Small Cell Lung Carcinoma
Conditions
Brief summary
This randomized, Phase I/III, multicenter, double-blinded, placebo-controlled study was designed to evaluate the safety and efficacy of atezolizumab (anti-programmed death-ligand 1 \[PD-L1\] antibody) in combination with carboplatin plus (+) etoposide compared with treatment with placebo + carboplatin + etoposide in chemotherapy-naive participants with ES-SCLC. Participants will be randomized in a 1:1 ratio to receive either atezolizumab + carboplatin + etoposide or placebo + carboplatin + etoposide on 21-day cycles for four cycles in the induction phase followed by maintenance with atezolizumab or placebo until progressive disease (PD) as assessed by the investigator using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). Treatment can be continued until persistent radiographic PD or symptomatic deterioration.
Interventions
Atezolizumab intravenous infusion was administered at a dose of 1200 mg on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4) and maintenance phase (Cycle 5 onward).
DRUGCarboplatin
Carboplatin intravenous infusion to achieve an initial target AUC of 5 mg/mL/min was administered on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4).
DRUGEtoposide
Etoposide intravenous infusion was administered at a dose of 100 mg/m\^2 on Days 1, 2, and 3 of each 21-day cycle during the induction phase (Cycles 1-4).
DRUGPlacebo
Placebo intravenous infusion was administered on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4) and maintenance phase (Cycle 5 onward).
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed ES-SCLC (per the Veterans Administration Lung Study Group \[VALG\] staging system) * No prior systemic treatment for ES-SCLC * Eastern Cooperative Oncology Group performance status of 0 or 1 * Measurable disease, as defined by RECIST v1.1 * Adequate hematologic and end organ function * Treatment-free for at least 6 months since last chemo/radiotherapy, among those treated (with curative intent) with prior chemo/radiotherapy for limited-stage SCLC
Exclusion criteria
* Active or untreated central nervous system (CNS) metastases as determined by computed tomography (CT) or magnetic resonance imaging (MRI) evaluation * Malignancies other than SCLC within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome * Pregnant or lactating women * History of autoimmune disease * History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted. * Positive test result for human immunodeficiency virus (HIV) * Active hepatitis B or hepatitis C * Severe infections at the time of randomization * Significant cardiovascular disease * Prior treatment with cluster of differentiation (CD) 137 agonists or immune checkpoint blockade therapies, anti-programmed death-1 (PD-1), and anti-PD-L1 therapeutic antibody * History of severe (or known) hypersensitivity to chimeric or humanized antibodies or fusion proteins or any component of atezolizumab formulation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Progression-Free Survival (PFS) as Assessed by the Investigator Using RECIST v1.1 in the Global Population | Baseline until PD or death, whichever occurs first (up to approximately 23 months) | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as at least 20% increase in the sum of the longest diameter of target lesions compared to baseline, or unequivocal progression in non-target lesion(s), or the appearance of new lesion(s). |
| Duration of Overall Survival (OS) in the Global Population | Baseline until death from any cause (up to approximately 23 months) | OS is defined as the time from randomization to death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFS Rate at 6 Months and at 1 Year in Global Population | 6 months, 1 year | PFS rates at 6 months and at 1 year is defined as the proportion of participants who are alive without disease progression 6 months and 1 year after randomization, respectively. |
| OS Rate at 1 Year and 2 Years in the Global Population | 1 year, 2 years | OS rates at 1 and 2 years is defined as the proportion of participants who are alive 1 year and 2 years after randomization, respectively. |
