Triple-negative Breast Cancer
Conditions
Keywords
advanced triple-negative breast cancer, triple-negative breast cancer, checkpoint inhibition, LAG525, spartalizumab, PDR001, carboplatin
Brief summary
The main purpose of this study was to assess the antitumor activity of three combinations: i) LAG525 + spartalizumab; ii) LAG525 + spartalizumab + carboplatin, and iii) LAG525 + carboplatin in participants with advanced triple-negative breast cancer (TNBC) in first or second line therapy.
Detailed description
This was an open-label, Phase II, randomized, multicenter study to assess the efficacy, safety, and pharmacokinetic characteristics of the following three combinations: LAG525 + spartalizumab (PDR001) (Arm 1), LAG525 + spartalizumab (PDR001) + carboplatin (Arm 2), and LAG525 + carboplatin (Arm 3) in participants with advanced triple-negative breast cancer (TNBC) which progressed after adjuvant or one prior line of systemic therapy for metastatic disease. Participants were assigned to one of the three treatment arms in a ratio of 1:1:1. In protocol amendment 3 (released on 28-Mar-2019), enrollment to treatment Arm 1 (LAG525 + spartalizumab) was prematurely closed due to a higher discontinuation rate due to progressive disease and all subsequent enrolled patients were randomized to Arms 2 and 3 only, in a ratio of 1:1. Study treatment continued until disease progression, unacceptable toxicity, pregnancy, investigator/participant decision, start of a new anti-neoplastic therapy, withdrawal of consent, lost to follow-up, death, or study was terminated by the sponsor. The investigator might decide to stop carboplatin after 6 cycles, even if the above criteria were not met. Participants who continued to derive clinical benefit from the treatment based on the investigator's evaluation following their completion of this trial might receive post-trial access (PTA) i.e. rollover protocol or a post-study drug supply (PSDS). The end of study was defined as the earliest occurrence of one of the following: (1) all participants had died or (2) discontinued from the study, or (3) another clinical study became available that could continue to provide study treatment in this participant population and all ongoing participants were eligible to be transferred to that clinical study.
Interventions
DRUGLAG525
LAG525 was a concentrate for solution for intravenous infusion, came in 100mg vials as a liquid formulation for infusion and was dosed at 400mg every 21 days. For all arms, LAG525 was infused first
DRUGPDR001
Spartalizumab was a concentrate for solution for intravenous infusion, came in 100mg vials as a liquid formulation for infusion and was dosed at 300mg every 21 days. Spartalizumab was infused after LAG525
DRUGCarboplatin
Carboplatin was a concentrate for solution for intravenous infusion, came in 100mg/mL and was dosed per area under the curve (AUC) 6 every 21 days. Carboplatin was infused once LAG525 and spartalizumab infusions were completed
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
* Had advanced (loco-regionally recurrent not amenable to curative therapy or metastatic) breast cancer * Had adequate bone marrow and organ function. * Had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Had measurable disease, i.e., at least one measurable lesion as per RECIST 1.1 criteria (Tumor lesions previously irradiated or subjected to other loco-regional therapy was to be considered measurable if disease progression at the treated site after completion of therapy is clearly documented) * Progressed after adjuvant or 1 prior systemic treatment in the metastatic setting. Patients with de novo metastatic disease were eligible if they received 1 prior line of therapy * Had received prior systemic treatment that included taxane-based chemotherapy for adjuvant or metastatic disease * Had a site of disease amenable to biopsy, and was willing to undergo a new tumor biopsy at screening and during therapy on this study, the latter if medically feasible. Patients with an available archival tumor tissue did not need to perform a tumor biopsy at screening if patient had not received anti-cancer therapy since the biopsy was taken. * Had histologically and/or cytologically confirmed diagnosis of advanced TNBC (based on most recently analyzed biopsy from locally recurrent or metastatic site, local lab) meeting the following criteria: HER2 negative in situ hybridization test or an IHC status of 0 or 1+, and ER and PR expression was \<1 percent as determined by immunohistochemistry (IHC)
Exclusion criteria
* Had received prior immune checkpoint inhibitors as anticancer treatment such as anti-LAG-3, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibody (any line of therapy) * Received prior neoadjuvant or adjuvant therapy with a platinum agent or mitomycin and experienced recurrence within 12 months after the end of the platinum-based or mitomycin containing therapy or received Platinum or mitomycin for metastatic disease * Had major surgery within 14 days prior to starting study treatment or had not recovered to grade 1 or less from major side effects * Presence of CTCAE grade 2 toxicity or higher due to prior cancer therapy. Exception to this criterion; patients with any grade of alopecia were allowed to enter the study. * Had received radiotherapy ≤ 4 weeks prior to randomization (≤ 2 weeks for limited field radiation for palliation), and had not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia) * Had a known hypersensitivity to other monoclonal antibodies, platinum-containing compounds, or to any of the excipients of LAG525, spartalizumab, or carboplatin * Had symptomatic central nervous system (CNS) metastases or CNS metastases that required local CNS-directed therapy (such as radiotherapy or surgery), or increasing doses of corticosteroids within the 2 weeks prior to first dose of study treatment. Patients with treated brain metastases would be neurologically stable and without CNS progression for at least 12 weeks prior to randomization and had discontinued corticosteroid treatment (with the exception of \< 10 mg/day of prednisone or equivalent for an indication other than CNS metastases) for at least 4 weeks before first dose of any study treatment * Had clinically significant cardiac disease or impaired cardiac function
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) Per Investigator's Assessment According to RECIST v1.1 | Up to approximately 14 months | Overall response rate (ORR) is defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 based on investigator's assessment. The 95% CIs were computed using two-sided exact binomial method. 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 |
|---|---|---|
| Duration of Response (DOR) Per Investigator's Assessment According to RECIST v1.1 | From first documented response up to disease progression or death due to underlying cancer, whichever occurs first, up to approximately 14 months | DOR is the time between the first documented response (CR or PR) and the first documented progression or death due to underlying cancer based on RECIST1.1 and as per investigator's assessment. The DOR distribution was estimated using the Kaplan-Meier method and the 95% confidence intervals using the method of Brookmeyer and Crowley. If progression or death did not occur, the participant was censored at the date of last adequate tumor assessment. CR: Disappearance of all non-nodal target lesions and any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Progression: at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. The sum must also demonstrate an absolute increase of at least 5 mm. |
| Time to Response (TTR) Per Investigator's Assessment According to RECIST v1.1 | From date of randomization to first documented response (CR or PR), up to approximately 14 months | TTR is the time from date of randomization to first documented response of CR or PR based on investigators' assessment and according to RECIST 1.1. Median TTR was summarized using descriptive statistics. 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. |
