Triple-Negative Breast Cancer
Conditions
Brief summary
This Phase 3, multicenter, randomized, double-blind, placebo controlled study is designed to evaluate the efficacy and safety of atezolizumab (MPDL3280A, an anti-programmed death-ligand 1 \[PD-L1\] antibody) administered in combination with paclitaxel compared with placebo in combination with paclitaxel in participants with previously untreated, inoperable locally advanced or metastatic, centrally confirmed TNBC. Participants will be randomized in a 2:1 ratio to receive atezolizumab or placebo plus paclitaxel until disease progression or unacceptable toxicity or end of study, whichever occurs first (maximum up to approximately 40 months). In addition, the Sponsor may decide to terminate the study at any time.
Interventions
Atezolizumab will be administered at a dose of 840 mg via IV infusion on Days 1 and 15 (± 3 days) of every 28-day cycle.
Placebo matching to atezolizumab will be administered via IV infusion on Days 1 and 15 (± 3 days) of every 28-day cycle.
DRUGPaclitaxel
Paclitaxel will be administered at a dose of 90 mg/m\^2 via IV infusion on Days 1, 8, and 15 of every 28-day cycle.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
The Sponsor and its agents; the study site personnel, including the investigator; and the participant will be blinded to treatment assignment.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants with locally advanced or metastatic, histologically documented TNBC (absence of human epidermal growth factor receptor 2 \[HER2\], estrogen receptor \[ER\], and progesterone receptor \[PR\] expression), not amenable to surgical therapy * Participants eligible for taxane monotherapy * No prior chemotherapy or targeted systemic therapy (including endocrine therapy) for inoperable locally advanced or metastatic TNBC * Availability of formalin-fixed paraffin-embedded (FFPE) tumor block (preferred) or at least 17 unstained slides, collected ≤3 months prior to randomization, with an associated pathology report, if available. If a tumour sample taken within 3 months before randomisation is not available and a tumour biopsy is not clinically feasible, the primary surgical resection sample or the most recent FFPE tumour biopsy sample may be used. Of these additional options, the most recent sample should be used. * Eastern Cooperative Oncology Group performance status of 0 or 1 * Life expectancy at least 12 weeks * Measurable disease, as defined by RECIST v1.1 * Adequate hematologic and end-organ function * Negative human immunodeficiency virus (HIV) test at screening. * Negative hepatitis B surface antigen (HBsAg) test at screening * Negative total hepatitis B core antibody (HBcAb) test at screening, or positive HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening. The HBV DNA test will be performed only for patients who have a positive HBcAb test. * Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening. The HCV RNA test will be performed only for patients who have a positive HCV antibody test. * Women of child bearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study drug * For men and women of child bearing potential: agreement to remain abstinent or use protocol defined contraceptive measures during the treatment period and for at least 5 months after the last dose of atezolizumab/placebo, or for at least 6 months after the last dose of paclitaxel
Exclusion criteria
* Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for at least 2 weeks prior to randomization * Known central nervous system (CNS) disease, except for treated asymptomatic CNS metastases * Leptomeningeal disease * Uncontrolled pleural effusion, pericardial effusion, or ascites * Uncontrolled tumor-related pain, or uncontrolled hypercalcemia or clinically significant (symptomatic) hypercalcemia * Malignancies other than TNBC within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer) * Pregnant or breast-feeding women, or intending to become pregnant during the study * Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease, cardiovascular disease, and presence of an abnormal electrocardiogram (ECG) * Serious infection requiring antibiotics within 2 weeks prior to randomization, including but not limited to infections requiring hospitalization or IV antibiotics, such as bacteremia, or severe pneumonia * Major surgical procedure within 4 weeks prior to randomization or anticipation of the need for a major surgical procedure during the study other than for diagnosis * Treatment with investigational therapy within 30 days prior to initiation of study treatment * History of hypersensitivity reactions to study drug or any component of the study drug formulation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the Subpopulation With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status | From Day 1 to disease progression (PD) or death from any cause, assessed up to primary completion date (approximately 26 months) | PFS is defined as the time from randomization to the first occurrence of PD, as determined by the investigator using RECIST v1.1, or death from any cause during the study, whichever occurs first. PD is defined as greater than or equal to (\>/=) 20 percent (%) relative increase and \>/=5 millimeter (mm) of absolute increase in the sum of diameters (SD) of target lesions (TLs), taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. |
