Small Cell Lung Carcinoma
Conditions
Brief summary
The purpose of this multicenter study in China is to evaluate the safety and efficacy of tiragolumab plus atezolizumab and carboplatin and etoposide (CE) compared with placebo plus atezolizumab and CE in participants with untreated extensive-stage small cell lung cancer.
Interventions
DRUGTiragolumab
Tiragolumab at a fixed dose of 600 milligrams (mg), administered by intravenous (IV) infusion, every 3 weeks (Q3W) on Day 1 of each 21-day cycle.
DRUGAtezolizumab
Atezolizumab at a fixed dose of 1200 mg, administered by IV infusion, Q3W on Day 1 of each 21-day cycle.
DRUGCarboplatin
Carboplatin administered IV to achieve an initial target area under the concentration time curve (AUC) of 5 mg/mL/min, Q3W on Day 1 of each 21-day cycle for 4 cycles.
DRUGEtoposide
Etoposide 100 mg/m\^2, administered by IV infusion, Q3W on Day 1, 2 and 3 of each 21-day cycle for 4 cycles.
Matching placebo, administered by IV infusion, Q3W on Day 1 of each 21-day 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
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 * Histologically or cytologically confirmed Extensive-Stage Small Cell Lung Cancer (ES-SCLC) per the modified Veterans Administration Lung Study Group (VALG) staging system * No prior systemic treatment for ES-SCLC * For participants who have received prior chemoradiotherapy for limited-stage SCLC must have had treatment with curative intent and a treatment-free interval of at least 6 months between the last dose/cycle of chemotherapy, thoracic radiotherapy, or chemoradiotherapy and the diagnosis of ES-SCLC * Measurable diseases as defined by RECIST v1.1 * Submission of a pre-treatment tumor tissue sample * Adequate hematologic and end-organ function * Participants not receiving therapeutic anticoagulation with International Normalized Ratio (INR) and Activated Clotting Time (aPTT) \</= 1.5 x ULN * Participants receiving therapeutic anticoagulation: stable anticoagulant regimen * Negative Human Immunodeficiency Virus (HIV) test at screening * Negative hepatitis B surface antigen (HBsAg) test at screening * Positive hepatitis B surface antibody (HBsAb) test at screening, or negative HBsAb at screening accompanied by either of the following: negative total hepatitis B core antibody (HBcAb) and/or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test * Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test * Negative Epstein-Barr virus (EBV) viral capsid antigen (VCA) IgM test or negative EBV polymerase chain reaction (PCR) test at screening * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs * For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm.
Exclusion criteria
* Symptomatic or actively progressing central nervous system (CNS) metastases * Spinal cord compression * Leptomeningeal disease * Uncontrolled pleural effusion, pericardial effusion, or ascites * Uncontrolled or symptomatic hypercalcemia * Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, and inherited liver disease, or current alcohol abuse * Malignancies other than SCLC within 5 years prior to randomization * Active or history of autoimmune disease or immune deficiencies * History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest Computer Tomography (CT) scan * Known active tuberculosis, Current treatment with anti-viral therapy for HBV or HCV * Severe chronic or active infection * Treatment with therapeutic oral or IV antibiotics * Significant cardiovascular disease * Major surgical procedure other than for diagnosis * Prior allogeneic bone marrow transplantation or solid organ transplant * Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition * Administration of a live, attenuated vaccine * Prior treatment with CD137 agonists, T-cell co-stimulating, or immune checkpoint blockade therapies * Treatment with systemic immunostimulatory agents * Treatment with systemic immunosuppressive medications * History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins * Known hypersensitivity to Chinese Hamster Ovary (CHO) cell products or to any component of the tiragolumab or atezolizumab formulations * History of allergic reactions to carboplatin or etoposide * Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after the final dose of atezolizumab or within 90 days after the final dose of tiragolumab or for 6 months after the final dose of carboplatin or etoposide.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Investigator-assessed Progression-free Survival (PFS) in the Primary Analysis Set (PAS) | From randomization to first occurrence of PD or death from any cause, whichever occurred first (up to approximately 32.3 months) | PFS was defined as the time from randomization to the first occurrence of PD, as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), or death from any cause, whichever occurred first in the PAS. PD was defined as at least a 20% increase in the sum of diameters (SOD) of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). Additionally, the sum must also demonstrate an absolute increase of ≥ 5 millimeters (mm) and unequivocal progression of existing non-target lesions. Kalpan-Meier (K-M) method was used to estimate median PFS. |
