Esophageal Cancer
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy and safety of atezolizumab plus tiragolumab in combination with paclitaxel and cisplatin (PC) compared with atezolizumab matching placebo plus tiragolumab matching placebo plus PC as first-line treatment in participants with unresectable locally advanced, unresectable recurrent, or metastatic esophageal carcinoma (EC). Participants will be randomized in a 1:1 ratio to receive one of the following treatment regimens during induction phase: Arm A: Atezolizumab plus Tiragolumab and PC Arm B: Atezolizumab placebo plus Tiragolumab placebo and PC Following the induction phase, participants will continue maintenance therapy with either atezolizumab plus tiragolumab (Arm A) or atezolizumab matching placebo plus tiragolumab matching placebo (Arm B).
Interventions
DRUGAtezolizumab
Atezolizumab at a fixed dose of 1200 milligrams (mg) administered by intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle.
DRUGTiragolumab
Tiragolumab at a fixed dose of 600 mg administered by IV infusion every Q3W on Day 1 of each 21-day cycle.
DRUGPaclitaxel
Paclitaxel 175 mg/m\^2 administered by IV infusion on Day 1 of each 21-day cycle for 6 cycles.
DRUGCisplatin
Cisplatin 60-80 mg/m\^2 administered by IV infusion on Day 1 of each 21-day cycle for 6 cycles.
Atezolizumab matching placebo administered by IV infusion, Q3W on Day 1 of each 21-day cycle.
Tiragolumab matching placebo administered by IV infusion, Q3W on Day 1 of each 21-day cycle.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Histologically confirmed EC * Unresectable locally advanced, unresectable recurrent, or metastatic disease * Measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 * Adequate hematologic and end-organ function * Female participants must be willing to avoid pregnancy and refrain from donating eggs during the treatment period and for 90 days after the final dose * Male participants with partners of childbearing potential must commit to the use of two methods of contraception and must not donate sperm for the study duration and 90 days after the final dose Key
Exclusion criteria
* Palliative radiation treatment for EC within 4 weeks prior to initiation of study treatment * Evidence of complete esophageal obstruction not amenable to treatment * Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases * Uncontrolled tumor-related pain, uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures * Active or history of autoimmune disease or immune deficiency or leptomeningeal disease * History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis * Malignancies other than EC within 2 years prior to screening with a negligible risk of metastasis or death adequately treated with expected curative outcome * Severe infection within 4 weeks prior to initiation of study treatment or any active infection that, in the opinion of the investigator, could impact patient safety * Positive test result for human immunodeficiency virus (HIV) * Active hepatitis B or hepatitis C * Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti-CTLA-4, anti-TIGIT, anti-PD-1, and anti-PD-L1 therapeutic antibodies * Treatment with any investigational therapy prior to initiation of study treatment * Poor peripheral venous access * Prior allogeneic stem cell or solid organ transplantation * Concurrent participation in another therapeutic clinical trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Independent Review Facility (IRF)-Assessed Progression-free Survival (PFS) | From randomization to the first occurrence of PD or death from any cause, whichever occurred first (up to approximately 19 months) | PFS was defined as the time from randomization to the first occurrence of progressive disease (PD) or death from any cause (whichever occurred first), as determined by an IRF according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). PD was defined as at least a 20% increase in the sum of diameters (SOD) of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). Additionally, the SOD must also demonstrate an absolute increase of ≥ 5 millimeters (mm) or unequivocal progression of existing non-target lesions. Kaplan-Meier (KM) method was used to estimate median PFS. |
| Overall Survival (OS) | From randomization to death from any cause (up to approximately 27.5 months) | OS was defined as the time from randomization to death from any cause. K-M method was used to estimate median OS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Investigator-assessed PFS | From randomization to the first occurrence of PD or death from any cause, whichever occurs first (up to approximately 19 months) | PFS was defined as the time from randomization to the first occurrence of PD or death from any cause (whichever occurred first), as determined by the investigator according to RECIST v1.1. PD was defined at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). Additionally, the SOD must also demonstrate an absolute increase of ≥ 5 mm or unequivocal progression of existing non-target lesions. K-M method was used to estimate median PFS. |
