Colorectal Cancer, Gastric Cancer, Hepatocellular Carcinoma, Oesophageal Adenocarcinoma, Oesophageal Squamous Cell Carcinoma
Conditions
Brief summary
The study is a phase 2 non-randomized, open-label, multi-cohort, multi-center study assessing the clinical benefit of SAR444245 (THOR-707) combined with other anticancer therapies for the treatment of participants aged 18 years and older with advanced and metastatic gastrointestinal cancer. This study is structured as a master protocol for the investigation of SAR444245 with other anticancer therapies. Sub study 01 - Cohort A aims to establish proof-of-concept that combining the non-alpha-IL2 SAR444245 with the anti-PD1 antibody pembrolizumab will result in a significant increase in the percentage of patients experiencing an objective response in the setting of advanced unresectable or metastatic esophageal squamous cell carcinoma (ESCC). Sub study 02 - Cohort B1, B2 and B3 would focus on non MSI-H tumors with a large unmet need to establish proof-of-concept that combining the non-alpha-IL2 SAR444245 with the anti-PD1 antibody pembrolizumab will result in a significant increase in the percentage of patients experiencing an objective response in the setting of advanced unresectable or metastatic gastric cancer or gastro-esophageal junction adenocarcinoma (GC/GEJ), especially with low PD-L1 expression or after progression on prior PD1/PD-L1-based regimens. Sub study 03 - Cohort C aims to establish proof-of-concept that combining the non-alpha-IL2 SAR444245 with the anti-PD1 antibody pembrolizumab will result in a significant increase in the percentage of patients experiencing an objective response in participants with advanced unresectable or metastatic HCC who relapsed on prior PD1/PD-L1-based regimens. Sub study 04 - Cohort D1 and D2 aims to establish proof-of-concept that combining the non-alpha-IL2 SAR444245 with either the anti-PD1 antibody pembrolizumab or with the anti-EGFR IgG1 antibody cetuximab will result in a significant increase in the percentage of patients experiencing an objective response in the setting of advanced unresectable or metastatic colorectal cancer (mCRC).
Detailed description
The duration of the study for an individual patient will start from the signature of the main informed consent and include a screening period of up to 28 days, a treatment period \[max 35 cycles {cohort A; B1,B2, B3, C and D1} = 735 days or until PD {cohort D2}\], an end-of-treatment visit at least 30 days following the last administration of study drug (or until the patient 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
Solution for infusion: intravenous infusion
DRUGPembrolizumab
Solution for infusion: intravenous infusion
DRUGCetuximab
Solution for infusion: intravenous 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 be ≥18 years of age (or country's legal age of majority if \>18 years), at the time of signing the informed consent. * Participants with: * Sub-study01: Histologically or cytologically confirmed diagnosis of advanced unresectable or metastatic esophageal cancer of the squamous cell carcinoma subtype. * Sub-study02: Histologically or cytologically confirmed diagnosis of advanced unresectable or metastatic GC or Siewert Type 2 & 3 GEJ. * Sub-study03: Histologically or cytologically confirmed diagnosis of advanced unresectable or metastatic hepatocellular carcinoma (HCC), or clinically by AASLD criteria in cirrhotic patients. * Sub-study04: Histologically or cytologically confirmed diagnosis of advanced unresectable or mCRC. Only patients with non-MSI-H disease are eligible. * Participants (all sub-studies) must have at least one measurable lesion. * Mandatory baseline biopsy for the first 20 participants to enroll in sub-study01, sub-study02 and sub-study04. On-treatment biopsy for at least 20 participants in sub-study04. On-treatment biopsies are otherwise optional per Investigator's discretion for the other cohorts. * Females are eligible to participate if they are 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 at least 120 days (for Cohort A, B1, B2, B3, C, and D1) or 60 days (for Cohort D2) \[corresponding to the time needed to eliminate any study intervention(s)\]. * and to refrain from donating or cryopreserving eggs for 120 days after discontinuing study treatment. * Males are 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 3 days \[corresponding to time needed to eliminate SAR444245\] after the last dose of SAR444245. * Capable of giving signed informed consent.