| Overall Survival (OS) in the PAS | From randomization to death from any cause (up to approximately 32.3 months) | OS was defined as the time from randomization to death from any cause in the PAS. K-M method was used to estimate median OS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Investigator-assessed PFS in the FAS | From randomization to first occurrence of PD or death from any cause, whichever occurred first (up to approximately 32.3 months) | PFS was defined as the time from randomization to the first occurrence of PD, as assessed by the investigator according to RECIST v1.1, or death from any cause, whichever occurred first in the FAS. 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). Additionally, the sum must also demonstrate an absolute increase of ≥ 5 mm and unequivocal progression of existing non-target lesions. K-M method was used to estimate median PFS. |
| OS in the FAS | From randomization to death from any cause (up to approximately 32.3 months) | OS was defined as the time from randomization to death from any cause in the FAS. K-M method was used to estimate median OS. |
| Investigator-assessed Confirmed Objective Response Rate (ORR) in the PAS | Up to approximately 32.3 months | ORR was defined as the percentage of participants with an objective response (OR), characterized by a confirmed complete response (CR) or partial response (PR) on two consecutive occasions ≥4 weeks apart, as assessed by the investigator according to RECIST v.1.1 in the PAS. CR was defined as the disappearance of all target and non-target lesions \& normalization of tumor marker level. Additionally, any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. Percentages have been rounded off. |
| Investigator-assessed Confirmed ORR in the FAS | Up to approximately 32.3 months | ORR was defined as the percentage of participants with an OR, characterized by a confirmed CR or PR on two consecutive occasions ≥4 weeks apart, as assessed by the investigator according to RECIST v.1.1 in the FAS. CR was defined as the disappearance of all target and non-target lesions \& normalization of tumor marker level. Additionally, any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. Percentages have been rounded off. |
| Investigator-assessed Duration of Response (DOR) in the PAS | From first occurrence of a documented OR to PD or death from any cause, whichever occurred first (up to approximately 32.3 months) | DOR was defined as the time from the first occurrence of a documented OR to PD, as determined by the investigator according to RECIST v1.1 or death from any cause, whichever occurred first in the PAS. OR was defined as either a CR or a PR on 2 consecutive occasions ≥ 4 weeks apart. CR was defined as disappearance of all target and non-target lesions \& normalization of tumor marker level. Additionally, any lymph nodes (whether target or non-target) must have a reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all 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 SOD at prior timepoints (including baseline). Additionally, the SOD must also demonstrate an absolute increase of ≥5 mm or unequivocal progression of existing non-target lesions. K-M method was used to estimate the median DOR. |
| Investigator-assessed DOR in the FAS | From first occurrence of a documented OR to PD or death from any cause, whichever occurred first (up to approximately 32.3 months) | DOR was defined as the time from the first occurrence of a documented OR to PD, as determined by the investigator according to RECIST v1.1 or death from any cause, whichever occurred first in the FAS. OR was defined as either a CR or a PR on 2 consecutive occasions ≥ 4 weeks apart. CR was defined as disappearance of all target and non-target lesions \& normalization of tumor marker level. Additionally, any lymph nodes (whether target or non-target) must have a reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all 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 SOD at prior timepoints (including baseline). Additionally, the SOD must also demonstrate an absolute increase of ≥5 mm or unequivocal progression of existing non-target lesions. K-M method was used to estimate the median DOR. |
| Investigator-assessed PFS Rates at 6 Months and 12 Months in the PAS | At Months 6 and 12 | PFS rate at 6 months and 12 months was defined as the percentage of participants who did not experience PD as determined by the investigator according to RECIST v1.1, or death from any cause at Months 6 and 12 in the PAS. 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 occurred first in the PAS. 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). Additionally, the SOD must also demonstrate an absolute increase of ≥ 5 mm or unequivocal progression of existing non-target lesions. K-M method was used to estimate the PFS rate. Percentages have been rounded off. |