| Progression-Free Survival (PFS) Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the Intent-to-Treat (ITT) Population | From Day 1 to disease progression (PD) or death from any cause, assessed up to primary completion date (approximately 26 months) | PFS is defined as the time from randomization to the first occurrence of PD, as determined by the investigator using RECIST v1.1, or death from any cause during the study, whichever occurs first. PD is defined as greater than or equal to (\>/=) 20 percent (%) relative increase and \>/=5 millimeter (mm) of absolute increase in the sum of diameters (SD) of target lesions (TLs), taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Are Alive at 12 and 18 Months | From Day 1 to death from any cause, assessed up to 12 and 18 months | — |
| Time to Deterioration (TTD) in Global Health Status/ Health Related Quality of Life (HRQoL) in the PRO Evaluable Population | From Day 1 to deterioration, assessed up 64 months | Deterioration in Global Health Status/HRQoL is defined as a decrease of at least 10 points on the Global Health Status /HRQoL scale (comprised of 2 items: 29 and 30) of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). The 2 items use 7-point scale (1 = very poor to 7 = Excellent). Scores are averaged, transformed to 0-100 scale; where higher score=better level of functioning or greater degree of symptoms. |
| Percentage of Participants Who Are Alive Without Progression Event at Month 12 Assessed Using RECIST v1.1 | From Day 1 to PD or death from any cause, assessed up to 12 months | PD is defined as \>/=20% relative increase and \>/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. |
| Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the PD-L1-Positive Population (Confirmed, Investigator-Assessed ) | From Day 1 to PD, assessed up to primary completion date (approximately 26 months) | Objective response is defined as complete response (CR) or partial response (PR), as determined by the investigator using RECIST v1.1 criteria. CR is defined as the disappearance of all TLs and SA reduction to less than (\<) 10mm for nodal TLs/ non-TLs. PR is defined as \>/=30% decrease in SD of TLs, taking as reference the baseline SD. Responses were confirmed after 8 weeks if within first 12 months or after 12 weeks if later. |
| Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the PD-L1-Positive Population (Unconfirmed, Investigator-Assessed) | From Day 1 to PD, assessed up to primary completion date (approximately 26 months) | Objective response is defined as complete response (CR) or partial response (PR), as determined by the investigator using RECIST v1.1 criteria. CR is defined as the disappearance of all TLs and SA reduction to less than (\<) 10mm for nodal TLs/ non-TLs. PR is defined as \>/=30% decrease in SD of TLs, taking as reference the baseline SD. |
| Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the Response-Evaluable Population (Confirmed, Investigator-Assessed ) | From Day 1 to PD, assessed up to primary completion date (approximately 26 months) | Objective response is defined as complete response (CR) or partial response (PR), as determined by the investigator using RECIST v1.1 criteria. CR is defined as the disappearance of all TLs and SA reduction to less than (\<) 10mm for nodal TLs/ non-TLs. PR is defined as \>/=30% decrease in SD of TLs, taking as reference the baseline SD. Responses were confirmed after 8 weeks if within first 12 months or after 12 weeks if later. |
| Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the Response-Evaluable Population (Unconfirmed, Investigator-Assessed ) | From Day 1 to PD, assessed up to primary completion date (approximately 26 months) | Objective response is defined as complete response (CR) or partial response (PR), as determined by the investigator using RECIST v1.1 criteria. CR is defined as the disappearance of all TLs and SA reduction to less than (\<) 10mm for nodal TLs/ non-TLs. PR is defined as \>/=30% decrease in SD of TLs, taking as reference the baseline SD. |
| Duration of Objective Response (DOR) Assessed Using RECIST v1.1 in DOR-evaluable Population (Unconfirmed) | From objective response to PD, assessed up to primary completion date (approximately 26 months) | DOR is defined as the time period from the date of initial CR or PR until the date of PD or death from any cause, whichever occurs first. CR is defined as the disappearance of all TLs and SA reduction to \<10mm for nodal TLs/ non-TLs. PR is defined as \>/=30% decrease in SD of TLs, taking as reference the baseline SD. PD is defined as \>/=20% relative increase and \>/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. |
| Percentage of Participants With Clinical Benefit Assessed Using RECIST v1.1 in Response-evaluable Population | From Day 1 to PD, assessed up to primary completion date (approximately 26 months) | Clinical benefit is defined as the achievement of CR, PR, or stable disease according to RECIST v1.1 that lasts for at least 6 months. CR is defined as the disappearance of all TLs and SA reduction to \<10mm for nodal TLs/ non-TLs. PR is defined as \>/=30% decrease in SD of TLs, taking as reference the baseline SD. PD is defined as \>/=20% relative increase and \>/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. Stable disease is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference smallest SD since treatment started. |
| Overall Survival (OS) in the PD-L1-Positive Subpopulation | From Day 1 to death from any cause, assessed up 36 months | OS is defined as the time from randomization to death from any cause. Results from a pre-specified interim analysis. |
| Maximum Observed Serum Concentration (Cmax) of Atezolizumab in PK-evaluable Population | C1D1 30 min postdose | — |