Exclusion criteria
* Eastern Cooperative Oncology Group (ECOG) performance status of ≥2. * Poor organ function. * Active brain metastases or leptomeningeal disease. * History of allogenic or 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 within 28 days prior to first IMP administration. * Comorbidity requiring corticosteroid therapy (\>10 mg prednisone/day or equivalent) within 2 weeks of IMP initiation. Inhaled or topical steroids are permitted, provided that they are not for treatment of an autoimmune disorder. Participants who require a brief course of steroids (eg, as prophylaxis for imaging studies due to hypersensitivity to contrast agents) are not excluded). * 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. * Participants with baseline SpO2 ≤92% (without oxygen therapy). - Participant has received prior IL2-based anticancer treatment. * Participants on sub-study02 cohort B1 and B2 or sub-study 04 - cohort D1 with prior treatment with an agent that blocks the PD-1/PD-L1 pathway. * Receipt of a live-virus or live attenuated-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 a patient's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohort A: Objective Response Rate (ORR) | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 8 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 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, B2 and B3: Objective Response Rate | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 25 months | ORR was defined as the percentage of participants who had a confirmed CR or PR as per RECIST v 1.1. 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. |
| Cohort C: Objective Response Rate | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 20 months | ORR was defined as the percentage of participants who had a confirmed CR or PR as per RECIST v 1.1. 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 D1 and D2: Objective Response Rate | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 8 months | ORR was defined as the percentage of participants who had a confirmed CR or PR as per RECIST v 1.1. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All Cohorts: Progression-Free Survival (PFS) | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 8 months (Cohort A, D1 and D2), 25 months (Cohort B1, B2 and B3), 20 months (Cohort C) | 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. 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). |
| Maximum Concentration Observed (Cmax) of Pegenzileukin | Day 1 Cycle 1 and Day 1 Cycle 4 (each cycle is 21 days) | Blood samples were collected at specified timepoints for the assessment of Cmax of pegenzileukin. The pharmacokinetic (PK) parameters were calculated using non-compartmental method. |
| Last Concentration Observed Above the Lower Limit of Quantification (Clast) of Pegenzileukin | Day 1 Cycle 1 and Day 1 Cycle 4 (each cycle is 21 days) | Blood samples were collected at specified timepoints for the assessment of Clast of pegenzileukin. The PK parameters were calculated using non-compartmental method. |
| Time of the Last Concentration Observed Above the Lower Limit of Quantification (Tlast) of Pegenzileukin | Day 1 Cycle 1 and Day 1 Cycle 4 (each cycle is 21 days) | Blood samples were collected at specified timepoints for the assessment of tlast of pegenzileukin. The PK parameters were calculated using non-compartmental method. |
| Area Under the Plasma Concentration Versus Time Curve Calculated Using the Trapezoidal Method From Time Zero to Tlast (AUClast) of Pegenzileukin | Day 1 Cycle 1 and Day 1 Cycle 4 (each cycle is 21 days) | Blood samples were collected at specified timepoints for the assessment of AUClast of pegenzileukin. The PK parameters were calculated using non-compartmental method. |
| All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | From first dose of study treatment administration (Day 1) up to 30 days post last dose of study treatment administration, up to approximately 9 months (Cohorts A, D1 and D2), 26 months (Cohorts B1, B2 and B3) and 21 months (Cohort C) | 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. |
| Observed Accumulation Ratio (Rac) of Pegenzileukin | Day 1 Cycle 1 and Day 1 Cycle 4 (each cycle is 21 days) | Blood samples were collected at specified timepoints for the assessment of Rac of pegenzileukin. Rac was calculated as AUC at Cycle 4 Day 1/AUC at Cycle 1 Day 1. The PK parameters were calculated using non-compartmental method. |
| Observed Accumulation Ratio Based on Cmax (Rac,Cmax) of Pegenzileukin | Day 1 Cycle 1 and Day 1 Cycle 4 (each cycle is 21 days) | Blood samples were collected at specified timepoints for the assessment of Rac,cmax of pegenzileukin. Rac,cmax was calculated as Cmax at Cycle 4 Day 1/Cmax at Cycle 1 Day 1. The PK parameters were calculated using non-compartmental method. |
| Cohort D2: Concentration Observed Just Before Intervention Administration During Repeated Dosing (Ctrough) of Cetuximab | Cycles 1, 2, 3, 4, 6 and 8 (each cycle is 21 days) | Blood samples were collected at specified timepoints for the assessment of Ctrough of Cetuximab. The PK parameters were calculated using non-compartmental method. |
| Cohort D2: Concentration at End of Infusion (Ceoi) of Cetuximab | Cycles 1, 2, 3, 4, 6 and 8 (each cycle is 21 days) | Blood samples were collected at specified timepoints for the assessment of Ceoi of Cetuximab. The PK parameters were calculated using non-compartmental method. |
| All Cohorts: Number of Participants With Anti-Drug Antibodies (ADAs) Against Pegenzileukin | From first dose of study treatment administration (Day 1) up to 30 days post last dose of study treatment administration, up to approximately 9 months (Cohorts A, D1 and D2), 26 months (Cohorts B1, B2 and B3) and 21 months (Cohort C) | Blood samples were collected at specified timepoints to assess the presence of ADA 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. |
| Area Under the Concentration Versus Time Curve Extrapolated to Infinity (AUC) of Pegenzileukin | Day 1 Cycle 1 and Day 1 Cycle 4 (each cycle is 21 days) | Blood samples were collected at specified timepoints for the assessment of AUC of pegenzileukin. The PK parameters were calculated using non-compartmental method. |
| All Cohorts: Time to Response (TTR) | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 8 months (Cohort A, D1 and D2), 25 months (Cohort B1, B2 and B3), 20 months (Cohort C) | 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. 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. |
| All Cohorts: Duration of Response (DOR) | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 8 months (Cohort A, D1 and D2), 25 months (Cohort B1, B2 and B3), 20 months (Cohort C) | DOR was defined as the time from the date of first tumor assessment at which the overall response was recorded as CR or PR that was subsequently confirmed to the date of first documentation of objective PD before the initiation of any post-treatment anti-cancer therapy or death due to any cause, whichever occurred first, as per RECIST v 1.1. 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. 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: Clinical Benefit Rate (CBR) | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 8 months (Cohort A, D1 and D2), 25 months (Cohort B1, B2 and B3), 20 months (Cohort C) | CBR was defined as the percentage of participants with clinical benefit (confirmed CR or PR as best overall response \[BOR\], or SD lasting at least 6 months), as per RECIST v 1.1. 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. BOR was defined as the best response recorded from the start of the study treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started). 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. |
Countries
Belgium, Chile, China, France, Italy, Netherlands, South Korea, Spain, United States
Participant flow
Recruitment details
This study was conducted at 29 centers (corresponds to number of site which screened at least one participant) in 9 countries. Out of 193 participants who were screened from 09 December 2021 to 26 October 2022, a total of 138 participants were enrolled in the study and were assigned to 1 of the 7 cohorts (Cohorts A, B1, B2, B3, C, D1 and D2) based on their disease type.