| Progression Free Survival (PFS) | From date of randomization to disease progression or death due to any cause, whichever occurs first, up to approximately 14 months | PFS is defined as time from date of randomization to the date of first documented progression or death due to any cause. PFS was assessed via investigator's assessment according to RECIST 1.1. PFS was censored at the date of the last adequate tumor assessment if no PFS event was observed prior to the analysis cut-off date or before the start of the new anticancer therapy date, whichever is earlier. The PFS distribution was estimated using the Kaplan-Meier method. The 95% confidence intervals were calculated using the method of Brookmeyer and Crowley. |
| Overall Survival (OS) | From date of randomization to date of death due to any cause, up to 18 months | OS is defined as the time from date of randomization to date of death due to any cause. If a participant was not known to have died, then OS was censored at the latest date the participant was known to be alive (on or before the cut-off date). The OS distribution was estimated using the Kaplan-Meier method. The 95% confidence intervals were calculated using the method of Brookmeyer and Crowley |
| Pharmacokinetics (PK) Parameter, Area Under the Plasma Concentration Versus Time Curve From Time 0 to 504 Hours (AUC0-504h) of LAG525 | Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days | Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUC0-504h was defined as the area under the plasma concentration-time curve from time zero to 504h. |
| PK Parameter, Cmax of LAG525 | Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days | Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Cmax is the maximum observed plasma LAG525 concentration |
| PK Parameter, AUClast of LAG525 | Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days | Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUClast is the area under the curve (AUC) from time zero to the last measurable concentration sampling time (tlast) of LAG525 |
| PK Parameter, Tmax of LAG525 | Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days | Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Tmax is the time to reach maximum LAG525 serum concentration. Actual time of sample collection was used (not the nominal time point as per scheduled assessment) |
| PK Parameter, AUC0-504h of PDR001 | Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days | Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUC0-504h was defined as the area under the plasma concentration-time curve from time zero to 504h. |
| PK Parameter, Cmax of PDR001 | Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days | Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Cmax is the maximum observed PDR001 serum concentration |
| PK Parameter, AUClast of PDR001 | Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days | Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUClast is the area under the curve (AUC) from time zero to the last measurable concentration sampling time (tlast) of PDR001 |
| PK Parameter, Tmax of PDR001 | Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days | Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Tmax is the time to reach maximum PDR001 serum concentration. Actual time of sample collection was used (not the nominal time point as per scheduled assessment) |
| Clinical Benefit Rate (CBR) Per Investigator's Assessment According to RECIST v1.1 | Up to approximately 14 months | CBR is defined as the percentage of participants with a best overall response (BOR) of confirmed CR or PR, or stable disease (SD) lasting 24 weeks or longer, according to RECIST 1.1 criteria. The 95% CI were computed using two-sided exact binomial method. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease. |
| PK Parameter, Cmax of Carboplatin (Total Platinum) | Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days | Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Cmax is the maximum observed carboplatin plasma concentration (determined as total platinum) |
| PK Parameter, AUClast of Carboplatin (Total Platinum) | Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days | Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUClast is the area under the curve (AUC) from time zero to the last measurable concentration sampling time (tlast) of carboplatin (determined as total platinum) |
| PK Parameter, AUClast of Carboplatin (Ultrafilterable Platinum) | Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days | Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUClast is the area under the curve (AUC) from time zero to the last measurable concentration sampling time (tlast) of carboplatin (determined as ultrafilterable platinum) |
| PK Parameter, Tmax of Carboplatin (Total Platinum) | Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days | Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Tmax is the time to reach maximum carboplatin plasma concentration (determined as total platinum). Actual time of sample collection was used (not the nominal time point as per scheduled assessment) |
| PK Parameter, AUC0-4h of Carboplatin (Ultrafilterable Platinum) | Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days | Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUC0-4h was defined as the area under the plasma concentration-time curve from time zero to 4h (determined as ultrafilterable platinum). |
| PK Parameter, Cmax of Carboplatin (Ultrafilterable Platinum) | Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days | Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Cmax is the maximum observed carboplatin plasma concentration (determined as ultrafilterable platinum) |
| PK Parameter, Tmax of Carboplatin (Ultrafilterable Platinum) | Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days | Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Tmax is the time to reach maximum carboplatin plasma concentration (determined as ultrafilterable platinum). Actual time of sample collection was used (not the nominal time point as per scheduled assessment) |
| Number of Participants With Anti-drug Antibodies (ADA) at Baseline for LAG525 | Baseline | Number of participants who had an ADA positive result at baseline for LAG525 |
| Number of Participants With Anti-drug Antibodies (ADA) on Treatment for LAG525 | From Cycle 1 to Cycle 7 (Day 1 pre-infusion) and end of treatment, assessed up to 3 years | Number of participants who were treatment-induced ADA positive for LAG525 (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive for LAG525 (post-baseline ADA positive with titer that was at least the fold titer change greater than the ADA-positive baseline titer) |
| Number of Participants With Anti-drug Antibodies (ADA) at Baseline for PDR001 | Baseline | Number of participants who had an ADA positive result at baseline for PDR001. |
| Number of Participants With Anti-drug Antibodies (ADA) on Treatment for PDR001 | From Cycle 1 to Cycle 7 (Day 1 pre-infusion) and end of treatment, assessed up to 2.8 years | Number of participants who were treatment-induced ADA positive for PDR001 (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive for PDR001 (post-baseline ADA positive with titer that was at least the fold titer change greater than the ADA-positive baseline titer) |
| PK Parameter, AUC0-4h of Carboplatin (Total Platinum) | Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days | Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUC0-4h was defined as the area under the plasma concentration-time curve from time zero to 4h (determined as total platinum). |
Countries
Argentina, Australia, Belgium, Canada, France, Germany, Hungary, Israel, Italy, Japan, Lebanon, Singapore, South Korea, Spain, Taiwan, Thailand, United States
Participant flow
Recruitment details
The study was conducted across 33 centers in 17 countries.