| Minimum Observed Plasma Concentration (Cmin) of Paclitaxel | Pre-dose (0 hours) on Day 1 of Cycle 3 (1 Cycle = 28 days) | — |
| Maximum Observed Plasma Concentration (Cmax) of Paclitaxel | Pre-dose (0 hours), 5-10 min before and after paclitaxel infusion, 60 min after paclitaxel infusion on Day 1 of Cycles 1 and 3 (paclitaxel infusion duration= 60 min) (1 Cycle = 28 days) | — |
| Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) | From Day 1 From baseline up to 64 months | Investigator text for AEs is coded using MedDRA version 25.1 |
| Percentage of Participants With Anti-Drug Antibodies' (ADAs) Against Atezolizumab in ADA Evaluable Population | Pre-dose (0 hours) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16, and at every 8 cycles thereafter until TD, at TD, and at 90-150 days after TD (maximum up to 45 months) (1 Cycle = 28 days) | — |
| Overall Survival by PD-L1 Status, Intent to Treat Population | From Day 1 up to 66 months | — |
| Progression Free Survival by PD-L1 Status, Intent to Treat Population | From Day 1 up to primary completion date (approximately 26 months) | — |
| Duration of Confirmed Response (C-DoR) in (C-DoR)-Evaluable Population | From objective response to PD, assessed up to primary completion date (approximately 26 months) | C-DoR is defined as the time from the first occurrence of a documented confirmed response (CR or PR) in C-DOR evaluable population until the date of disease progression per RECIST v1.1 or death from any cause, whichever occurs first. Responses were confirmed after 8 weeks if within first 12 months or after 12 weeks if later. |
| Minimum Observed Serum Concentration (Cmin) of Atezolizumab in PK Evaluable Population | Pre-dose (0 hours) on Day 1 of Cycles 2-4 and at treatment discontinuation (TD), (approximately 9 months). | — |
| Overall Survival (OS) in the ITT Population | From Day 1 to death from any cause, assessed up to end of study (up to approximately 36 months) | OS is defined as the time from randomization to death from any cause. Results from a pre-specified interim analysis. |
Countries
Argentina, Brazil, Canada, China, Croatia, Czechia, France, Germany, Greece, India, Israel, Italy, Japan, Morocco, Romania, Russia, Saudi Arabia, Slovakia, South Africa, Spain, Turkey (Türkiye), United Kingdom, United States, Vietnam
Participant flow
Pre-assignment details
The target population included subjects with previously untreated inoperable locally advanced or metastatic TNBC.
Participants by arm
| Arm | Count |
|---|---|
| Placebo and Paclitaxel Participants will receive placebo matching to atezolizumab via IV infusion on Days 1 and 15 (± 3 days) of every 28-day cycle along with paclitaxel administered at a dose of 90 mg/m\^2 via IV infusion on Days 1, 8, and 15 of every 28-day cycle until disease progression or unacceptable toxicity. | 220 |
| Atezolizumab and Paclitaxel Participants will receive atezolizumab at a dose of 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 (± 3 days) of every 28-day cycle along with paclitaxel administered at a dose of 90 mg per square meter (mg/m\^2) via IV infusion on Days 1, 8, and 15 of every 28-day cycle until disease progression or unacceptable toxicity. | 431 |
| Total | 651 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 119 | 229 |
| Overall Study | Lost to Follow-up | 4 | 13 |
| Overall Study | Other | 0 | 4 |
| Overall Study | Physician Decision | 2 | 1 |
| Overall Study | Progressive Disease | 0 | 3 |
| Overall Study | Study Terminated By Sponsor | 74 | 143 |
| Overall Study | Withdrawal by Subject | 21 | 37 |
Baseline characteristics
| Characteristic | Placebo and Paclitaxel | Atezolizumab and Paclitaxel | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 44 Participants | 109 Participants | 153 Participants |
| Age, Categorical Between 18 and 65 years | 176 Participants | 322 Participants | 498 Participants |
| Age, Continuous | 52.7 Years STANDARD_DEVIATION 12.2 | 54.8 Years STANDARD_DEVIATION 12.6 | 54.0 Years STANDARD_DEVIATION 12.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 23 Participants | 44 Participants | 67 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 174 Participants | 332 Participants | 506 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 23 Participants | 55 Participants | 78 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 66 Participants | 123 Participants | 189 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 21 Participants | 31 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 14 Participants | 37 Participants | 51 Participants |
| Race (NIH/OMB) White | 128 Participants | 246 Participants | 374 Participants |
| Sex: Female, Male Female | 220 Participants | 430 Participants | 650 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 229 / 431 | 119 / 220 |
| other Total, other adverse events | 421 / 431 | 209 / 220 |
| serious Total, serious adverse events | 112 / 431 | 40 / 220 |
Outcome results
Primary
Progression-Free Survival (PFS) Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the Intent-to-Treat (ITT) Population
PFS is defined as the time from randomization to the first occurrence of PD, as determined by the investigator using RECIST v1.1, or death from any cause during the study, whichever occurs first. PD is defined as greater than or equal to (\>/=) 20 percent (%) relative increase and \>/=5 millimeter (mm) of absolute increase in the sum of diameters (SD) of target lesions (TLs), taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions.