Pre-assignment details
Note: Reason for not completed = Reason for permanent full intervention discontinuation.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy Participants with advanced unresectable or metastatic ESCC, regardless of PD-L1 expression (any CPS), who had received at least 1 but no more than 2 prior lines of treatment and had progressed after primary or secondary resistance to an anti-PD-1/PD-L1 based regimen were included in this cohort. Participants received pegenzileukin 24 mcg/kg along with pembrolizumab 200 mg via IV infusion 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. | 5 |
| CohortB1:GC/GEJ PD-1/PD-L1 naïve Non-MSI-H CPS>=1:Pegenzileukin24mcg/kg+Pembrolizumab as 1-3LTherapy Participants with advanced unresectable or metastatic GC or Siewert Type 2 & 3 GEJ and for whom SOC was not in best interest or where no SOC was established, non-MSI-H disease and had not received more than 2 prior lines of treatment that did not include an anti-PD-1/PD-L1-based regimen with the level of PD-L1 expression at baseline as CPS \>=1 GC/GEJ were included in this cohort. Participants received pegenzileukin 24 mcg/kg along with pembrolizumab 200 mg via IV infusion q3w on Day 1 of each cycle (each cycle is 21 days) (as 1-3L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35. | 22 |
| CohortB2:GC/GEJ PD-1/PD-L1 naïve Non-MSI-H CPS<1:Pegenzileukin24mcg/kg+Pembrolizumab as 1-3LTherapy Participants with advanced unresectable or metastatic GC or Siewert Type 2 & 3 GEJ and for whom SOC was not in best interest or where no SOC was established, non-MSI-H disease and had not received more than 2 prior lines of treatment that did not include an anti-PD-1/PD-L1-based regimen with the level of PD-L1 expression at baseline as CPS \<1 GC/GEJ were included in this cohort. Participants received pegenzileukin 24 mcg/kg along with pembrolizumab 200 mg via IV infusion q3w on Day 1 of each cycle (each cycle is 21 days) (as 1-3L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35. | 19 |
| Cohort B3: GC/GEJ Post PD-1/PD-L1 Non-MSI-H: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2-4L Therapy Participants with advanced unresectable or metastatic GC or Siewert Type 2 & 3 GEJ and for whom SOC was not in best interest or where no SOC was established, non-MSI-H disease and had received atleast 1 and no more than 3 prior lines of treatment and had progressed after primary or secondary resistance to an anti-PD-1/PD-L1-based regimen (regardless of the disease CPS status) were included in this cohort. Participants received pegenzileukin 24 mcg/kg along with pembrolizumab 200 mg via IV infusion q3w on Day 1 of each cycle (each cycle is 21 days) (as 2-4L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35. | 18 |
| Cohort C: HCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy Participants with advanced unresectable or metastatic HCC, regardless of any CPS, who relapsed on prior PD-1/PD-L1-based regimens, with at least SD as best response and with no more than 2 prior lines of treatment were included in this cohort. Participants received pegenzileukin 24 mcg/kg along with pembrolizumab 200 mg via IV infusion 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. | 20 |
| Cohort D1: CRC Non-MSI-H Any RAS: Pegenzileukin 24 mcg/kg + Pembrolizumab as 3-6L Therapy Participants with advanced unresectable or metastatic CRC, regardless of any CPS, non-MSI-H disease, any RAS type, who had progressed on prior regimens having contained fluoropyrimidine, oxaliplatin, irinotecan, with either bevacizumab or cetuximab, and with no more than 5 prior lines of treatments were included in this cohort. Participants received pegenzileukin 24 mcg/kg along with pembrolizumab 200 mg via IV infusion q3w on Day 1 of each cycle (each cycle is 21 days) (as 3-6L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35. | 30 |
| Cohort D2: CRC Non-MSI-H RAS Wild Type: Pegenzileukin 24 mcg/kg + Cetuximab as 3-6L Therapy Participants with advanced unresectable or metastatic CRC, regardless of any CPS, non-MSI-H disease, RAS wild type, who had progressed on prior regimens having contained fluoropyrimidine, oxaliplatin, irinotecan, with either bevacizumab or cetuximab, and with no more than 5 prior lines of treatments were included in this cohort. Participants received pegenzileukin 24 mcg/kg q3w on Day 1 of each cycle along with cetuximab as an initial loading dose of 400 mg/m\^2 on Cycle 1 Day 1 followed by 250 mg/m\^2 starting via IV infusion once weekly from Cycle 1 Day 8 (each cycle is 21 days) (as 3-6L therapy) until PD. | 24 |
| Total | 138 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse event: Not related to COVID-19 | 0 | 5 | 3 | 1 | 3 | 2 | 0 |
