Non-small Cell Lung Cancer, Pleural Mesothelioma
Conditions
Brief summary
The Primary Objective was: -To determine the antitumor activity of SAR444245 in combination with other anticancer therapies. The Secondary Objectives were: * To confirm the dose and to assess the safety profile of SAR444245 when combined with other anticancer therapies. * To assess other indicators of antitumor activity. * To assess the pharmacokinetic (PK) profile of SAR444245 when given in combination with pembrolizumab. * To assess the immunogenicity of SAR444245.
Detailed description
The duration of the study for an individual participant started from the signature of the main informed consent and included a screening period of up to 28 days, a treatment period \[max 35 cycles {cohorts A1, A2, and B1} = 735 days or until PD {cohort C1}\], an end-of-treatment visit at least 30 days following the last administration of study drug (or until the participant receives another anticancer therapy, whichever is earlier), and a follow-up visit 3 months after treatment discontinuation and every 3 months following, until disease progression, or initiation of another antitumor treatment, or death, whichever is earlier
Interventions
DRUGTHOR-707
Intravenous infusion: solution for infusion
DRUGPembrolizumab
Intravenous infusion: solution for infusion
Sponsors
Merck Sharp & Dohme LLC
Sanofi
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant must have been ≥18 years of age (or country's legal age of majority if \>18 years), at the time of signing the informed consent. * Histologically or cytologically confirmed diagnosis of Stage IV NSCLC (cohorts A1, A2, and B1), or unresectable malignant pleural mesothelioma (cohort C1). * Cohort A1: PD-L1 expression TPS ≥ 50% * Cohort A2: PD-L1 expression TPS 1 - 49% * Prior anticancer therapy * Cohorts A1 and A2: No prior systemic therapy for advanced/metastatic NSCLC. Participants who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 6 months prior to the development of metastatic disease. * Cohort B1: One prior anti-PD1/PD-L1 regimen (may include chemotherapy) plus one additional chemotherapy regimen * Cohort C1: One or two prior systemic treatments that include pemetrexed-based regimen in combination with platinum agent. * All cohorts must have had a measurable disease * Mandatory baseline biopsy for the first 20 participants to enroll in cohorts A1, A2 * Cohort B1: Based on the Investigator's judgment, either docetaxel or pemetrexed is not the best treatment option for the participant. * Females were eligible to participate if they were not pregnant or breastfeeding, not a woman of childbearing potential (WOCBP) or are a WOCBP that agrees: * to use approved contraception method and submit to regular pregnancy testing prior to treatment and for 150 days after discontinuing study treatment * to refrain from donating or cryopreserving eggs for 150 days after discontinuing study treatment. * Males were eligible to participate if they agree to refrain from donating or cryopreserving sperm, and either abstain from heterosexual intercourse OR use approved contraception during study treatment and for at least 210 days after discontinuing study treatment. * Capable of giving signed informed consent.