| Investigator-assessed PFS Rates at 6 Months and 12 Months in the FAS | At Months 6 and 12 | PFS rate at 6 months and 12 months was defined as the percentage of participants who did not experience PD, as determined by the investigator according to RECIST v1.1 or death from any cause, at Months 6 and 12 in the FAS. 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 occurred first in the FAS. 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). Additionally, the SOD must also demonstrate an absolute increase of ≥ 5 mm or unequivocal progression of existing non-target lesions. K-M method was used to estimate the PFS rate. Percentages have been rounded off. |
| OS Rate at 12 Months and 24 Months in the PAS | At Months 12 and 24 | OS rate at 12 months and 24 months was defined as the percentage of participants who did not experience death from any cause at the specified timepoints in the PAS. OS was defined as the time from randomization to death from any cause in the PAS. K-M method was used to estimate OS rate. Percentages have been rounded off. |
| OS Rates at 12 Months and 24 Months in the FAS | At Months 12 and 24 | OS rate at 12 months and 24 months was defined as the percentage of participants who did not experience death from any cause at the specified timepoints in the FAS. OS was defined as the time from randomization to death from any cause in the FAS. K-M method was used to estimate OS rate. Percentages have been rounded off. |
| Time to Confirmed Deterioration (TTCD) in Participant-reported Physical Functioning (PF) and Global Health Status (GHS), as Measured by European Organisation for Research and Treatment of Cancer Quality-of-life Core 30 (EORTC QLQ-C30) in the PAS | Up to approximately 32.3 months | TTCD=time from randomization to first confirmed clinically meaningful deterioration (CCMD) in PAS. EORTC QLQ-C30=cancer-specific instrument with 30 questions to evaluate 5 aspects of participant functioning (physical, emotional, role, cognitive, social), 3 symptom scales (fatigue, nausea, vomiting, pain), GHS/quality-of-life (QoL), \& 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties). PF was scored on 4-point scale: 1=Not at all to 4=Very much. GHS/QoL was scored on 7-point scale: 1=Very poor to 7=Excellent. Scores were linearly transformed to range of 0-100. High score for PF or GHS/QoL scale=high/healthy level of functioning/better health-related quality-of-life (HRQoL). CCMD= ≥ 10-point decrease from baseline in PF or GHS scale score held for at least 2 consecutive assessments or an initial clinically meaningful decrease from baseline followed by death from any cause within 3 weeks. K-M method was used to estimate median TTCD. |
| TTCD in Participant-reported PF and GHS, as Measured by Respective Scales of EORTC QLQ-C30 in the FAS | Up to approximately 32.3 months | TTCD was defined as time from randomization to first CCMD in FAS. EORTC QLQ-C30 is a cancer-specific instrument with 30 questions to evaluate 5 aspects of participant functioning (physical, emotional, role, cognitive, social), 3 symptom scales (fatigue, nausea, vomiting, pain), GHS/QoL, \& 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties). PF was scored on 4-point scale: 1=Not at all to 4=Very much. GHS/QoL was scored on 7-point scale: 1=Very poor to 7=Excellent. Scores were linearly transformed to range of 0-100. High score for PF or GHS/QoL scale=high/healthy level of functioning/better HRQoL. CCMD was defined as ≥ 10-point decrease from baseline in PF or GHS scale score held for at least 2 consecutive assessments or an initial clinically meaningful decrease from baseline followed by death from any cause within 3 weeks. K-M method was used to estimate median TTCD. |
| Number of Participants With Adverse Events (AEs) | Up to approximately 57 months | An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE was therefore any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. 1 participant randomized to the tiragolumab arm did not receive any dose of tiragolumab and was moved to the placebo arm for safety analysis. |
| Number of Participants With Cytokine-release Syndrome (CRS), With Severity Determined by the American Society for Transplantation and Cell Therapy (ASTCT) Consensus Grading Scale | Up to approximately 57 months | CRS was defined as supraphysiologic response following administration of any immune therapy that results in activation/engagement of endogenous or infused T cells and/or other immune effector cells. Symptoms may be progressive, including fever at onset, and may also include hypotension, capillary leak (hypoxia), and end-organ dysfunction. Severity of CRS was determined per ASTCT Consensus Grading Criteria, which categorizes CRS into 5 grades: Grade 1: Fever (≥38◦Celsius), with/without constitutional symptoms, in absence of hypotension \& hypoxia; Grade 2: Fever with hypotension not requiring vasopressors and/or hypoxia requiring low-flow oxygen; Grade 3: Fever with hypotension requiring one vasopressor, with/without vasopressin, and/or hypoxia requiring high-flow oxygen; Grade 4: Fever accompanied by hypotension requiring multiple vasopressors (excluding vasopressin) and/or hypoxia requiring positive-pressure ventilation; Grade 5: death due to CRS. |