| Time to Deterioration (TTD) Per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30) and Supplemental Lung Cancer Module (QLQ-LC13) in the Global Population | Baseline until deterioration per symptom subscale (up to approximately 23 months) | TTD according to the EORTC QLQ-C30 and EORTC QLQ-LC13 measures were evaluated in each of the following linearly transformed symptom scores: cough, dyspnea (single item), dyspnea (multi-item subscale), chest pain, or arm/shoulder pain. The linear transformation gives each individual symptom subscale a possible score of 0 to 100. For the symptom to be considered deteriorated, a score increase of ≥10 points above baseline must be held for at least two consecutive assessments or an initial score increase of ≥10 points is followed by death within 3 weeks from the last assessment. A ≥ 10-point change in the symptoms subscale score is perceived by participants as clinically significant. |
| Percentage of Participants With at Least One Adverse Event in the Global Population | Baseline until up to 90 days after end of treatment (up to approximately 49 months) | The percentage of participants with at least one adverse event in the global population. |
| Percentage of Participants With Objective Response Rate (ORR) as Assessed by the Investigator Using RECIST v1.1 in the Global Population | Baseline until partial response (PR) or complete response (CR), whichever occurs first (up to approximately 23 months) | Objective response (OR) is defined as complete response (CR) or partial response (PR) as determined by the investigator according to RECIST v1.1. |
| Maximum Observed Serum Concentration (Cmax) of Atezolizumab in the Global Population | Post-dose Day 1 of Cycle 1 (cycle length = 21 days) | Atezolizumab maximum observed plasma concentration (Cmax; 30 minutes following the end of the atezolizumab infusion) for each respective day. |
| Minimum Observed Serum Concentration (Cmin) of Atezolizumab in the Global Population | Predose on Day 1 of Cycles 1, 3, 4, 8, 16 and 24 (cycle length = 21 days) | Atezolizumab pre-dose plasma concentration (Cmin) for each respective day. |
| Plasma Concentration of Carboplatin in the Global Population | Predose, before end of infusion, and after end of carboplatin infusion on Day 1 of Cycle 1 and Cycle 3 (cycle = 21 days) | Plasma concentration of carboplatin in the Global population. |
| Plasma Concentration of Etoposide in the Global Population | Predose, before end of infusion, 1 and 4 hours after end of carboplatin infusion on Day 1 of Cycle 1 and Cycle 3 (cycle = 21 days) | Plasma concentration of etoposide in the Global Population. |
| Percentage of Participants With Anti-Drug Antibodies (ADA) to Atezolizumab in the Global Population | Predose (0 hours [H]) on Day (D) 1 of Cycles (C) 1, 2, 3, 4, 8, 16, and every 8 cycles (Q8C) thereafter (cycle = 21 days) until treatment discontinuation (up to 23 months) and 120 days after last dose (up to approximately 23 months overall) | The baseline prevalence and post-baseline incidence of ADAs against atezolizumab. |
| Duration of Response (DOR) as Assessed by the Investigator Using RECIST v1.1 in the Global Population | First occurrence of PR or CR until PD or death, whichever occurs first (up to approximately 23 months) | DOR is defined as the time interval from first occurrence of a documented objective response to the time of disease progression as determined by the investigator using RECIST v1.1 or death from any cause, whichever comes first. |
Countries
Australia, Austria, Brazil, Chile, China, Czechia, France, Germany, Greece, Hungary, Italy, Japan, Mexico, Poland, Russia, Serbia, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at 114 centers in 21 countries: United States of America, Poland, Japan, Russia, Spain, Austria, Hungary, Czech Republic, South Korea, Italy, Serbia, Australia, Greece, United Kingdom, Germany, Taiwan, France, Chile, Brazil, Mexico, and China.
