Triple Negative Breast Neoplasms
Conditions
Brief summary
This study will evaluate the efficacy and safety of atezolizumab plus chemotherapy compared with placebo plus chemotherapy in patients with inoperable recurrent triple-negative breast cancer (TNBC).
Interventions
DRUGAtezolizumab
Atezolizumab will be administered, 1200 mg by IV infusion with : gemcitabine 1000 mg/m2, followed by carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle or with capecitabine 1000 mg/m2, twice daily orally on Days 1 to 14, followed by a 7-day rest period in each 3-week treatment cycle
DRUGPlacebo
Placebo will be administered, 1200 mg by IV infusion with : gemcitabine 1000 mg/m2, followed by carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle or with capecitabine 1000 mg/m2, twice daily orally on Days 1 to 14, followed by a 7-day rest period in each 3-week treatment cycle
DRUGGemcitabine
Gemcitabine 1000 mg/m2, followed by carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle
DRUGCapecitabine
Capecitabine 1000 mg/m2, twice daily orally on Days 1 to 14, followed by a 7-day rest period in each 3-week treatment cycle
DRUGCarboplatin
Carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle
Sponsors
Hoffmann-La Roche
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed triple negative breast cancer (TNBC) that is either locally recurrent, inoperable and cannot be treated with curative intent or is metastatic * Documented disease progression occurring within 12 months from the last treatment with curative intent * Prior treatment (of early breast cancer) with an anthracycline and taxane * Have not received prior chemotherapy or targeted systemic therapy for their locally advanced inoperable or metastatic recurrence. Prior radiation therapy for recurrent disease is permitted * Measurable or non-measurable disease, as defined by RECIST 1.1 * Availability of a representative formalin-fixed, paraffin-embedded (FFPE) tumour block (preferred) or at least 17 unstained slides obtained from relapsed metastatic or locally advanced diseases may be submitted, if clinically feasible, with an associated pathology report, if available. If a fresh tumour sample is not clinically feasible, either the diagnosis sample, the primary surgical resection sample, or the most recent FFPE tumour biopsy sample should be used. * Eastern Cooperative Oncology Group performance status 0-1 * Life expectancy ≥ 12 weeks * Adequate haematologic and end-organ function * Negative human immunodeficiency virus (HIV) test ---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 negative HBsAg and 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. * Women of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of ≤1% per year during the treatment period and for at least 5 months after the last dose of atezolizumab or 6 months after the last dose of capecitabine, whichever is later. In addition, women must refrain from donating eggs during the same time period. * Men must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agree to refrain from donating sperm Inclusion criteria for patients enrolled after the recruitment of all-comers is complete: -PD-L1-positive tumour status (assessed centrally prior to randomisation), defined as PD-L1 expression on tumour-infiltrating immune cells (IC) of 1% or greater.
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 \> 2 weeks prior to randomisation * Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases. * Symptomatic or rapid visceral progression * No prior treatment with an anthracycline and taxane * History of leptomeningeal disease * Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) (patients with indwelling catheters such as PleurX® are allowed) * Uncontrolled tumour-related pain * Uncontrolled or symptomatic hypercalcemia * Malignancies other than TNBC within 5 years prior to randomisation) * Significant cardiovascular disease, within 3 months prior to randomisation, unstable arrhythmias, or unstable angina * Presence of an abnormal ECG * Severe infection requiring oral or IV antibiotics within 4 weeks prior to randomisation, including but not limited to hospitalization for complications of infection, bacteraemia, or severe pneumonia. * Current treatment with anti-viral therapy for HBV. * Major surgical procedure within 4 weeks prior to randomisation or anticipation of the need for a major surgical procedure during the course of the study other than for diagnosis * Treatment with investigational therapy within 28 days prior to randomisation * Pregnant or lactating, or intending to become pregnant during or within 5 months after the last dose of atezolizumab, or within 6 months after the last dose of capecitabine, whichever is later.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) in PD-L1-positive Population | Time from randomization to death (Up to 68 months) | OS was defined as time from randomization to death from any cause. Participants without a reported death event at the time of the analysis were censored on the date they were last known to be alive. If no post-baseline data were available, OS was censored at the date of randomization +1 day. |
| OS in Modified Intent-to-treat (mITT) Population | Time from randomization to death (Up to 68 months) | OS was defined as time from randomization to death from any cause. Participants without a reported death event at the time of the analysis were censored on the date they were last known to be alive. If no post-baseline data were available, OS was censored at the date of randomization +1 day. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ORR in Response-evaluable Population, Subset of mITT Population | Baseline up to end of study (Up to 68 months) | ORR was defined as percentage of participants with measurable disease at baseline who achieved a documented unconfirmed OR. OR was defined as either a CR or PR, as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. Percentages have been rounded off to nearest whole number. |
| Confirmed Objective Response Rate (C-ORR) in Response-evaluable Population Subset of PD-L1-positive Population | Up to 68 months | C-ORR was defined as percentage of participants with measurable disease at baseline who achieved a documented confirmed OR. OR was defined as either a CR or PR, as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. Percentages have been rounded off to nearest whole number. |
| C-ORR in Response-evaluable Population Subset of mITT Population | Up to 68 months | C-ORR was defined as percentage of participants with measurable disease at baseline who achieved a documented confirmed OR. OR was defined as either a CR or PR, as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. Percentages have been rounded off to nearest whole number. |
| DoR for Confirmed Responders (C-DoR) in C-DoR-evaluable Population Subset of PD-L1-positive Population | Time from the first occurrence of a documented OR until the date of PD/death (Up to 68 months) | C-DoR was defined as the time from the first occurrence of a documented confirmed response (CR or PR) until the date of PD as determined by the investigator from tumor assessments using RECIST v1.1 or death from any cause, whichever occurs first. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. |
| C-DoR in C-DoR-evaluable Population Subset of mITT Population | Time from the first occurrence of a documented OR until the date of PD/death (Up to 68 months) | C-DoR was defined as the time from the first occurrence of a documented confirmed response (CR or PR) until the date of PD as determined by the investigator from tumor assessments using RECIST v1.1 or death from any cause, whichever occurs first. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. |
