Esophageal Squamous Cell Carcinoma
Conditions
Keywords
esophageal squamous cell carcinoma
Brief summary
The study aimed to evaluate the efficacy and safety of sitravatinib in combination with tislelizumab as a second- or third-line treatment for participants with locally advanced, unresectable, or metastatic esophageal squamous cell carcinoma (ESCC) who experienced disease progression following prior systemic chemotherapy.
Interventions
DRUGSitravatinib
100 mg orally once daily
DRUGTislelizumab
200 mg intravenously once every 3 weeks
DRUGDocetaxel
75 milligrams per square meter of body surface area (mg/m2) intravenously on Day 1 of every 21-day cycle
DRUGIrinotecan
125 mg/m2 intravenously on Days 1 and 8 of every 21-day cycle
Sponsors
BeiGene
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Histologically or cytologically confirmed locally advanced unresectable or metastatic ESCC, not amenable to treatment with curative intent 2. At least 1 measurable lesion as defined per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as determined by local site investigator/radiology assessment ≤ 28 days before randomization Note: Lesions that had been previously irradiated were considered evaluable provided 3. Eastern Cooperative Oncology Group (ECOG) score ≤ 1 4. Adequate organ function as indicated by the following laboratory values as indicated by the laboratory tests performed ≤ 7 days before randomization Key
Exclusion criteria
1. Have any contraindication for receiving treatment with both docetaxel and irinotecan 2. Participants with tumor located around important vascular structures as shown by imaging or the investigator determines that the tumor is likely to invade important blood vessels and may cause fatal bleeding (ie, radiologic evidence of tumors invading or abutting major blood vessels) 3. Participants with tumor that invades into organs located adjacent to the esophageal disease site (eg, aorta or respiratory tract) that has an increased risk of fistula during the study treatment period as assessed by the investigator 4. History of gastrointestinal perforation and/or fistula or aorto-esophageal fistula within 6 months before randomization 5. Have received prior anticancer agents that have same mechanism of action as sitravatinib (eg, receptor tyrosine kinases (RTKs) with a similar target profile or Vascular Endothelial Growth Factor (VEGF)/Vascular Endothelial Growth Factor Receptor-targeted (VEGFR) monoclonal antibodies) Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Arms A and C: Overall Response Rate (ORR) | Through study completion data cut-off date of February 26th, 2024 (maximum time on study was 12 months) | ORR is defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) as assessed by the investigator per the Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Through study completion data cut-off date of February 26th, 2024 (maximum time on study was 12 months) | Defined as the time from randomization until the date of death due to any cause. Kaplan-Meier methodology was used to estimate the median OS. |
| Disease Control Rate (DCR) | Through study completion data cut-off date of February 26th, 2024 (maximum time on study was 12 months) | Defined as the percentage of participants whose best overall response is complete response, partial response, or stable disease, as assessed by the investigator per RECIST v1.1 |
| Clinical Benefit Rate (CBR) | Through study completion data cut-off date of February 26th, 2024 (maximum time on study was 12 months) | Defined as the percentage of participants with a complete response, partial response, or durable stable disease (defined as stable disease for 24 weeks or longer, as assessed by the investigator per RECIST v.1.1. |
| Duration of Response (DOR) | Through study completion data cut-off date of February 26th, 2024 (maximum time on study was 12 months) | Defined as the time from the first occurrence of a documented objective response to the time of documented disease progression assessed by the investigator or death from any cause, whichever occurred first, in all randomized participants with documented objective responses. |
| Arms A and B: Overall Response Rate (ORR) | Through study completion data cut-off date of February 26th, 2024 (maximum time on study was 12 months) | ORR is defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) as assessed by the investigator per RECIST v1.1. Analysis of ORR in Arm A compared to Arm B was specified as a secondary endpoint in the Protocol (please see the primary outcome measure for Arm C results) |
| Number of Participants With Adverse Events | From the first dose to 30 days after the last dose or the start of new anticancer therapy, whichever occurred first (maximum time on treatment was 8.9 months for Arm A, 7.7 months for Arm B, and 8.0 months for Arm C). | Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), which includes laboratory tests, and vital signs, according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 |
| Progression Free Survival (PFS) | Through study completion data cut-off date of February 26th, 2024 (maximum time on study was 12 months) | Defined as the time from randomization until first documentation of disease progression as assessed by the investigator per RECIST v1.1 or death from any cause, whichever occurred first. Kaplan-Meier methodology was used to estimate the median PFS. |
Countries
China
Participant flow
Recruitment details
Participants were enrolled across multiple study centers in China. The first participant provided consent on October 3, 2022, and the last participant completed the study on February 26, 2024.