| Overall Study | Adverse event: Related to Coronavirus Disease 2019 (COVID-19) | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Other | 1 | 1 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Progressive disease | 3 | 13 | 13 | 17 | 17 | 28 | 24 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 2 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Total | Cohort D2: CRC Non-MSI-H RAS Wild Type: Pegenzileukin 24 mcg/kg + Cetuximab as 3-6L Therapy | Cohort D1: CRC Non-MSI-H Any RAS: Pegenzileukin 24 mcg/kg + Pembrolizumab as 3-6L Therapy | Cohort C: HCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Cohort B3: GC/GEJ Post PD-1/PD-L1 Non-MSI-H: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2-4L Therapy | CohortB2:GC/GEJ PD-1/PD-L1 naïve Non-MSI-H CPS<1:Pegenzileukin24mcg/kg+Pembrolizumab as 1-3LTherapy | CohortB1:GC/GEJ PD-1/PD-L1 naïve Non-MSI-H CPS>=1:Pegenzileukin24mcg/kg+Pembrolizumab as 1-3LTherapy |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 63.2 years STANDARD_DEVIATION 4.4 | 60.8 years STANDARD_DEVIATION 11 | 61.7 years STANDARD_DEVIATION 10 | 62.7 years STANDARD_DEVIATION 12.1 | 65.7 years STANDARD_DEVIATION 8.8 | 58.3 years STANDARD_DEVIATION 10.9 | 56.5 years STANDARD_DEVIATION 13.1 | 58.1 years STANDARD_DEVIATION 10.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 16 Participants | 4 Participants | 0 Participants | 3 Participants | 6 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 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 | 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 17 Participants | 1 Participants | 0 Participants | 3 Participants | 1 Participants | 2 Participants | 8 Participants |
| Race (NIH/OMB) White | 3 Participants | 103 Participants | 18 Participants | 30 Participants | 14 Participants | 10 Participants | 15 Participants | 13 Participants |
| Sex: Female, Male Female | 2 Participants | 42 Participants | 7 Participants | 11 Participants | 6 Participants | 4 Participants | 7 Participants | 5 Participants |
| Sex: Female, Male Male | 3 Participants | 96 Participants | 17 Participants | 19 Participants | 14 Participants | 14 Participants | 12 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 5 | 16 / 22 | 15 / 19 | 12 / 18 | 6 / 20 | 24 / 30 | 18 / 24 |
| other Total, other adverse events | 5 / 5 | 20 / 22 | 18 / 19 | 17 / 18 | 19 / 20 | 30 / 30 | 24 / 24 |
| serious Total, serious adverse events | 2 / 5 | 17 / 22 | 13 / 19 | 9 / 18 | 7 / 20 | 19 / 30 | 11 / 24 |
Outcome results
Primary
Cohort A: 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 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 maximum exposure of study treatment; approximately 8 months
Population: The efficacy population included 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 A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Cohort A: Objective Response Rate (ORR) | 20.0 percentage of participants |
Primary
Cohort C: Objective Response Rate
ORR was defined as the percentage of participants who had a confirmed CR or PR as per RECIST v 1.1. 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 20 months
Population: The efficacy population included 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 A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Cohort C: Objective Response Rate | 5.0 percentage of participants |
Primary
Cohorts B1, B2 and B3: Objective Response Rate
ORR was defined as the percentage of participants who had a confirmed CR or PR as per RECIST v 1.1. 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 25 months
Population: The efficacy population included 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 A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Cohorts B1, B2 and B3: Objective Response Rate | 13.6 percentage of participants |
| CohortB2:GC/GEJ PD-1/PD-L1 naïve Non-MSI-H CPS<1:Pegenzileukin24 mcg/kg+Pembrolizumab as 1-3LTherapy | Cohorts B1, B2 and B3: Objective Response Rate | 5.3 percentage of participants |
| Cohort B3: GC/GEJ Post PD-1/PD-L1 Non-MSI-H: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2-4L Therapy | Cohorts B1, B2 and B3: Objective Response Rate | 11.1 percentage of participants |
Primary
Cohorts D1 and D2: Objective Response Rate
ORR was defined as the percentage of participants who had a confirmed CR or PR as per RECIST v 1.1. 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 8 months
Population: The efficacy population included 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 A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Cohorts D1 and D2: Objective Response Rate | 0 percentage of participants |
| CohortB2:GC/GEJ PD-1/PD-L1 naïve Non-MSI-H CPS<1:Pegenzileukin24 mcg/kg+Pembrolizumab as 1-3LTherapy | Cohorts D1 and D2: Objective Response Rate | 8.3 percentage of participants |
Secondary
All Cohorts: Clinical Benefit Rate (CBR)
CBR was defined as the percentage of participants with clinical benefit (confirmed CR or PR as best overall response \[BOR\], or SD lasting at least 6 months), as per RECIST v 1.1. 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. BOR was defined as the best response recorded from the start of the study treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started). 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 8 months (Cohort A, D1 and D2), 25 months (Cohort B1, B2 and B3), 20 months (Cohort C)
Population: The efficacy population included 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 A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | All Cohorts: Clinical Benefit Rate (CBR) | 40.0 percentage of participants |