| IRF-assessed Confirmed Objective Response Rate (ORR) | Up to approximately 19 months | IRF-assessed confirmed ORR was defined as the percentage of participants with an objective response (OR), characterized by a complete response (CR) or partial response (PR) on 2 consecutive occasions ≥ 4 weeks apart, as determined by an IRF according to RECIST v1.1. CR was defined as disappearance of all target lesions. \& normalization of tumor marker level. Additionally, any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. |
| Investigator-assessed Confirmed ORR | Up to approximately 19 months | Investigator-assessed confirmed ORR was defined as the percentage of participants with an OR, characterized by a CR or a PR on 2 consecutive occasions ≥ 4 weeks apart, as determined by the investigator according to RECIST v1.1. CR was defined as disappearance of all target lesions. \& normalization of tumor marker level. Additionally, any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. |
| IRF-assessed Duration of Objective Response (DOR) | From the first occurrence of a of a confirmed OR to PD or death from any cause, whichever occurred first (up to approximately 19 months) | DOR was defined as the time from the first occurrence of a confirmed OR to PD or death from any cause (whichever occurred first), as determined by an IRF according to RECIST v1.1. OR was defined as either a CR or a PR on 2 consecutive occasions ≥ 4 weeks apart. CR was defined as disappearance of all target lesions. \& normalization of tumor marker level. Additionally, any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on study (including baseline). Additionally, the SOD must also demonstrate an absolute increase of ≥ 5 mm or unequivocal progression of existing non-target lesions. K-M method was used to estimate median DOR. |
| Investigator-assessed DOR | From the first occurrence of a of a confirmed OR to PD or death from any cause, whichever occurred first (up to approximately 19 months) | DOR was defined as the time from the first occurrence of a confirmed OR to PD or death from any cause (whichever occurred first), as determined by an IRF according to RECIST v1.1. OR was defined as either a CR or a PR on 2 consecutive occasions ≥ 4 weeks apart. CR was defined as disappearance of all target lesions. \& normalization of tumor marker level. Additionally, any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on study (including baseline). Additionally, the SOD must also demonstrate an absolute increase of ≥ 5 mm or unequivocal progression of existing non-target lesions. K-M method was used to estimate median DOR. |
| Time to Confirmed Deterioration (TTCD) in Participant-reported Physical Functioning, as Measured by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) | Up to approximately 27 months | Clinically meaningful changes in physical functioning as measured by the EORTC QLQ-C30. EORTC QLQ-C30 is a self-reported measure, consisting of 30 questions that assess 5 aspects of participants functioning (physical, emotional, role, cognitive and social), 3 symptom scales (fatigue, nausea and vomiting, and pain), global health status/quality of life (GHS/QoL), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties) within the previous week. Physical functioning was scored on a 4-point scale: 1=Not at all, 2=A little, 3=Quite a bit, 4=Very much. Scores were linearly transformed to a range of 0 to 100, with higher scores (i.e. closer to 100) reflecting better functioning. Participants were considered "Worsened" if their baseline score decreased by ≥10 points. K-M method was used to estimate median TTCD. |
| TTCD in Participant-reported Role Functioning (RF), as Measured by EORTC QLQ-C30 | Up to approximately 27 months | Clinically meaningful changes in role functioning as measured by the EORTC QLQ-C30. EORTC QLQ-C30 is a self-reported measure, consisting of 30 questions that assess 5 aspects of participants functioning (physical, emotional, role, cognitive and social), 3 symptom scales (fatigue, nausea and vomiting, and pain), GHS/QoL, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties) within the previous week. Role functioning was scored on a 4-point scale: 1=Not at all, 2=A little, 3=Quite a bit, 4=Very much. Scores were linearly transformed to a range of 0 to 100, with higher scores (i.e. closer to 100) reflecting better functioning. Participants were considered "Worsened" if their baseline score decreased by ≥10 points. K-M method was used to estimate median TTCD. |
| TTCD in Participant-Reported GHS/QoL, as Measured by EORTC QLQ-C30 | Up to approximately 27 months | Clinically meaningful changes in GHS/QoL as measured by the EORTC QLQ-C30. EORTC QLQ-C30 is a self-reported measure, consisting of 30 questions that assess 5 aspects of participants functioning (physical, emotional, role, cognitive and social), 3 symptom scales (fatigue, nausea and vomiting, and pain), GHS/QoL, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties) within the previous week. GHS and QoL items were scored on a 7-point scale, with scores ranging from 1=Very poor to 7=Excellent. Scores were linearly transformed to a range of 0 to 100, with higher scores (i.e. closer to 100) reflecting better GHS/QoL. Participants were considered "Worsened" if their baseline score decreased by ≥10 points. K-M method was used to estimate median TTCD. |