Pre-assignment details
A total of 132 participants were screened of which 88 participants were enrolled in the study and 87 participants received at least one dose of study treatment (1 participant was not treated due to physician decision)
Participants by arm
| Arm | Count |
|---|---|
| LAG525 + PDR001 Participants received LAG525 and PDR001 administered as infusion once every 3 weeks | 20 |
| LAG525+ PDR001+ Carboplatin Participants received LAG525, PDR001 and carboplatin administered as infusion once every 3 weeks. | 34 |
| LAG525 + Carboplatin Participants received LAG525 and carboplatin administered as infusion once every 3 weeks | 34 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 | 3 |
| Overall Study | Death | 0 | 0 | 1 |
| Overall Study | Patient decision | 0 | 1 | 1 |
| Overall Study | Physician Decision | 3 | 6 | 6 |
| Overall Study | Progressive disease | 15 | 23 | 23 |
| Overall Study | Terminated by sponsor (end of study definition was met) | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | LAG525 + PDR001 | LAG525+ PDR001+ Carboplatin | LAG525 + Carboplatin | Total |
|---|---|---|---|---|
| Age, Continuous | 53.8 Years STANDARD_DEVIATION 10.22 | 50.9 Years STANDARD_DEVIATION 10.88 | 53.3 Years STANDARD_DEVIATION 10.78 | 52.5 Years STANDARD_DEVIATION 10.65 |
| Race/Ethnicity, Customized Asian | 8 Participants | 8 Participants | 7 Participants | 23 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Missing | 0 Participants | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 12 Participants | 23 Participants | 25 Participants | 60 Participants |
| Sex: Female, Male Female | 20 Participants | 34 Participants | 34 Participants | 88 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 7 / 19 | 2 / 34 | 7 / 34 | 1 / 34 | 16 / 34 |
| other Total, other adverse events | 17 / 19 | 0 / 19 | 34 / 34 | 11 / 34 | 33 / 34 | 3 / 34 |
| serious Total, serious adverse events | 6 / 19 | 0 / 19 | 12 / 34 | 6 / 34 | 14 / 34 | 2 / 34 |
Outcome results
Primary
Overall Response Rate (ORR) Per Investigator's Assessment According to RECIST v1.1
Overall response rate (ORR) is defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 based on investigator's assessment. The 95% CIs were computed using two-sided exact binomial method. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to approximately 14 months
Population: Full Analysis Set (FAS): All participants to whom study treatment was assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LAG525 + PDR001 | Overall Response Rate (ORR) Per Investigator's Assessment According to RECIST v1.1 | 5.0 Percentage of participants |
| LAG525+ PDR001+ Carboplatin | Overall Response Rate (ORR) Per Investigator's Assessment According to RECIST v1.1 | 32.4 Percentage of participants |
| LAG525 + Carboplatin | Overall Response Rate (ORR) Per Investigator's Assessment According to RECIST v1.1 | 17.6 Percentage of participants |
Secondary
Clinical Benefit Rate (CBR) Per Investigator's Assessment According to RECIST v1.1
CBR is defined as the percentage of participants with a best overall response (BOR) of confirmed CR or PR, or stable disease (SD) lasting 24 weeks or longer, according to RECIST 1.1 criteria. The 95% CI were computed using two-sided exact binomial method. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
Time frame: Up to approximately 14 months
Population: FAS: All participants to whom study treatment was assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LAG525 + PDR001 | Clinical Benefit Rate (CBR) Per Investigator's Assessment According to RECIST v1.1 | 5.0 Percentage of Participants |
| LAG525+ PDR001+ Carboplatin | Clinical Benefit Rate (CBR) Per Investigator's Assessment According to RECIST v1.1 | 35.3 Percentage of Participants |
| LAG525 + Carboplatin | Clinical Benefit Rate (CBR) Per Investigator's Assessment According to RECIST v1.1 | 20.6 Percentage of Participants |
Secondary
Duration of Response (DOR) Per Investigator's Assessment According to RECIST v1.1
DOR is the time between the first documented response (CR or PR) and the first documented progression or death due to underlying cancer based on RECIST1.1 and as per investigator's assessment. The DOR distribution was estimated using the Kaplan-Meier method and the 95% confidence intervals using the method of Brookmeyer and Crowley. If progression or death did not occur, the participant was censored at the date of last adequate tumor assessment. CR: Disappearance of all non-nodal target lesions and any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Progression: at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. The sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: From first documented response up to disease progression or death due to underlying cancer, whichever occurs first, up to approximately 14 months
Population: Participants with a confirmed CR or PR
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LAG525 + PDR001 | Duration of Response (DOR) Per Investigator's Assessment According to RECIST v1.1 | 4.9 Months |