| Time to Confirmed Deterioration (TTD) in Global Health Status/Quality of Life (GHS/QoL) According to the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) in PD-L1-positive Population | Up to 68 months | TTD in GHS/QoL, defined by a minimally important decrease of ≥10 points at 2 consecutive assessment time-points on the GHS/QoL scale (Items 29, 30) of EORTC QLQ-C30, which consists of 30 questions that assess 5 aspects of participant functioning (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, and pain), GHS and QoL, & six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) with a recall period of the previous week. Participant responses to questions regarding GHS (Question 29: GHS; How would you rate your overall health during the past week?) & QoL (Question 30: QoL; How would you rate your overall quality of life during the past week?) were assessed & were scored on a 7-point scale (1= Very poor; 7=Excellent). Scores are linearly transformed on a scale of 0 to 100, with a high score indicating better QoL. |
| TTD in GHS/QoL According to EORTC QLQ-C30 in mITT Population | Up to 68 months | TTD in GHS/QoL, defined by a minimally important decrease of ≥10 points at 2 consecutive assessment time-points on the GHS/QoL scale (Items 29, 30) of EORTC QLQ-C30, which consists of 30 questions that assess 5 aspects of participant functioning (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, and pain), GHS and QoL, & six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) with a recall period of the previous week. Participant responses to questions regarding GHS (Question 29: GHS; How would you rate your overall health during the past week?) & QoL (Question 30: QoL; How would you rate your overall quality of life during the past week?) were assessed & were scored on a 7-point scale (1= Very poor; 7=Excellent). Scores are linearly transformed on a scale of 0 to 100, with a high score indicating better QoL. |
| Number of Participants With Adverse Events (AEs) | From treatment initiation up to 90 days after last dose (up to 71 months) | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions that worsen during a study are also considered AEs. |
| Serum Concentration of Atezolizumab | Pre-dose on Day 1 of Cycles 1, 2, 3 and 4; Post-dose on Day 1 of Cycles 1 and 3 and Treatment Discontinuation Visit (up to 69 months) (1 Cycle= 3 weeks) | — |
| Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab | Cycles 1 to 4 and Treatment Discontinuation visit (up to 69 months) | Number of ADA-positive participants after drug administration was determined for participants exposed to atezolizumab. For determining post-baseline incidence, participants were considered to be ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure, or if they were ADA-positive at baseline and the titer of 1 or more post-baseline samples was at least 0.60 titer units (t.u.) greater than the baseline titer result. The sum of participants who were ADA-positive at postbaseline visits of Cycles 1 to 4 and treatment discontinuation has been reported here. |
| Number of Participants With PD-L1 Protein Expression in Screening Tumour Tissue and Post-baseline Assessment | Baseline up to 68 months | — |
| 12-month Survival Rate in PD-L1-positive Population | 12 months | 12-month survival rate was defined as the percentage of participants alive 12 months after randomization. The 12-month survival rates were estimated by Kaplan-Meier methodology. Percentages have been rounded off to the nearest whole number. |
| 12-month Survival Rate in mITT Population | 12 months | 12-month survival rate was defined as the percentage of participants alive 12 months after randomization. The 12-month survival rates were estimated by Kaplan-Meier methodology. Percentages have been rounded off to nearest whole number. |
| 18-month Survival Rate in PD-L1-positive Population | 18 months | 18-month survival rate was defined as the percentage of participants alive 18 months after randomization. The 18-month survival rates were estimated by Kaplan-Meier methodology. Percentages have been rounded off to nearest whole number. |
| 18-month Survival Rate in mITT Population | 18 months | 18-month survival rate was defined as the percentage of participants alive 18 months after randomization. The 18-month survival rates were estimated by Kaplan-Meier methodology. Percentages have been rounded off to nearest whole number. |
| Progression-free Survival (PFS) in PD-L1-positive Population | Time from randomization to the first occurrence of PD or death (Up to 68 months) | PFS was defined as the time from randomization to the first occurrence of PD, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), or death from any cause, whichever occurs first. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 millimeters (mm). Data for participants not experiencing PD or death were censored at the last tumour assessment date. If no tumor assessment was performed after randomisation, data were censored at the date of randomisation +1 day. |
| PFS in mITT Population | Time from randomization to the first occurrence of PD or death (Up to 68 months) | PFS was defined as the time from randomization to the first occurrence of PD, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Data for participants not experiencing PD or death were censored at the last tumour assessment date. If no tumor assessment was performed after randomisation, data were censored at the date of randomisation +1 day. |
| Objective Response Rate (ORR) in Response-evaluable Population, Subset of PD-L1-positive Population | Baseline up to end of study (Up to 68 months) | ORR was defined as percentage of participants with measurable disease at baseline who achieved a documented unconfirmed objective response (OR). OR was defined as either a complete response (CR) or a partial response (PR), as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD, in the absence of CR. Percentages have been rounded off to nearest whole number. |
| Duration of Objective Response (DoR) in DoR-evaluable Population Subset of PD-L1-positive Population | Time from the first occurrence of a documented OR until the date of PD/death (Up to 68 months) | DoR was defined as the time from the first occurrence of a documented unconfirmed response (CR or PR) until the date of PD as determined by the investigator from tumor assessments using RECIST v1.1 or death from any cause, whichever occurs first. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. |
| DoR in DoR-evaluable Population Subset of mITT Population | Time from the first occurrence of a documented OR until the date of PD/death (Up to 68 months) | DoR was defined as the time from the first occurrence of a documented unconfirmed response (CR or PR) until the date of PD as determined by the investigator from tumor assessments using RECIST v1.1 or death from any cause, whichever occurs first. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. |
| Clinical Benefit Rate (CBR) in Response-evaluable Population Subset of PD-L1-positive Population | Up to 68 months | CBR was defined as the percentage of participants with either an unconfirmed CR or PR or stable disease (SD) that lasts at least 6 months as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Percentages have been rounded off to nearest whole number. |