Time frame: From Day 1 to disease progression (PD) or death from any cause, assessed up to primary completion date (approximately 26 months)
Population: ITT population: all randomized participants, whether or not the assigned study treatment was received
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo and Paclitaxel | Progression-Free Survival (PFS) Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the Intent-to-Treat (ITT) Population | 5.55 Months |
| Atezolizumab and Paclitaxel | Progression-Free Survival (PFS) Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the Intent-to-Treat (ITT) Population | 5.68 Months |
p-value: 0.134395% CI: [0.7, 1.05]Log Rank
Comparison: Unstratified Analysisp-value: 0.128595% CI: [0.7, 1.05]Log Rank
Primary
Progression-Free Survival (PFS) Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the Subpopulation With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status
PFS is defined as the time from randomization to the first occurrence of PD, as determined by the investigator using RECIST v1.1, or death from any cause during the study, whichever occurs first. PD is defined as greater than or equal to (\>/=) 20 percent (%) relative increase and \>/=5 millimeter (mm) of absolute increase in the sum of diameters (SD) of target lesions (TLs), taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions.
Time frame: From Day 1 to disease progression (PD) or death from any cause, assessed up to primary completion date (approximately 26 months)
Population: PD-L1-positive subpopulation: participants in the ITT population whose PD-L1 status was IC1/2/3 at the time of randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo and Paclitaxel | Progression-Free Survival (PFS) Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the Subpopulation With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status | 5.72 Months |
| Atezolizumab and Paclitaxel | Progression-Free Survival (PFS) Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the Subpopulation With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status | 5.95 Months |
Comparison: Stratified Analysisp-value: 0.203295% CI: [0.6, 1.12]Log Rank
Comparison: Unstratified Analysisp-value: 0.260195% CI: [0.62, 1.14]Log Rank
Secondary
Duration of Confirmed Response (C-DoR) in (C-DoR)-Evaluable Population
C-DoR is defined as the time from the first occurrence of a documented confirmed response (CR or PR) in C-DOR evaluable population until the date of disease progression per RECIST v1.1 or death from any cause, whichever occurs first. Responses were confirmed after 8 weeks if within first 12 months or after 12 weeks if later.
Time frame: From objective response to PD, assessed up to primary completion date (approximately 26 months)
Population: Duration of confirmed response (C-DoR)-evaluable population: participants in the ITT population with measurable disease at baseline and with a confirmed objective response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo and Paclitaxel | Duration of Confirmed Response (C-DoR) in (C-DoR)-Evaluable Population | 5.75 Months |
| Atezolizumab and Paclitaxel | Duration of Confirmed Response (C-DoR) in (C-DoR)-Evaluable Population | 7.66 Months |
Comparison: Unstratified Analysisp-value: 0.0122795% CI: [0.42, 0.9]Log Rank
Secondary
Duration of Objective Response (DOR) Assessed Using RECIST v1.1 in DOR-evaluable Population (Unconfirmed)
DOR is defined as the time period from the date of initial CR or PR until the date of PD or death from any cause, whichever occurs first. CR is defined as the disappearance of all TLs and SA reduction to \<10mm for nodal TLs/ non-TLs. PR is defined as \>/=30% decrease in SD of TLs, taking as reference the baseline SD. PD is defined as \>/=20% relative increase and \>/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions.
