Resectable Esophageal Squamous Cell Carcinoma
Conditions
Keywords
Tislelizumab, PET, Chemotherapy, Chemoradiotherapy
Brief summary
The purpose of this study is to evaluate the pathological complete response (pCR) in participants receiving tislelizumab plus chemotherapy/chemoradiotherapy as neoadjuvant treatment.
Detailed description
This study enrolled participants with esophageal squamous cell carcinoma who were eligible to have their tumor removed by surgery (also called surgical resection). The treatment phase of the study included the following: * Induction therapy, in which participants received 1 cycle of chemotherapy; * Neoadjuvant therapy (neoadjuvant refers to treatment that occurs before surgery, which can make the tumor easier to remove). In this study participants received neoadjuvant therapy based on their response to induction therapy. Response to induction therapy was assessed using the maximum standardized uptake value (SUVmax) measured using a Positron Emission Tomography (PET) scan. The SUV number refers to the level of brightness on the PET scan which reflects metabolic activity; increased metabolic activity can indicate cancerous growth. * Participants with a decrease in SUVmax of 35% or more after induction therapy received neoadjuvant treatment with tislelizumab plus chemotherapy. * Participants with a decrease in SUVmax less than 35% after induction therapy received neoadjuvant treatment with tislelizumab plus chemotherapy and radiotherapy. * Surgery to remove the remaining tumor (resection) was to occur 4-6 weeks after completion of neoadjuvant treatment. After surgery participants were followed until death, lost to follow-up, withdrawal of consent, or until the study was completed
Interventions
DRUGTislelizumab
Administered intravenously on Day 1 of each 21-Day Cycle.
DRUGPaclitaxel
135 mg/m\^2 administered intravenously on Day 1 of each 21-Day Cycle.
DRUGCisplatin
80 mg/m\^2 administered intravenously on Day 1 of each 21-Day Cycle.
DRUG5-fluorouracil
1000 mg/m\^2 administered intravenously over Day 1 through 4 of each 21-Day Cycle.
RADIATIONRadiotherapy
40 grays/20 fractions
PROCEDURESurgical resection
Performed as indicated in the treatment arm.
Sponsors
BeiGene
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
Key Inclusion Criteria: * Eastern Cooperative Oncology Group Performance Status of 0 or 1. * Histologically confirmed esophageal squamous cell carcinoma (ESCC). * Stage cT1-2N+M0 and cT3NanyM0 (per The American Joint Committee on Cancer 8th Edition). * Evaluation by the investigator to confirm eligibility for an R0 resection with curative intent. * Adequate hematologic and organ function, defined by protocol-specified laboratory test results obtained within 14 days before first dose. Key
Exclusion criteria
* Ineligible for treatment with any of the chemotherapy doublets of protocol-specified chemotherapy. * Any prior therapy for current ESCC, including investigational agents, chemotherapy, radiotherapy, targeted therapy agents, or prior therapy with an anti-programmed cell death protein-1, anti-programmed cell death protein ligand-1, anti-programmed cell death protein ligand-2, or any other antibody or drug specifically targeting T-Cell co-stimulation or checkpoint pathways. * History of fistula due to primary tumor invasion. * Participants with high risk of fistula or sign of perforation evaluated by investigator. * Any condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days before first dose. \* Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent) and topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption, and short course (≤ 7 days) of corticosteroid prescribed prophylactically or for the treatment of a non-autoimmune condition are permitted. * Active autoimmune diseases or history of autoimmune diseases that may relapse. \* Controlled Type I diabetes, hypothyroidism only requiring hormone replacement, controlled celiac disease, skin diseases (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. * History of interstitial lung disease, non-infectious pneumonitis or uncontrolled diseases including pulmonary fibrosis, acute lung diseases. * With infections requiring systemic antibacterial, antifungal, or antiviral therapy, including tuberculosis infection. * Severe infections within 4 weeks before first dose, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia. * Receive therapeutic oral or intravenous antibiotics within 2 weeks before first dose. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Complete Response (pCR) Rate | pCR was determined from samples taken during surgery; surgery occurred 4-6 weeks after the last dose of chemotherapy, approximately Day 71-86 | The pCR rate was defined as the percentage of participants with absence of residual tumor in the resected primary tumor and all resected lymph nodes after completion of neoadjuvant treatment. pCR rates were assessed by a pathologist at each site. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| R0 Resection Rate | Resection was planned to occur 4-6 weeks after the last dose of chemotherapy, approximately Day 71-86 | Defined as the percentage of participants with R0 resection. R0 resection refers to a surgical procedure where the entire tumor is completely removed with no evidence of residual cancer tissue at the surgical margins. |