| Serum Concentration of Tiragolumab at Specified Timepoints | Pre-dose on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16; 30 minutes-end of infusion (EOI) on Day 1 of Cycle 1; Treatment discontinuation visit(TDV) (up to approximately 32.3 months) (1 Cycle=21 days) | — |
| Serum Concentration of Atezolizumab at Specified Timepoints | Pre-dose on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16; 30 minutes-EOI on Day 1 of Cycle 1; TDV (up to approximately 32.3 months) (1 Cycle=21 days) | — |
| Maximum Plasma Concentration (Cmax) of Tiragolumab | 30 mins-EOI on Day 1 of Cycle 1 (1 Cycle=21 days) | Only sparse pharmacokinetic samples were collected in this study. With the focus on only Cmax and Cmin, there are no additional PK timepoints not reported. |
| Minimum Plasma Concentration (Cmin) of Tiragolumab | Pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12, 16 (1 Cycle=21 days) | — |
| Cmax of Atezolizumab | 30 mins-EOI on Day 1 of Cycle 1 (1 Cycle= 21 days) | — |
| Cmin of Atezolizumab | Pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12, 16 (1 Cycle=21 days) | — |
| Number of Participants With Anti-Drug Antibodies (ADAs) to Tiragolumab | Up to approximately 32.3 months | Participants were considered to be ADA positive if they were ADA negative at baseline but developed an ADA response following tiragolumab administration (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples was greater than the titer of the baseline sample by a scientifically reasonable margin such as at least 0.60 titer unit (t.u.) greater than the baseline titer result (treatment-enhanced ADA response). Participants with a positive post-baseline sample have been reported here. |
Countries
China
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
A total of 123 participants with untreated extensive-stage small cell lung cancer (ES-SCLC) took part in the study at 17 investigative sites in China from 21 December 2020 to 17 November 2025.
Pre-assignment details
Participants were randomized in a 1:1 ratio to receive tiragolumab plus atezolizumab and carboplatin + etoposide (CE) or placebo plus atezolizumab and CE. The study is considered "Completed" because all the pre-planned study activities and analyses have been performed.
Participants by arm
| Arm | Count |
|---|---|
| Placebo + Atezolizumab + Carboplatin + Etoposide Participants received atezolizumab, 1200 mg, followed by tiragolumab matching placebo, and carboplatin, at a dose targeting initial target AUC of 5 mg/mL/min as an IV infusion, Q3W, on Day 1 of each 21-day cycle along with etoposide, 100 mg/m\^2, as an IV infusion on Days 1, 2 and 3 of each 21-day cycle for 4 cycles as induction treatment. (1 Cycle = 21 days). Participants then received maintenance treatment with atezolizumab, 1200 mg, followed by tiragolumab matching placebo given as an IV infusion, Q3W, from Day 1 of Cycle 5 until disease progression, loss of clinical benefit, unacceptable toxicity, or symptomatic deterioration attributed to disease progression. | 62 |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide Participants received atezolizumab, 1200 mg, tiragolumab, 600 mg, and carboplatin, at a dose targeting initial target AUC of 5 mg/mL/min as an IV infusion, Q3W, on Day 1 along with etoposide, 100 mg/m\^2, as an IV infusion on Days 1, 2 and 3 of each 21-day cycle for 4 cycles as induction treatment. (1 Cycle = 21 days). Participants then received maintenance treatment with atezolizumab, 1200 mg, followed by tiragolumab, 600 mg, given as an IV infusion, Q3W, from Day 1 of Cycle 5 until disease progression, loss of clinical benefit, unacceptable toxicity, or symptomatic deterioration attributed to disease progression. | 61 |
| Total | 123 |
Baseline characteristics
| Characteristic | Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Total | Placebo + Atezolizumab + Carboplatin + Etoposide |
|---|---|---|---|
| Age, Continuous | 62.0 years STANDARD_DEVIATION 7.8 | 61.4 years STANDARD_DEVIATION 7.9 | 60.9 years STANDARD_DEVIATION 8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 61 Participants | 123 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 61 Participants | 123 Participants | 62 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 8 Participants | 16 Participants | 8 Participants |
| Sex: Female, Male Male | 53 Participants | 107 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 41 / 63 | 44 / 60 |
| other Total, other adverse events | 60 / 63 | 60 / 60 |
| serious Total, serious adverse events | 23 / 63 | 22 / 60 |
Outcome results
Primary
Investigator-Assessed Progression-Free Survival (PFS) in the Primary Analysis Set (PAS)
PFS was defined as time from randomization to the first occurrence of disease progression (PD), as assessed by the investigator using 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 at least 5 millimeters (mm).