Time frame: From objective response to PD, assessed up to primary completion date (approximately 26 months)
Population: Duration of response (DoR)-evaluable population: participants in the ITT population with measurable disease at baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo and Paclitaxel | Duration of Objective Response (DOR) Assessed Using RECIST v1.1 in DOR-evaluable Population (Unconfirmed) | 5.45 Months |
| Atezolizumab and Paclitaxel | Duration of Objective Response (DOR) Assessed Using RECIST v1.1 in DOR-evaluable Population (Unconfirmed) | 6.41 Months |
p-value: 0.064195% CI: [0.54, 1.02]Log Rank
Secondary
Maximum Observed Plasma Concentration (Cmax) of Paclitaxel
Time frame: Pre-dose (0 hours), 5-10 min before and after paclitaxel infusion, 60 min after paclitaxel infusion on Day 1 of Cycles 1 and 3 (paclitaxel infusion duration= 60 min) (1 Cycle = 28 days)
Population: PK-evaluable population: first 60 participants who received any dose of Paclitaxel and who have at least one evaluable post-baseline PK sample. For all safety, PK and immunogenicity analyses, participants were grouped according to the treatment actually received, including cases in which atezolizumab was received in error.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo and Paclitaxel | Maximum Observed Plasma Concentration (Cmax) of Paclitaxel | C3D1 Post-Dose | 666 ng/mL | Geometric Coefficient of Variation 339 |
| Placebo and Paclitaxel | Maximum Observed Plasma Concentration (Cmax) of Paclitaxel | C1D1 Post-Dose | 518 ng/mL | Geometric Coefficient of Variation 290.7 |
| Atezolizumab and Paclitaxel | Maximum Observed Plasma Concentration (Cmax) of Paclitaxel | C1D1 Post-Dose | 301 ng/mL | Geometric Coefficient of Variation 1501 |
| Atezolizumab and Paclitaxel | Maximum Observed Plasma Concentration (Cmax) of Paclitaxel | C3D1 Post-Dose | 276 ng/mL | Geometric Coefficient of Variation 1360 |
Secondary
Maximum Observed Serum Concentration (Cmax) of Atezolizumab in PK-evaluable Population
Time frame: C1D1 30 min postdose
Population: PK-evaluable population: all participants who received any dose of Atezolizumab and who have at least one evaluable post-baseline PK sample. For all safety, PK and immunogenicity analyses, participants were grouped according to the treatment actually received, including cases in which atezolizumab was received in error.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo and Paclitaxel | Maximum Observed Serum Concentration (Cmax) of Atezolizumab in PK-evaluable Population | 321 μg/mL | Standard Deviation 90.5 |
Secondary
Minimum Observed Plasma Concentration (Cmin) of Paclitaxel
Time frame: Pre-dose (0 hours) on Day 1 of Cycle 3 (1 Cycle = 28 days)
Population: PK-evaluable population: first 60 participants who received any dose of Paclitaxel and who have at least one evaluable post-baseline PK sample. For all safety, PK and immunogenicity analyses, participants were grouped according to the treatment actually received, including cases in which atezolizumab was received in error.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Placebo and Paclitaxel | Minimum Observed Plasma Concentration (Cmin) of Paclitaxel | 1.51 ng/mL |
| Atezolizumab and Paclitaxel | Minimum Observed Plasma Concentration (Cmin) of Paclitaxel | 1.67 ng/mL |
Secondary
Minimum Observed Serum Concentration (Cmin) of Atezolizumab in PK Evaluable Population
Time frame: Pre-dose (0 hours) on Day 1 of Cycles 2-4 and at treatment discontinuation (TD), (approximately 9 months).