Exclusion criteria
Participants were excluded from the study if any of the following criteria applied: * Eastern Cooperative Oncology Group (ECOG) performance status of ≥ 2. * Poor bone marrow reserve * Poor organ function * Participants with baseline SpO2 ≤ 92%. * Active brain metastases or leptomeningeal disease. * History of allogenic tissue/solid organ transplant * Last administration of prior antitumor therapy or any investigational treatment within 28 days or less than 5 times the half-life, whichever is shorter; major surgery or local intervention within 28 days. * Has received prior IL-2-based anticancer treatment. * Comorbidity requiring corticosteroid therapy * Antibiotic use (excluding topical antibiotics) ≤14 days prior to first dose of IMP * Severe or unstable cardiac condition within 6 months prior to starting study treatment * Active, known, or suspected autoimmune disease that has required systemic treatment in the past 2 years * Known second malignancy either progressing or requiring active treatment within the last 3 years * Cohorts A1, A2, and C1: Prior treatment with an agent (approved or investigational) that blocks the PD1/PD-L1 pathway (participants who joined a study with an anti-PD1/PD-L1 but have written confirmation they were on control arm are allowed). * Receipt of a live-virus vaccination within 28 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted. The above information is not intended to contain all considerations relevant to the potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohorts A1 and A2: Objective Response Rate (ORR) | From first dose of study treatment administration (Day 1) up to approximately 21 months | ORR was defined as the percentage of participants who had a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. CR. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 millimeter (mm) (\<1 centimeter \[cm\]). PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. |
| Cohorts B1: Objective Response Rate | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 14 months | ORR was defined as the percentage of participants who had a confirmed CR or PR as per RECIST v1.1. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm (\<1 cm). PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. |
| Cohorts C1: Objective Response Rate | From first dose of study treatment administration (Day 1) up to approximately 21 months | ORR was defined as the percentage of participants who had a confirmed CR or PR assessed by the investigator as per modified RECIST (mRECIST) v1.1. CR. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm (\<1 cm). PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All Cohorts: Duration of Response (DOR) | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 27 months (Cohorts A1 and A2), 14 months (Cohort B1), and 24 months (Cohort C1) | DOR was defined as time from date of first tumor assessment at which overall response was recorded as CR or PR that was subsequently confirmed to date of first documentation of objective PD before initiation of any post-treatment anti-cancer therapy or death due to any cause, whichever occurred first, as per RECIST v 1.1 (NSCLS) and assessed by investigator as per mRECIST v1.1 (mesothelioma). CR: disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm (\<1 cm). PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. PD:at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (this included baseline sum if that was smallest on study), in addition to relative increase of 20%, sum must have also demonstrated an absolute increase of at least 5 mm (0.5 cm). |
| All Cohorts: Clinical Benefit Rate (CBR) | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 27 months (Cohorts A1 and A2), 14 months (Cohort B1), and 24 months (Cohort C1) | The CBR was defined as the percentage of participants with clinical benefit: confirmed CR or PR as best overall response (BOR), or stable disease (SD) that lasted at least 6 months as per RECIST v 1.1 (NSCLS) and assessed by investigator as per mRECIST v1.1 (mesothelioma). CR: disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm (\<1 cm). PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. BOR was the best response observed from start of the study treatment until PD, death, cut-off date or initiation of post-treatment anticancer therapy, whichever occurred first. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. |