| CBR in Response-evaluable Population Subset of mITT Population | Up to 68 months | CBR was defined as the percentage of participants with either an unconfirmed CR or PR or SD that lasts at least 6 months as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Percentages have been rounded off to nearest whole number. |
Other
| Measure | Time frame | Description |
|---|---|---|
| PFS in China Population | Time from randomization to the first occurrence of PD or death (Up to 68 months) | PFS was defined as the time from randomization to the first occurrence of PD, as determined by the investigator according to RECIST 1.1, or death from any cause, whichever occurs first. |
| ORR in China Population | Baseline up to end of study (Up to 68 months) | ORR was defined as percentage of participants with measurable disease at baseline who achieved a documented unconfirmed OR. OR was defined as either a CR or PR, as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. |
| DoR in China Population | Time from the first occurrence of a documented OR until the date of PD/death (Up to 68 months) | DoR was defined as the time from the first occurrence of a documented unconfirmed response (CR or PR) until the date of PD as determined by the investigator from tumor assessments using RECIST v1.1 or death from any cause, whichever occurs first. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. |
| CBR in China Population | Up to 68 months | CBR was defined as the percentage of participants with either an unconfirmed CR or PR or SD that lasts at least 6 months as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. |
| C-ORR in China Population | Up to 68 months | C-ORR was defined as percentage of participants with measurable disease at baseline who achieved a documented confirmed OR. OR was defined as either a CR or PR, as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. |
| C-DoR in China Population | Time from the first occurrence of a documented OR until the date of PD/death (Up to 68 months) | C-DoR was defined as the time from the first occurrence of a documented confirmed response (CR or PR) until the date of PD as determined by the investigator from tumor assessments using RECIST v1.1 or death from any cause, whichever occurs first. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. |
| TTD in GHS/QoL According to EORTC QLQ-C30 in China Population | Up to 68 months | TTD in GHS/QoL, defined by a minimally important decrease of ≥10 points at 2 consecutive assessment time-points on the GHS/QoL scale (Items 29, 30) of EORTC QLQ-C30, which consists of 30 questions that assess 5 aspects of participant functioning (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, and pain), GHS and QoL, & six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) with a recall period of the previous week. Participant responses to questions regarding GHS (Question 29: GHS; How would you rate your overall health during the past week?) & QoL (Question 30: QoL; How would you rate your overall quality of life during the past week?) were assessed & were scored on a 7-point scale (1= Very poor; 7=Excellent). Scores are linearly transformed on a scale of 0 to 100, with a high score indicating better QoL. |
| 12-month Survival Rate in China Population | 12 months | 12-month survival rate was defined as the percentage of participants alive 12 months after randomization. |
| OS in China Population | Time from randomization to death (Up to 68 months) | OS was defined as time from randomization to death from any cause. |
| 18-month Survival Rate in China Population | 18 months | 18-month survival rate was defined as the percentage of participants alive 18 months after randomization. |
Countries
Argentina, Bosnia and Herzegovina, Brazil, Chile, China, Cuba, Finland, France, Germany, Hungary, Italy, Kazakhstan, Mexico, Montenegro, Morocco, Panama, Peru, Poland, Portugal, Russia, Serbia, Singapore, South Africa, South Korea, Spain, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
A total of 595 participants with inoperable locally advanced or metastatic Triple-negative Breast Cancer (TNBC) took part in the study at 126 investigative sites in 28 countries from 11 January 2018 to 23 October 2024.
Pre-assignment details
Participants were randomized in a 1:1 ratio to receive atezolizumab with chemotherapy or placebo with chemotherapy.
Participants by arm
| Arm | Count |
|---|---|
| Placebo + Chemotherapy Participants received atezolizumab matching placebo, by IV infusion on Day 1 of each cycle along with either gemcitabine, 1000 mg/m\^2, followed by carboplatin target AUC 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each cycle or capecitabine, 1000 mg/m\^2, BID, orally on Days 1 to 14, followed by a 7-day rest period in each cycle (1 Cycle= 3 weeks). Treatment was continued until PD, unacceptable toxicity, death or participant or investigator decision to discontinue treatment. | 298 |
| Atezolizumab + Chemotherapy Participants received atezolizumab 1200 mg, by IV infusion on Day 1 of each cycle along with either gemcitabine, 1000 mg/m\^2, followed by carboplatin target AUC 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each cycle or capecitabine, 1000 mg/m\^2, BID, orally on Days 1 to 14, followed by a 7-day rest period in each cycle (1 Cycle = 3 weeks). Treatment was continued until PD, unacceptable toxicity, death or participant or investigator decision to discontinue treatment. | 297 |
| Total | 595 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 228 | 215 |
| Overall Study | Lost to Follow-up | 13 | 16 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Protocol Deviation | 0 | 1 |
| Overall Study | Reason not Specified | 0 | 1 |
| Overall Study | Study Ended by Sponsor | 37 | 38 |
| Overall Study | Withdrawal by Subject | 20 | 25 |
Baseline characteristics
| Characteristic | Atezolizumab + Chemotherapy | Total | Placebo + Chemotherapy |
|---|---|---|---|
| Age, Continuous | 48.6 years STANDARD_DEVIATION 10.9 | 49.0 years STANDARD_DEVIATION 11.3 | 49.4 years STANDARD_DEVIATION 11.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 51 Participants | 110 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 218 Participants | 440 Participants | 222 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 28 Participants | 45 Participants | 17 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 5 Participants | 8 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 69 Participants | 135 Participants | 66 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 19 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 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 | 28 Participants | 48 Participants | 20 Participants |
| Race (NIH/OMB) White | 184 Participants | 383 Participants | 199 Participants |
| Sex: Female, Male Female | 297 Participants | 595 Participants | 298 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 233 / 294 | 226 / 293 |
| other Total, other adverse events | 278 / 294 | 276 / 293 |
| serious Total, serious adverse events | 57 / 294 | 69 / 293 |
Outcome results
Primary
OS in Modified Intent-to-treat (mITT) Population
OS was defined as time from randomization to death from any cause. Participants without a reported death event at the time of the analysis were censored on the date they were last known to be alive. If no post-baseline data were available, OS was censored at the date of randomization +1 day.