Pre-assignment details
The total study population included 503 participants. The Global population included 403 participants. An additional 100 participants enrolled during the China Extension. The total China population included 10 Chinese participants from the Global population plus 100 participants from the China extension. 10 participants were part of the Global as well as China populations. Separate analyses were performed for the Global population and the China population in the study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo + Carboplatin + Etoposide - All All participants in the Global or China population received intravenous infusions of placebo in combination with carboplatin to achieve an initial target AUC of 5 mg/mL/min followed by etoposide 100 mg/m\^2 on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m\^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) placebo on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor. | 251 |
| Atezolizumab + Carboplatin + Etoposide - All All participants in the Global or China population received intravenous infusions of atezolizumab 1200 milligrams (mg) in combination with carboplatin to achieve an initial target area under the concentration-time curve (AUC) of 5 milligrams per milliliter per minute (mg/mL/min) followed by etoposide 100 milligrams per square meter (mg/m\^2) on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m\^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) atezolizumab 1200 mg on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor. | 252 |
| Total | 503 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| China Period | Death | 0 | 0 | 46 | 48 |
| China Period | Lost to Follow-up | 0 | 0 | 1 | 1 |
| China Period | Physician Decision | 0 | 0 | 0 | 1 |
| China Period | Study Terminated By Sponsor | 0 | 0 | 3 | 4 |
| China Period | Withdrawal by Subject | 0 | 0 | 3 | 3 |
| Global Period | Death | 167 | 151 | 0 | 0 |
| Global Period | Lost to Follow-up | 2 | 4 | 0 | 0 |
| Global Period | Physician Decision | 0 | 2 | 0 | 0 |
| Global Period | Study Terminated By Sponsor | 21 | 26 | 0 | 0 |
| Global Period | Withdrawal by Subject | 12 | 18 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo + Carboplatin + Etoposide - All | Atezolizumab + Carboplatin + Etoposide - All | Total |
|---|---|---|---|
| Age, Continuous China | 60.7 years STANDARD_DEVIATION 8.8 | 59.7 years STANDARD_DEVIATION 9 | 60.2 years STANDARD_DEVIATION 8.9 |
| Age, Continuous Global | 63.6 years STANDARD_DEVIATION 9 | 63.8 years STANDARD_DEVIATION 8.8 | 63.7 years STANDARD_DEVIATION 8.9 |
| Ethnicity (NIH/OMB) China Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) China Not Hispanic or Latino | 53 Participants | 57 Participants | 110 Participants |
| Ethnicity (NIH/OMB) China Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Global Hispanic or Latino | 8 Participants | 8 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Global Not Hispanic or Latino | 185 Participants | 187 Participants | 372 Participants |
| Ethnicity (NIH/OMB) Global Unknown or Not Reported | 9 Participants | 6 Participants | 15 Participants |
| Race (NIH/OMB) China American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) China Asian | 53 Participants | 57 Participants | 110 Participants |
| Race (NIH/OMB) China Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) China More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) China Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) China Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) China White | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Global American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Global Asian | 36 Participants | 33 Participants | 69 Participants |
| Race (NIH/OMB) Global Black or African American | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Global More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Global Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Global Unknown or Not Reported | 4 Participants | 4 Participants | 8 Participants |
| Race (NIH/OMB) Global White | 159 Participants | 163 Participants | 322 Participants |
| Sex: Female, Male China Female | 12 Participants | 11 Participants | 23 Participants |
| Sex: Female, Male China Male | 41 Participants | 46 Participants | 87 Participants |
| Sex: Female, Male Global Female | 70 Participants | 72 Participants | 142 Participants |
| Sex: Female, Male Global Male | 132 Participants | 129 Participants | 261 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 11 / 196 | 5 / 198 | 1 / 52 | 3 / 57 |
| other Total, other adverse events | 187 / 196 | 191 / 198 | 52 / 52 | 56 / 57 |
| serious Total, serious adverse events | 69 / 196 | 81 / 198 | 14 / 52 | 22 / 57 |
Outcome results
Primary
Duration of Overall Survival (OS) in the Global Population
OS is defined as the time from randomization to death from any cause.