| LAG525+ PDR001+ Carboplatin | Duration of Response (DOR) Per Investigator's Assessment According to RECIST v1.1 | 13.6 Months |
| LAG525 + Carboplatin | Duration of Response (DOR) Per Investigator's Assessment According to RECIST v1.1 | 12.6 Months |
Secondary
Number of Participants With Anti-drug Antibodies (ADA) at Baseline for LAG525
Number of participants who had an ADA positive result at baseline for LAG525
Time frame: Baseline
Population: LAG525 Immunogenicity (IG) prevalence set: all participants in the FAS wo received at least one dose of LAG525 with a determinant baseline LAG525 IG sample or at least one determinant post-baseline LAG525 IG sample.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LAG525 + PDR001 | Number of Participants With Anti-drug Antibodies (ADA) at Baseline for LAG525 | 0 Participants |
| LAG525+ PDR001+ Carboplatin | Number of Participants With Anti-drug Antibodies (ADA) at Baseline for LAG525 | 0 Participants |
| LAG525 + Carboplatin | Number of Participants With Anti-drug Antibodies (ADA) at Baseline for LAG525 | 1 Participants |
Secondary
Number of Participants With Anti-drug Antibodies (ADA) at Baseline for PDR001
Number of participants who had an ADA positive result at baseline for PDR001.
Time frame: Baseline
Population: PDR001 Immunogenicity (IG) prevalence set: all participants in the FAS who received at least one dose of PDR001 with a determinant baseline PDR001 IG sample or at least one determinant post-baseline PDR001 IG sample
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LAG525 + PDR001 | Number of Participants With Anti-drug Antibodies (ADA) at Baseline for PDR001 | 3 Participants |
| LAG525+ PDR001+ Carboplatin | Number of Participants With Anti-drug Antibodies (ADA) at Baseline for PDR001 | 6 Participants |
Secondary
Number of Participants With Anti-drug Antibodies (ADA) on Treatment for LAG525
Number of participants who were treatment-induced ADA positive for LAG525 (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive for LAG525 (post-baseline ADA positive with titer that was at least the fold titer change greater than the ADA-positive baseline titer)
Time frame: From Cycle 1 to Cycle 7 (Day 1 pre-infusion) and end of treatment, assessed up to 3 years
Population: LAG525 immunogenicity incidence set: all participants in the LAG525 immunogenicity prevalence set with a determinant LAG525 baseline IG sample and at least one determinant LAG525 post-baseline IG sample.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LAG525 + PDR001 | Number of Participants With Anti-drug Antibodies (ADA) on Treatment for LAG525 | 0 Participants |
| LAG525+ PDR001+ Carboplatin | Number of Participants With Anti-drug Antibodies (ADA) on Treatment for LAG525 | 0 Participants |
| LAG525 + Carboplatin | Number of Participants With Anti-drug Antibodies (ADA) on Treatment for LAG525 | 1 Participants |
Secondary
Number of Participants With Anti-drug Antibodies (ADA) on Treatment for PDR001
Number of participants who were treatment-induced ADA positive for PDR001 (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive for PDR001 (post-baseline ADA positive with titer that was at least the fold titer change greater than the ADA-positive baseline titer)
Time frame: From Cycle 1 to Cycle 7 (Day 1 pre-infusion) and end of treatment, assessed up to 2.8 years
Population: PDR001 Immunogenicity incidence set: all subjects in the PDR001 Immunogenicity prevalence set with a determinant PDR001 baseline IG sample and at least one determinant PDR001 post-baseline IG sample.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LAG525 + PDR001 | Number of Participants With Anti-drug Antibodies (ADA) on Treatment for PDR001 | 1 Participants |
| LAG525+ PDR001+ Carboplatin | Number of Participants With Anti-drug Antibodies (ADA) on Treatment for PDR001 | 0 Participants |
Secondary
Overall Survival (OS)
OS is defined as the time from date of randomization to date of death due to any cause. If a participant was not known to have died, then OS was censored at the latest date the participant was known to be alive (on or before the cut-off date). The OS distribution was estimated using the Kaplan-Meier method. The 95% confidence intervals were calculated using the method of Brookmeyer and Crowley
Time frame: From date of randomization to date of death due to any cause, up to 18 months
Population: FAS: All participants to whom study treatment was assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LAG525 + PDR001 | Overall Survival (OS) | 6.1 Months |
| LAG525+ PDR001+ Carboplatin | Overall Survival (OS) | 11.6 Months |
| LAG525 + Carboplatin | Overall Survival (OS) | 8.0 Months |
Secondary
Pharmacokinetics (PK) Parameter, Area Under the Plasma Concentration Versus Time Curve From Time 0 to 504 Hours (AUC0-504h) of LAG525
Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUC0-504h was defined as the area under the plasma concentration-time curve from time zero to 504h.