| All Cohorts: Progression Free Survival (PFS) | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 27 months (Cohorts A1 and A2), 14 months (Cohort B1), and 24 months (Cohort C1) | The PFS was defined as the time from the date of first study treatment to the date of the first documentation of objective PD, or death due to any cause, whichever occurred first as per RECIST v 1.1 (NSCLS) and assessed by investigator as per mRECIST v1.1 (mesothelioma). PD was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that was the smallest on study), in addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm (0.5 cm). |
| All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | From first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment; approximately 28 months (Cohorts A1 and A2), 15 months (Cohort B1), and 25 months (Cohort C1) | An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was any AE that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. TEAEs were defined as AEs that developed, worsened (according to the investigator's opinion) or became serious during the TE period. |
| All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycles 1, 2, 4, 7, 10, and 15 (each cycle is 21 days) | Blood samples were collected at specified timepoints for the assessment of Ceoi of pegenzileukin. |
| All Cohorts: Number of Participants With Anti-Drug Antibodies (ADAs) Against Pegenzileukin | From first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment; approximately 28 months (Cohorts A1 and A2), 15 months (Cohort B1), and 25 months (Cohort C1) | Blood samples were collected at specified timepoints to assess the presence of ADAs against pegenzileukin. Treatment-emergent ADA was defined as at least one treatment-induced or treatment-boosted ADA. Treatment-induced ADA was defined as ADA that developed during the TE period and without pre-existing ADA (including participants without pre-treatment samples). Treatment-boosted ADA was defined as pre-existing ADA that was boosted during the TE period to a significant higher titer than the baseline. Number of participants with treatment-emergent ADA is presented. |
| All Cohorts: Plasma Concentrations of Pegenzileukin | Days 2 and 3 of Cycle 1 (each cycle is 21 days) | Blood samples were collected at specified timepoints for the assessment of plasma concentrations of pegenzileukin. The pharmacokinetic (PK) parameters were calculated using non-compartmental method. |
| All Cohorts: Number of Participants With Dose Limiting Toxicities (DLTs) | From Day 1 to Day 21 of Cycle 1 (each cycle is 21 days) | Selected events that occurred during DLT observation period were considered as DLT unless due to PD or to a cause obviously unrelated to pegenzileukin. Selected events included: grade (G) 4 neutropenia for \>=7 consecutive days, G3 or 4 neutropenia complicated by fever or microbiologically or radiographically documented infection, G3 or 4 thrombocytopenia associated with clinically significant bleeding that required clinical intervention; G3 or above alanine aminotransferase or aspartate aminotransferase in combination with a bilirubin \>2 times upper limit of normal with no evidence of cholestasis or another cause such as viral infection or other drugs;G3 or above vascular leak syndrome, hypotension, and cytokine release syndrome;any other G3; G3 or 4 non-hematologic laboratory value; any death not clearly due to the underlying disease or extraneous causes;any toxicity that required permanent discontinuation of the study treatment(s). |
| All Cohorts: Time to Response (TTR) | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 27 months (Cohorts A1 and A2), 14 months (Cohort B1), and 24 months (Cohort C1) | TTR was defined as the time from the date of first study treatment administration to the first tumor assessment at which the overall response was recorded as PR or CR that was subsequently confirmed as per RECIST v 1.1 (NSCLC) and assessed by the investigator as per mRECIST v1.1 (mesothelioma). CR was defined as the disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm (\<1 cm). PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. |
Countries
Argentina, Australia, Chile, France, Italy, Japan, Poland, South Korea, Spain, Taiwan, United States
Participant flow
Recruitment details
This study was conducted at 31 centers (corresponds to number of sites which screened at least one participant) in 11 countries. Out of 152 participants who were screened from 23 September 2021 to 07 October 2022, 106 participants were enrolled in the study and were assigned to 1 of the 4 cohorts (Cohorts A1, A2, B1, and C1) based on their disease type.
Pre-assignment details