Time frame: Up to 32.3 months
Population: Primary Analysis Set (PAS) included all randomized participants without presence or history of brain metastases at baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Atezolizumab + Carboplatin + Etoposide | Investigator-Assessed Progression-Free Survival (PFS) in the Primary Analysis Set (PAS) | 5.39 months |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Investigator-Assessed Progression-Free Survival (PFS) in the Primary Analysis Set (PAS) | 5.59 months |
p-value: 0.034895% CI: [0.43, 0.97]Log Rank
Primary
Overall Survival (OS) in the PAS
OS was defined as the time from the date of randomization to the date of death from any cause.
Time frame: Up to 32.3 months
Population: PAS included all randomized participants without presence or history of brain metastases at baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Atezolizumab + Carboplatin + Etoposide | Overall Survival (OS) in the PAS | 13.54 months |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Overall Survival (OS) in the PAS | 18.69 months |
p-value: 0.610595% CI: [0.56, 1.4]Log Rank
Secondary
Cmax of Atezolizumab
Time frame: Cycle 1 Day 1, 30 mins post EOI (cycle length= 21 days)
Population: Atezolizumab PK evaluable set included all participants who received at least one dose of atezolizumab treatment and who have at least one post-baseline PK sample available.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Atezolizumab + Carboplatin + Etoposide | Cmax of Atezolizumab | 355 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 28.9 |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Cmax of Atezolizumab | 370 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 36.5 |
Secondary
Cmin of Atezolizumab
Time frame: Pre-dose, Day 1 of Cycles 2, 3, 4, 8, 12, 16 (cycle length= 21 days)
Population: Atezolizumab PK evaluable set included all participants who received at least one dose of atezolizumab treatment and who have at least one post-baseline PK sample available. Overall number of participants analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analyses at the specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo + Atezolizumab + Carboplatin + Etoposide | Cmin of Atezolizumab | Pre-dose: Cycle 8 Day 1 | 151 μg/mL | Geometric Coefficient of Variation 41.6 |
| Placebo + Atezolizumab + Carboplatin + Etoposide | Cmin of Atezolizumab | Pre-dose: Cycle 16 Day 1 | 177 μg/mL | Geometric Coefficient of Variation 55 |
| Placebo + Atezolizumab + Carboplatin + Etoposide | Cmin of Atezolizumab | Pre-dose: Cycle 4 Day 1 | 111 μg/mL | Geometric Coefficient of Variation 88.6 |
| Placebo + Atezolizumab + Carboplatin + Etoposide | Cmin of Atezolizumab | Pre-dose: Cycle 2 Day 1 | 63.8 μg/mL | Geometric Coefficient of Variation 76.5 |
| Placebo + Atezolizumab + Carboplatin + Etoposide | Cmin of Atezolizumab | Pre-dose: Cycle 12 Day 1 | 139 μg/mL | Geometric Coefficient of Variation 155 |
| Placebo + Atezolizumab + Carboplatin + Etoposide | Cmin of Atezolizumab | Pre-dose: Cycle 3 Day 1 | 88.5 μg/mL | Geometric Coefficient of Variation 166 |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Cmin of Atezolizumab | Pre-dose: Cycle 12 Day 1 | 172 μg/mL | Geometric Coefficient of Variation 35 |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Cmin of Atezolizumab | Pre-dose: Cycle 4 Day 1 | 99.2 μg/mL | Geometric Coefficient of Variation 62.7 |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Cmin of Atezolizumab | Pre-dose: Cycle 8 Day 1 | 151 μg/mL | Geometric Coefficient of Variation 31.8 |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Cmin of Atezolizumab | Pre-dose: Cycle 3 Day 1 | 96.6 μg/mL | Geometric Coefficient of Variation 46.6 |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Cmin of Atezolizumab | Pre-dose: Cycle 16 Day 1 | 169 μg/mL | Geometric Coefficient of Variation 30.1 |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Cmin of Atezolizumab | Pre-dose: Cycle 2 Day 1 | 68.1 μg/mL | Geometric Coefficient of Variation 33.7 |
Secondary
Investigator-Assessed Confirmed Objective Response Rate (ORR) in the PAS
ORR was defined as the percentage of participants with either a confirmed complete response (CR) or partial response (PR) on two consecutive occasions ≥4 weeks apart as assessed by investigator according to RECIST v.1.1. CR was defined as disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters in the absence of CR. Percentages have been rounded off.