Pre-assignment details
Participants were randomly assigned to one of three treatment groups in a 2:1:2 ratio. Randomization was stratified by PD-L1 expressions status (Tumor Area Positivity \[TAP\] score ≥ 10% versus TAP score \< 10%)
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Tislelizumab + Sitravatinib Sitravatinib was administered orally at a dose of 100 mg once daily, while tislelizumab was given intravenously at 200 mg once every three weeks. | 39 |
| Arm B: Sitravatinib Sitravatinib was administered orally at a dose of 100 mg once daily. | 19 |
| Arm C: Investigator-chosen Chemotherapy (ICC) Investigators selected either docetaxel, administered intravenously at 75 mg/m² on Day 1 of each 21-day cycle, or irinotecan, given intravenously at 125 mg/m² on Days 1 and 8 of each 21-day cycle. | 38 |
| Total | 96 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 20 | 5 | 19 |
| Overall Study | Study Terminated By Sponsor | 18 | 13 | 16 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 3 |
Baseline characteristics
| Characteristic | Arm A: Tislelizumab + Sitravatinib | Arm B: Sitravatinib | Arm C: Investigator-chosen Chemotherapy (ICC) | Total |
|---|---|---|---|---|
| Age, Continuous | 59.1 years STANDARD_DEVIATION 7.73 | 61.9 years STANDARD_DEVIATION 7.87 | 60.4 years STANDARD_DEVIATION 8.06 | 60.2 years STANDARD_DEVIATION 7.87 |
| Race/Ethnicity, Customized Asian | 39 Participants | 19 Participants | 38 Participants | 96 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 37 Participants | 17 Participants | 35 Participants | 89 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 20 / 39 | 5 / 19 | 19 / 38 |
| other Total, other adverse events | 39 / 39 | 19 / 19 | 34 / 34 |
| serious Total, serious adverse events | 22 / 39 | 6 / 19 | 15 / 34 |
Outcome results
Primary
Arms A and C: Overall Response Rate (ORR)
ORR is defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) as assessed by the investigator per the Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1.
Time frame: Through study completion data cut-off date of February 26th, 2024 (maximum time on study was 12 months)
Population: The Intent-to-Treat (ITT) analysis set included all randomized participants; for the primary analysis of ORR only Arms A and C were included, results for Arm B are included in the secondary Outcome Measures section.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Tislelizumab + Sitravatinib | Arms A and C: Overall Response Rate (ORR) | 10.3 percentage of participants |
| Arm C: Investigator-chosen Chemotherapy (ICC) | Arms A and C: Overall Response Rate (ORR) | 5.3 percentage of participants |
95% CI: [0.3, 23.9]
95% CI: [-9.3, 19.5]
Secondary
Arms A and B: Overall Response Rate (ORR)
ORR is defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) as assessed by the investigator per RECIST v1.1. Analysis of ORR in Arm A compared to Arm B was specified as a secondary endpoint in the Protocol (please see the primary outcome measure for Arm C results)
Time frame: Through study completion data cut-off date of February 26th, 2024 (maximum time on study was 12 months)
Population: ITT analysis set for Arms A and B
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Tislelizumab + Sitravatinib | Arms A and B: Overall Response Rate (ORR) | 10.3 percentage of participants |
| Arm C: Investigator-chosen Chemotherapy (ICC) | Arms A and B: Overall Response Rate (ORR) | 21.1 percentage of participants |
95% CI: [0.1, 2.7]
Secondary
Clinical Benefit Rate (CBR)
Defined as the percentage of participants with a complete response, partial response, or durable stable disease (defined as stable disease for 24 weeks or longer, as assessed by the investigator per RECIST v.1.1.
