Recurrent or Metastatic Nasopharyngeal Cancer
Conditions
Brief summary
This study was designed to compare the efficacy and safety of tislelizumab (BGB-A317) combined with gemcitabine plus cisplatin versus placebo combined with gemcitabine plus cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal cancer.
Interventions
DRUGTislelizumab
200 mg intravenously (IV) once every 3 weeks (Q3W)
DRUGPlacebo
Placebo to match tislelizumab (administered intravenously Q3W)
DRUGGemcitabine
1 gram per square meter of body surface area (g/m\^2) on Day 1 and day 8 of each cycle, administered as an IV infusion within 30 minutes, for 4 to 6 cycles
DRUGCisplatin
80 milligrams per square meter of body surface area (mg/m\^2) on Day 1 of each cycle, administered as an IV infusion for over 4 hours if possible or with proper infusion time based on local clinical guidelines or clinical practice and according to the treating physician's clinical judgment, for 4 to 6 cycles.
Sponsors
BeiGene
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 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments 2. Aged between 18 to 75 years on the day of signing the informed consent form (or the legal age of consent in the jurisdiction in which the study is taking place) 3. Histologically or cytologically confirmed, recurrent or metastatic NPC 4. Participants must be able to provide fresh or archival tumor tissues (formalin-fixed paraffin-embedded \[FFPE\] blocks or approximately 10 \[≥ 6\] freshly cut unstained FFPE slides) with an associated pathological report. The archival tumor tissues must be collected within 2 years before screening. In the absence of sufficient archival tumor tissues, a fresh biopsy of a tumor lesion at baseline is mandatory 5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 6. Must have ≥ 1 measurable lesions as defined per RECIST v1.1 7. Must be treatment-naive for recurrent or metastatic NPC. Key
Exclusion criteria
1. Participants with locally recurrence suitable for curative surgery or radiotherapy 2. Received any approved systemic anticancer therapy, including hormonal therapy, within 28 days prior to initiation of study treatment. The following exception is allowed: * Palliative radiotherapy for bone metastases or soft tissue lesions should be completed \> 7 days prior to baseline imaging. 3. Has received any immunotherapy (including but not limited to interferons, interleukin 2, tumor necrosis factor interleukin, and thymoxin) or any investigational therapies within 14 days or 5 half-lives (whichever is longer) of randomization 4. Received prior therapies targeting programmed cell death protein-1 (PD-1) or programmed cell death protein ligand-1 (PD-L1) 5. Active leptomeningeal disease or uncontrolled, untreated brain metastasis 6. Active autoimmune diseases or history of autoimmune diseases that may relapse 7. Any active malignancy ≤ 2 years before randomization except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast) NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival as Assessed by the Independent Review Committee (IRC) | Through the study interim data analysis cutoff date of March 26th, 2021 (maximum time on study follow-up was 23 months) | Defined as the time from randomization to the first objectively documented disease progression, or death from any cause, whichever occurred first, as assessed by the IRC per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Kaplan-Meier methodology was used to estimate the median PFS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) as Assessed by the IRC | Through the study interim data analysis cutoff date of March 26th, 2021 (maximum time on study follow-up was 23 months) | Defined as the time from the first occurrence of a documented objective response to the time of relapse, or death from any cause, whichever occurred first, as assessed by the IRC per RECIST v1.1 in all randomized participants with documented objective responses. |
| Overall Survival (OS) as Assessed by the IRC | Through study completion data cut-off date of December 8th, 2023 or last available date showing participants alive (maximum time on study follow-up was 53 months) | Defined as the time from the date of randomization to the date of death due to any cause. |
| PFS as Assessed by the Investigator | Through the interim analysis data cut-off date of March 26th, 2021 (up to approximately 23 months) | Defined as the time from randomization to the first objectively documented disease progression, or death from any cause, whichever occurred first, as assessed by the investigator per RECIST v1.1. |
| Overall Response Rate (ORR) as Assessed by the IRC | Through the study interim data analysis cutoff date of March 26th, 2021 (maximum time on study follow-up was 23 months) | Defined as the percentage of participants who had complete response or partial response as assessed by the IRC per RECIST v1.1 in all randomized participants with measurable disease at Baseline. |
| Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Global Health Status | Baseline to Cycle 6 (Each cycle is 21 days) | Change from baseline in EORTC QLQ-C30 Global Health Status/Quality of Life score. The EORTC QLQ-C30 v3.0 is a questionnaire that assesses quality of life of participants with cancer. It includes global health status and quality of life questions related to overall health in which participants respond based on a 7-point scale, where 1 is very poor and 7 is excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. A higher score indicates better health outcomes. |
| Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck-351 (EORTC QLQ-H&N35) Index Score | Baseline to Cycle 6 (Each cycle is 21 days) | The QLQ-H&N35 consists of thirty-five questions that are associated with eighteen symptom scales (pain, swallowing, senses, speech, social eating, social contact, sexuality, problem with teeth, problem opening mouth, dry mouth, problem with sense smell, cough, felt ill, pain med, nutritional supplements, feeding tube, weight loss and weight gain).. Raw scores are transformed into a 0 to 100 scale via linear transformation. The index score is calculated as an average of the 18 symptom scales. A negative change from baseline score indicates improvement in symptoms. |
| Number of Participants With Adverse Events | From first dose to 30 days after last dose or new anticancer therapy, or until Dec 8, 2023 data cut-off; max treatment duration: 231 weeks (Arm A), 202 weeks (Arm B). | Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), including laboratory tests, vital signs, electrocardiograms (ECGs), and physical examinations (PEs ), graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. For Arm B, only adverse events reported prior to participants crossing over to receive tislelizumab monotherapy are included. |
| Progression-free Survival After Next Line of Treatment (PFS2) as Assessed by the Investigator | Through the study completion data cut-off date of December 8th, 2023 (maximum time on study follow-up was 53 months) | Defined as the time from randomization to second/subsequent disease progression after initiation of new anticancer therapy, or death from any cause, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method. |
Countries
China, Taiwan, Thailand
Participant flow
Recruitment details
Participants were enrolled in multiple study centers in China, Thailand, and Taiwan. The first participant was consented on March 27th 2019, and the last participant completed on December 8th 2023.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Tislelizumab + Gemcitabine + Cisplatin Participants received tislelizumab 200 mg intravenously (IV) once every 3 weeks (Q3W), gemcitabine 1 g/m\^2 IV on days 1 and 8 of each 21-day cycle and cisplatin 80 mg/m\^2 IV on day 1 of each cycle for 4 to 6 treatment cycles. Participants may have received treatment for longer at the Investigator's discretion until disease progression. Participants with confirmed disease progression may have continued to receive tislelizumab monotherapy. | 131 |
| Arm B: Placebo + Gemcitabine + Cisplatin Participants received placebo IV once every 3 weeks, gemcitabine 1 g/m\^2 IV on days 1 and 8 of each 21-day cycle and cisplatin 80 mg/m\^2 IV on day 1 of each cycle for 4 to 6 treatment cycles. Participants may have received treatment for longer at the Investigator's discretion until disease progression. Participants with confirmed disease progression may have crossed over to receive tislelizumab 200 mg IV Q3W monotherapy. | 132 |
| Total | 263 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 57 | 66 |
| Overall Study | Lost to Follow-up | 7 | 5 |
| Overall Study | Miscellaneous | 1 | 0 |
| Overall Study | Study Concluded by Sponsor | 51 | 41 |
| Overall Study | Withdrawal by Subject | 15 | 20 |
Baseline characteristics
| Characteristic | Arm A: Tislelizumab + Gemcitabine + Cisplatin | Arm B: Placebo + Gemcitabine + Cisplatin | Total |
|---|---|---|---|
| Age, Continuous | 49.0 years STANDARD_DEVIATION 10.62 | 49.5 years STANDARD_DEVIATION 10.76 | 49.3 years STANDARD_DEVIATION 10.67 |
| Baseline Target Lesions Sum of Diameters Assessed by Investigator (mm) | 65.49 Millimeters (mm) STANDARD_DEVIATION 49.004 | 57.56 Millimeters (mm) STANDARD_DEVIATION 40.389 | 61.51 Millimeters (mm) STANDARD_DEVIATION 44.978 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment China | 122 participants | 126 participants | 248 participants |
| Region of Enrollment Taiwan | 4 participants | 5 participants | 9 participants |
| Region of Enrollment Thailand | 5 participants | 1 participants | 6 participants |
| Sex: Female, Male Female | 28 Participants | 29 Participants | 57 Participants |
| Sex: Female, Male Male | 103 Participants | 103 Participants | 206 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 57 / 133 | 31 / 130 | 35 / 70 |
| other Total, other adverse events | 133 / 133 | 129 / 130 | 60 / 70 |
| serious Total, serious adverse events | 47 / 133 | 46 / 130 | 15 / 70 |
Outcome results
Primary
Progression-free Survival as Assessed by the Independent Review Committee (IRC)
Defined as the time from randomization to the first objectively documented disease progression, or death from any cause, whichever occurred first, as assessed by the IRC per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Kaplan-Meier methodology was used to estimate the median PFS.