Time frame: Time from randomization to death (Up to 68 months)
Population: mITT population included all participants randomized under the protocol versions prior to version 4.0 (referred to as all-comers, i.e., PD-L1(SP142)-positive and PD-L1(SP142)-negative participants, grouped according to their assigned treatment arm, whether or not the assigned study treatment was received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Chemotherapy | OS in Modified Intent-to-treat (mITT) Population | 9.79 months |
| Atezolizumab + Chemotherapy | OS in Modified Intent-to-treat (mITT) Population | 10.35 months |
p-value: 0.613995% CI: [0.76, 1.18]Log Rank
Primary
Overall Survival (OS) in PD-L1-positive Population
OS was defined as time from randomization to death from any cause. Participants without a reported death event at the time of the analysis were censored on the date they were last known to be alive. If no post-baseline data were available, OS was censored at the date of randomization +1 day.
Time frame: Time from randomization to death (Up to 68 months)
Population: PD-L1 positive population included all participants randomized in the study whose PD-L1 status was tumor-infiltrating IC of 1% or greater (IC1/2/3) at the time of randomization, grouped according to their assigned treatment arm, whether or not the assigned study treatment was received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Chemotherapy | Overall Survival (OS) in PD-L1-positive Population | 11.24 months |
| Atezolizumab + Chemotherapy | Overall Survival (OS) in PD-L1-positive Population | 12.09 months |
p-value: 0.589195% CI: [0.73, 1.2]Log Rank
Secondary
12-month Survival Rate in mITT Population
12-month survival rate was defined as the percentage of participants alive 12 months after randomization. The 12-month survival rates were estimated by Kaplan-Meier methodology. Percentages have been rounded off to nearest whole number.
Time frame: 12 months
Population: mITT population included all participants randomized under the protocol versions prior to version 4.0 (referred to as all-comers, i.e., PD-L1(SP142)-positive and PD-L1(SP142)-negative participants), grouped according to their assigned treatment arm, whether or not the assigned study treatment was received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Chemotherapy | 12-month Survival Rate in mITT Population | 42.44 percentage of participants |
| Atezolizumab + Chemotherapy | 12-month Survival Rate in mITT Population | 46.20 percentage of participants |
p-value: 0.47595% CI: [-6.55, 14.07]Z-test
Secondary
12-month Survival Rate in PD-L1-positive Population
12-month survival rate was defined as the percentage of participants alive 12 months after randomization. The 12-month survival rates were estimated by Kaplan-Meier methodology. Percentages have been rounded off to the nearest whole number.
Time frame: 12 months
Population: PD-L1 positive population included all participants randomized in the study whose PD-L1 status was tumor-infiltrating IC of 1% or greater (IC1/2/3) at the time of randomization, grouped according to their assigned treatment arm, whether or not the assigned study treatment was received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Chemotherapy | 12-month Survival Rate in PD-L1-positive Population | 47.58 percentage of participants |
| Atezolizumab + Chemotherapy | 12-month Survival Rate in PD-L1-positive Population | 50.26 percentage of participants |
p-value: 0.626495% CI: [-8.14, 13.51]Z-test
Secondary
18-month Survival Rate in mITT Population
18-month survival rate was defined as the percentage of participants alive 18 months after randomization. The 18-month survival rates were estimated by Kaplan-Meier methodology. Percentages have been rounded off to nearest whole number.
Time frame: 18 months
Population: mITT population included all participants randomized under the protocol versions prior to version 4.0 (referred to as all-comers, i.e., PD-L1(SP142)-positive and PD-L1(SP142)-negative participants), grouped according to their assigned treatment arm, whether or not the assigned study treatment was received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Chemotherapy | 18-month Survival Rate in mITT Population | 25.68 percentage of participants |
| Atezolizumab + Chemotherapy | 18-month Survival Rate in mITT Population | 27.05 percentage of participants |
p-value: 0.773895% CI: [-7.96, 10.69]Z-test
Secondary
18-month Survival Rate in PD-L1-positive Population
18-month survival rate was defined as the percentage of participants alive 18 months after randomization. The 18-month survival rates were estimated by Kaplan-Meier methodology. Percentages have been rounded off to nearest whole number.
Time frame: 18 months
Population: PD-L1 positive population included all participants randomized in the study whose PD-L1 status was tumor-infiltrating IC of 1% or greater (IC1/2/3) at the time of randomization, grouped according to their assigned treatment arm, whether or not the assigned study treatment was received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Chemotherapy | 18-month Survival Rate in PD-L1-positive Population | 32.48 percentage of participants |
| Atezolizumab + Chemotherapy | 18-month Survival Rate in PD-L1-positive Population | 33.63 percentage of participants |
p-value: 0.831595% CI: [-9.45, 11.75]Z-test
Secondary
CBR in Response-evaluable Population Subset of mITT Population
CBR was defined as the percentage of participants with either an unconfirmed CR or PR or SD that lasts at least 6 months as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Percentages have been rounded off to nearest whole number.
Time frame: Up to 68 months
Population: mITT population included all participants randomized under the protocol versions prior to version 4.0 (referred to as all-comers, i.e., PD-L1(SP142)-positive and PD-L1(SP142)-negative participants), grouped according to their assigned treatment arm, whether or not the assigned study treatment was received. Response-evaluable population included participants randomized in the study with measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Chemotherapy | CBR in Response-evaluable Population Subset of mITT Population | 36.3 percentage of participants |
| Atezolizumab + Chemotherapy | CBR in Response-evaluable Population Subset of mITT Population | 35.1 percentage of participants |
Secondary
C-DoR in C-DoR-evaluable Population Subset of mITT Population
C-DoR was defined as the time from the first occurrence of a documented confirmed response (CR or PR) until the date of PD as determined by the investigator from tumor assessments using RECIST v1.1 or death from any cause, whichever occurs first. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression.