| CohortB2:GC/GEJ PD-1/PD-L1 naïve Non-MSI-H CPS<1:Pegenzileukin24 mcg/kg+Pembrolizumab as 1-3LTherapy | All Cohorts: Clinical Benefit Rate (CBR) | 22.7 percentage of participants |
| Cohort B3: GC/GEJ Post PD-1/PD-L1 Non-MSI-H: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2-4L Therapy | All Cohorts: Clinical Benefit Rate (CBR) | 10.5 percentage of participants |
| Cohort B3: GC/GEJ Post PD-1/PD-L1 Non-MSI-H: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2-4L Therapy | All Cohorts: Clinical Benefit Rate (CBR) | 11.1 percentage of participants |
| Cohort C: HCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | All Cohorts: Clinical Benefit Rate (CBR) | 10.0 percentage of participants |
| Cohort D1: CRC Non-MSI-H Any RAS: Pegenzileukin 24 mcg/kg + Pembrolizumab as 3-6L Therapy | All Cohorts: Clinical Benefit Rate (CBR) | 6.7 percentage of participants |
| Cohort D2: CRC Non-MSI-H RAS Wild Type: Pegenzileukin 24 mcg/kg + Cetuximab as 3-6L Therapy | All Cohorts: Clinical Benefit Rate (CBR) | 12.5 percentage of participants |
Secondary
All Cohorts: Duration of Response (DOR)
DOR was defined as the time from the date of first tumor assessment at which the overall response was recorded as CR or PR that was subsequently confirmed to the date of first documentation of objective PD before the initiation of any post-treatment anti-cancer therapy or death due to any cause, whichever occurred first, as per RECIST v 1.1. 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. 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 8 months (Cohort A, D1 and D2), 25 months (Cohort B1, B2 and B3), 20 months (Cohort C)
Population: The efficacy population included 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 A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | All Cohorts: Duration of Response (DOR) | NA months |
| CohortB2:GC/GEJ PD-1/PD-L1 naïve Non-MSI-H CPS<1:Pegenzileukin24 mcg/kg+Pembrolizumab as 1-3LTherapy | All Cohorts: Duration of Response (DOR) | 13.1 months |
| Cohort B3: GC/GEJ Post PD-1/PD-L1 Non-MSI-H: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2-4L Therapy | All Cohorts: Duration of Response (DOR) | NA months |
| Cohort B3: GC/GEJ Post PD-1/PD-L1 Non-MSI-H: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2-4L Therapy | All Cohorts: Duration of Response (DOR) | 8.8 months |
| Cohort C: HCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | All Cohorts: Duration of Response (DOR) | NA months |
| Cohort D2: CRC Non-MSI-H RAS Wild Type: Pegenzileukin 24 mcg/kg + Cetuximab as 3-6L Therapy | All Cohorts: Duration of Response (DOR) | 4.1 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 ADA 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 administration (Day 1) up to 30 days post last dose of study treatment administration, up to approximately 9 months (Cohorts A, D1 and D2), 26 months (Cohorts B1, B2 and B3) and 21 months (Cohort C)
Population: The ADA population included all participants from 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 A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | All Cohorts: Number of Participants With Anti-Drug Antibodies (ADAs) Against Pegenzileukin | 1 Participants |
| CohortB2:GC/GEJ PD-1/PD-L1 naïve Non-MSI-H CPS<1:Pegenzileukin24 mcg/kg+Pembrolizumab as 1-3LTherapy | All Cohorts: Number of Participants With Anti-Drug Antibodies (ADAs) Against Pegenzileukin | 2 Participants |
| Cohort B3: GC/GEJ Post PD-1/PD-L1 Non-MSI-H: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2-4L Therapy | All Cohorts: Number of Participants With Anti-Drug Antibodies (ADAs) Against Pegenzileukin | 5 Participants |
| Cohort B3: GC/GEJ Post PD-1/PD-L1 Non-MSI-H: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2-4L Therapy | All Cohorts: Number of Participants With Anti-Drug Antibodies (ADAs) Against Pegenzileukin | 0 Participants |
| Cohort C: HCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | All Cohorts: Number of Participants With Anti-Drug Antibodies (ADAs) Against Pegenzileukin | 3 Participants |
| Cohort D1: CRC Non-MSI-H Any RAS: Pegenzileukin 24 mcg/kg + Pembrolizumab as 3-6L Therapy | All Cohorts: Number of Participants With Anti-Drug Antibodies (ADAs) Against Pegenzileukin | 11 Participants |
| Cohort D2: CRC Non-MSI-H RAS Wild Type: Pegenzileukin 24 mcg/kg + Cetuximab as 3-6L Therapy | All Cohorts: Number of Participants With Anti-Drug Antibodies (ADAs) Against Pegenzileukin | 3 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 administration (Day 1) up to 30 days post last dose of study treatment administration, up to approximately 9 months (Cohorts A, D1 and D2), 26 months (Cohorts B1, B2 and B3) and 21 months (Cohort C)
Population: The exposed population included 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 A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/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 | 5 Participants |
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/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 | 2 Participants |