Time frame: Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days
Population: LAG525 pharmacokinetic analysis set (PAS-LAG525) including all participants who provided at least one evaluable LAG525 PK concentration. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LAG525 + PDR001 | Pharmacokinetics (PK) Parameter, Area Under the Plasma Concentration Versus Time Curve From Time 0 to 504 Hours (AUC0-504h) of LAG525 | Cycle 1 | 1270 day*microgram/miliLiter (day*ug/mL) | Geometric Coefficient of Variation 25.8 |
| LAG525 + PDR001 | Pharmacokinetics (PK) Parameter, Area Under the Plasma Concentration Versus Time Curve From Time 0 to 504 Hours (AUC0-504h) of LAG525 | Cycle 3 | 2060 day*microgram/miliLiter (day*ug/mL) | Geometric Coefficient of Variation 60.1 |
| LAG525+ PDR001+ Carboplatin | Pharmacokinetics (PK) Parameter, Area Under the Plasma Concentration Versus Time Curve From Time 0 to 504 Hours (AUC0-504h) of LAG525 | Cycle 1 | 1350 day*microgram/miliLiter (day*ug/mL) | Geometric Coefficient of Variation 22.4 |
| LAG525+ PDR001+ Carboplatin | Pharmacokinetics (PK) Parameter, Area Under the Plasma Concentration Versus Time Curve From Time 0 to 504 Hours (AUC0-504h) of LAG525 | Cycle 3 | 2200 day*microgram/miliLiter (day*ug/mL) | Geometric Coefficient of Variation 34.4 |
| LAG525 + Carboplatin | Pharmacokinetics (PK) Parameter, Area Under the Plasma Concentration Versus Time Curve From Time 0 to 504 Hours (AUC0-504h) of LAG525 | Cycle 1 | 1180 day*microgram/miliLiter (day*ug/mL) | Geometric Coefficient of Variation 23.4 |
| LAG525 + Carboplatin | Pharmacokinetics (PK) Parameter, Area Under the Plasma Concentration Versus Time Curve From Time 0 to 504 Hours (AUC0-504h) of LAG525 | Cycle 3 | 1990 day*microgram/miliLiter (day*ug/mL) | Geometric Coefficient of Variation 31.3 |
Secondary
PK Parameter, AUC0-4h of Carboplatin (Total Platinum)
Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUC0-4h was defined as the area under the plasma concentration-time curve from time zero to 4h (determined as total platinum).
Time frame: Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days
Population: Carboplatin (plasma) PAS including all participants who provided at least one evaluable carboplatin PK plasma concentration. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LAG525 + PDR001 | PK Parameter, AUC0-4h of Carboplatin (Total Platinum) | Cycle 1 | 45000 hour*nanogram/miliLiter (hr*ng/mL) | Geometric Coefficient of Variation 23 |
| LAG525 + PDR001 | PK Parameter, AUC0-4h of Carboplatin (Total Platinum) | Cycle 3 | 42700 hour*nanogram/miliLiter (hr*ng/mL) | Geometric Coefficient of Variation 27.6 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, AUC0-4h of Carboplatin (Total Platinum) | Cycle 1 | 45200 hour*nanogram/miliLiter (hr*ng/mL) | Geometric Coefficient of Variation 16.1 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, AUC0-4h of Carboplatin (Total Platinum) | Cycle 3 | 43500 hour*nanogram/miliLiter (hr*ng/mL) | Geometric Coefficient of Variation 29.2 |
Secondary
PK Parameter, AUC0-4h of Carboplatin (Ultrafilterable Platinum)
Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUC0-4h was defined as the area under the plasma concentration-time curve from time zero to 4h (determined as ultrafilterable platinum).
Time frame: Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days
Population: Carboplatin (plasma ultrafiltrate) PAS including all participants who provided at least one evaluable carboplatin PK plasma ultrafiltrate concentration. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LAG525 + PDR001 | PK Parameter, AUC0-4h of Carboplatin (Ultrafilterable Platinum) | Cycle 1 | 43600 hour*nanogram/miliLiter (hr*ng/mL) | Geometric Coefficient of Variation 13.1 |
| LAG525 + PDR001 | PK Parameter, AUC0-4h of Carboplatin (Ultrafilterable Platinum) | Cycle 3 | 41100 hour*nanogram/miliLiter (hr*ng/mL) | Geometric Coefficient of Variation 30.5 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, AUC0-4h of Carboplatin (Ultrafilterable Platinum) | Cycle 1 | 44700 hour*nanogram/miliLiter (hr*ng/mL) | Geometric Coefficient of Variation 23.4 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, AUC0-4h of Carboplatin (Ultrafilterable Platinum) | Cycle 3 | 41000 hour*nanogram/miliLiter (hr*ng/mL) | Geometric Coefficient of Variation 12.8 |
Secondary
PK Parameter, AUC0-504h of PDR001
Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUC0-504h was defined as the area under the plasma concentration-time curve from time zero to 504h.