Time frame: Time from the first occurrence of a documented OR until the date of PD/death (Up to 68 months)
Population: mITT population included all participants randomized under the protocol versions prior to version 4.0 (referred to as all-comers, i.e., PD-L1(SP142)-positive and PD-L1(SP142)-negative participants), grouped according to their assigned treatment arm, whether or not the assigned study treatment was received. C-DOR-evaluable population included participants randomized in the study with measurable disease at baseline and a confirmed OR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Chemotherapy | C-DoR in C-DoR-evaluable Population Subset of mITT Population | 6.51 months |
| Atezolizumab + Chemotherapy | C-DoR in C-DoR-evaluable Population Subset of mITT Population | 7.43 months |
p-value: 0.985395% CI: [0.61, 1.61]Log Rank
Secondary
Clinical Benefit Rate (CBR) in Response-evaluable Population Subset of PD-L1-positive Population
CBR was defined as the percentage of participants with either an unconfirmed CR or PR or stable disease (SD) that lasts at least 6 months as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Percentages have been rounded off to nearest whole number.
Time frame: Up to 68 months
Population: PD-L1 positive population included all participants randomized in the study whose PD-L1 status was tumor-infiltrating immune cells IC of 1% or greater (IC1/2/3) at the time of randomization, grouped according to their assigned treatment arm, whether or not the assigned study treatment was received. Response-evaluable population included participants randomized in the study with measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Chemotherapy | Clinical Benefit Rate (CBR) in Response-evaluable Population Subset of PD-L1-positive Population | 34.6 percentage of participants |
| Atezolizumab + Chemotherapy | Clinical Benefit Rate (CBR) in Response-evaluable Population Subset of PD-L1-positive Population | 42.9 percentage of participants |
Secondary
Confirmed Objective Response Rate (C-ORR) in Response-evaluable Population Subset of PD-L1-positive Population
C-ORR was defined as percentage of participants with measurable disease at baseline who achieved a documented confirmed OR. OR was defined as either a CR or PR, as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. Percentages have been rounded off to nearest whole number.
Time frame: Up to 68 months
Population: PD-L1 positive population included all participants randomized in the study whose PD-L1 status was tumor-infiltrating IC of 1% or greater (IC1/2/3) at the time of randomization, grouped according to their assigned treatment arm, whether or not the assigned study treatment was received. Response-evaluable population included participants randomized in the study with measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Chemotherapy | Confirmed Objective Response Rate (C-ORR) in Response-evaluable Population Subset of PD-L1-positive Population | 19.5 percentage of participants |
| Atezolizumab + Chemotherapy | Confirmed Objective Response Rate (C-ORR) in Response-evaluable Population Subset of PD-L1-positive Population | 31.2 percentage of participants |
p-value: 0.017295% CI: [1.47, 21.87]Cochran-Mantel-Haenszel
Secondary
C-ORR in Response-evaluable Population Subset of mITT Population
C-ORR was defined as percentage of participants with measurable disease at baseline who achieved a documented confirmed OR. OR was defined as either a CR or PR, as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. Percentages have been rounded off to nearest whole number.
Time frame: Up to 68 months
Population: mITT population included all participants randomized under the protocol versions prior to version 4.0 (referred to as all-comers, i.e., PD-L1(SP142)-positive and PD-L1(SP142)-negative participants), grouped according to their assigned treatment arm, whether or not the assigned study treatment was received. Response-evaluable population included participants randomized in the study with measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Chemotherapy | C-ORR in Response-evaluable Population Subset of mITT Population | 23.2 percentage of participants |
| Atezolizumab + Chemotherapy | C-ORR in Response-evaluable Population Subset of mITT Population | 23.4 percentage of participants |
Comparison: Stratified Analysisp-value: 0.867995% CI: [-9.41, 9.77]Cochran-Mantel-Haenszel
Secondary
DoR for Confirmed Responders (C-DoR) in C-DoR-evaluable Population Subset of PD-L1-positive Population
C-DoR was defined as the time from the first occurrence of a documented confirmed response (CR or PR) until the date of PD as determined by the investigator from tumor assessments using RECIST v1.1 or death from any cause, whichever occurs first. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression.
Time frame: Time from the first occurrence of a documented OR until the date of PD/death (Up to 68 months)
Population: PD-L1 population included all participants randomized in the study whose PD-L1 status was tumor-infiltrating IC of 1% or greater (IC1/2/3) at the time of randomization, grouped according to their assigned treatment arm, whether or not the assigned study treatment was received. C-DOR-evaluable population included participants randomized in the study with measurable disease at baseline and a confirmed OR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Chemotherapy | DoR for Confirmed Responders (C-DoR) in C-DoR-evaluable Population Subset of PD-L1-positive Population | 5.78 months |
| Atezolizumab + Chemotherapy | DoR for Confirmed Responders (C-DoR) in C-DoR-evaluable Population Subset of PD-L1-positive Population | 7.92 months |
p-value: 0.284695% CI: [0.46, 1.26]Log Rank
Secondary
DoR in DoR-evaluable Population Subset of mITT Population
DoR was defined as the time from the first occurrence of a documented unconfirmed response (CR or PR) until the date of PD as determined by the investigator from tumor assessments using RECIST v1.1 or death from any cause, whichever occurs first. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression.
Time frame: Time from the first occurrence of a documented OR until the date of PD/death (Up to 68 months)
Population: mITT population included all participants randomized under the protocol versions prior to version 4.0 (referred to as all-comers, i.e., PD-L1(SP142)-positive and PD-L1(SP142)-negative participants), grouped according to their assigned treatment arm, whether or not the assigned study treatment was received. DOR-evaluable population included participants randomized in the study with measurable disease at baseline and an OR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Chemotherapy | DoR in DoR-evaluable Population Subset of mITT Population | 5.22 months |
| Atezolizumab + Chemotherapy | DoR in DoR-evaluable Population Subset of mITT Population | 5.70 months |
p-value: 0.822595% CI: [0.63, 1.43]Log Rank
Secondary
Duration of Objective Response (DoR) in DoR-evaluable Population Subset of PD-L1-positive Population
DoR was defined as the time from the first occurrence of a documented unconfirmed response (CR or PR) until the date of PD as determined by the investigator from tumor assessments using RECIST v1.1 or death from any cause, whichever occurs first. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression.