| CohortB2:GC/GEJ PD-1/PD-L1 naïve Non-MSI-H CPS<1:Pegenzileukin24 mcg/kg+Pembrolizumab as 1-3LTherapy | All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TESAEs | 17 Participants |
| CohortB2:GC/GEJ PD-1/PD-L1 naïve Non-MSI-H CPS<1:Pegenzileukin24 mcg/kg+Pembrolizumab as 1-3LTherapy | All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TEAEs | 22 Participants |
| Cohort B3: GC/GEJ Post PD-1/PD-L1 Non-MSI-H: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2-4L Therapy | All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TESAEs | 13 Participants |
| Cohort B3: GC/GEJ Post PD-1/PD-L1 Non-MSI-H: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2-4L Therapy | All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TEAEs | 19 Participants |
| Cohort B3: GC/GEJ Post PD-1/PD-L1 Non-MSI-H: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2-4L Therapy | All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TESAEs | 9 Participants |
| Cohort B3: GC/GEJ Post PD-1/PD-L1 Non-MSI-H: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2-4L Therapy | All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TEAEs | 18 Participants |
| Cohort C: HCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/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 | 19 Participants |
| Cohort C: HCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/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 | 7 Participants |
| Cohort D1: CRC Non-MSI-H Any RAS: Pegenzileukin 24 mcg/kg + Pembrolizumab as 3-6L Therapy | All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TESAEs | 19 Participants |
| Cohort D1: CRC Non-MSI-H Any RAS: Pegenzileukin 24 mcg/kg + Pembrolizumab as 3-6L Therapy | All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TEAEs | 30 Participants |
| Cohort D2: CRC Non-MSI-H RAS Wild Type: Pegenzileukin 24 mcg/kg + Cetuximab as 3-6L Therapy | All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TESAEs | 11 Participants |
| Cohort D2: CRC Non-MSI-H RAS Wild Type: Pegenzileukin 24 mcg/kg + Cetuximab as 3-6L Therapy | All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TEAEs | 24 Participants |
Secondary
All Cohorts: Progression-Free Survival (PFS)
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. 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 8 months (Cohort A, D1 and D2), 25 months (Cohort B1, B2 and B3), 20 months (Cohort C)
Population: The efficacy population included 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 A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | All Cohorts: Progression-Free Survival (PFS) | NA months |
| CohortB2:GC/GEJ PD-1/PD-L1 naïve Non-MSI-H CPS<1:Pegenzileukin24 mcg/kg+Pembrolizumab as 1-3LTherapy | All Cohorts: Progression-Free Survival (PFS) | 1.9 months |
| Cohort B3: GC/GEJ Post PD-1/PD-L1 Non-MSI-H: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2-4L Therapy | All Cohorts: Progression-Free Survival (PFS) | 2.0 months |
| Cohort B3: GC/GEJ Post PD-1/PD-L1 Non-MSI-H: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2-4L Therapy | All Cohorts: Progression-Free Survival (PFS) | 2.1 months |
| Cohort C: HCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | All Cohorts: Progression-Free Survival (PFS) | 2.1 months |
| Cohort D1: CRC Non-MSI-H Any RAS: Pegenzileukin 24 mcg/kg + Pembrolizumab as 3-6L Therapy | All Cohorts: Progression-Free Survival (PFS) | 2.0 months |
| Cohort D2: CRC Non-MSI-H RAS Wild Type: Pegenzileukin 24 mcg/kg + Cetuximab as 3-6L Therapy | All Cohorts: Progression-Free Survival (PFS) | 2.1 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. 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 8 months (Cohort A, D1 and D2), 25 months (Cohort B1, B2 and B3), 20 months (Cohort C)
Population: The efficacy population included 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 A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | All Cohorts: Time to Response (TTR) | 1.9 months | — |
| CohortB2:GC/GEJ PD-1/PD-L1 naïve Non-MSI-H CPS<1:Pegenzileukin24 mcg/kg+Pembrolizumab as 1-3LTherapy | All Cohorts: Time to Response (TTR) | 2.1 months | Standard Deviation 0.2 |
| Cohort B3: GC/GEJ Post PD-1/PD-L1 Non-MSI-H: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2-4L Therapy | All Cohorts: Time to Response (TTR) | 4.2 months | — |
| Cohort B3: GC/GEJ Post PD-1/PD-L1 Non-MSI-H: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2-4L Therapy | All Cohorts: Time to Response (TTR) | 3.0 months | Standard Deviation 1.3 |
| Cohort C: HCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | All Cohorts: Time to Response (TTR) | 6.0 months | — |
| Cohort D2: CRC Non-MSI-H RAS Wild Type: Pegenzileukin 24 mcg/kg + Cetuximab as 3-6L Therapy | All Cohorts: Time to Response (TTR) | 2.0 months | Standard Deviation 0.1 |
Secondary
Area Under the Concentration Versus Time Curve Extrapolated to Infinity (AUC) of Pegenzileukin
Blood samples were collected at specified timepoints for the assessment of AUC of pegenzileukin. The PK parameters were calculated using non-compartmental method.