Time frame: Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days
Population: PDR001 pharmacokinetic analysis set (PAS-PDR001) including all participants who provided at least one evaluable PDR001 PK concentration. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LAG525 + PDR001 | PK Parameter, AUC0-504h of PDR001 | Cycle 1 | 819 day*ug/mL | Standard Deviation 23.6 |
| LAG525 + PDR001 | PK Parameter, AUC0-504h of PDR001 | Cycle 3 | 1490 day*ug/mL | Standard Deviation 41 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, AUC0-504h of PDR001 | Cycle 1 | 907 day*ug/mL | Standard Deviation 29.1 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, AUC0-504h of PDR001 | Cycle 3 | 1710 day*ug/mL | Standard Deviation 29.5 |
Secondary
PK Parameter, AUClast of Carboplatin (Total Platinum)
Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUClast is the area under the curve (AUC) from time zero to the last measurable concentration sampling time (tlast) of carboplatin (determined as total platinum)
Time frame: Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days
Population: Carboplatin (plasma) PAS including all participants who provided at least one evaluable carboplatin PK plasma concentration. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LAG525 + PDR001 | PK Parameter, AUClast of Carboplatin (Total Platinum) | Cycle 1 | 42000 ng/mL | Geometric Coefficient of Variation 30.8 |
| LAG525 + PDR001 | PK Parameter, AUClast of Carboplatin (Total Platinum) | Cycle 3 | 40800 ng/mL | Geometric Coefficient of Variation 38.1 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, AUClast of Carboplatin (Total Platinum) | Cycle 1 | 38900 ng/mL | Geometric Coefficient of Variation 56.3 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, AUClast of Carboplatin (Total Platinum) | Cycle 3 | 42600 ng/mL | Geometric Coefficient of Variation 43.3 |
Secondary
PK Parameter, AUClast of Carboplatin (Ultrafilterable Platinum)
Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUClast is the area under the curve (AUC) from time zero to the last measurable concentration sampling time (tlast) of carboplatin (determined as ultrafilterable platinum)
Time frame: Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days
Population: Carboplatin (plasma ultrafiltrate) PAS including all participants who provided at least one evaluable carboplatin PK plasma ultrafiltrate concentration. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LAG525 + PDR001 | PK Parameter, AUClast of Carboplatin (Ultrafilterable Platinum) | Cycle 1 | 41400 ng/mL | Geometric Coefficient of Variation 13 |
| LAG525 + PDR001 | PK Parameter, AUClast of Carboplatin (Ultrafilterable Platinum) | Cycle 3 | 37400 ng/mL | Geometric Coefficient of Variation 30.1 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, AUClast of Carboplatin (Ultrafilterable Platinum) | Cycle 1 | 35600 ng/mL | Geometric Coefficient of Variation 65.2 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, AUClast of Carboplatin (Ultrafilterable Platinum) | Cycle 3 | 36300 ng/mL | Geometric Coefficient of Variation 68.2 |
Secondary
PK Parameter, AUClast of LAG525
Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUClast is the area under the curve (AUC) from time zero to the last measurable concentration sampling time (tlast) of LAG525
Time frame: Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days
Population: PAS-LAG525 including all participants who provided at least one evaluable LAG525 PK concentration. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LAG525 + PDR001 | PK Parameter, AUClast of LAG525 | Cycle 1 | 1170 day*ug/mL | Geometric Coefficient of Variation 32 |
| LAG525 + PDR001 | PK Parameter, AUClast of LAG525 | Cycle 3 | 240 day*ug/mL | Geometric Coefficient of Variation 9775.4 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, AUClast of LAG525 | Cycle 1 | 1310 day*ug/mL | Geometric Coefficient of Variation 41.1 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, AUClast of LAG525 | Cycle 3 | 2040 day*ug/mL | Geometric Coefficient of Variation 49.8 |
| LAG525 + Carboplatin | PK Parameter, AUClast of LAG525 | Cycle 1 | 1010 day*ug/mL | Geometric Coefficient of Variation 151.2 |
| LAG525 + Carboplatin | PK Parameter, AUClast of LAG525 | Cycle 3 | 1490 day*ug/mL | Geometric Coefficient of Variation 196.4 |
Secondary
PK Parameter, AUClast of PDR001
Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUClast is the area under the curve (AUC) from time zero to the last measurable concentration sampling time (tlast) of PDR001
Time frame: Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days
Population: PAS-PDR001 including all participants who provided at least one evaluable PDR001 PK concentration. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LAG525 + PDR001 | PK Parameter, AUClast of PDR001 | Cycle 1 | 780 day*ug/mL | Geometric Coefficient of Variation 24.4 |
| LAG525 + PDR001 | PK Parameter, AUClast of PDR001 | Cycle 3 | 374 day*ug/mL | Geometric Coefficient of Variation 2703.2 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, AUClast of PDR001 | Cycle 1 | 890 day*ug/mL | Geometric Coefficient of Variation 44.6 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, AUClast of PDR001 | Cycle 3 | 1500 day*ug/mL | Geometric Coefficient of Variation 55.7 |
Secondary
PK Parameter, Cmax of Carboplatin (Total Platinum)
Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Cmax is the maximum observed carboplatin plasma concentration (determined as total platinum)
Time frame: Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days
Population: Carboplatin (plasma) PAS including all participants who provided at least one evaluable carboplatin PK plasma concentration. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LAG525 + PDR001 | PK Parameter, Cmax of Carboplatin (Total Platinum) | Cycle 1 | 22300 ng/mL | Geometric Coefficient of Variation 32 |