Time frame: Time from the first occurrence of a documented OR until the date of PD/death (Up to 68 months)
Population: PD-L1 positive population included all participants randomized in the study whose PD-L1 status was tumor-infiltrating IC of 1% or greater (IC1/2/3) at the time of randomization, grouped according to their assigned treatment arm, whether or not the assigned study treatment was received. DOR-evaluable population included participants randomized in the study with measurable disease at baseline and an OR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Chemotherapy | Duration of Objective Response (DoR) in DoR-evaluable Population Subset of PD-L1-positive Population | 4.14 months |
| Atezolizumab + Chemotherapy | Duration of Objective Response (DoR) in DoR-evaluable Population Subset of PD-L1-positive Population | 6.60 months |
p-value: 0.135995% CI: [0.48, 1.11]Log Rank
Secondary
Number of Participants With Adverse Events (AEs)
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions that worsen during a study are also considered AEs.
Time frame: From treatment initiation up to 90 days after last dose (up to 71 months)
Population: Safety-evaluable population included participants who received any amount of any study drug (atezolizumab/placebo or chemotherapy).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo + Chemotherapy | Number of Participants With Adverse Events (AEs) | 283 Participants |
| Atezolizumab + Chemotherapy | Number of Participants With Adverse Events (AEs) | 281 Participants |
Secondary
Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab
Number of ADA-positive participants after drug administration was determined for participants exposed to atezolizumab. For determining post-baseline incidence, participants were considered to be ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure, or if they were ADA-positive at baseline and the titer of 1 or more post-baseline samples was at least 0.60 titer units (t.u.) greater than the baseline titer result. The sum of participants who were ADA-positive at postbaseline visits of Cycles 1 to 4 and treatment discontinuation has been reported here.
Time frame: Cycles 1 to 4 and Treatment Discontinuation visit (up to 69 months)
Population: Safety-evaluable population included participants who received any amount of any study drug (atezolizumab/placebo or chemotherapy). Overall number analyzed included participants with data available for analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo + Chemotherapy | Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab | 20 Participants |
Secondary
Number of Participants With PD-L1 Protein Expression in Screening Tumour Tissue and Post-baseline Assessment
Time frame: Baseline up to 68 months
Population: FAS population included all participants randomized in the study, grouped according to their assigned treatment arm, whether or not the assigned study treatment was received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo + Chemotherapy | Number of Participants With PD-L1 Protein Expression in Screening Tumour Tissue and Post-baseline Assessment | Baseline IC0- Post-baseline IC 0 | 3 Participants |
| Placebo + Chemotherapy | Number of Participants With PD-L1 Protein Expression in Screening Tumour Tissue and Post-baseline Assessment | Baseline IC1/2/3- Post-baseline IC 0 | 0 Participants |
| Placebo + Chemotherapy | Number of Participants With PD-L1 Protein Expression in Screening Tumour Tissue and Post-baseline Assessment | Baseline IC0- Post-baseline IC1/2/3 | 0 Participants |
| Placebo + Chemotherapy | Number of Participants With PD-L1 Protein Expression in Screening Tumour Tissue and Post-baseline Assessment | Baseline IC1/2/3- Post-baseline IC1/2/3 | 6 Participants |
| Atezolizumab + Chemotherapy | Number of Participants With PD-L1 Protein Expression in Screening Tumour Tissue and Post-baseline Assessment | Baseline IC1/2/3- Post-baseline IC1/2/3 | 2 Participants |
| Atezolizumab + Chemotherapy | Number of Participants With PD-L1 Protein Expression in Screening Tumour Tissue and Post-baseline Assessment | Baseline IC0- Post-baseline IC 0 | 0 Participants |
| Atezolizumab + Chemotherapy | Number of Participants With PD-L1 Protein Expression in Screening Tumour Tissue and Post-baseline Assessment | Baseline IC0- Post-baseline IC1/2/3 | 0 Participants |
| Atezolizumab + Chemotherapy | Number of Participants With PD-L1 Protein Expression in Screening Tumour Tissue and Post-baseline Assessment | Baseline IC1/2/3- Post-baseline IC 0 | 0 Participants |
Secondary
Objective Response Rate (ORR) in Response-evaluable Population, Subset of PD-L1-positive Population
ORR was defined as percentage of participants with measurable disease at baseline who achieved a documented unconfirmed objective response (OR). OR was defined as either a complete response (CR) or a partial response (PR), as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD, in the absence of CR. Percentages have been rounded off to nearest whole number.
Time frame: Baseline up to end of study (Up to 68 months)
Population: PD-L1 positive population included all participants randomized in the study whose PD-L1 status was tumor-infiltrating IC of 1% or greater (IC1/2/3) at the time of randomization, grouped according to their assigned treatment arm, whether or not the assigned study treatment was received. Response-evaluable Population included participants randomized in the study with measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Chemotherapy | Objective Response Rate (ORR) in Response-evaluable Population, Subset of PD-L1-positive Population | 28.3 percentage of participants |
| Atezolizumab + Chemotherapy | Objective Response Rate (ORR) in Response-evaluable Population, Subset of PD-L1-positive Population | 39.6 percentage of participants |
p-value: 0.033795% CI: [0.24, 22.37]Cochran-Mantel-Haenszel
Secondary
ORR in Response-evaluable Population, Subset of mITT Population
ORR was defined as percentage of participants with measurable disease at baseline who achieved a documented unconfirmed OR. OR was defined as either a CR or PR, as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. Percentages have been rounded off to nearest whole number.