The study was terminated based on strategic sponsor decision not driven by any safety concerns. The Cohorts B2 and A3 were not initiated and no participants were enrolled. Note: Reason for not completed = Reason for permanent full intervention discontinuation.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A1:NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy Participants with previously untreated Stage IV NSCLC and PD-L1 TPS of \>=50% were included in this cohort. Participants received pegenzileukin 24 μg/kg along with pembrolizumab 200 mg via IV infusion over 30 minutes q3w on Day 1 of each cycle (each cycle is 21 days) (as 1L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35. | 17 |
| Cohort A2:NSCLC, PD-L1 TPS 1%-49%:Pegenzileukin 24 μg/kg+Pembrolizumab as 1L Therapy Participants with previously untreated Stage IV NSCLC and PD-L1 TPS of 1%-49% were included in this cohort. Participants received pegenzileukin 24 μg/kg along with pembrolizumab 200 mg via IV infusion over 30 minutes q3w on Day 1 of each cycle (each cycle is 21 days) (as 1L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35. | 20 |
| Cohort B1: NSCLC:Pegenzileukin 24 μg/kg+Pembrolizumab as 2/3L Therapy Participants with NSCLC for whom SOC was not in their best interest or where no SOC was established were included in this cohort. Participants received pegenzileukin 24 μg/kg along with pembrolizumab 200 mg via IV infusion over 30 minutes q3w on Day 1 of each cycle (each cycle is 21 days) (as 2/3L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35. | 40 |
| Cohort C1:Mesothelioma:Pegenzileukin 24 μg /kg+Pembrolizumab as 2/3L Therapy Participants with mesothelioma who had no SOC established and had experienced PD during or after at least one but no more than 2 prior regimens were included in this cohort. Participants received pegenzileukin 24 μg/kg along with pembrolizumab 200 mg via IV infusion over 30 minutes q3w on Day 1 of each cycle (each cycle is 21 days) (as 2/3L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35. | 29 |
| Total | 106 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse event: Not related to Coronavirus Disease 2019 (COVID-19) | 3 | 4 | 7 | 6 |
| Overall Study | Other | 1 | 0 | 0 | 1 |
| Overall Study | Poor compliance to protocol | 0 | 0 | 1 | 0 |
| Overall Study | Progressive disease | 5 | 14 | 30 | 21 |
| Overall Study | Withdrawal by Subject | 3 | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Cohort A1:NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy | Total | Cohort C1:Mesothelioma:Pegenzileukin 24 μg /kg+Pembrolizumab as 2/3L Therapy | Cohort B1: NSCLC:Pegenzileukin 24 μg/kg+Pembrolizumab as 2/3L Therapy | Cohort A2:NSCLC, PD-L1 TPS 1%-49%:Pegenzileukin 24 μg/kg+Pembrolizumab as 1L Therapy |
|---|---|---|---|---|---|
| Age, Continuous | 65.3 years STANDARD_DEVIATION 10.4 | 66.3 years STANDARD_DEVIATION 10.8 | 69.1 years STANDARD_DEVIATION 10.7 | 63.6 years STANDARD_DEVIATION 11.6 | 68.8 years STANDARD_DEVIATION 8.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 6 Participants | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 22 Participants | 16 Participants | 5 Participants | 0 Participants |
| Race (NIH/OMB) White | 16 Participants | 78 Participants | 12 Participants | 32 Participants | 18 Participants |
| Sex: Female, Male Female | 8 Participants | 35 Participants | 8 Participants | 13 Participants | 6 Participants |
| Sex: Female, Male Male | 9 Participants | 71 Participants | 21 Participants | 27 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 17 | 13 / 20 | 26 / 40 | 18 / 29 |
| other Total, other adverse events | 16 / 17 | 18 / 20 | 38 / 40 | 27 / 29 |
| serious Total, serious adverse events | 6 / 17 | 11 / 20 | 21 / 40 | 13 / 29 |
Outcome results
Primary
Cohorts A1 and A2: Objective Response Rate (ORR)
ORR was defined as the percentage of participants who had a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. CR. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 millimeter (mm) (\<1 centimeter \[cm\]). PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From first dose of study treatment administration (Day 1) up to approximately 21 months
Population: The efficacy population consisted of all participants from the exposed population with at least one evaluable post-baseline tumor assessment or who permanently discontinued study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A1:NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy | Cohorts A1 and A2: Objective Response Rate (ORR) | 41.2 percentage of participants |
| Cohort A2:NSCLC, PD-L1 TPS 1%-49%:Pegenzileukin 24 μg/kg+Pembrolizumab as 1L Therapy | Cohorts A1 and A2: Objective Response Rate (ORR) | 15.0 percentage of participants |
Primary
Cohorts B1: Objective Response Rate