Population: PK-evaluable population: all participants who received any dose of Atezolizumab and who have at least one evaluable post-baseline PK sample. For all safety, PK and immunogenicity analyses, participants were grouped according to the treatment actually received, including cases in which atezolizumab was received in error.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo and Paclitaxel | Minimum Observed Serum Concentration (Cmin) of Atezolizumab in PK Evaluable Population | C2D1 predose | 139 μg/mL | Standard Deviation 53.3 |
| Placebo and Paclitaxel | Minimum Observed Serum Concentration (Cmin) of Atezolizumab in PK Evaluable Population | C3D1 predose | 208 μg/mL | Standard Deviation 78.3 |
| Placebo and Paclitaxel | Minimum Observed Serum Concentration (Cmin) of Atezolizumab in PK Evaluable Population | C4D1 predose | 242 μg/mL | Standard Deviation 84.8 |
Secondary
Overall Survival by PD-L1 Status, Intent to Treat Population
Time frame: From Day 1 up to 66 months
Population: ITT population: all randomized participants, whether or not the assigned study treatment was received
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo and Paclitaxel | Overall Survival by PD-L1 Status, Intent to Treat Population | PD-L1 IC0 | 20.30 Months |
| Placebo and Paclitaxel | Overall Survival by PD-L1 Status, Intent to Treat Population | PD-L1 IC1/2/3 | 28.29 Months |
| Atezolizumab and Paclitaxel | Overall Survival by PD-L1 Status, Intent to Treat Population | PD-L1 IC0 | 16.30 Months |
| Atezolizumab and Paclitaxel | Overall Survival by PD-L1 Status, Intent to Treat Population | PD-L1 IC1/2/3 | 22.05 Months |
Secondary
Overall Survival (OS) in the ITT Population
OS is defined as the time from randomization to death from any cause. Results from a pre-specified interim analysis.
Time frame: From Day 1 to death from any cause, assessed up to end of study (up to approximately 36 months)
Population: ITT population: all randomized participants, whether or not the assigned study treatment was received
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo and Paclitaxel | Overall Survival (OS) in the ITT Population | 22.80 Months |
| Atezolizumab and Paclitaxel | Overall Survival (OS) in the ITT Population | 19.19 Months |
Comparison: Stratified analysisp-value: 0.342595% CI: [0.88, 1.43]Log Rank
Comparison: Unstratified Analysisp-value: 0.216695% CI: [0.92, 1.48]Log Rank
Secondary
Overall Survival (OS) in the PD-L1-Positive Subpopulation
OS is defined as the time from randomization to death from any cause. Results from a pre-specified interim analysis.
Time frame: From Day 1 to death from any cause, assessed up 36 months
Population: PD-L1-positive subpopulation: participants in the ITT population whose PD-L1 status was IC1/2/3 at the time of randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo and Paclitaxel | Overall Survival (OS) in the PD-L1-Positive Subpopulation | 28.29 Months |
| Atezolizumab and Paclitaxel | Overall Survival (OS) in the PD-L1-Positive Subpopulation | 22.05 Months |
Comparison: Stratified Analysisp-value: 0.579895% CI: [0.76, 1.64]Log Rank
Comparison: Unstratified Analysisp-value: 0.403595% CI: [0.8, 1.72]Log Rank
Secondary
Percentage of Participants Who Are Alive at 12 and 18 Months
Time frame: From Day 1 to death from any cause, assessed up to 12 and 18 months
Population: ITT population: all randomized participants, whether or not the assigned study treatment was received
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo and Paclitaxel | Percentage of Participants Who Are Alive at 12 and 18 Months | 12 months | 73.47 Percentage of Participants |
| Placebo and Paclitaxel | Percentage of Participants Who Are Alive at 12 and 18 Months | 18 months | 56.18 Percentage of Participants |
| Atezolizumab and Paclitaxel | Percentage of Participants Who Are Alive at 12 and 18 Months | 12 months | 68.86 Percentage of Participants |
| Atezolizumab and Paclitaxel | Percentage of Participants Who Are Alive at 12 and 18 Months | 18 months | 52.32 Percentage of Participants |
Secondary
Percentage of Participants Who Are Alive Without Progression Event at Month 12 Assessed Using RECIST v1.1
PD is defined as \>/=20% relative increase and \>/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions.