Time frame: Baseline up to end of study (Up to 68 months)
Population: mITT population included all participants randomized under the protocol versions prior to version 4.0 (referred to as all-comers, i.e., PD-L1 (SP142)-positive and PD-L1 (SP142)-negative participants), grouped according to their assigned treatment arm, whether or not the assigned study treatment was received. Response-evaluable Population included participants randomized in the study with measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Chemotherapy | ORR in Response-evaluable Population, Subset of mITT Population | 32.1 percentage of participants |
| Atezolizumab + Chemotherapy | ORR in Response-evaluable Population, Subset of mITT Population | 31.0 percentage of participants |
p-value: 0.975595% CI: [-11.63, 9.34]Cochran-Mantel-Haenszel
Secondary
PFS in mITT Population
PFS was defined as the time from randomization to the first occurrence of PD, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Data for participants not experiencing PD or death were censored at the last tumour assessment date. If no tumor assessment was performed after randomisation, data were censored at the date of randomisation +1 day.
Time frame: Time from randomization to the first occurrence of PD or death (Up to 68 months)
Population: mITT population included all participants randomized under the protocol versions prior to version 4.0 (referred to as all-comers, i.e., PD-L1(SP142)-positive and PD-L1(SP142)-negative participants), grouped according to their assigned treatment arm, whether or not the assigned study treatment was received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Chemotherapy | PFS in mITT Population | 3.58 months |
| Atezolizumab + Chemotherapy | PFS in mITT Population | 3.71 months |
p-value: 0.731795% CI: [0.78, 1.19]Log Rank
Secondary
Progression-free Survival (PFS) in PD-L1-positive Population
PFS was defined as the time from randomization to the first occurrence of PD, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), or death from any cause, whichever occurs first. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 millimeters (mm). Data for participants not experiencing PD or death were censored at the last tumour assessment date. If no tumor assessment was performed after randomisation, data were censored at the date of randomisation +1 day.
Time frame: Time from randomization to the first occurrence of PD or death (Up to 68 months)
Population: PD-L1 positive population included all participants randomized in the study whose PD-L1 status was tumor-infiltrating IC of 1% or greater (IC1/2/3) at the time of randomization, grouped according to their assigned treatment arm, whether or not the assigned study treatment was received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Chemotherapy | Progression-free Survival (PFS) in PD-L1-positive Population | 3.58 months |
| Atezolizumab + Chemotherapy | Progression-free Survival (PFS) in PD-L1-positive Population | 4.21 months |
p-value: 0.138795% CI: [0.67, 1.06]Log Rank
Secondary
Serum Concentration of Atezolizumab
Time frame: Pre-dose on Day 1 of Cycles 1, 2, 3 and 4; Post-dose on Day 1 of Cycles 1 and 3 and Treatment Discontinuation Visit (up to 69 months) (1 Cycle= 3 weeks)
Population: Pharmacokinetic (PK)-evaluable population included participants who received any dose of study medication and who had at least one evaluable post-baseline PK sample. Number analyzed is the number of participants with data available for analyses at the specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo + Chemotherapy | Serum Concentration of Atezolizumab | Cycle 1 Day 1 Post-dose | 442 micrograms/millilitre (µg/mL) | Geometric Coefficient of Variation 59.7 |
| Placebo + Chemotherapy | Serum Concentration of Atezolizumab | Cycle 1 Day 1 Predose | NA micrograms/millilitre (µg/mL) | — |
| Placebo + Chemotherapy | Serum Concentration of Atezolizumab | Cycle 2 Day 1 Pre-dose | 87.2 micrograms/millilitre (µg/mL) | Geometric Coefficient of Variation 72.7 |
| Placebo + Chemotherapy | Serum Concentration of Atezolizumab | Cycle 3 Day 1 Predose | 140 micrograms/millilitre (µg/mL) | Geometric Coefficient of Variation 42.9 |
| Placebo + Chemotherapy | Serum Concentration of Atezolizumab | Cycle 3 Day 1 Postdose | 517 micrograms/millilitre (µg/mL) | Geometric Coefficient of Variation 47.7 |
| Placebo + Chemotherapy | Serum Concentration of Atezolizumab | Cycle 4 Day 1 Predose | 157 micrograms/millilitre (µg/mL) | Geometric Coefficient of Variation 104.9 |
| Placebo + Chemotherapy | Serum Concentration of Atezolizumab | Treatment Discontinuation | 120 micrograms/millilitre (µg/mL) | Geometric Coefficient of Variation 189.7 |
Secondary
Time to Confirmed Deterioration (TTD) in Global Health Status/Quality of Life (GHS/QoL) According to the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) in PD-L1-positive Population
TTD in GHS/QoL, defined by a minimally important decrease of ≥10 points at 2 consecutive assessment time-points on the GHS/QoL scale (Items 29, 30) of EORTC QLQ-C30, which consists of 30 questions that assess 5 aspects of participant functioning (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, and pain), GHS and QoL, & six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) with a recall period of the previous week. Participant responses to questions regarding GHS (Question 29: GHS; How would you rate your overall health during the past week?) & QoL (Question 30: QoL; How would you rate your overall quality of life during the past week?) were assessed & were scored on a 7-point scale (1= Very poor; 7=Excellent). Scores are linearly transformed on a scale of 0 to 100, with a high score indicating better QoL.
Time frame: Up to 68 months
Population: PD-L1 positive population included all participants randomized in the study whose PD-L1 status was tumor-infiltrating IC of 1% or greater (IC1/2/3) at the time of randomization, grouped according to their assigned treatment arm, whether or not the assigned study treatment was received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Chemotherapy | Time to Confirmed Deterioration (TTD) in Global Health Status/Quality of Life (GHS/QoL) According to the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) in PD-L1-positive Population | 6.77 months |
| Atezolizumab + Chemotherapy | Time to Confirmed Deterioration (TTD) in Global Health Status/Quality of Life (GHS/QoL) According to the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) in PD-L1-positive Population | 9.43 months |
Comparison: Stratified Analysisp-value: 0.411795% CI: [0.63, 1.21]Log Rank
Secondary
TTD in GHS/QoL According to EORTC QLQ-C30 in mITT Population
TTD in GHS/QoL, defined by a minimally important decrease of ≥10 points at 2 consecutive assessment time-points on the GHS/QoL scale (Items 29, 30) of EORTC QLQ-C30, which consists of 30 questions that assess 5 aspects of participant functioning (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, and pain), GHS and QoL, & six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) with a recall period of the previous week. Participant responses to questions regarding GHS (Question 29: GHS; How would you rate your overall health during the past week?) & QoL (Question 30: QoL; How would you rate your overall quality of life during the past week?) were assessed & were scored on a 7-point scale (1= Very poor; 7=Excellent). Scores are linearly transformed on a scale of 0 to 100, with a high score indicating better QoL.