ORR was defined as the percentage of participants who had a confirmed CR or PR as per RECIST v1.1. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm (\<1 cm). PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 14 months
Population: The efficacy population consisted of all participants from the exposed population with at least one evaluable post-baseline tumor assessment or who permanently discontinued study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A1:NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy | Cohorts B1: Objective Response Rate | 2.5 percentage of participants |
Primary
Cohorts C1: Objective Response Rate
ORR was defined as the percentage of participants who had a confirmed CR or PR assessed by the investigator as per modified RECIST (mRECIST) v1.1. CR. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm (\<1 cm). PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From first dose of study treatment administration (Day 1) up to approximately 21 months
Population: The efficacy population consisted of all participants from the exposed population with at least one evaluable post-baseline tumor assessment or who permanently discontinued study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A1:NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy | Cohorts C1: Objective Response Rate | 3.4 percentage of participants |
Secondary
All Cohorts: Clinical Benefit Rate (CBR)
The CBR was defined as the percentage of participants with clinical benefit: confirmed CR or PR as best overall response (BOR), or stable disease (SD) that lasted at least 6 months as per RECIST v 1.1 (NSCLS) and assessed by investigator as per mRECIST v1.1 (mesothelioma). CR: disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm (\<1 cm). PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. BOR was the best response observed from start of the study treatment until PD, death, cut-off date or initiation of post-treatment anticancer therapy, whichever occurred first. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time frame: From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 27 months (Cohorts A1 and A2), 14 months (Cohort B1), and 24 months (Cohort C1)
Population: The efficacy population consisted of all participants from the exposed population with at least one evaluable post-baseline tumor assessment or who permanently discontinued study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A1:NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy | All Cohorts: Clinical Benefit Rate (CBR) | 58.8 percentage of participants |
| Cohort A2:NSCLC, PD-L1 TPS 1%-49%:Pegenzileukin 24 μg/kg+Pembrolizumab as 1L Therapy | All Cohorts: Clinical Benefit Rate (CBR) | 30.0 percentage of participants |
| Cohort B1: NSCLC:Pegenzileukin 24 μg/kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Clinical Benefit Rate (CBR) | 5.0 percentage of participants |
| Cohort C1:Mesothelioma:Pegenzileukin 24 μg /kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Clinical Benefit Rate (CBR) | 10.3 percentage of participants |
Secondary
All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin
Blood samples were collected at specified timepoints for the assessment of Ceoi of pegenzileukin.
Time frame: Cycles 1, 2, 4, 7, 10, and 15 (each cycle is 21 days)
Population: The PK population consisted of all participants from exposed population with at least 1 PK concentration available after the first dose of study treatment. Only participants with data collected at specified timepoints are reported. Eventually, the participants discontinued as they progressed in the study. Hence, fewer participants at each cycle and no participants returned on Cycle 15 in Cohort B1 Arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A1:NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 10 | 412.5 ng/mL | Standard Deviation 109.4 |
| Cohort A1:NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 15 | 352.0 ng/mL | — |
| Cohort A1:NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 1 | 510.2 ng/mL | Standard Deviation 164.1 |
| Cohort A1:NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 4 | 403.7 ng/mL | Standard Deviation 122.6 |
| Cohort A1:NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 7 | 509.3 ng/mL | Standard Deviation 103.9 |
| Cohort A1:NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 2 | 445.8 ng/mL | Standard Deviation 90.6 |
| Cohort A2:NSCLC, PD-L1 TPS 1%-49%:Pegenzileukin 24 μg/kg+Pembrolizumab as 1L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 7 | 554.3 ng/mL | Standard Deviation 129.3 |
| Cohort A2:NSCLC, PD-L1 TPS 1%-49%:Pegenzileukin 24 μg/kg+Pembrolizumab as 1L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 4 | 413.9 ng/mL | Standard Deviation 103.9 |
