Carcinoma, Transitional Cell
Conditions
Brief summary
This Phase III, open-label, randomized, multicenter study is to evaluate the efficacy and safety of adjuvant treatment with atezolizumab compared with observation in participants with muscle-invasive UC who are at high risk for recurrence following resection. Eligible participants were randomized by a 1:1 ratio into atezolizumab group or control group.
Interventions
DRUGAtezolizumab
Atezolizumab will be administered at a dose of 1200 milligrams (mg).
Sponsors
Hoffmann-La Roche
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
* Histologically confirmed muscle-invasive UC (also termed transitional cell carcinoma) of the bladder or upper urinary tract (i.e., renal pelvis or ureters) * For participants treated with prior neoadjuvant chemotherapy: tumor stage of ypT2-4a or ypN+ (ypT2-4 or ypN+ for participants with upper urinary tract UC) and M0 * For participants who have not received prior neoadjuvant chemotherapy: tumor stage of pT3-4a or pN+ (pT3-4 or pN+ for participants with upper urinary tract UC) and M0 * Representative formalin-fixed paraffin-embedded tumor specimens from surgical resection (i.e., radical cystectomy, nephroureterectomy, or lymph node dissection) in paraffin blocks (blocks preferred) or at least 15 unstained slides, with an associated pathology report, for central testing and determined to be evaluable for tumor programmed death-ligand 1 (PD-L1) expression prior to study enrollment * Absence of residual disease and absence of metastasis, as confirmed by a negative baseline computed tomography (CT) or magnetic resonance imaging scan of the pelvis, abdomen, and chest no more than 4 weeks prior to randomization * Full recovery from cystectomy or nephroureterectomy within 14 weeks following surgery * Eastern Cooperative Oncology Group performance status of less than or equal to (\</=) 2 * Life expectancy greater than or equal to (\>/=) 12 weeks * Adequate hematologic and end-organ function * For women who are not postmenopausal or surgically sterile: agreement to remain abstinent or use contraceptive methods that result in a failure rate of less than (\<) 1 percent (%) per year during the treatment period and for at least 5 months after the last dose of atezolizumab
Exclusion criteria
* Any approved anti-cancer therapy within 3 weeks prior to initiation of study treatment * Adjuvant chemotherapy or radiation therapy for UC following surgical resection * Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days or five half-lives of the drug prior to enrollment * Malignancies other than UC within 5 years prior to Cycle 1, Day 1 * Pregnancy or breastfeeding * Significant cardiovascular disease * Severe infections within 4 weeks prior to Cycle 1, Day 1 * Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1, Day 1 * History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins * Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation * History of autoimmune disease * Prior allogeneic stem cell or solid organ transplant * History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan * Positive test for human immunodeficiency virus and/or active hepatitis B or hepatitis C or tuberculosis * Administration of a live, attenuated vaccine within 4 weeks before Cycle 1 Day 1 * Prior treatment with cluster of differentiation 137 (CD137) agonists or immune checkpoint blockade therapies, including anti-CD40, anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), anti-programmed death-1 (anti-PD-1), and anti-PD-L1 therapeutic antibodies
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-Free Survival (DFS), as Assessed by Investigator | Randomization up to first occurrence of DFS event (up to approximately 50 months) | DFS is defined as the time from randomization to the time of first occurrence of a DFS event. DFS events include: local (pelvic) recurrence of UC (including soft tissue and regional lymph nodes); urinary tract recurrence of UC (including all pathological stages and grades); distant metastasis of UC; or death from any cause. Tumor assessment will be performed using radiographic evaluations. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease-Specific Survival (DSS), as Assessed by Investigator | Randomization until death due to UC (up to approximately 50 months) | DSS is defined as the time from randomization until the date of death from UC. |
| Distant Metastasis-Free Survival (DMFS) | Randomization up to diagnosis of distant metastases or death from any cause (up to approximately 50 months) | DMFS is defined as the time from randomization to the date of diagnosis of distant (that is, non-locoregional) metastases or death from any cause. Tumor assessment will be performed using radiographic evaluations. |
| Non-Urinary Tract Recurrence-Free Survival (NURFS) | Randomization up to time of first occurrence of a NURFS event (up to approximately 50 months) | NURFS is defined as the time from randomization to the time of first occurrence of a NURFS event. NURFS events include: local (pelvic) recurrence of UC (including soft tissue and regional lymph nodes); distant metastasis of UC; or death from any cause. Tumor assessment will be performed using radiographic evaluations. |