Time frame: Up to 68 months
Population: mITT population included all participants randomized under the protocol versions prior to version 4.0 (referred to as all-comers, i.e., PD-L1(SP142)-positive and PD-L1(SP142)-negative participants), grouped according to their assigned treatment arm, whether or not the assigned study treatment was received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Chemotherapy | TTD in GHS/QoL According to EORTC QLQ-C30 in mITT Population | 7.66 months |
| Atezolizumab + Chemotherapy | TTD in GHS/QoL According to EORTC QLQ-C30 in mITT Population | 8.90 months |
Comparison: Stratified Analysisp-value: 0.721595% CI: [0.68, 1.3]Log Rank
Other Pre-specified
12-month Survival Rate in China Population
12-month survival rate was defined as the percentage of participants alive 12 months after randomization.
Time frame: 12 months
Population: As pre-specified in the SAP, analysis for China population was to be conducted based on data maturity and estimated treatment effect from the global population. As the results for global population did not meet pre-specified criteria, a separate analysis for China subpopulation was not conducted.
Other Pre-specified
18-month Survival Rate in China Population
18-month survival rate was defined as the percentage of participants alive 18 months after randomization.
Time frame: 18 months
Population: As pre-specified in the SAP, analysis for China population was to be conducted based on data maturity and estimated treatment effect from the global population. As the results for the global population did not meet pre-specified criteria, a separate analysis for China subpopulation was not conducted.
Other Pre-specified
CBR in China Population
CBR was defined as the percentage of participants with either an unconfirmed CR or PR or SD that lasts at least 6 months as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm.
Time frame: Up to 68 months
Population: As pre-specified in the SAP, analysis for China population was to be conducted based on data maturity and estimated treatment effect from the global population. As the results for the global population were did not meet pre-specified criteria, a separate analysis for China subpopulation was not conducted.
Other Pre-specified
C-DoR in China Population
C-DoR was defined as the time from the first occurrence of a documented confirmed response (CR or PR) until the date of PD as determined by the investigator from tumor assessments using RECIST v1.1 or death from any cause, whichever occurs first. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression.
Time frame: Time from the first occurrence of a documented OR until the date of PD/death (Up to 68 months)
Population: As pre-specified in the SAP, analysis for China population was to be conducted based on data maturity and estimated treatment effect from the global population. As the results for the global population did not meet pre-specified criteria, a separate analysis for China subpopulation was not conducted.
Other Pre-specified
C-ORR in China Population
C-ORR was defined as percentage of participants with measurable disease at baseline who achieved a documented confirmed OR. OR was defined as either a CR or PR, as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR.
Time frame: Up to 68 months
Population: As pre-specified in the SAP, analysis for China population was to be conducted based on data maturity and estimated treatment effect from the global population. As the results for the global population were did not meet pre-specified criteria, a separate analysis for China subpopulation was not conducted.
Other Pre-specified
DoR in China Population
DoR was defined as the time from the first occurrence of a documented unconfirmed response (CR or PR) until the date of PD as determined by the investigator from tumor assessments using RECIST v1.1 or death from any cause, whichever occurs first. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression.
Time frame: Time from the first occurrence of a documented OR until the date of PD/death (Up to 68 months)
Population: As pre-specified in the SAP, analysis for China population was to be conducted based on data maturity and estimated treatment effect from the global population. As the results for the global population were did not meet pre-specified criteria, a separate analysis for China subpopulation was not conducted.
Other Pre-specified
ORR in China Population
ORR was defined as percentage of participants with measurable disease at baseline who achieved a documented unconfirmed OR. OR was defined as either a CR or PR, as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR.
Time frame: Baseline up to end of study (Up to 68 months)
Population: As pre-specified in the SAP, analysis for China population was to be conducted based on data maturity and estimated treatment effect from the global population. As the results for the global population were did not meet pre-specified criteria, a separate analysis for China subpopulation was not conducted.
Other Pre-specified
OS in China Population
OS was defined as time from randomization to death from any cause.
Time frame: Time from randomization to death (Up to 68 months)
Population: As pre-specified in the SAP, analysis for China population was to be conducted based on data maturity and the estimated treatment effect from the global population. As the results for global population did not meet pre-specified criteria, a separate analysis for China subpopulation was not conducted.
Other Pre-specified
PFS in China Population
PFS was defined as the time from randomization to the first occurrence of PD, as determined by the investigator according to RECIST 1.1, or death from any cause, whichever occurs first.
Time frame: Time from randomization to the first occurrence of PD or death (Up to 68 months)
Population: As pre-specified in the SAP, analysis for China population was to be conducted based on data maturity and estimated treatment effect from the global population. As the results for the global population did not meet pre-specified criteria, a separate analysis for China subpopulation was not conducted.
Other Pre-specified
TTD in GHS/QoL According to EORTC QLQ-C30 in China Population
TTD in GHS/QoL, defined by a minimally important decrease of ≥10 points at 2 consecutive assessment time-points on the GHS/QoL scale (Items 29, 30) of EORTC QLQ-C30, which consists of 30 questions that assess 5 aspects of participant functioning (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, and pain), GHS and QoL, & six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) with a recall period of the previous week. Participant responses to questions regarding GHS (Question 29: GHS; How would you rate your overall health during the past week?) & QoL (Question 30: QoL; How would you rate your overall quality of life during the past week?) were assessed & were scored on a 7-point scale (1= Very poor; 7=Excellent). Scores are linearly transformed on a scale of 0 to 100, with a high score indicating better QoL.
Time frame: Up to 68 months
Population: As pre-specified in the SAP, analysis for China population was to be conducted based on data maturity and estimated treatment effect from the global population. As the results for the global population did not meet pre-specified criteria, a separate analysis for China subpopulation was not conducted.