| Cohort A2:NSCLC, PD-L1 TPS 1%-49%:Pegenzileukin 24 μg/kg+Pembrolizumab as 1L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 1 | 434.1 ng/mL | Standard Deviation 232.2 |
| Cohort A2:NSCLC, PD-L1 TPS 1%-49%:Pegenzileukin 24 μg/kg+Pembrolizumab as 1L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 2 | 418.7 ng/mL | Standard Deviation 215.3 |
| Cohort A2:NSCLC, PD-L1 TPS 1%-49%:Pegenzileukin 24 μg/kg+Pembrolizumab as 1L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 10 | 483.0 ng/mL | — |
| Cohort A2:NSCLC, PD-L1 TPS 1%-49%:Pegenzileukin 24 μg/kg+Pembrolizumab as 1L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 15 | 265.0 ng/mL | — |
| Cohort B1: NSCLC:Pegenzileukin 24 μg/kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 1 | 535.8 ng/mL | Standard Deviation 402.6 |
| Cohort B1: NSCLC:Pegenzileukin 24 μg/kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 7 | 590.3 ng/mL | Standard Deviation 234 |
| Cohort B1: NSCLC:Pegenzileukin 24 μg/kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 10 | 152.0 ng/mL | — |
| Cohort B1: NSCLC:Pegenzileukin 24 μg/kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 4 | 507.1 ng/mL | Standard Deviation 168.6 |
| Cohort B1: NSCLC:Pegenzileukin 24 μg/kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 2 | 585.6 ng/mL | Standard Deviation 496.9 |
| Cohort C1:Mesothelioma:Pegenzileukin 24 μg /kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 15 | 567.0 ng/mL | — |
| Cohort C1:Mesothelioma:Pegenzileukin 24 μg /kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 1 | 457.0 ng/mL | Standard Deviation 140.9 |
| Cohort C1:Mesothelioma:Pegenzileukin 24 μg /kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 2 | 442.0 ng/mL | Standard Deviation 131.7 |
| Cohort C1:Mesothelioma:Pegenzileukin 24 μg /kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 4 | 400.4 ng/mL | Standard Deviation 125.8 |
| Cohort C1:Mesothelioma:Pegenzileukin 24 μg /kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 7 | 486.5 ng/mL | Standard Deviation 251.3 |
| Cohort C1:Mesothelioma:Pegenzileukin 24 μg /kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin | Cycle 10 | 443.0 ng/mL | Standard Deviation 169 |
Secondary
All Cohorts: Duration of Response (DOR)
DOR was defined as time from date of first tumor assessment at which overall response was recorded as CR or PR that was subsequently confirmed to date of first documentation of objective PD before initiation of any post-treatment anti-cancer therapy or death due to any cause, whichever occurred first, as per RECIST v 1.1 (NSCLS) and assessed by investigator as per mRECIST v1.1 (mesothelioma). CR: disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm (\<1 cm). PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. PD:at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (this included baseline sum if that was smallest on study), in addition to relative increase of 20%, sum must have also demonstrated an absolute increase of at least 5 mm (0.5 cm).
Time frame: From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 27 months (Cohorts A1 and A2), 14 months (Cohort B1), and 24 months (Cohort C1)
Population: The efficacy population consisted of all participants from the exposed population with at least one evaluable post-baseline tumor assessment or who permanently discontinued study treatment. Only participants with confirmed CR or PR were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A1:NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy | All Cohorts: Duration of Response (DOR) | NA months |
| Cohort A2:NSCLC, PD-L1 TPS 1%-49%:Pegenzileukin 24 μg/kg+Pembrolizumab as 1L Therapy | All Cohorts: Duration of Response (DOR) | NA months |
| Cohort B1: NSCLC:Pegenzileukin 24 μg/kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Duration of Response (DOR) | NA months |
| Cohort C1:Mesothelioma:Pegenzileukin 24 μg /kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Duration of Response (DOR) | NA months |
Secondary
All Cohorts: Number of Participants With Anti-Drug Antibodies (ADAs) Against Pegenzileukin
Blood samples were collected at specified timepoints to assess the presence of ADAs against pegenzileukin. Treatment-emergent ADA was defined as at least one treatment-induced or treatment-boosted ADA. Treatment-induced ADA was defined as ADA that developed during the TE period and without pre-existing ADA (including participants without pre-treatment samples). Treatment-boosted ADA was defined as pre-existing ADA that was boosted during the TE period to a significant higher titer than the baseline. Number of participants with treatment-emergent ADA is presented.