Time frame: Day 1 Cycle 1 and Day 1 Cycle 4 (each cycle is 21 days)
Population: The PK population included all participants from exposed population with at least one PK concentration available after the first dose of study treatment. Same dose of pegenzileukin was administered to all participants in Cohorts A, B1, B2, B3, C, D1 and D2 of the study. Hence PK analysis was combined for all the cohorts. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Area Under the Concentration Versus Time Curve Extrapolated to Infinity (AUC) of Pegenzileukin | Day 1 Cycle 1 | 9270 ng*h/mL | Standard Deviation 1990 |
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Area Under the Concentration Versus Time Curve Extrapolated to Infinity (AUC) of Pegenzileukin | Day 1 Cycle 4 | 7330 ng*h/mL | Standard Deviation 2340 |
Secondary
Area Under the Plasma Concentration Versus Time Curve Calculated Using the Trapezoidal Method From Time Zero to Tlast (AUClast) of Pegenzileukin
Blood samples were collected at specified timepoints for the assessment of AUClast of pegenzileukin. The PK parameters were calculated using non-compartmental method.
Time frame: Day 1 Cycle 1 and Day 1 Cycle 4 (each cycle is 21 days)
Population: The PK population included all participants from exposed population with at least one PK concentration available after the first dose of study treatment. Same dose of pegenzileukin was administered to all participants in Cohorts A, B1, B2, B3, C, D1 and D2 of the study. Hence PK analysis was combined for all the cohorts. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Area Under the Plasma Concentration Versus Time Curve Calculated Using the Trapezoidal Method From Time Zero to Tlast (AUClast) of Pegenzileukin | Day 1 Cycle 1 | 8940 ng*h/mL | Standard Deviation 1930 |
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Area Under the Plasma Concentration Versus Time Curve Calculated Using the Trapezoidal Method From Time Zero to Tlast (AUClast) of Pegenzileukin | Day 1 Cycle 4 | 7100 ng*h/mL | Standard Deviation 2330 |
Secondary
Cohort D2: Concentration at End of Infusion (Ceoi) of Cetuximab
Blood samples were collected at specified timepoints for the assessment of Ceoi of Cetuximab. The PK parameters were calculated using non-compartmental method.
Time frame: Cycles 1, 2, 3, 4, 6 and 8 (each cycle is 21 days)
Population: The PK population included 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Cohort D2: Concentration at End of Infusion (Ceoi) of Cetuximab | Cycle 1 | 245352.9 ng/mL | Standard Deviation 57442.3 |
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Cohort D2: Concentration at End of Infusion (Ceoi) of Cetuximab | Cycle 2 | 209111.1 ng/mL | Standard Deviation 52687.6 |
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Cohort D2: Concentration at End of Infusion (Ceoi) of Cetuximab | Cycle 3 | 214857.1 ng/mL | Standard Deviation 69955.9 |
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Cohort D2: Concentration at End of Infusion (Ceoi) of Cetuximab | Cycle 4 | 236700.0 ng/mL | Standard Deviation 63756.6 |
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Cohort D2: Concentration at End of Infusion (Ceoi) of Cetuximab | Cycle 6 | 233777.8 ng/mL | Standard Deviation 53473.8 |
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Cohort D2: Concentration at End of Infusion (Ceoi) of Cetuximab | Cycle 8 | 248500.0 ng/mL | Standard Deviation 59991.7 |
Secondary
Cohort D2: Concentration Observed Just Before Intervention Administration During Repeated Dosing (Ctrough) of Cetuximab
Blood samples were collected at specified timepoints for the assessment of Ctrough of Cetuximab. The PK parameters were calculated using non-compartmental method.
Time frame: Cycles 1, 2, 3, 4, 6 and 8 (each cycle is 21 days)
Population: The PK population included 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Cohort D2: Concentration Observed Just Before Intervention Administration During Repeated Dosing (Ctrough) of Cetuximab | Cycle 4 | 88670.0 ng/mL | Standard Deviation 53487.3 |
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Cohort D2: Concentration Observed Just Before Intervention Administration During Repeated Dosing (Ctrough) of Cetuximab | Cycle 6 | 84377.8 ng/mL | Standard Deviation 39150 |
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Cohort D2: Concentration Observed Just Before Intervention Administration During Repeated Dosing (Ctrough) of Cetuximab | Cycle 8 | 118375.0 ng/mL | Standard Deviation 51770.9 |
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Cohort D2: Concentration Observed Just Before Intervention Administration During Repeated Dosing (Ctrough) of Cetuximab | Cycle 1 | 0.0 ng/mL | Standard Deviation 0 |
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Cohort D2: Concentration Observed Just Before Intervention Administration During Repeated Dosing (Ctrough) of Cetuximab | Cycle 2 | 61689.5 ng/mL | Standard Deviation 29031.6 |
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Cohort D2: Concentration Observed Just Before Intervention Administration During Repeated Dosing (Ctrough) of Cetuximab | Cycle 3 | 61647.1 ng/mL | Standard Deviation 41623.9 |
Secondary
Last Concentration Observed Above the Lower Limit of Quantification (Clast) of Pegenzileukin
Blood samples were collected at specified timepoints for the assessment of Clast of pegenzileukin. The PK parameters were calculated using non-compartmental method.