Time frame: Baseline until death from any cause (up to approximately 23 months)
Population: The ITT population was defined as all randomized participants, regardless of whether the participant received the assigned treatment.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Placebo + Carboplatin + Etoposide | Duration of Overall Survival (OS) in the Global Population | 10.3 Months | 95% Confidence Interval 9.3 |
| Atezolizumab + Carboplatin + Etoposide | Duration of Overall Survival (OS) in the Global Population | 12.3 Months | 95% Confidence Interval 10.8 |
p-value: 0.006995% CI: [0.54, 0.91]Log Rank
Primary
Duration of Progression-Free Survival (PFS) as Assessed by the Investigator Using RECIST v1.1 in the Global Population
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as at least 20% increase in the sum of the longest diameter of target lesions compared to baseline, or unequivocal progression in non-target lesion(s), or the appearance of new lesion(s).
Time frame: Baseline until PD or death, whichever occurs first (up to approximately 23 months)
Population: The ITT population was defined as all randomized participants, regardless of whether the participant received the assigned treatment.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Placebo + Carboplatin + Etoposide | Duration of Progression-Free Survival (PFS) as Assessed by the Investigator Using RECIST v1.1 in the Global Population | 4.3 Months | 95% Confidence Interval 4.2 |
| Atezolizumab + Carboplatin + Etoposide | Duration of Progression-Free Survival (PFS) as Assessed by the Investigator Using RECIST v1.1 in the Global Population | 5.2 Months | 95% Confidence Interval 4.4 |
p-value: 0.01795% CI: [0.62, 0.96]Log Rank
Secondary
Duration of Response (DOR) as Assessed by the Investigator Using RECIST v1.1 in the Global Population
DOR is defined as the time interval from first occurrence of a documented objective response to the time of disease progression as determined by the investigator using RECIST v1.1 or death from any cause, whichever comes first.
Time frame: First occurrence of PR or CR until PD or death, whichever occurs first (up to approximately 23 months)
Population: The ITT population was defined as all randomized participants, regardless of whether the participant received the assigned treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Carboplatin + Etoposide | Duration of Response (DOR) as Assessed by the Investigator Using RECIST v1.1 in the Global Population | 3.1 Months |
| Atezolizumab + Carboplatin + Etoposide | Duration of Response (DOR) as Assessed by the Investigator Using RECIST v1.1 in the Global Population | 4.1 Months |
p-value: 0.006395% CI: [0.562, 0.911]Log Rank
Secondary
Maximum Observed Serum Concentration (Cmax) of Atezolizumab in the Global Population
Atezolizumab maximum observed plasma concentration (Cmax; 30 minutes following the end of the atezolizumab infusion) for each respective day.
Time frame: Post-dose Day 1 of Cycle 1 (cycle length = 21 days)
Population: PK analyses were based on PK observations from all participants who had received atezolizumab, carboplatin, or etoposide treatment and who provided at least one evaluable atezolizumab PK sample.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Carboplatin + Etoposide | Maximum Observed Serum Concentration (Cmax) of Atezolizumab in the Global Population | 389 μg/mL | Standard Deviation 135 |
Secondary
Minimum Observed Serum Concentration (Cmin) of Atezolizumab in the Global Population
Atezolizumab pre-dose plasma concentration (Cmin) for each respective day.
Time frame: Predose on Day 1 of Cycles 1, 3, 4, 8, 16 and 24 (cycle length = 21 days)
Population: PK analyses were based on PK observations from all participants who had received atezolizumab, carboplatin, or etoposide treatment and who provided at least one evaluable atezolizumab PK sample.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo + Carboplatin + Etoposide | Minimum Observed Serum Concentration (Cmin) of Atezolizumab in the Global Population | Cycle 1 Day 1 | NA μg/mL | — |
| Placebo + Carboplatin + Etoposide | Minimum Observed Serum Concentration (Cmin) of Atezolizumab in the Global Population | Cycle 3 Day1 | 80.6 μg/mL | Standard Deviation 32.1 |
| Placebo + Carboplatin + Etoposide | Minimum Observed Serum Concentration (Cmin) of Atezolizumab in the Global Population | Cycle 4 Day 1 | 138 μg/mL | Standard Deviation 56.4 |
| Placebo + Carboplatin + Etoposide | Minimum Observed Serum Concentration (Cmin) of Atezolizumab in the Global Population | Cycle 8 Day 1 | 186 μg/mL | Standard Deviation 73.5 |
| Placebo + Carboplatin + Etoposide | Minimum Observed Serum Concentration (Cmin) of Atezolizumab in the Global Population | Cycle 16 Day 1 | 196 μg/mL | Standard Deviation 63.1 |
| Placebo + Carboplatin + Etoposide | Minimum Observed Serum Concentration (Cmin) of Atezolizumab in the Global Population | Cycle 24 Day 1 | 221 μg/mL | Standard Deviation 43.4 |
Secondary
OS Rate at 1 Year and 2 Years in the Global Population
OS rates at 1 and 2 years is defined as the proportion of participants who are alive 1 year and 2 years after randomization, respectively.