Time frame: From first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment; approximately 28 months (Cohorts A1 and A2), 15 months (Cohort B1), and 25 months (Cohort C1)
Population: The ADA population consisted of all participants from the exposed population with at least one ADA result (positive, negative or inconclusive) after the first dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A1:NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy | All Cohorts: Number of Participants With Anti-Drug Antibodies (ADAs) Against Pegenzileukin | 0 Participants |
| Cohort A2:NSCLC, PD-L1 TPS 1%-49%:Pegenzileukin 24 μg/kg+Pembrolizumab as 1L Therapy | All Cohorts: Number of Participants With Anti-Drug Antibodies (ADAs) Against Pegenzileukin | 0 Participants |
| Cohort B1: NSCLC:Pegenzileukin 24 μg/kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Number of Participants With Anti-Drug Antibodies (ADAs) Against Pegenzileukin | 2 Participants |
| Cohort C1:Mesothelioma:Pegenzileukin 24 μg /kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Number of Participants With Anti-Drug Antibodies (ADAs) Against Pegenzileukin | 0 Participants |
Secondary
All Cohorts: Number of Participants With Dose Limiting Toxicities (DLTs)
Selected events that occurred during DLT observation period were considered as DLT unless due to PD or to a cause obviously unrelated to pegenzileukin. Selected events included: grade (G) 4 neutropenia for \>=7 consecutive days, G3 or 4 neutropenia complicated by fever or microbiologically or radiographically documented infection, G3 or 4 thrombocytopenia associated with clinically significant bleeding that required clinical intervention; G3 or above alanine aminotransferase or aspartate aminotransferase in combination with a bilirubin \>2 times upper limit of normal with no evidence of cholestasis or another cause such as viral infection or other drugs;G3 or above vascular leak syndrome, hypotension, and cytokine release syndrome;any other G3; G3 or 4 non-hematologic laboratory value; any death not clearly due to the underlying disease or extraneous causes;any toxicity that required permanent discontinuation of the study treatment(s).
Time frame: From Day 1 to Day 21 of Cycle 1 (each cycle is 21 days)
Population: The DLT-evaluable population consisted of all exposed participants in the safety run-in who had been observed for at least 21 days. Any participants who had experienced a DLT during DLT observation period were also DLT-evaluable.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A1:NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy | All Cohorts: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Cohort A2:NSCLC, PD-L1 TPS 1%-49%:Pegenzileukin 24 μg/kg+Pembrolizumab as 1L Therapy | All Cohorts: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Cohort B1: NSCLC:Pegenzileukin 24 μg/kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Number of Participants With Dose Limiting Toxicities (DLTs) | 1 Participants |
| Cohort C1:Mesothelioma:Pegenzileukin 24 μg /kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
Secondary
All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was any AE that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. TEAEs were defined as AEs that developed, worsened (according to the investigator's opinion) or became serious during the TE period.
Time frame: From first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment; approximately 28 months (Cohorts A1 and A2), 15 months (Cohort B1), and 25 months (Cohort C1)
Population: The exposed population consisted of all participants who had given their informed consent and received at least one dose of study treatment (pegenzileukin or other anticancer therapies).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A1:NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy | All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TEAEs | 16 Participants |
| Cohort A1:NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy | All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TESAEs | 6 Participants |
| Cohort A2:NSCLC, PD-L1 TPS 1%-49%:Pegenzileukin 24 μg/kg+Pembrolizumab as 1L Therapy | All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TESAEs | 11 Participants |
| Cohort A2:NSCLC, PD-L1 TPS 1%-49%:Pegenzileukin 24 μg/kg+Pembrolizumab as 1L Therapy | All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TEAEs | 20 Participants |
| Cohort B1: NSCLC:Pegenzileukin 24 μg/kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TEAEs | 40 Participants |
| Cohort B1: NSCLC:Pegenzileukin 24 μg/kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TESAEs | 21 Participants |
| Cohort C1:Mesothelioma:Pegenzileukin 24 μg /kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TEAEs | 29 Participants |
| Cohort C1:Mesothelioma:Pegenzileukin 24 μg /kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TESAEs | 13 Participants |
Secondary
All Cohorts: Plasma Concentrations of Pegenzileukin
Blood samples were collected at specified timepoints for the assessment of plasma concentrations of pegenzileukin. The pharmacokinetic (PK) parameters were calculated using non-compartmental method.