Time frame: From Day 1 to PD or death from any cause, assessed up to 12 months
Population: ITT population: all randomized participants, whether or not the assigned study treatment was received
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo and Paclitaxel | Percentage of Participants Who Are Alive Without Progression Event at Month 12 Assessed Using RECIST v1.1 | 16.22 Percentage of Participants |
| Atezolizumab and Paclitaxel | Percentage of Participants Who Are Alive Without Progression Event at Month 12 Assessed Using RECIST v1.1 | 21.63 Percentage of Participants |
Secondary
Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs)
Investigator text for AEs is coded using MedDRA version 25.1
Time frame: From Day 1 From baseline up to 64 months
Population: Safety-evaluable population: participants who received any amount of any study drug. For all safety, PK and immunogenicity analyses, participants were grouped according to the treatment actually received, including cases in which atezolizumab was received in error.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo and Paclitaxel | Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) | Percentage of participants with at least one AE | 97.7 Percentage of participants |
| Placebo and Paclitaxel | Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) | Percentage of participants with at least one SAE | 18.4 Percentage of participants |
| Atezolizumab and Paclitaxel | Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) | Percentage of participants with at least one AE | 99.1 Percentage of participants |
| Atezolizumab and Paclitaxel | Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) | Percentage of participants with at least one SAE | 25.9 Percentage of participants |
Secondary
Percentage of Participants With Anti-Drug Antibodies' (ADAs) Against Atezolizumab in ADA Evaluable Population
Time frame: Pre-dose (0 hours) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16, and at every 8 cycles thereafter until TD, at TD, and at 90-150 days after TD (maximum up to 45 months) (1 Cycle = 28 days)
Population: Anti-Drug Antibody (ADA) population:~* Baseline ADA-evaluable population: all participants with at least one evaluable ADA assay result from a baseline sample~* Post baseline ADA-Evaluable population: all participants with at least one evaluable ADA assay result from at least one post-baseline sample.~For all safety, PK and immunogenicity analyses, participants were grouped according to the treatment actually received, including cases in which atezolizumab was received in error.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo and Paclitaxel | Percentage of Participants With Anti-Drug Antibodies' (ADAs) Against Atezolizumab in ADA Evaluable Population | Percentage of participants positive for ADA at Baseline | 1.5 Percentage of Participants |
| Placebo and Paclitaxel | Percentage of Participants With Anti-Drug Antibodies' (ADAs) Against Atezolizumab in ADA Evaluable Population | Percentage of participants positive for ADA Post-baseline | 14.7 Percentage of Participants |
Secondary
Percentage of Participants With Clinical Benefit Assessed Using RECIST v1.1 in Response-evaluable Population
Clinical benefit is defined as the achievement of CR, PR, or stable disease according to RECIST v1.1 that lasts for at least 6 months. CR is defined as the disappearance of all TLs and SA reduction to \<10mm for nodal TLs/ non-TLs. PR is defined as \>/=30% decrease in SD of TLs, taking as reference the baseline SD. PD is defined as \>/=20% relative increase and \>/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. Stable disease is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference smallest SD since treatment started.
Time frame: From Day 1 to PD, assessed up to primary completion date (approximately 26 months)
Population: Clinical Benefit Rate analysis included all participants with unconfirmed PR/CR or SD of at least 6 months duration
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo and Paclitaxel | Percentage of Participants With Clinical Benefit Assessed Using RECIST v1.1 in Response-evaluable Population | 49.8 Percentage of Participants |
| Atezolizumab and Paclitaxel | Percentage of Participants With Clinical Benefit Assessed Using RECIST v1.1 in Response-evaluable Population | 57.1 Percentage of Participants |
Secondary
Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the PD-L1-Positive Population (Confirmed, Investigator-Assessed )
Objective response is defined as complete response (CR) or partial response (PR), as determined by the investigator using RECIST v1.1 criteria. CR is defined as the disappearance of all TLs and SA reduction to less than (\<) 10mm for nodal TLs/ non-TLs. PR is defined as \>/=30% decrease in SD of TLs, taking as reference the baseline SD. Responses were confirmed after 8 weeks if within first 12 months or after 12 weeks if later.
Time frame: From Day 1 to PD, assessed up to primary completion date (approximately 26 months)
Population: PD-L1-positive subpopulation: participants in the ITT population whose PD-L1 status was IC1/2/3 at the time of randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo and Paclitaxel | Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the PD-L1-Positive Population (Confirmed, Investigator-Assessed ) | 40.6 Percentage of Participants |
| Atezolizumab and Paclitaxel | Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the PD-L1-Positive Population (Confirmed, Investigator-Assessed ) | 49.2 Percentage of Participants |
p-value: 0.152695% CI: [0.87, 2.37]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the PD-L1-Positive Population (Unconfirmed, Investigator-Assessed)
Objective response is defined as complete response (CR) or partial response (PR), as determined by the investigator using RECIST v1.1 criteria. CR is defined as the disappearance of all TLs and SA reduction to less than (\<) 10mm for nodal TLs/ non-TLs. PR is defined as \>/=30% decrease in SD of TLs, taking as reference the baseline SD.