Time frame: Up to 32.3 months
Population: PAS included all randomized participants without presence or history of brain metastases at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Atezolizumab + Carboplatin + Etoposide | Investigator-Assessed Confirmed Objective Response Rate (ORR) in the PAS | 58.9 percentage of participants |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Investigator-Assessed Confirmed Objective Response Rate (ORR) in the PAS | 81.5 percentage of participants |
p-value: 0.013695% CI: [4.12, 39.03]Chi-square with Schouten Correction
Secondary
Investigator-Assessed Confirmed ORR in the FAS
ORR was defined as the percentage of participants with either a confirmed CR or PR on two consecutive occasions ≥4 weeks apart as assessed by investigator according to RECIST v.1.1. CR was defined as disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters in the absence of CR. Percentages have been rounded off.
Time frame: Up to 32.3 months
Population: FAS included all randomized participants whether or not the participants received the assigned study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Atezolizumab + Carboplatin + Etoposide | Investigator-Assessed Confirmed ORR in the FAS | 59.7 percentage of participants |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Investigator-Assessed Confirmed ORR in the FAS | 77.0 percentage of participants |
p-value: 0.049395% CI: [-0.22, 33.6]Chi-square with Schouten Correction
Secondary
Investigator-Assessed DOR in the FAS
DOR was defined as the time interval from the date of the first occurrence of a confirmed objective response until the first date of PD as determined by the investigator using RECIST v1.1 or death from any cause, whichever occurs first. DOR was evaluated for participants who had an objective response of CR or PR. CR was defined as the disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. 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 at least 5 mm.
Time frame: Up to 32.3 months
Population: FAS included all randomized participants whether or not the participants received the assigned study treatment. Overall number analyzed is the number of participants with objective response i.e., responders.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Atezolizumab + Carboplatin + Etoposide | Investigator-Assessed DOR in the FAS | 5.45 months |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Investigator-Assessed DOR in the FAS | 5.55 months |
Secondary
Investigator-Assessed Duration of Response (DOR) in the PAS
DOR was defined as the time interval from the date of the first occurrence of a confirmed objective response until the first date of PD as determined by the investigator using RECIST v1.1 or death from any cause, whichever occurs first. DOR was evaluated for participants who had an objective response of CR or PR. CR was defined as the disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. 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 at least 5 mm.
Time frame: Up to 32.3 months
Population: PAS included all randomized participants without presence or history of brain metastases at baseline. Overall number analyzed is the number of participants with objective response i.e., responders.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Atezolizumab + Carboplatin + Etoposide | Investigator-Assessed Duration of Response (DOR) in the PAS | 5.45 months |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Investigator-Assessed Duration of Response (DOR) in the PAS | 5.52 months |
Secondary
Investigator-Assessed PFS Rates at 6 Months and 12 Months in the FAS
PFS was defined as time from randomization to the first occurrence of PD, as assessed by the investigator using RECIST v1.1, or death from any cause, whichever occurs first. PFS rate at 6 months and 12 months defined as the percentage of participants who have not experienced PD as determined by the investigator according to RECIST v1.1 or death from any cause at 6 and 12 months. 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 at least 5 mm. K-M method was used to estimate PFS rate. Percentages have been rounded off. The event free rate used the K-M approach to estimate, which accounts for the censoring, the specific nature of time-to-event data. Naive calculation based on patient proportion will introduce bias.
Time frame: Month 6, Month 12
Population: FAS included all randomized participants whether or not the participants received the assigned study treatment. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available at the specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Atezolizumab + Carboplatin + Etoposide | Investigator-Assessed PFS Rates at 6 Months and 12 Months in the FAS | Month 6 | 38.52 percentage of participants |
| Placebo + Atezolizumab + Carboplatin + Etoposide | Investigator-Assessed PFS Rates at 6 Months and 12 Months in the FAS | Month 12 | 12.70 percentage of participants |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Investigator-Assessed PFS Rates at 6 Months and 12 Months in the FAS | Month 6 | 46.71 percentage of participants |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Investigator-Assessed PFS Rates at 6 Months and 12 Months in the FAS | Month 12 | 26.06 percentage of participants |
Comparison: 12 Monthsp-value: 0.064295% CI: [-0.79, 27.51]Z-test
Comparison: 6 Monthsp-value: 0.363395% CI: [-9.46, 25.82]Z-test
Secondary
Investigator-Assessed PFS Rates at 6 Months and 12 Months in the PAS
PFS = time from randomization to the first occurrence of PD, per investigator per RECIST v1.1/ death from any cause, whichever occurs first. PFS rate at 6 and 12 = the percentage of participants who have not experienced PD per investigator per RECIST v1.1/ death from any cause at 6 and 12 months. PD =at least a 20% increase in the sum of diameters of target lesions, taking as reference the SOD at prior timepoints (including baseline), in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Kaplan-Meier (K-M) method was used to estimate PFS rate. Percentages have been rounded off. Abbreviation used in Statistical Analysis section - Event Free Rate - EFR. The event free rate (for example the inv-PFS free rate of 10.24% at 12-months) used the K-M approach to estimate, which accounts for the censoring, the specific nature of time-to-event data. Naive calculation based on patient proportion will introduce bias.