Time frame: 1 year, 2 years
Population: The ITT population was defined as all randomized participants, regardless of whether the participant received the assigned treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Carboplatin + Etoposide | OS Rate at 1 Year and 2 Years in the Global Population | 1 Year | 38.23 Percentage of participants |
| Placebo + Carboplatin + Etoposide | OS Rate at 1 Year and 2 Years in the Global Population | 2 Years | NA Percentage of participants |
| Atezolizumab + Carboplatin + Etoposide | OS Rate at 1 Year and 2 Years in the Global Population | 2 Years | NA Percentage of participants |
| Atezolizumab + Carboplatin + Etoposide | OS Rate at 1 Year and 2 Years in the Global Population | 1 Year | 51.69 Percentage of participants |
Comparison: OS Rate at 1 yearp-value: 0.009595% CI: [3.29, 23.64]Z-test
Secondary
Percentage of Participants With Anti-Drug Antibodies (ADA) to Atezolizumab in the Global Population
The baseline prevalence and post-baseline incidence of ADAs against atezolizumab.
Time frame: Predose (0 hours [H]) on Day (D) 1 of Cycles (C) 1, 2, 3, 4, 8, 16, and every 8 cycles (Q8C) thereafter (cycle = 21 days) until treatment discontinuation (up to 23 months) and 120 days after last dose (up to approximately 23 months overall)
Population: ADA analyses were based on ADA observations from participants who had received atezolizumab treatment and were evaluated for immunogenicity.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Carboplatin + Etoposide | Percentage of Participants With Anti-Drug Antibodies (ADA) to Atezolizumab in the Global Population | Baseline evaluable participants | 2.0 Percentage of participants |
| Placebo + Carboplatin + Etoposide | Percentage of Participants With Anti-Drug Antibodies (ADA) to Atezolizumab in the Global Population | Post-baseline evaluable participants | 18.6 Percentage of participants |
Secondary
Percentage of Participants With at Least One Adverse Event in the Global Population
The percentage of participants with at least one adverse event in the global population.
Time frame: Baseline until up to 90 days after end of treatment (up to approximately 49 months)
Population: The safety population included all treated participants, defined as participants who received any amount of any component of study treatment. For the safety analyses, patrticipants who received any amount of atezolizumab were analyzed as part of the Atezo + CE arm, even if atezolizumab was given in error.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Carboplatin + Etoposide | Percentage of Participants With at Least One Adverse Event in the Global Population | 96.4 Percentage of participants |
| Atezolizumab + Carboplatin + Etoposide | Percentage of Participants With at Least One Adverse Event in the Global Population | 100.0 Percentage of participants |
Secondary
Percentage of Participants With Objective Response Rate (ORR) as Assessed by the Investigator Using RECIST v1.1 in the Global Population
Objective response (OR) is defined as complete response (CR) or partial response (PR) as determined by the investigator according to RECIST v1.1.