| Percentage of Participants With Adverse Events (AEs) | Screening up to approximately 80 months | Percentage of participants with at least one Adverse Event. |
| Overall Survival (OS) | Randomization until death due to any cause (up to approximately 80 months) | Overall survival is defined as the time from randomization to the date of death from any cause, regardless of whether the death occurs during study treatment or following treatment discontinuation. |
| EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score | Day 1 of Cycle 1 up to approximately 50 months (Cycle length = 21 days) | The EQ-5D-5L is a generic preference-based HRQoL questionnaire that provides a single index value for health status and is used to inform pharmacoeconomic evaluations and to measure general health status. Visual analog scale (VAS) allows the patient to indicate, on a scale of 0-100, how his or her health is on the day of assessment, with 100 being the best imaginable health state and 0 being the worst imaginable health state. |
| Minimum Observed Serum Atezolizumab Concentration (Cmin) | Pre-dose (Hour 0) on Day 1 of Cycles 1, 2, 3, 4, every 8 cycles from Cycle 8, at treatment discontinuation, 120 days after treatment discontinuation (up to approximately 50 months))(Cycle length = 21 days) | Minimum observed serum atezolizumab concentration (Cmin) prior to infusion on Day 1 of Cycles 1, 2, 3, and 4; every 8 cycles starting on Cycle 8; at treatment discontinuation; and at 120 days after the last dose of atezolizumab. |
| Maximum Observed Serum Atezolizumab Concentration (Cmax) | Day 1 of Cycle 1 (Cycle length = 21 days) | Maximum observed serum atezolizumab concentration (Cmax) after infusion on Day 1 of Cycle 1. |
| Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab | Baseline up to approximately 50 months | Percentage of participants with anti-therapeutic antibodies to atezolizumab. |
Countries
Australia, Belgium, Canada, China, Czechia, Finland, France, Germany, Greece, Israel, Italy, Japan, Netherlands, Poland, Russia, Serbia, South Korea, Spain, Switzerland, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Observation Participants underwent observation starting on Day 1 for 16 cycles (up to 1 year). | 403 |
| Atezolizumab Participants received intravenous (IV) atezolizumab on Day 1 of each 21-day cycle for 16 cycles (up to 1 year). | 406 |
| Total | 809 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 162 | 171 |
| Overall Study | Lost to Follow-up | 14 | 12 |
| Overall Study | Non-specified other | 1 | 1 |
| Overall Study | Withdrawal by Subject | 55 | 44 |
Baseline characteristics
| Characteristic | Atezolizumab | Total | Observation |
|---|---|---|---|
| Age, Continuous | 66.0 Years STANDARD_DEVIATION 9 | 65.9 Years STANDARD_DEVIATION 9.1 | 65.9 Years STANDARD_DEVIATION 9.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 25 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 369 Participants | 726 Participants | 357 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 21 Participants | 58 Participants | 37 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Number of Participants | 1 Number of Participants | 0 Number of Participants |
| Race/Ethnicity, Customized Asian | 64 Number of Participants | 132 Number of Participants | 68 Number of Participants |
| Race/Ethnicity, Customized Black or African American | 3 Number of Participants | 6 Number of Participants | 3 Number of Participants |
| Race/Ethnicity, Customized Other | 6 Number of Participants | 10 Number of Participants | 4 Number of Participants |
| Race/Ethnicity, Customized Unknown | 12 Number of Participants | 33 Number of Participants | 21 Number of Participants |
| Race/Ethnicity, Customized White | 320 Number of Participants | 627 Number of Participants | 307 Number of Participants |
| Sex: Female, Male Female | 84 Participants | 171 Participants | 87 Participants |
| Sex: Female, Male Male | 322 Participants | 638 Participants | 316 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 162 / 403 | 171 / 406 |
| other Total, other adverse events | 234 / 398 | 324 / 390 |
| serious Total, serious adverse events | 72 / 398 | 122 / 390 |
Outcome results
Primary
Disease-Free Survival (DFS), as Assessed by Investigator
DFS is defined as the time from randomization to the time of first occurrence of a DFS event. DFS events include: local (pelvic) recurrence of UC (including soft tissue and regional lymph nodes); urinary tract recurrence of UC (including all pathological stages and grades); distant metastasis of UC; or death from any cause. Tumor assessment will be performed using radiographic evaluations.
Time frame: Randomization up to first occurrence of DFS event (up to approximately 50 months)
Population: The ITT population is defined as all randomized patients, whether or not the patient received the assigned treatment (atezolizumab/observation).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Observation | Disease-Free Survival (DFS), as Assessed by Investigator | 16.6 Months |
| Atezolizumab | Disease-Free Survival (DFS), as Assessed by Investigator | 19.4 Months |
p-value: 0.244695% CI: [0.735, 1.081]Log Rank
Secondary
Disease-Specific Survival (DSS), as Assessed by Investigator
DSS is defined as the time from randomization until the date of death from UC.