Time frame: Month 6, Month 12
Population: PAS included all randomized participants without presence or history of brain metastases at baseline. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available at the specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Atezolizumab + Carboplatin + Etoposide | Investigator-Assessed PFS Rates at 6 Months and 12 Months in the PAS | Month 6 | 39.11 percentage of participants |
| Placebo + Atezolizumab + Carboplatin + Etoposide | Investigator-Assessed PFS Rates at 6 Months and 12 Months in the PAS | Month 12 | 10.24 percentage of participants |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Investigator-Assessed PFS Rates at 6 Months and 12 Months in the PAS | Month 6 | 47.20 percentage of participants |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Investigator-Assessed PFS Rates at 6 Months and 12 Months in the PAS | Month 12 | 27.69 percentage of participants |
Comparison: 12 Monthsp-value: 0.020595% CI: [2.69, 32.21]Z-test
Comparison: 6 Monthsp-value: 0.396895% CI: [-10.62, 26.81]Z-test
Secondary
Maximum Plasma Concentration (Cmax) of Tiragolumab
Only sparse pharmacokinetic samples were collected in this study. With the focus on only Cmax and Cmin, there are no additional PK timepoints not reported
Time frame: Cycle 1 Day 1, 30 mins post end of infusion (EOI) (cycle length= 21 days)
Population: PK-evaluable population included all participants who received at least one dose of tiragolumab treatment and who have at least one post-baseline PK sample available.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Atezolizumab + Carboplatin + Etoposide | Maximum Plasma Concentration (Cmax) of Tiragolumab | 175 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 19.3 |
Secondary
Minimum Plasma Concentration (Cmin) of Tiragolumab
Time frame: Pre-dose, Day 1 of Cycles 2, 3, 4, 8, 12, 16 (cycle length= 21 days)
Population: PK-evaluable population included all participants who received at least one dose of tiragolumab treatment and who have at least one post-baseline PK sample available. Overall number of participants analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analyses at the specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo + Atezolizumab + Carboplatin + Etoposide | Minimum Plasma Concentration (Cmin) of Tiragolumab | Pre-dose: Cycle 8 Day 1 | 64.5 μg/mL | Geometric Coefficient of Variation 44.7 |
| Placebo + Atezolizumab + Carboplatin + Etoposide | Minimum Plasma Concentration (Cmin) of Tiragolumab | Pre-dose: Cycle 2 Day 1 | 27.0 μg/mL | Geometric Coefficient of Variation 51.6 |
| Placebo + Atezolizumab + Carboplatin + Etoposide | Minimum Plasma Concentration (Cmin) of Tiragolumab | Pre-dose: Cycle 3 Day 1 | 39.4 μg/mL | Geometric Coefficient of Variation 79.9 |
| Placebo + Atezolizumab + Carboplatin + Etoposide | Minimum Plasma Concentration (Cmin) of Tiragolumab | Pre-dose: Cycle 4 Day 1 | 48.0 μg/mL | Geometric Coefficient of Variation 40 |
| Placebo + Atezolizumab + Carboplatin + Etoposide | Minimum Plasma Concentration (Cmin) of Tiragolumab | Pre-dose: Cycle 12 Day 1 | 53.6 μg/mL | Geometric Coefficient of Variation 193 |
| Placebo + Atezolizumab + Carboplatin + Etoposide | Minimum Plasma Concentration (Cmin) of Tiragolumab | Pre-dose: Cycle 16 Day 1 | 71.9 μg/mL | Geometric Coefficient of Variation 58.8 |
Secondary
OS in the FAS
OS was defined as the time from the date of randomization to the date of death from any cause.