Time frame: Baseline until partial response (PR) or complete response (CR), whichever occurs first (up to approximately 23 months)
Population: The ITT population was defined as all randomized participants, regardless of whether the participant received the assigned treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Carboplatin + Etoposide | Percentage of Participants With Objective Response Rate (ORR) as Assessed by the Investigator Using RECIST v1.1 in the Global Population | 76.7 Percentage of participants |
| Atezolizumab + Carboplatin + Etoposide | Percentage of Participants With Objective Response Rate (ORR) as Assessed by the Investigator Using RECIST v1.1 in the Global Population | 74.1 Percentage of participants |
95% CI: [0.55, 1.37]
Secondary
PFS Rate at 6 Months and at 1 Year in Global Population
PFS rates at 6 months and at 1 year is defined as the proportion of participants who are alive without disease progression 6 months and 1 year after randomization, respectively.
Time frame: 6 months, 1 year
Population: The ITT population was defined as all randomized participants, regardless of whether the participant received the assigned treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Carboplatin + Etoposide | PFS Rate at 6 Months and at 1 Year in Global Population | 6 Months | 22.39 Percentage of participants |
| Placebo + Carboplatin + Etoposide | PFS Rate at 6 Months and at 1 Year in Global Population | 1 Year | 5.35 Percentage of participants |
| Atezolizumab + Carboplatin + Etoposide | PFS Rate at 6 Months and at 1 Year in Global Population | 6 Months | 30.86 Percentage of participants |
| Atezolizumab + Carboplatin + Etoposide | PFS Rate at 6 Months and at 1 Year in Global Population | 1 Year | 12.62 Percentage of participants |
Comparison: PFS Rate at 6 monthsp-value: 0.059395% CI: [-0.33, 17.27]Z-test
Comparison: PFS Rate at 1 yearp-value: 0.013395% CI: [1.52, 13.02]Z-test
Secondary
Plasma Concentration of Carboplatin in the Global Population
Plasma concentration of carboplatin in the Global population.
Time frame: Predose, before end of infusion, and after end of carboplatin infusion on Day 1 of Cycle 1 and Cycle 3 (cycle = 21 days)
Population: PK analyses were based on PK observations from all participants who had received atezolizumab, carboplatin, or etoposide treatment and who provided at least one evaluable atezolizumab PK sample.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo + Carboplatin + Etoposide | Plasma Concentration of Carboplatin in the Global Population | Post Infusion on Day 1 of Cycle 3 | 7180 ng/mL | Standard Deviation 1630 |
| Placebo + Carboplatin + Etoposide | Plasma Concentration of Carboplatin in the Global Population | Pre-Dose on Day 1 of Cycle 3 | 144 ng/mL | Standard Deviation 58.3 |
| Placebo + Carboplatin + Etoposide | Plasma Concentration of Carboplatin in the Global Population | Pre-Dose on Day 1 of Cycle 1 | NA ng/mL | — |
| Placebo + Carboplatin + Etoposide | Plasma Concentration of Carboplatin in the Global Population | Before End of Infusion on Day 1 of Cycle 1 | 13300 ng/mL | Standard Deviation 4880 |
| Placebo + Carboplatin + Etoposide | Plasma Concentration of Carboplatin in the Global Population | Post Infusion on Day 1 of Cycle 1 | 7200 ng/mL | Standard Deviation 1880 |
| Placebo + Carboplatin + Etoposide | Plasma Concentration of Carboplatin in the Global Population | Before End of Infusion on Day 1 of Cycle 3 | 13900 ng/mL | Standard Deviation 3590 |
| Atezolizumab + Carboplatin + Etoposide | Plasma Concentration of Carboplatin in the Global Population | Post Infusion on Day 1 of Cycle 1 | 6860 ng/mL | Standard Deviation 1670 |
| Atezolizumab + Carboplatin + Etoposide | Plasma Concentration of Carboplatin in the Global Population | Before End of Infusion on Day 1 of Cycle 1 | 11200 ng/mL | Standard Deviation 5060 |
| Atezolizumab + Carboplatin + Etoposide | Plasma Concentration of Carboplatin in the Global Population | Pre-Dose on Day 1 of Cycle 3 | 126 ng/mL | Standard Deviation 48.1 |
| Atezolizumab + Carboplatin + Etoposide | Plasma Concentration of Carboplatin in the Global Population | Post Infusion on Day 1 of Cycle 3 | 6540 ng/mL | Standard Deviation 2200 |
| Atezolizumab + Carboplatin + Etoposide | Plasma Concentration of Carboplatin in the Global Population | Before End of Infusion on Day 1 of Cycle 3 | 11300 ng/mL | Standard Deviation 5090 |
| Atezolizumab + Carboplatin + Etoposide | Plasma Concentration of Carboplatin in the Global Population | Pre-Dose on Day 1 of Cycle 1 | NA ng/mL | — |
Secondary
Plasma Concentration of Etoposide in the Global Population
Plasma concentration of etoposide in the Global Population.