| 1-year/3-year Disease-free Survival (DFS) Rate | 1 year and 3 years after surgery | The DFS rate is defined as the percentage of participants free from disease events at 1 year and 3 years after the first date of no disease (R0 resection as surgery outcome). Disease events include local or distant recurrence or death due to any cause. The DFS rate was analyzed only for participants who underwent R0 resection. Disease-free rates were estimated using the Kaplan-Meier method with 95% confidence intervals estimated using the Greenwood formula. |
| 1-year/3-year Event-free Survival (EFS) Rate | 1 year and 3 years after first dose date | The EFS rate is defined as the percentage of participants free from EFS events at 1 year and 3 years after the first dose. The EFS events include progression of disease that precludes definitive surgery, local or distant recurrence, or death due to any cause. Event-free rates were estimated using the Kaplan-Meier method with 95% confidence intervals estimated using the Greenwood formula. |
| Objective Response Rate (ORR) | ORR was assessed prior to surgery, Day 71 to 86 | The ORR is defined as the percentage of participants who have a complete response or partial response before surgery as assessed by the investigator per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) in all participants with measurable disease at baseline. Tumor response was assessed by computed tomography (CT) or magnetic resonance imaging (MRI) of the neck, chest, and abdomen. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Number Of Participants Experiencing Treatment-Emergent Adverse Events | From the first dose of study drug up to 30 days after last dose of any component of treatment or surgery or the initiation of subsequent anticancer therapy, whichever occurred first. Up to approximately 9 months. | Immune-mediated AEs were reported until 90 days after the last dose of tislelizumab |
Countries
China
Participant flow
Recruitment details
This study was conducted at 8 study centers in China.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A (Responder) Participants received induction therapy of one 21-day cycle with cisplatin and paclitaxel administered on Day 1. Following the induction phase, participants with a decrease in positron emission tomography (PET) Standardized Uptake Value (SUV)max ≥ 35% then received neoadjuvant therapy consisting of 200 mg tislelizumab on Day 1 of each 21-day cycle for 3 cycles and chemotherapy doublet (cisplatin + paclitaxel) for 2 cycles. After neoadjuvant treatment, participants were assessed for disease resectability and underwent surgical resection of the tumor approximately 4 to 6 weeks later. | 30 |
| Cohort B (Non-responder) Participants received induction therapy of one 21-day cycle with cisplatin and paclitaxel administered on Day 1. Following the induction phase, participants with a decrease in PET SUVmax \< 35% then received neoadjuvant therapy consisting of 200 mg tislelizumab on Day 1 of each 21-day cycle for 3 cycles and investigator-chosen chemotherapy doublet (paclitaxel + cisplatin or 5-fluorouracil + cisplatin) for 2 cycles plus concurrent radiotherapy. After neoadjuvant treatment, participants were assessed for disease resectability and underwent surgical resection of the tumor approximately 4 to 6 weeks later. | 40 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 8 | 17 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Sponsor Ended Study | 20 | 22 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort A (Responder) | Total | Cohort B (Non-responder) |
|---|---|---|---|
| Age, Continuous | 64.6 years STANDARD_DEVIATION 8.16 | 63.7 years STANDARD_DEVIATION 7.53 | 63.1 years STANDARD_DEVIATION 7.06 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 70 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 30 Participants | 70 Participants | 40 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment China | 30 participants | 70 participants | 40 participants |
| Sex: Female, Male Female | 6 Participants | 8 Participants | 2 Participants |
| Sex: Female, Male Male | 24 Participants | 62 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 8 / 30 | 17 / 40 |
| other Total, other adverse events | 30 / 30 | 39 / 40 |
| serious Total, serious adverse events | 8 / 30 | 12 / 40 |
Outcome results
Primary
Pathological Complete Response (pCR) Rate
The pCR rate was defined as the percentage of participants with absence of residual tumor in the resected primary tumor and all resected lymph nodes after completion of neoadjuvant treatment. pCR rates were assessed by a pathologist at each site.