Time frame: Through study completion data cut-off date of February 26th, 2024 (maximum time on study was 12 months)
Population: ITT analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Tislelizumab + Sitravatinib | Clinical Benefit Rate (CBR) | 17.9 percentage of participants |
| Arm C: Investigator-chosen Chemotherapy (ICC) | Clinical Benefit Rate (CBR) | 26.3 percentage of participants |
| Arm C: Investigator-chosen Chemotherapy (ICC) | Clinical Benefit Rate (CBR) | 5.3 percentage of participants |
95% CI: [0.7, 40.8]
95% CI: [0.1, 2.9]
95% CI: [-2.3, 29.5]
95% CI: [-34.7, 13.8]
Secondary
Disease Control Rate (DCR)
Defined as the percentage of participants whose best overall response is complete response, partial response, or stable disease, as assessed by the investigator per RECIST v1.1
Time frame: Through study completion data cut-off date of February 26th, 2024 (maximum time on study was 12 months)
Population: ITT analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Tislelizumab + Sitravatinib | Disease Control Rate (DCR) | 64.1 percentage of participants |
| Arm C: Investigator-chosen Chemotherapy (ICC) | Disease Control Rate (DCR) | 63.2 percentage of participants |
| Arm C: Investigator-chosen Chemotherapy (ICC) | Disease Control Rate (DCR) | 42.1 percentage of participants |
95% CI: [0.9, 6.8]
95% CI: [0.3, 3.7]
95% CI: [-1.5, 43.3]
95% CI: [-24.5, 28.4]
Secondary
Duration of Response (DOR)
Defined as the time from the first occurrence of a documented objective response to the time of documented disease progression assessed by the investigator or death from any cause, whichever occurred first, in all randomized participants with documented objective responses.
Time frame: Through study completion data cut-off date of February 26th, 2024 (maximum time on study was 12 months)
Population: ITT analysis Set. Only participants with best overall response of complete response or partial response confirmed per RECIST v1.1 were included in the analysis, and percentages were based on the number of responders
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Tislelizumab + Sitravatinib | Duration of Response (DOR) | 5.2 months |
| Arm C: Investigator-chosen Chemotherapy (ICC) | Duration of Response (DOR) | 4.6 months |
| Arm C: Investigator-chosen Chemotherapy (ICC) | Duration of Response (DOR) | NA months |
Secondary
Number of Participants With Adverse Events
Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), which includes laboratory tests, and vital signs, according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0
Time frame: From the first dose to 30 days after the last dose or the start of new anticancer therapy, whichever occurred first (maximum time on treatment was 8.9 months for Arm A, 7.7 months for Arm B, and 8.0 months for Arm C).
Population: The Safety Analysis Set includes all participants who received at least 1 dose of any component of study treatments.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: Tislelizumab + Sitravatinib | Number of Participants With Adverse Events | TEAEs | 39 Participants |
| Arm A: Tislelizumab + Sitravatinib | Number of Participants With Adverse Events | SAEs | 22 Participants |
| Arm C: Investigator-chosen Chemotherapy (ICC) | Number of Participants With Adverse Events | TEAEs | 19 Participants |
| Arm C: Investigator-chosen Chemotherapy (ICC) | Number of Participants With Adverse Events | SAEs | 6 Participants |
| Arm C: Investigator-chosen Chemotherapy (ICC) | Number of Participants With Adverse Events | TEAEs | 34 Participants |
| Arm C: Investigator-chosen Chemotherapy (ICC) | Number of Participants With Adverse Events | SAEs | 15 Participants |
Secondary
Overall Survival (OS)
Defined as the time from randomization until the date of death due to any cause. Kaplan-Meier methodology was used to estimate the median OS.
Time frame: Through study completion data cut-off date of February 26th, 2024 (maximum time on study was 12 months)
Population: ITT analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Tislelizumab + Sitravatinib | Overall Survival (OS) | 6.1 months |
| Arm C: Investigator-chosen Chemotherapy (ICC) | Overall Survival (OS) | 9.1 months |
| Arm C: Investigator-chosen Chemotherapy (ICC) | Overall Survival (OS) | 5.5 months |
95% CI: [0.45, 1.61]
Secondary
Progression Free Survival (PFS)
Defined as the time from randomization until first documentation of disease progression as assessed by the investigator per RECIST v1.1 or death from any cause, whichever occurred first. Kaplan-Meier methodology was used to estimate the median PFS.
Time frame: Through study completion data cut-off date of February 26th, 2024 (maximum time on study was 12 months)
Population: ITT analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Tislelizumab + Sitravatinib | Progression Free Survival (PFS) | 3.4 months |
| Arm C: Investigator-chosen Chemotherapy (ICC) | Progression Free Survival (PFS) | 5.6 months |
| Arm C: Investigator-chosen Chemotherapy (ICC) | Progression Free Survival (PFS) | 2.6 months |
95% CI: [0.29, 0.96]
95% CI: [0.79, 4.82]