Time frame: Randomization until death due to UC (up to approximately 50 months)
Population: The ITT population is defined as all randomized patients, whether or not the patient received the assigned treatment (atezolizumab/observation).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Observation | Disease-Specific Survival (DSS), as Assessed by Investigator | NA Months |
| Atezolizumab | Disease-Specific Survival (DSS), as Assessed by Investigator | NA Months |
p-value: 0.223595% CI: [0.626, 1.116]Log Rank
Secondary
Distant Metastasis-Free Survival (DMFS)
DMFS is defined as the time from randomization to the date of diagnosis of distant (that is, non-locoregional) metastases or death from any cause. Tumor assessment will be performed using radiographic evaluations.
Time frame: Randomization up to diagnosis of distant metastases or death from any cause (up to approximately 50 months)
Population: The ITT population is defined as all randomized patients, whether or not the patient received the assigned treatment (atezolizumab/observation).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Observation | Distant Metastasis-Free Survival (DMFS) | 31.1 Months |
| Atezolizumab | Distant Metastasis-Free Survival (DMFS) | 27.5 Months |
p-value: 0.429195% CI: [0.743, 1.134]Log Rank
Secondary
EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score
The EQ-5D-5L is a generic preference-based HRQoL questionnaire that provides a single index value for health status and is used to inform pharmacoeconomic evaluations and to measure general health status. Visual analog scale (VAS) allows the patient to indicate, on a scale of 0-100, how his or her health is on the day of assessment, with 100 being the best imaginable health state and 0 being the worst imaginable health state.
Time frame: Day 1 of Cycle 1 up to approximately 50 months (Cycle length = 21 days)
Population: The ITT population is defined as all randomized patients, whether or not the patient received the assigned treatment (atezolizumab/observation).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Observation | EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score | Cycle 3 Day 1 | 78.64 Score on scale | Standard Deviation 15.73 |
| Observation | EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score | Cycle 11 Day 1 | 81.39 Score on scale | Standard Deviation 17.02 |
| Observation | EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score | Cycle 7 Day 1 | 80.81 Score on scale | Standard Deviation 16.37 |
| Observation | EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score | Cycle 13 Day 1 | 81.39 Score on scale | Standard Deviation 16.99 |
| Observation | EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score | Cycle 5 Day 1 | 79.94 Score on scale | Standard Deviation 16.32 |
| Observation | EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score | Cycle 15 Day 1 | 82.78 Score on scale | Standard Deviation 16.01 |
| Observation | EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score | Cycle 9 Day 1 | 81.24 Score on scale | Standard Deviation 15.7 |
| Observation | EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score | Treatment Discontinuation | 82.68 Score on scale | Standard Deviation 16.19 |
| Observation | EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score | Cycle 1 Day 1 | 77.41 Score on scale | Standard Deviation 15.74 |
| Atezolizumab | EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score | Treatment Discontinuation | 81.91 Score on scale | Standard Deviation 15.96 |
| Atezolizumab | EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score | Cycle 1 Day 1 | 78.89 Score on scale | Standard Deviation 16.13 |
| Atezolizumab | EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score | Cycle 3 Day 1 | 81.05 Score on scale | Standard Deviation 14.96 |
| Atezolizumab | EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score | Cycle 5 Day 1 | 81.95 Score on scale | Standard Deviation 14.32 |
| Atezolizumab | EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score | Cycle 7 Day 1 | 82.39 Score on scale | Standard Deviation 14.43 |
| Atezolizumab | EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score | Cycle 9 Day 1 | 82.06 Score on scale | Standard Deviation 15.34 |
| Atezolizumab | EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score | Cycle 11 Day 1 | 82.81 Score on scale | Standard Deviation 14.96 |
| Atezolizumab | EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score | Cycle 13 Day 1 | 82.59 Score on scale | Standard Deviation 14.81 |
| Atezolizumab | EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score | Cycle 15 Day 1 | 83.67 Score on scale | Standard Deviation 14.47 |
Secondary
Maximum Observed Serum Atezolizumab Concentration (Cmax)
Maximum observed serum atezolizumab concentration (Cmax) after infusion on Day 1 of Cycle 1.