Time frame: pCR was determined from samples taken during surgery; surgery occurred 4-6 weeks after the last dose of chemotherapy, approximately Day 71-86
Population: The Efficacy Evaluable Analysis Set included all participants who received neoadjuvant treatment followed by surgery.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A (Responder) | Pathological Complete Response (pCR) Rate | 30.0 percentage of participants |
| Cohort B (Non-responder) | Pathological Complete Response (pCR) Rate | 34.4 percentage of participants |
Secondary
1-year/3-year Disease-free Survival (DFS) Rate
The DFS rate is defined as the percentage of participants free from disease events at 1 year and 3 years after the first date of no disease (R0 resection as surgery outcome). Disease events include local or distant recurrence or death due to any cause. The DFS rate was analyzed only for participants who underwent R0 resection. Disease-free rates were estimated using the Kaplan-Meier method with 95% confidence intervals estimated using the Greenwood formula.
Time frame: 1 year and 3 years after surgery
Population: The Efficacy Evaluable Analysis Set with R0 resection included all participants who received neoadjuvant treatment followed by surgery with R0 resection. No participants were on follow-up for 3 years after surgery, so DFS rate at 3 years was not assessed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort A (Responder) | 1-year/3-year Disease-free Survival (DFS) Rate | 1 Year | 79.0 percentage of participants |
| Cohort B (Non-responder) | 1-year/3-year Disease-free Survival (DFS) Rate | 1 Year | 74.2 percentage of participants |
Secondary
1-year/3-year Event-free Survival (EFS) Rate
The EFS rate is defined as the percentage of participants free from EFS events at 1 year and 3 years after the first dose. The EFS events include progression of disease that precludes definitive surgery, local or distant recurrence, or death due to any cause. Event-free rates were estimated using the Kaplan-Meier method with 95% confidence intervals estimated using the Greenwood formula.
Time frame: 1 year and 3 years after first dose date
Population: The Safety Analysis Set included all participants who received at least one dose of any component of study drugs.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort A (Responder) | 1-year/3-year Event-free Survival (EFS) Rate | 1 Year | 87.1 percentage of participants |
| Cohort A (Responder) | 1-year/3-year Event-free Survival (EFS) Rate | 3 Years | 75.5 percentage of participants |
| Cohort B (Non-responder) | 1-year/3-year Event-free Survival (EFS) Rate | 1 Year | 67.8 percentage of participants |
| Cohort B (Non-responder) | 1-year/3-year Event-free Survival (EFS) Rate | 3 Years | 59.9 percentage of participants |
Secondary
Number Of Participants Experiencing Treatment-Emergent Adverse Events
Immune-mediated AEs were reported until 90 days after the last dose of tislelizumab
Time frame: From the first dose of study drug up to 30 days after last dose of any component of treatment or surgery or the initiation of subsequent anticancer therapy, whichever occurred first. Up to approximately 9 months.
Population: The Safety Analysis Set included all participants who received at least one dose of any component of study drugs.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A (Responder) | Number Of Participants Experiencing Treatment-Emergent Adverse Events | 30 Participants |
| Cohort B (Non-responder) | Number Of Participants Experiencing Treatment-Emergent Adverse Events | 39 Participants |
Secondary
Objective Response Rate (ORR)
The ORR is defined as the percentage of participants who have a complete response or partial response before surgery as assessed by the investigator per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) in all participants with measurable disease at baseline. Tumor response was assessed by computed tomography (CT) or magnetic resonance imaging (MRI) of the neck, chest, and abdomen. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: ORR was assessed prior to surgery, Day 71 to 86
Population: The Safety Analysis Set with Measurable Disease at Baseline included all participants who had measurable disease at baseline and received at least one dose of any component of study drugs.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A (Responder) | Objective Response Rate (ORR) | 71.4 percentage of participants |
| Cohort B (Non-responder) | Objective Response Rate (ORR) | 42.4 percentage of participants |
Secondary
R0 Resection Rate
Defined as the percentage of participants with R0 resection. R0 resection refers to a surgical procedure where the entire tumor is completely removed with no evidence of residual cancer tissue at the surgical margins.
Time frame: Resection was planned to occur 4-6 weeks after the last dose of chemotherapy, approximately Day 71-86
Population: The Efficacy Evaluable Analysis Set included all participants who received neoadjuvant treatment followed by surgery.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A (Responder) | R0 Resection Rate | 95.0 percentage of participants |
| Cohort B (Non-responder) | R0 Resection Rate | 90.6 percentage of participants |