| LAG525 + PDR001 | PK Parameter, Cmax of Carboplatin (Total Platinum) | Cycle 3 | 20900 ng/mL | Geometric Coefficient of Variation 33.4 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, Cmax of Carboplatin (Total Platinum) | Cycle 1 | 21400 ng/mL | Geometric Coefficient of Variation 32.2 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, Cmax of Carboplatin (Total Platinum) | Cycle 3 | 20000 ng/mL | Geometric Coefficient of Variation 199.2 |
Secondary
PK Parameter, Cmax of Carboplatin (Ultrafilterable Platinum)
Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Cmax is the maximum observed carboplatin plasma concentration (determined as ultrafilterable platinum)
Time frame: Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days
Population: Carboplatin (plasma ultrafiltrate) PAS including all participants who provided at least one evaluable carboplatin PK plasma ultrafiltrate concentration. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LAG525 + PDR001 | PK Parameter, Cmax of Carboplatin (Ultrafilterable Platinum) | Cycle 1 | 23200 ng/mL | Geometric Coefficient of Variation 19.8 |
| LAG525 + PDR001 | PK Parameter, Cmax of Carboplatin (Ultrafilterable Platinum) | Cycle 3 | 22300 ng/mL | Geometric Coefficient of Variation 40.1 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, Cmax of Carboplatin (Ultrafilterable Platinum) | Cycle 1 | 25700 ng/mL | Geometric Coefficient of Variation 24.2 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, Cmax of Carboplatin (Ultrafilterable Platinum) | Cycle 3 | 14700 ng/mL | Geometric Coefficient of Variation 4159.6 |
Secondary
PK Parameter, Cmax of LAG525
Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Cmax is the maximum observed plasma LAG525 concentration
Time frame: Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days
Population: PAS-LAG525 including all participants who provided at least one evaluable LAG525 PK concentration. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LAG525 + PDR001 | PK Parameter, Cmax of LAG525 | Cycle 1 | 127 ug/mL | Geometric Coefficient of Variation 26.5 |
| LAG525 + PDR001 | PK Parameter, Cmax of LAG525 | Cycle 3 | 144 ug/mL | Geometric Coefficient of Variation 48.9 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, Cmax of LAG525 | Cycle 1 | 136 ug/mL | Geometric Coefficient of Variation 21.1 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, Cmax of LAG525 | Cycle 3 | 181 ug/mL | Geometric Coefficient of Variation 29.5 |
| LAG525 + Carboplatin | PK Parameter, Cmax of LAG525 | Cycle 1 | 128 ug/mL | Geometric Coefficient of Variation 17.9 |
| LAG525 + Carboplatin | PK Parameter, Cmax of LAG525 | Cycle 3 | 168 ug/mL | Geometric Coefficient of Variation 26.6 |
Secondary
PK Parameter, Cmax of PDR001
Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Cmax is the maximum observed PDR001 serum concentration
Time frame: Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days
Population: PAS-PDR001 including all participants who provided at least one evaluable PDR001 PK concentration. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LAG525 + PDR001 | PK Parameter, Cmax of PDR001 | Cycle 1 | 78.0 ug/mL | Geometric Coefficient of Variation 18.9 |
| LAG525 + PDR001 | PK Parameter, Cmax of PDR001 | Cycle 3 | 95.1 ug/mL | Geometric Coefficient of Variation 41.4 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, Cmax of PDR001 | Cycle 1 | 82.4 ug/mL | Geometric Coefficient of Variation 25.1 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, Cmax of PDR001 | Cycle 3 | 117 ug/mL | Geometric Coefficient of Variation 26.8 |
Secondary
PK Parameter, Tmax of Carboplatin (Total Platinum)
Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Tmax is the time to reach maximum carboplatin plasma concentration (determined as total platinum). Actual time of sample collection was used (not the nominal time point as per scheduled assessment)
Time frame: Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days
Population: Carboplatin (plasma) PAS including all participants who provided at least one evaluable carboplatin PK plasma concentration.Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LAG525 + PDR001 | PK Parameter, Tmax of Carboplatin (Total Platinum) | Cycle 1 | 0.857 hr | Geometric Coefficient of Variation 35.5 |
| LAG525 + PDR001 | PK Parameter, Tmax of Carboplatin (Total Platinum) | Cycle 3 | 0.789 hr | Geometric Coefficient of Variation 33 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, Tmax of Carboplatin (Total Platinum) | Cycle 1 | 0.720 hr | Geometric Coefficient of Variation 31.9 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, Tmax of Carboplatin (Total Platinum) | Cycle 3 | 0.720 hr | Geometric Coefficient of Variation 34.8 |
Secondary
PK Parameter, Tmax of Carboplatin (Ultrafilterable Platinum)
Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Tmax is the time to reach maximum carboplatin plasma concentration (determined as ultrafilterable platinum). Actual time of sample collection was used (not the nominal time point as per scheduled assessment)
Time frame: Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days
Population: Carboplatin (plasma ultrafiltrate) PAS including all participants who provided at least one evaluable carboplatin PK plasma ultrafiltrate concentration. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LAG525 + PDR001 | PK Parameter, Tmax of Carboplatin (Ultrafilterable Platinum) | Cycle 1 | 0.802 hr | Geometric Coefficient of Variation 42.5 |
| LAG525 + PDR001 | PK Parameter, Tmax of Carboplatin (Ultrafilterable Platinum) | Cycle 3 | 0.828 hr | Geometric Coefficient of Variation 39.7 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, Tmax of Carboplatin (Ultrafilterable Platinum) | Cycle 1 | 0.660 hr | Geometric Coefficient of Variation 34.4 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, Tmax of Carboplatin (Ultrafilterable Platinum) | Cycle 3 | 0.686 hr | Geometric Coefficient of Variation 34.6 |
Secondary
PK Parameter, Tmax of LAG525
Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Tmax is the time to reach maximum LAG525 serum concentration. Actual time of sample collection was used (not the nominal time point as per scheduled assessment)
Time frame: Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days
Population: PAS-LAG525 including all participants who provided at least one evaluable LAG525 PK concentration. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LAG525 + PDR001 | PK Parameter, Tmax of LAG525 | Cycle 1 | 1.51 hr | Geometric Coefficient of Variation 40.7 |
| LAG525 + PDR001 | PK Parameter, Tmax of LAG525 | Cycle 3 | 1.64 hr | Geometric Coefficient of Variation 13.4 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, Tmax of LAG525 | Cycle 1 | 1.76 hr | Geometric Coefficient of Variation 35.5 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, Tmax of LAG525 | Cycle 3 | 1.58 hr | Geometric Coefficient of Variation 15 |
| LAG525 + Carboplatin | PK Parameter, Tmax of LAG525 | Cycle 1 | 1.58 hr | Geometric Coefficient of Variation 23.1 |
| LAG525 + Carboplatin | PK Parameter, Tmax of LAG525 | Cycle 3 | 1.77 hr | Geometric Coefficient of Variation 37.4 |
Secondary
PK Parameter, Tmax of PDR001
Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Tmax is the time to reach maximum PDR001 serum concentration. Actual time of sample collection was used (not the nominal time point as per scheduled assessment)
Time frame: Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days
Population: PAS-PDR001 including all participants who provided at least one evaluable PDR001 PK concentration. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LAG525 + PDR001 | PK Parameter, Tmax of PDR001 | Cycle 1 | 1.43 hr | Geometric Coefficient of Variation 34.7 |
| LAG525 + PDR001 | PK Parameter, Tmax of PDR001 | Cycle 3 | 1.67 hr | Geometric Coefficient of Variation 13.6 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, Tmax of PDR001 | Cycle 1 | 1.71 hr | Geometric Coefficient of Variation 29.7 |
| LAG525+ PDR001+ Carboplatin | PK Parameter, Tmax of PDR001 | Cycle 3 | 1.61 hr | Geometric Coefficient of Variation 13.9 |
Secondary
Progression Free Survival (PFS)
PFS is defined as time from date of randomization to the date of first documented progression or death due to any cause. PFS was assessed via investigator's assessment according to RECIST 1.1. PFS was censored at the date of the last adequate tumor assessment if no PFS event was observed prior to the analysis cut-off date or before the start of the new anticancer therapy date, whichever is earlier. The PFS distribution was estimated using the Kaplan-Meier method. The 95% confidence intervals were calculated using the method of Brookmeyer and Crowley.
Time frame: From date of randomization to disease progression or death due to any cause, whichever occurs first, up to approximately 14 months
Population: FAS: All participants to whom study treatment was assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LAG525 + PDR001 | Progression Free Survival (PFS) | 1.4 Months |
| LAG525+ PDR001+ Carboplatin | Progression Free Survival (PFS) | 4.3 Months |
| LAG525 + Carboplatin | Progression Free Survival (PFS) | 3.0 Months |
Secondary
Time to Response (TTR) Per Investigator's Assessment According to RECIST v1.1
TTR is the time from date of randomization to first documented response of CR or PR based on investigators' assessment and according to RECIST 1.1. Median TTR was summarized using descriptive statistics. 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 first documented response (CR or PR), up to approximately 14 months
Population: Participants with a confirmed CR or PR
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LAG525 + PDR001 | Time to Response (TTR) Per Investigator's Assessment According to RECIST v1.1 | 1.5 Months |
| LAG525+ PDR001+ Carboplatin | Time to Response (TTR) Per Investigator's Assessment According to RECIST v1.1 | 1.7 Months |
| LAG525 + Carboplatin | Time to Response (TTR) Per Investigator's Assessment According to RECIST v1.1 | 1.4 Months |
Post Hoc
All Collected Deaths
On-treatment deaths were collected from first dose of study medication to 30 days after the last dose of study medication for a maximum duration of 2.9 years. Extended safety follow up deaths were collected from day 31 post treatment up to 150 days post-treatment, for a maximum duration of 3.2 years. Post-treatment deaths were collected after 150 days post-treatment, for a maximum duration of 3.2 years.
Time frame: Up to 2.9 years (on-treatment), up to 3.2 years (extended safety follow-up and post-treatment)
Population: Safety set: all participants who received at least one dose of study treatment (i.e., at least one dose of any component of the study treatment, including incomplete infusion of spartalizumab, LAG525 or carboplatin).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LAG525 + PDR001 | All Collected Deaths | On-treatment | 0 Participants |
| LAG525 + PDR001 | All Collected Deaths | Extended safety follow-up deaths | 7 Participants |
| LAG525 + PDR001 | All Collected Deaths | Post-treatment deaths | 8 Participants |
| LAG525 + PDR001 | All Collected Deaths | All deaths | 15 Participants |
| LAG525+ PDR001+ Carboplatin | All Collected Deaths | All deaths | 24 Participants |
| LAG525+ PDR001+ Carboplatin | All Collected Deaths | On-treatment | 2 Participants |
| LAG525+ PDR001+ Carboplatin | All Collected Deaths | Post-treatment deaths | 15 Participants |
| LAG525+ PDR001+ Carboplatin | All Collected Deaths | Extended safety follow-up deaths | 7 Participants |
| LAG525 + Carboplatin | All Collected Deaths | All deaths | 28 Participants |
| LAG525 + Carboplatin | All Collected Deaths | Extended safety follow-up deaths | 16 Participants |
| LAG525 + Carboplatin | All Collected Deaths | Post-treatment deaths | 11 Participants |
| LAG525 + Carboplatin | All Collected Deaths | On-treatment | 1 Participants |