Time frame: Day 1 of Cycle 1 (Cycle length = 21 days)
Population: The pharmacokinetic-evaluable population is defined as all patients who received any dose of atezolizumab and who have evaluable pharmacokinetic (PK) samples.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Observation | Maximum Observed Serum Atezolizumab Concentration (Cmax) | 365 µg/mL | Standard Deviation 121 |
Secondary
Minimum Observed Serum Atezolizumab Concentration (Cmin)
Minimum observed serum atezolizumab concentration (Cmin) prior to infusion on Day 1 of Cycles 1, 2, 3, and 4; every 8 cycles starting on Cycle 8; at treatment discontinuation; and at 120 days after the last dose of atezolizumab.
Time frame: Pre-dose (Hour 0) on Day 1 of Cycles 1, 2, 3, 4, every 8 cycles from Cycle 8, at treatment discontinuation, 120 days after treatment discontinuation (up to approximately 50 months))(Cycle length = 21 days)
Population: The pharmacokinetic-evaluable population is defined as all patients who received any dose of atezolizumab and who have evaluable pharmacokinetic (PK) samples.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Observation | Minimum Observed Serum Atezolizumab Concentration (Cmin) | Cycle 2 Day 1 | 78.4 µg/mL | Standard Deviation 25.2 |
| Observation | Minimum Observed Serum Atezolizumab Concentration (Cmin) | Cycle 3 Day 1 | 125 µg/mL | Standard Deviation 46 |
| Observation | Minimum Observed Serum Atezolizumab Concentration (Cmin) | Cycle 4 Day 1 | 152 µg/mL | Standard Deviation 71.1 |
| Observation | Minimum Observed Serum Atezolizumab Concentration (Cmin) | Cycle 8 Day 1 | 203 µg/mL | Standard Deviation 92 |
| Observation | Minimum Observed Serum Atezolizumab Concentration (Cmin) | Cycle 16 Day 1 | 225 µg/mL | Standard Deviation 106 |
| Observation | Minimum Observed Serum Atezolizumab Concentration (Cmin) | Day 120 Post Last Dose MPDL3280A | 15.9 µg/mL | Standard Deviation 19.5 |
| Observation | Minimum Observed Serum Atezolizumab Concentration (Cmin) | Study Drug or Study Phase Comp or Early Disc | 164 µg/mL | Standard Deviation 106 |
Secondary
Non-Urinary Tract Recurrence-Free Survival (NURFS)
NURFS is defined as the time from randomization to the time of first occurrence of a NURFS event. NURFS events include: local (pelvic) recurrence of UC (including soft tissue and regional lymph nodes); distant metastasis of UC; or death from any cause. Tumor assessment will be performed using radiographic evaluations.
Time frame: Randomization up to time of first occurrence of a NURFS event (up to approximately 50 months)
Population: The ITT population is defined as all randomized patients, whether or not the patient received the assigned treatment (atezolizumab/observation).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Observation | Non-Urinary Tract Recurrence-Free Survival (NURFS) | 19.5 Months |
| Atezolizumab | Non-Urinary Tract Recurrence-Free Survival (NURFS) | 22.1 Months |
p-value: 0.199495% CI: [0.722, 1.07]Log Rank
Secondary
Overall Survival (OS)
Overall survival is defined as the time from randomization to the date of death from any cause, regardless of whether the death occurs during study treatment or following treatment discontinuation.
Time frame: Randomization until death due to any cause (up to approximately 80 months)
Population: The ITT population is defined as all randomized patients, whether or not the patient received the assigned treatment (atezolizumab/observation).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Observation | Overall Survival (OS) | 59.0 Months |
| Atezolizumab | Overall Survival (OS) | 61.4 Months |
Comparison: Stratified analysis based on PDL1 status, tumor stage after resection, and nodal status.p-value: 0.317295% CI: [0.726, 1.109]Log Rank
Secondary
Percentage of Participants With Adverse Events (AEs)
Percentage of participants with at least one Adverse Event.
Time frame: Screening up to approximately 80 months
Population: The safety population is defined as patients who received at least one dose of atezolizumab, and all patients who did not receive any dose of atezolizumab who had at least one post-baseline safety assessment (e.g.,adverse event, lab, vital signs, ECG, etc.), regardless of their assigned treatment (atezolizumab/observation).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Observation | Percentage of Participants With Adverse Events (AEs) | 79.1 Percentage of Participants |
| Atezolizumab | Percentage of Participants With Adverse Events (AEs) | 94.4 Percentage of Participants |
Secondary
Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab
Percentage of participants with anti-therapeutic antibodies to atezolizumab.
Time frame: Baseline up to approximately 50 months
Population: The anti-drug antibodies (ADA)-evaluable population is defined as all patients treated with atezolizumab who have at least one post-baseline ADA result.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Observation | Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab | 29.3 Percentage of Participants |