Time frame: Predose, before end of infusion, 1 and 4 hours after end of carboplatin infusion on Day 1 of Cycle 1 and Cycle 3 (cycle = 21 days)
Population: PK analyses were based on PK observations from all participants who had received atezolizumab, carboplatin, or etoposide treatment and who provided at least one evaluable atezolizumab PK sample.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo + Carboplatin + Etoposide | Plasma Concentration of Etoposide in the Global Population | Pre-Dose on Day 1 of Cycle 1 | NA ng/mL | — |
| Placebo + Carboplatin + Etoposide | Plasma Concentration of Etoposide in the Global Population | Before End of Infusion on Day 1 of Cycle 1 | 17000 ng/mL | Standard Deviation 3640 |
| Placebo + Carboplatin + Etoposide | Plasma Concentration of Etoposide in the Global Population | 1 Hour Post Infusion on Day 1 of Cycle 1 | 11100 ng/mL | Standard Deviation 2010 |
| Placebo + Carboplatin + Etoposide | Plasma Concentration of Etoposide in the Global Population | 4 Hours Post Infusion on Day 1 of Cycle 1 | 7640 ng/mL | Standard Deviation 2360 |
| Placebo + Carboplatin + Etoposide | Plasma Concentration of Etoposide in the Global Population | Pre-Dose on Day 1 of Cycle 3 | NA ng/mL | — |
| Placebo + Carboplatin + Etoposide | Plasma Concentration of Etoposide in the Global Population | Before End of Infusion on Day 1 of Cycle 3 | 16600 ng/mL | Standard Deviation 2180 |
| Placebo + Carboplatin + Etoposide | Plasma Concentration of Etoposide in the Global Population | 1 Hour Post Infusion on Day 1 of Cycle 3 | 12400 ng/mL | Standard Deviation 3740 |
| Placebo + Carboplatin + Etoposide | Plasma Concentration of Etoposide in the Global Population | 4 Hours Post Infusion on Day 1 of Cycle 3 | 6740 ng/mL | Standard Deviation 1230 |
| Atezolizumab + Carboplatin + Etoposide | Plasma Concentration of Etoposide in the Global Population | 4 Hours Post Infusion on Day 1 of Cycle 3 | 7960 ng/mL | Standard Deviation 2090 |
| Atezolizumab + Carboplatin + Etoposide | Plasma Concentration of Etoposide in the Global Population | Pre-Dose on Day 1 of Cycle 1 | NA ng/mL | — |
| Atezolizumab + Carboplatin + Etoposide | Plasma Concentration of Etoposide in the Global Population | Pre-Dose on Day 1 of Cycle 3 | NA ng/mL | — |
| Atezolizumab + Carboplatin + Etoposide | Plasma Concentration of Etoposide in the Global Population | Before End of Infusion on Day 1 of Cycle 1 | 19400 ng/mL | Standard Deviation 2860 |
| Atezolizumab + Carboplatin + Etoposide | Plasma Concentration of Etoposide in the Global Population | 1 Hour Post Infusion on Day 1 of Cycle 3 | 12200 ng/mL | Standard Deviation 2810 |
| Atezolizumab + Carboplatin + Etoposide | Plasma Concentration of Etoposide in the Global Population | 1 Hour Post Infusion on Day 1 of Cycle 1 | 12600 ng/mL | Standard Deviation 1960 |
| Atezolizumab + Carboplatin + Etoposide | Plasma Concentration of Etoposide in the Global Population | Before End of Infusion on Day 1 of Cycle 3 | 17700 ng/mL | Standard Deviation 3600 |
| Atezolizumab + Carboplatin + Etoposide | Plasma Concentration of Etoposide in the Global Population | 4 Hours Post Infusion on Day 1 of Cycle 1 | 7300 ng/mL | Standard Deviation 1230 |
Secondary