Time frame: Up to 32.3 months
Population: FAS included all randomized participants whether or not the participants received the assigned study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Atezolizumab + Carboplatin + Etoposide | OS in the FAS | 14.88 months |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | OS in the FAS | 17.31 months |
p-value: 0.936395% CI: [0.64, 1.52]Log Rank
Secondary
Overall Survival Rate at 12 Months and 24 Months in the PAS
OS was defined as the time from the date of randomization to the date of death from any cause. OS rate at 12 months and 24 months was defined as the percentage of participants who did not experience death from any cause at 12 months and 24 months. Percentages have been rounded off.
Time frame: Month 12, Month 24
Population: PAS included all randomized participants without presence or history of brain metastases at baseline. Overall number of participants analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available at the specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Atezolizumab + Carboplatin + Etoposide | Overall Survival Rate at 12 Months and 24 Months in the PAS | Month 12 | 51.50 percentage of participants |
| Placebo + Atezolizumab + Carboplatin + Etoposide | Overall Survival Rate at 12 Months and 24 Months in the PAS | Month 24 | 32.94 percentage of participants |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Overall Survival Rate at 12 Months and 24 Months in the PAS | Month 12 | 71.97 percentage of participants |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Overall Survival Rate at 12 Months and 24 Months in the PAS | Month 24 | 32.44 percentage of participants |
Comparison: 12 Monthsp-value: 0.026195% CI: [2.43, 38.5]Z-test
Comparison: 24 Monthsp-value: 0.957295% CI: [-18.79, 17.79]Z-test
Secondary
Overall Survival Rates at 12 Months and 24 Months in the FAS
OS was defined as the time from the date of randomization to the date of death from any cause. OS rate at 12 months and 24 months was defined as the percentage of participants who did not experience death from any cause at 12 months and 24 months. Percentages have been rounded off.
Time frame: Month 12, Month 24
Population: FAS included all randomized participants whether or not the participants received the assigned study treatment. Overall number of participants analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available at the specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Atezolizumab + Carboplatin + Etoposide | Overall Survival Rates at 12 Months and 24 Months in the FAS | 12 Months | 54.73 percentage of participants |
| Placebo + Atezolizumab + Carboplatin + Etoposide | Overall Survival Rates at 12 Months and 24 Months in the FAS | 24 Months | 34.65 percentage of participants |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Overall Survival Rates at 12 Months and 24 Months in the FAS | 12 Months | 68.61 percentage of participants |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | Overall Survival Rates at 12 Months and 24 Months in the FAS | 24 Months | 32.11 percentage of participants |
Comparison: 12 Monthsp-value: 0.114595% CI: [-3.36, 31.12]Z-test
Comparison: 24 Monthsp-value: 0.773495% CI: [-19.83, 14.75]Z-test
Secondary
Percentage of Participants With Adverse Events
An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An adverse event can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product, any new disease or exacerbation of an existing disease (a worsening in the character, frequency, or severity of a known condition), recurrence of an intermittent medical condition not present at baseline, any deterioration in a laboratory value or other clinical test that is associated with symptoms or leads to a change in study treatment or concomitant treatment or discontinuation from study drug or adverse events that are related to a protocol-mandated intervention, including those that occur prior to assignment of study treatment.
Time frame: Up to 66 months
Secondary
Percentage of Participants With Anti-Drug Antibodies (ADAs) to Tiragolumab
Time frame: Predose on Day 1 of Cycles (each cycle=21 days) 1, 2, 3, 4, 8, 12, 16 and at TD visit (up to approximately 49 months)
Secondary
PFS in the FAS
PFS was defined as time from randomization to the first occurrence of PD, as assessed by the investigator using 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 at least 5 mm.
Time frame: Up to 32.3 months
Population: FAS included all randomized participants whether or not the participants received the assigned study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Atezolizumab + Carboplatin + Etoposide | PFS in the FAS | 5.39 months |
| Tiragolumab + Atezolizumab + Carboplatin + Etoposide | PFS in the FAS | 5.59 months |
p-value: 0.104495% CI: [0.49, 1.07]Log Rank
Secondary
Time to Confirmed Deterioration (TTCD) Assessed Using European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core (QLQ-C30) Score in the PAS
Time frame: Up to approximately 66 months
Secondary
TTCD Assessed Using EORTC QLQ-C30 Score in the FAS
Time frame: Up to approximately 66 months