Time frame: Through the study interim data analysis cutoff date of March 26th, 2021 (maximum time on study follow-up was 23 months)
Population: ITT analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Tislelizumab + Gemcitabine + Cisplatin | Progression-free Survival as Assessed by the Independent Review Committee (IRC) | 9.2 Months |
| Arm B: Placebo + Gemcitabine + Cisplatin | Progression-free Survival as Assessed by the Independent Review Committee (IRC) | 7.4 Months |
Comparison: The null hypothesis to be tested is that progression-free survival (PFS) in Arm A is less than or equal to PFS in Arm B. This is compared against the alternative hypothesis, which posits that PFS in Arm A is greater than PFS in Arm B.95% CI: [0.38, 0.73]
Secondary
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Global Health Status
Change from baseline in EORTC QLQ-C30 Global Health Status/Quality of Life score. The EORTC QLQ-C30 v3.0 is a questionnaire that assesses quality of life of participants with cancer. It includes global health status and quality of life questions related to overall health in which participants respond based on a 7-point scale, where 1 is very poor and 7 is excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. A higher score indicates better health outcomes.
Time frame: Baseline to Cycle 6 (Each cycle is 21 days)
Population: The HRQoL analysis set includes all randomized participants who received any dose of study drug and completed at least one HRQoL assessment. Only participants with data at both baseline and the each postbaseline visit are included in the summary statistics for change from baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Tislelizumab + Gemcitabine + Cisplatin | Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Global Health Status | 0.2 score on a scale | Standard Deviation 25.18 |
| Arm B: Placebo + Gemcitabine + Cisplatin | Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Global Health Status | -0.1 score on a scale | Standard Deviation 20.72 |
Secondary
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck-351 (EORTC QLQ-H&N35) Index Score
The QLQ-H&N35 consists of thirty-five questions that are associated with eighteen symptom scales (pain, swallowing, senses, speech, social eating, social contact, sexuality, problem with teeth, problem opening mouth, dry mouth, problem with sense smell, cough, felt ill, pain med, nutritional supplements, feeding tube, weight loss and weight gain).. Raw scores are transformed into a 0 to 100 scale via linear transformation. The index score is calculated as an average of the 18 symptom scales. A negative change from baseline score indicates improvement in symptoms.
Time frame: Baseline to Cycle 6 (Each cycle is 21 days)
Population: The HRQoL analysis set includes all randomized participants who received any dose of study drug and completed at least one HRQoL assessment. Only participants with data at both baseline and the each postbaseline visit are included in the summary statistics for change from baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Tislelizumab + Gemcitabine + Cisplatin | Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck-351 (EORTC QLQ-H&N35) Index Score | -0.3 score on a scale | Standard Deviation 6.4 |
| Arm B: Placebo + Gemcitabine + Cisplatin | Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck-351 (EORTC QLQ-H&N35) Index Score | -0.3 score on a scale | Standard Deviation 7.17 |
Secondary
Duration of Response (DOR) as Assessed by the IRC
Defined as the time from the first occurrence of a documented objective response to the time of relapse, or death from any cause, whichever occurred first, as assessed by the IRC per RECIST v1.1 in all randomized participants with documented objective responses.