Time frame: From Day 1 to PD, assessed up to primary completion date (approximately 26 months)
Population: PD-L1-positive subpopulation: participants in the ITT population whose PD-L1 status was IC1/2/3 at the time of randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo and Paclitaxel | Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the PD-L1-Positive Population (Unconfirmed, Investigator-Assessed) | 55.4 Percentage of Participants |
| Atezolizumab and Paclitaxel | Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the PD-L1-Positive Population (Unconfirmed, Investigator-Assessed) | 63.4 Percentage of Participants |
p-value: 0.183495% CI: [0.85, 2.31]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the Response-Evaluable Population (Confirmed, Investigator-Assessed )
Objective response is defined as complete response (CR) or partial response (PR), as determined by the investigator using RECIST v1.1 criteria. CR is defined as the disappearance of all TLs and SA reduction to less than (\<) 10mm for nodal TLs/ non-TLs. PR is defined as \>/=30% decrease in SD of TLs, taking as reference the baseline SD. Responses were confirmed after 8 weeks if within first 12 months or after 12 weeks if later.
Time frame: From Day 1 to PD, assessed up to primary completion date (approximately 26 months)
Population: Response-evaluable population: participants in the ITT population with measurable disease at baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo and Paclitaxel | Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the Response-Evaluable Population (Confirmed, Investigator-Assessed ) | 32.4 Percentage of Participants |
| Atezolizumab and Paclitaxel | Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the Response-Evaluable Population (Confirmed, Investigator-Assessed ) | 39.9 Percentage of Participants |
p-value: 0.051395% CI: [1, 2.02]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the Response-Evaluable Population (Unconfirmed, Investigator-Assessed )
Objective response is defined as complete response (CR) or partial response (PR), as determined by the investigator using RECIST v1.1 criteria. CR is defined as the disappearance of all TLs and SA reduction to less than (\<) 10mm for nodal TLs/ non-TLs. PR is defined as \>/=30% decrease in SD of TLs, taking as reference the baseline SD.
Time frame: From Day 1 to PD, assessed up to primary completion date (approximately 26 months)
Population: Response-evaluable population: participants in the ITT population with measurable disease at baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo and Paclitaxel | Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the Response-Evaluable Population (Unconfirmed, Investigator-Assessed ) | 47.5 Percentage of Participants |
| Atezolizumab and Paclitaxel | Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the Response-Evaluable Population (Unconfirmed, Investigator-Assessed ) | 53.6 Percentage of Participants |
p-value: 0.122695% CI: [0.93, 1.81]Cochran-Mantel-Haenszel
Secondary
Progression Free Survival by PD-L1 Status, Intent to Treat Population
Time frame: From Day 1 up to primary completion date (approximately 26 months)
Population: ITT population: all randomized participants, whether or not the assigned study treatment was received
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo and Paclitaxel | Progression Free Survival by PD-L1 Status, Intent to Treat Population | PD-L1 IC0 | 5.49 Months |
| Placebo and Paclitaxel | Progression Free Survival by PD-L1 Status, Intent to Treat Population | PD-L1 IC1/2/3 | 5.72 Months |
| Atezolizumab and Paclitaxel | Progression Free Survival by PD-L1 Status, Intent to Treat Population | PD-L1 IC0 | 5.45 Months |
| Atezolizumab and Paclitaxel | Progression Free Survival by PD-L1 Status, Intent to Treat Population | PD-L1 IC1/2/3 | 5.95 Months |
Secondary
Time to Deterioration (TTD) in Global Health Status/ Health Related Quality of Life (HRQoL) in the PRO Evaluable Population
Deterioration in Global Health Status/HRQoL is defined as a decrease of at least 10 points on the Global Health Status /HRQoL scale (comprised of 2 items: 29 and 30) of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). The 2 items use 7-point scale (1 = very poor to 7 = Excellent). Scores are averaged, transformed to 0-100 scale; where higher score=better level of functioning or greater degree of symptoms.
Time frame: From Day 1 to deterioration, assessed up 64 months
Population: PRO-evaluable populations: participants in the ITT population with baseline PRO assessment and at least one post-baseline PRO assessment in the questionnaire of interest (European Organization for the Research and Treatment of Cancer \[EORTC\] Quality-of-life Questionnaire \[QLQ\] C30, EORTC QLQ BR-23 or FACT-G)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo and Paclitaxel | Time to Deterioration (TTD) in Global Health Status/ Health Related Quality of Life (HRQoL) in the PRO Evaluable Population | 17.35 Months |
| Atezolizumab and Paclitaxel | Time to Deterioration (TTD) in Global Health Status/ Health Related Quality of Life (HRQoL) in the PRO Evaluable Population | 28.68 Months |
p-value: 0.646595% CI: [0.71, 1.24]Log Rank