| TTCD in Participant-reported Dysphagia, as Measured by European Organisation for Research and Treatment of Cancer Quality-of-life Esophageal Cancer, Module 18 Questionnaire (EORTC QLQ-OES18) | Up to approximately 27 months | Clinically meaningful changes in dysphagia as measured by the EORTC QLQ-OES18. EORTC QLQ-OES18 is a modular supplement to the EORTC QLQ-C30 questionnaire for use in participants with esophageal cancer. EORTC QLQ-OES18 consists of 4 multiple-item scale (dysphagia, eating, reflux, and pain) and 6 single items (trouble swallowing saliva, choked when swallowing, dry mouth, trouble with taste, trouble with coughing, and trouble talking) with a recall period of the previous week. Each symptom item was scored on a 4-point scale: 1=Not at all, 2=A little, 3=Quite a bit, 4=Very much. Scores were linearly transformed to a range of 0 to 100, with higher transformed scores (i.e. closer to 100) reflecting worse symptoms. Participants were considered "Worsened" if their baseline score increased by ≥ 10 points. K-M method was used to estimate median TTCD. |
| Number of Participants With Adverse Events (AEs) | Up to approximately 49.6 months | An AE was any untoward medical occurrence in a participant administered a pharmaceutical product, and which does not necessarily have a causal relationship with the treatment. An AE was therefore any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. |
| Number of Participants With Cytokine-release Syndrome (CRS), With Severity Determined by the American Society for Transplantation and Cell Therapy (ASTCT) Consensus Grading Scale | Up to approximately 49.6 months | CRS was defined as supraphysiologic response following administration of any immune therapy that results in activation/engagement of endogenous or infused T cells and/or other immune effector cells. Symptoms may be progressive, including fever at onset, and may also include hypotension, capillary leak (hypoxia), and end-organ dysfunction. Severity of CRS was determined per ASTCT Consensus Grading Criteria, which categorizes CRS into 5 grades: Grade 1: fever (≥38◦Celsius), with/without constitutional symptoms, in absence of hypotension \& hypoxia; Grade 2: fever with hypotension not requiring vasopressors and/or hypoxia requiring low-flow oxygen; Grade 3: fever with hypotension requiring one vasopressor, with/without vasopressin, and/or hypoxia requiring high-flow oxygen; Grade 4: fever accompanied by hypotension requiring multiple vasopressors (excluding vasopressin) and/or hypoxia requiring positive-pressure ventilation; Grade 5: death due to CRS. |
| Minimum Serum Concentration (Cmin) of Tiragolumab | Pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12, and 16 (1 Cycle=21 days) | — |
| Maximum Serum Concentration (Cmax) of Tiragolumab | 30 minutes post-dose on Day 1 of Cycle 1 (1 Cycle=21 days) | — |
| Cmin of Atezolizumab | Pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12, and 16 (1 Cycle=21 days) | — |
| Cmax of Atezolizumab | 30 minutes post-dose on Day 1 of Cycle 1 (1 Cycle=21 days) | — |
| Number of Participants With Anti-drug Antibodies (ADAs) to Tiragolumab | Up to approximately 27.5 months | Participants were considered to be ADA positive if they were ADA negative at baseline but developed an ADA response following tiragolumab administration (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples was greater than the titer of the baseline sample by a scientifically reasonable margin such as at least 0.60 titer unit (t.u.) greater than the baseline titer result (treatment-enhanced ADA response). Participants with a positive post-baseline sample have been reported here. |
| Number of Participants With ADAs to Atezolizumab | Up to approximately 27.5 months | Participants were considered to be ADA positive if they were ADA negative at baseline but developed an ADA response following atezolizumab administration (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples was greater than the titer of the baseline sample by a scientifically reasonable margin such as at least 0.60 t.u. greater than the baseline titer result (treatment-enhanced ADA response). Participants with a positive post-baseline sample have been reported here. |
Countries
China, Hong Kong, South Korea, Taiwan, Thailand
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
A total of 461 participants with unresectable locally advanced, unresectable recurrent, or metastatic esophageal squamous cell carcinoma (ESCC) took part in the study at 67 investigative sites across 5 countries from 30 October 2020 to 28 August 2025.
Pre-assignment details
Overall, 461 participants were enrolled and randomized in the study with a 1:1 allocation ratio between treatment arms. Participants received the same drugs as induction and maintenance treatments except for chemotherapy. The study is considered "Completed" because all the pre-planned study activities and analyses have been performed.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 62.5 years STANDARD_DEVIATION 8.1 |
| Race/Ethnicity, Customized Ethnicity: Not Hispanic or Latino | 229 Participants |
| Race/Ethnicity, Customized Race: Asian | 229 Participants |
| Sex: Female, Male Female | 29 Participants |
| Sex: Female, Male Male | 200 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 192 / 232 | 177 / 229 |
| other Total, other adverse events | 223 / 227 | 225 / 228 |
| serious Total, serious adverse events | 89 / 227 | 99 / 228 |
Outcome results
None listed