Time frame: Through the study interim data analysis cutoff date of March 26th, 2021 (maximum time on study follow-up was 23 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Tislelizumab + Gemcitabine + Cisplatin | Duration of Response (DOR) as Assessed by the IRC | 8.5 months |
| Arm B: Placebo + Gemcitabine + Cisplatin | Duration of Response (DOR) as Assessed by the IRC | 6.1 months |
Secondary
Number of Participants With Adverse Events
Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), including laboratory tests, vital signs, electrocardiograms (ECGs), and physical examinations (PEs ), graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. For Arm B, only adverse events reported prior to participants crossing over to receive tislelizumab monotherapy are included.
Time frame: From first dose to 30 days after last dose or new anticancer therapy, or until Dec 8, 2023 data cut-off; max treatment duration: 231 weeks (Arm A), 202 weeks (Arm B).
Population: The Safety analysis set includes all randomized participants who received any dose of any component of study drug. Two participants randomized to Arm B who received 100 mg tislelizumab in error were analyzed as part of Arm A for the Safety Analysis Set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: Tislelizumab + Gemcitabine + Cisplatin | Number of Participants With Adverse Events | TEAEs | 133 Participants |
| Arm A: Tislelizumab + Gemcitabine + Cisplatin | Number of Participants With Adverse Events | SAEs | 47 Participants |
| Arm B: Placebo + Gemcitabine + Cisplatin | Number of Participants With Adverse Events | TEAEs | 129 Participants |
| Arm B: Placebo + Gemcitabine + Cisplatin | Number of Participants With Adverse Events | SAEs | 46 Participants |
Secondary
Overall Response Rate (ORR) as Assessed by the IRC
Defined as the percentage of participants who had complete response or partial response as assessed by the IRC per RECIST v1.1 in all randomized participants with measurable disease at Baseline.
Time frame: Through the study interim data analysis cutoff date of March 26th, 2021 (maximum time on study follow-up was 23 months)
Population: ITT analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Tislelizumab + Gemcitabine + Cisplatin | Overall Response Rate (ORR) as Assessed by the IRC | 69.5 percentage of participants |
| Arm B: Placebo + Gemcitabine + Cisplatin | Overall Response Rate (ORR) as Assessed by the IRC | 55.3 percentage of participants |
95% CI: [1.11, 3.07]
Secondary
Overall Survival (OS) as Assessed by the IRC
Defined as the time from the date of randomization to the date of death due to any cause.
Time frame: Through study completion data cut-off date of December 8th, 2023 or last available date showing participants alive (maximum time on study follow-up was 53 months)
Population: ITT analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Tislelizumab + Gemcitabine + Cisplatin | Overall Survival (OS) as Assessed by the IRC | 45.3 Months |
| Arm B: Placebo + Gemcitabine + Cisplatin | Overall Survival (OS) as Assessed by the IRC | 31.8 Months |
95% CI: [0.51, 1.05]
Secondary
PFS as Assessed by the Investigator
Defined as the time from randomization to the first objectively documented disease progression, or death from any cause, whichever occurred first, as assessed by the investigator per RECIST v1.1.
Time frame: Through the interim analysis data cut-off date of March 26th, 2021 (up to approximately 23 months)
Population: ITT analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Tislelizumab + Gemcitabine + Cisplatin | PFS as Assessed by the Investigator | 9.8 months |
| Arm B: Placebo + Gemcitabine + Cisplatin | PFS as Assessed by the Investigator | 7.6 months |
Comparison: The null hypothesis to be tested is that progression-free survival (PFS) in Arm A is less than or equal to PFS in Arm B. This is compared against the alternative hypothesis, which posits that PFS in Arm A is greater than PFS in Arm B.95% CI: [0.38, 0.76]
Secondary
Progression-free Survival After Next Line of Treatment (PFS2) as Assessed by the Investigator
Defined as the time from randomization to second/subsequent disease progression after initiation of new anticancer therapy, or death from any cause, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method.
Time frame: Through the study completion data cut-off date of December 8th, 2023 (maximum time on study follow-up was 53 months)
Population: ITT analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Tislelizumab + Gemcitabine + Cisplatin | Progression-free Survival After Next Line of Treatment (PFS2) as Assessed by the Investigator | 45.3 months |
| Arm B: Placebo + Gemcitabine + Cisplatin | Progression-free Survival After Next Line of Treatment (PFS2) as Assessed by the Investigator | 20.5 months |