Time to Deterioration (TTD) Per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30) and Supplemental Lung Cancer Module (QLQ-LC13) in the Global Population
TTD according to the EORTC QLQ-C30 and EORTC QLQ-LC13 measures were evaluated in each of the following linearly transformed symptom scores: cough, dyspnea (single item), dyspnea (multi-item subscale), chest pain, or arm/shoulder pain. The linear transformation gives each individual symptom subscale a possible score of 0 to 100. For the symptom to be considered deteriorated, a score increase of ≥10 points above baseline must be held for at least two consecutive assessments or an initial score increase of ≥10 points is followed by death within 3 weeks from the last assessment. A ≥ 10-point change in the symptoms subscale score is perceived by participants as clinically significant.
Time frame: Baseline until deterioration per symptom subscale (up to approximately 23 months)
Population: The ITT population was defined as all randomized participants, regardless of whether the participant received the assigned treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo + Carboplatin + Etoposide | Time to Deterioration (TTD) Per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30) and Supplemental Lung Cancer Module (QLQ-LC13) in the Global Population | Cough | NA Month |
| Placebo + Carboplatin + Etoposide | Time to Deterioration (TTD) Per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30) and Supplemental Lung Cancer Module (QLQ-LC13) in the Global Population | Pain in Chest | NA Month |
| Placebo + Carboplatin + Etoposide | Time to Deterioration (TTD) Per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30) and Supplemental Lung Cancer Module (QLQ-LC13) in the Global Population | Pain in Arm or Shoulder | NA Month |
| Placebo + Carboplatin + Etoposide | Time to Deterioration (TTD) Per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30) and Supplemental Lung Cancer Module (QLQ-LC13) in the Global Population | Dyspnea | 5.6 Month |
| Atezolizumab + Carboplatin + Etoposide | Time to Deterioration (TTD) Per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30) and Supplemental Lung Cancer Module (QLQ-LC13) in the Global Population | Dyspnea | NA Month |
| Atezolizumab + Carboplatin + Etoposide | Time to Deterioration (TTD) Per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30) and Supplemental Lung Cancer Module (QLQ-LC13) in the Global Population | Cough | 20.3 Month |
| Atezolizumab + Carboplatin + Etoposide | Time to Deterioration (TTD) Per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30) and Supplemental Lung Cancer Module (QLQ-LC13) in the Global Population | Pain in Arm or Shoulder | NA Month |
| Atezolizumab + Carboplatin + Etoposide | Time to Deterioration (TTD) Per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30) and Supplemental Lung Cancer Module (QLQ-LC13) in the Global Population | Pain in Chest | NA Month |
Comparison: Coughp-value: 0.360495% CI: [0.795, 1.874]Log Rank
Comparison: Pain in Chestp-value: 0.771295% CI: [0.722, 1.553]Log Rank
Comparison: Pain in Arm or Shoulderp-value: 0.692295% CI: [0.747, 1.552]Log Rank
Comparison: Dyspneap-value: 0.06595% CI: [0.549, 1.019]Log Rank