Time frame: Days 2 and 3 of Cycle 1 (each cycle is 21 days)
Population: The PK population consisted of all participants from exposed population with at least one PK concentration available after the first dose of study treatment. Only participants with data collected at specified timepoints are reported. Limited or no participants returned on the Cycle 1 Day 3 for sample collection.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A1:NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy | All Cohorts: Plasma Concentrations of Pegenzileukin | Day 2 Cycle 1 | 214.7 nanogram/milliliter (ng/mL) | Standard Deviation 81.8 |
| Cohort A1:NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy | All Cohorts: Plasma Concentrations of Pegenzileukin | Day 3 Cycle 1 | 42.7 nanogram/milliliter (ng/mL) | Standard Deviation 14.8 |
| Cohort A2:NSCLC, PD-L1 TPS 1%-49%:Pegenzileukin 24 μg/kg+Pembrolizumab as 1L Therapy | All Cohorts: Plasma Concentrations of Pegenzileukin | Day 2 Cycle 1 | 227.6 nanogram/milliliter (ng/mL) | Standard Deviation 77.7 |
| Cohort B1: NSCLC:Pegenzileukin 24 μg/kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Plasma Concentrations of Pegenzileukin | Day 3 Cycle 1 | 121.0 nanogram/milliliter (ng/mL) | — |
| Cohort B1: NSCLC:Pegenzileukin 24 μg/kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Plasma Concentrations of Pegenzileukin | Day 2 Cycle 1 | 212.0 nanogram/milliliter (ng/mL) | Standard Deviation 63.9 |
| Cohort C1:Mesothelioma:Pegenzileukin 24 μg /kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Plasma Concentrations of Pegenzileukin | Day 2 Cycle 1 | 200.8 nanogram/milliliter (ng/mL) | Standard Deviation 61.4 |
| Cohort C1:Mesothelioma:Pegenzileukin 24 μg /kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Plasma Concentrations of Pegenzileukin | Day 3 Cycle 1 | 56.3 nanogram/milliliter (ng/mL) | Standard Deviation 12.7 |
Secondary
All Cohorts: Progression Free Survival (PFS)
The PFS was defined as the time from the date of first study treatment to the date of the first documentation of objective PD, or death due to any cause, whichever occurred first as per RECIST v 1.1 (NSCLS) and assessed by investigator as per mRECIST v1.1 (mesothelioma). PD was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that was the smallest on study), in addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm (0.5 cm).
Time frame: From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 27 months (Cohorts A1 and A2), 14 months (Cohort B1), and 24 months (Cohort C1)
Population: The efficacy population consisted of all participants from the exposed population with at least one evaluable post-baseline tumor assessment or who permanently discontinued study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A1:NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy | All Cohorts: Progression Free Survival (PFS) | 10.3 months |
| Cohort A2:NSCLC, PD-L1 TPS 1%-49%:Pegenzileukin 24 μg/kg+Pembrolizumab as 1L Therapy | All Cohorts: Progression Free Survival (PFS) | 3.9 months |
| Cohort B1: NSCLC:Pegenzileukin 24 μg/kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Progression Free Survival (PFS) | 2.1 months |
| Cohort C1:Mesothelioma:Pegenzileukin 24 μg /kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Progression Free Survival (PFS) | 2.3 months |
Secondary
All Cohorts: Time to Response (TTR)
TTR was defined as the time from the date of first study treatment administration to the first tumor assessment at which the overall response was recorded as PR or CR that was subsequently confirmed as per RECIST v 1.1 (NSCLC) and assessed by the investigator as per mRECIST v1.1 (mesothelioma). CR was defined as the disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm (\<1 cm). PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 27 months (Cohorts A1 and A2), 14 months (Cohort B1), and 24 months (Cohort C1)
Population: The efficacy population consisted of all participants from the exposed population with at least one evaluable post-baseline tumor assessment or who permanently discontinued study treatment. Only participants with confirmed CR or PR were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A1:NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy | All Cohorts: Time to Response (TTR) | 2.3 months | Standard Deviation 0.8 |
| Cohort A2:NSCLC, PD-L1 TPS 1%-49%:Pegenzileukin 24 μg/kg+Pembrolizumab as 1L Therapy | All Cohorts: Time to Response (TTR) | 3.4 months | Standard Deviation 1.4 |
| Cohort B1: NSCLC:Pegenzileukin 24 μg/kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Time to Response (TTR) | 2.2 months | — |
| Cohort C1:Mesothelioma:Pegenzileukin 24 μg /kg+Pembrolizumab as 2/3L Therapy | All Cohorts: Time to Response (TTR) | 4.1 months | — |