participants |
| Canakinumab + Pembrolizumab | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | CD8: <3% | 13.0 Percentage of participants |
| Canakinumab + Pembrolizumab | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | CD8: >=3% | 22.2 Percentage of participants |
| Pembrolizumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | CD8: <3% | 0 Percentage of participants |
| Pembrolizumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | hs-IL-6: >=Q2 (5.36 pg/mL) to <Q3 (12.03 pg/mL) | 16.7 Percentage of participants |
| Pembrolizumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | PD-L1: >=50% | 0 Percentage of participants |
| Pembrolizumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | PD-L1: <1% | 14.3 Percentage of participants |
| Pembrolizumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | hs-IL-6: >=Q3 (12.03 pg/mL) | 0 Percentage of participants |
| Pembrolizumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | PD-L1: 1-49% | 16.7 Percentage of participants |
| Pembrolizumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | hs-IL-6: <Q1 (2.52 mg/L) | 14.3 Percentage of participants |
| Pembrolizumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | hs-CRP: >=2mg/L | 0 Percentage of participants |
| Pembrolizumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | CD8: >=3% | 33.3 Percentage of participants |
| Pembrolizumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | hs-IL-6: >=Q1 (2.52 pg/mL) to <Q2 (5.36 pg/mL) | 33.3 Percentage of participants |
| Pembrolizumab Monotherapy | Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | hs-CRP: <2mg/L | 37.5 Percentage of participants |
Secondary
Overall Response Rate (ORR) Based on Local Investigator Assessment Using RECIST v1.1
ORR is defined as the percentage of subjects with confirmed best overall response of complete response (CR) or partial response (PR), as per local investigator's assessment by RECIST 1.1. 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 date of randomization to date of surgery, assessed up to 6 weeks
Population: FAS including all subjects to whom study treatment was assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Canakinumab Monotherapy | Overall Response Rate (ORR) Based on Local Investigator Assessment Using RECIST v1.1 | 0 Percentage of participants |
| Canakinumab + Pembrolizumab | Overall Response Rate (ORR) Based on Local Investigator Assessment Using RECIST v1.1 | 8.6 Percentage of participants |
| Pembrolizumab Monotherapy | Overall Response Rate (ORR) Based on Local Investigator Assessment Using RECIST v1.1 | 11.1 Percentage of participants |
Secondary
Pembrolizumab ADA Incidence
Pembrolizumab ADA incidence on treatment was calculated as the percentage of participants who were pembrolizumab treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and pembrolizumab treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)
Time frame: From baseline (Predose on Day 1 of Cycle 1) up to 26 days after last dose of study treatment (assessed up to 10.7 weeks). Cycle = 21 days
Population: All subjects randomized to canakinumab in combination with pembrolizumab or pembrolizumab monotherapy who received at least one dose of pembrolizumab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Canakinumab Monotherapy | Pembrolizumab ADA Incidence | 3 Participants |
| Canakinumab + Pembrolizumab | Pembrolizumab ADA Incidence | 4 Participants |
Secondary
Pembrolizumab ADA Prevalence
Pembrolizumab ADA prevalence at baseline was calculated as the percentage of participants who had a pembrolizumab ADA positive result at baseline
Time frame: Predose (0 hour) on Day 1 of Cycle 1 (Cycle = 21 days)
Population: All subjects randomized to canakinumab in combination with pembrolizumab or pembrolizumab monotherapy who received at least one dose of pembrolizumab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Canakinumab Monotherapy | Pembrolizumab ADA Prevalence | 4 Participants |
| Canakinumab + Pembrolizumab | Pembrolizumab ADA Prevalence | 3 Participants |
Secondary
Serum Canakinumab Concentration
Canakinumab serum concentrations were determined at the specified time points.
Time frame: Predose (0 hour) on Day 1 of Cycles 1 and 2 (Cycle =21 days)
Population: All participants who received at least one dose of canakinumab with at least one evaluable pharmacokinetic (PK) sample. Number analyzed corresponds to the number of participants with an evaluable PK sample at the specified time point
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Canakinumab Monotherapy | Serum Canakinumab Concentration | Cycle 1 | 0 microgram/miliLiter (ug/mL) | Geometric Coefficient of Variation 0 |
| Canakinumab Monotherapy | Serum Canakinumab Concentration | Cycle 2 | 10.9 microgram/miliLiter (ug/mL) | Geometric Coefficient of Variation 32.9 |
| Canakinumab + Pembrolizumab | Serum Canakinumab Concentration | Cycle 1 | 0 microgram/miliLiter (ug/mL) | Geometric Coefficient of Variation 0 |
| Canakinumab + Pembrolizumab | Serum Canakinumab Concentration | Cycle 2 | 10.3 microgram/miliLiter (ug/mL) | Geometric Coefficient of Variation 41 |
Secondary
Serum Pembrolizumab Concentration
Pembrolizumab serum concentrations were determined at the specified time points.
Time frame: Predose (0 hour) and 0.5 hours post dose on Day 1 of Cycle 1 and predose on Cycle 2 (Cycle =21 days)
Population: All participants who received at least one dose of pembrolizumab with at least one evaluable PK sample. Number analyzed corresponds to the number of participants with an evaluable PK sample at the specified time point
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Canakinumab Monotherapy | Serum Pembrolizumab Concentration | Cycle 1 predose | 0 ug/mL | Geometric Coefficient of Variation 0 |
| Canakinumab Monotherapy | Serum Pembrolizumab Concentration | Cyle 1 0.5 hours post dose | 65.5 ug/mL | Geometric Coefficient of Variation 23.8 |
| Canakinumab Monotherapy | Serum Pembrolizumab Concentration | Cycle 2 predose | 16.0 ug/mL | Geometric Coefficient of Variation 43.4 |
| Canakinumab + Pembrolizumab | Serum Pembrolizumab Concentration | Cycle 1 predose | 0 ug/mL | Geometric Coefficient of Variation 0 |
| Canakinumab + Pembrolizumab | Serum Pembrolizumab Concentration | Cyle 1 0.5 hours post dose | 65.5 ug/mL | Geometric Coefficient of Variation 19.9 |
| Canakinumab + Pembrolizumab | Serum Pembrolizumab Concentration | Cycle 2 predose | 35.5 ug/mL | Geometric Coefficient of Variation 13.7 |
Secondary
Surgical Feasibility Rate
Surgical feasibility rate was defined as the percentage of subjects who underwent surgery following study treatment.
Time frame: Up to 6 weeks after first dose
Population: FAS including all subjects to whom study treatment was assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Canakinumab Monotherapy | Surgical Feasibility Rate | 91.4 Percentage of participants |
| Canakinumab + Pembrolizumab | Surgical Feasibility Rate | 97.1 Percentage of participants |
| Pembrolizumab Monotherapy | Surgical Feasibility Rate | 100 Percentage of participants |