Time frame: Day 1 Cycle 1 and Day 1 Cycle 4 (each cycle is 21 days)
Population: The PK population included all participants from exposed population with at least one PK concentration available after the first dose of study treatment. Same dose of pegenzileukin was administered to all participants in Cohorts A, B1, B2, B3, C, D1 and D2 of the study. Hence PK analysis was combined for all the cohorts. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Last Concentration Observed Above the Lower Limit of Quantification (Clast) of Pegenzileukin | Day 1 Cycle 1 | 17.6 ng/mL | Standard Deviation 13.4 |
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Last Concentration Observed Above the Lower Limit of Quantification (Clast) of Pegenzileukin | Day 1 Cycle 4 | 13.0 ng/mL | Standard Deviation 6.11 |
Secondary
Maximum Concentration Observed (Cmax) of Pegenzileukin
Blood samples were collected at specified timepoints for the assessment of Cmax of pegenzileukin. The pharmacokinetic (PK) parameters were calculated using non-compartmental method.
Time frame: Day 1 Cycle 1 and Day 1 Cycle 4 (each cycle is 21 days)
Population: The PK population included all participants from exposed population with at least one PK concentration available after the first dose of study treatment. Same dose of pegenzileukin was administered to all participants in Cohorts A, B1, B2, B3, C, D1 and D2 of the study. Hence PK analysis was combined for all the cohorts. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Maximum Concentration Observed (Cmax) of Pegenzileukin | Day 1 Cycle 1 | 417 nanograms per milliliter (ng/mL) | Standard Deviation 109 |
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Maximum Concentration Observed (Cmax) of Pegenzileukin | Day 1 Cycle 4 | 369 nanograms per milliliter (ng/mL) | Standard Deviation 118 |
Secondary
Observed Accumulation Ratio Based on Cmax (Rac,Cmax) of Pegenzileukin
Blood samples were collected at specified timepoints for the assessment of Rac,cmax of pegenzileukin. Rac,cmax was calculated as Cmax at Cycle 4 Day 1/Cmax at Cycle 1 Day 1. The PK parameters were calculated using non-compartmental method.
Time frame: Day 1 Cycle 1 and Day 1 Cycle 4 (each cycle is 21 days)
Population: The PK population included all participants from exposed population with at least one PK concentration available after the first dose of study treatment. Same dose of pegenzileukin was administered to all participants in Cohorts A, B1, B2, B3, C, D1 and D2 of the study. Hence PK analysis was combined for all the cohorts. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Observed Accumulation Ratio Based on Cmax (Rac,Cmax) of Pegenzileukin | 0.887 ratio | Standard Deviation 0.173 |
Secondary
Observed Accumulation Ratio (Rac) of Pegenzileukin
Blood samples were collected at specified timepoints for the assessment of Rac of pegenzileukin. Rac was calculated as AUC at Cycle 4 Day 1/AUC at Cycle 1 Day 1. The PK parameters were calculated using non-compartmental method.
Time frame: Day 1 Cycle 1 and Day 1 Cycle 4 (each cycle is 21 days)
Population: The PK population included all participants from exposed population with at least one PK concentration available after the first dose of study treatment. Same dose of pegenzileukin was administered to all participants in Cohorts A, B1, B2, B3, C, D1 and D2 of the study. Hence PK analysis was combined for all the cohorts. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Observed Accumulation Ratio (Rac) of Pegenzileukin | 0.772 ratio | Standard Deviation 0.15 |
Secondary
Time of the Last Concentration Observed Above the Lower Limit of Quantification (Tlast) of Pegenzileukin
Blood samples were collected at specified timepoints for the assessment of tlast of pegenzileukin. The PK parameters were calculated using non-compartmental method.
Time frame: Day 1 Cycle 1 and Day 1 Cycle 4 (each cycle is 21 days)
Population: The PK population included all participants from exposed population with at least one PK concentration available after the first dose of study treatment. Same dose of pegenzileukin was administered to all participants in Cohorts A, B1, B2, B3, C, D1 and D2 of the study. Hence PK analysis was combined for all the cohorts. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Time of the Last Concentration Observed Above the Lower Limit of Quantification (Tlast) of Pegenzileukin | Day 1 Cycle 1 | 69.45 Hours (h) |
| Cohort A: ESCC Post PD-1/PD-L1: Pegenzileukin 24 mcg/kg + Pembrolizumab as 2/3L Therapy | Time of the Last Concentration Observed Above the Lower Limit of Quantification (Tlast) of Pegenzileukin | Day 1 Cycle 4 | 68.82 Hours (h) |