Study of Atezolizumab Plus Carboplatin and Etoposide With or Without Tiragolumab in Participants With Untreated Extensive-Stage Small Cell Lung Cancer

Hoffmann-La Roche123 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

123

Conditions

Small Cell Lung Carcinoma

Interventions

TiragolumabDRUG

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.

AtezolizumabDRUG

Atezolizumab at a fixed dose of 1200 mg, administered by IV infusion, Q3W on Day 1 of each 21-day cycle.

CarboplatinDRUG

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (16)

Beijing Cancer Hospital

Beijing, China

Beijing Chest Hospital

Beijing, China

Outcomes

Primary Outcomes

Investigator-assessed Progression-free Survival (PFS) in the Primary Analysis Set (PAS)

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.

Time frame: From randomization to first occurrence of PD or death from any cause, whichever occurred first (up to approximately 32.3 months)

Overall Survival (OS) 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 median OS.

Time frame: From randomization to death from any cause (up to approximately 32.3 months)

Secondary Outcomes

Investigator-assessed PFS in the FAS

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.

Time frame: From randomization to first occurrence of PD or death from any cause, whichever occurred first (up to approximately 32.3 months)

OS 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 median OS.

Data from ClinicalTrials.gov

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Etoposide 100 mg/m\^2, administered by IV infusion, Q3W on Day 1, 2 and 3 of each 21-day cycle for 4 cycles.

Tiragolumab Matching PlaceboDRUG

Matching placebo, administered by IV infusion, Q3W on Day 1 of each 21-day cycle.

the First Affiliated Hospital of Bengbu Medical College

the First Hospital of Jilin University

Changchun, China

Fujian Provincial Cancer Hospital

Fuzhou, China

Cancer Center of Guangzhou Medical University

Guangzhou, China

Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University

Hangzhou, China

Zhejiang Cancer Hospital

Hangzhou, China

Harbin Medical University Cancer Hospital

Harbin, China

The 1st Affiliated Hospital of Nanchang Unversity

Nanchang, China

...and 6 more locations

Time frame: From randomization to death from any cause (up to approximately 32.3 months)

Investigator-assessed Confirmed Objective Response Rate (ORR) in the PAS

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.

Time frame: Up to approximately 32.3 months

Investigator-assessed Confirmed ORR in the FAS

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.

Time frame: Up to approximately 32.3 months

Investigator-assessed Duration of Response (DOR) in the PAS

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.

Time frame: From first occurrence of a documented OR to PD or death from any cause, whichever occurred first (up to approximately 32.3 months)

Investigator-assessed DOR in the FAS

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.

Time frame: From first occurrence of a documented OR to PD or death from any cause, whichever occurred first (up to approximately 32.3 months)

Investigator-assessed PFS Rates at 6 Months and 12 Months in the PAS

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.

Time frame: At Months 6 and 12

Investigator-assessed PFS Rates at 6 Months and 12 Months in the FAS

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.

Time frame: At Months 6 and 12

OS Rate at 12 Months and 24 Months in the PAS

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.

Time frame: At Months 12 and 24

OS Rates at 12 Months and 24 Months in the FAS

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 frame: At Months 12 and 24

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

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.

Time frame: Up to approximately 32.3 months

TTCD in Participant-reported PF and GHS, as Measured by Respective Scales of EORTC QLQ-C30 in the FAS

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.

Time frame: Up to approximately 32.3 months

Number of Participants With Adverse Events (AEs)

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.

Time frame: Up to approximately 57 months

Number of Participants With Cytokine-release Syndrome (CRS), With Severity Determined by the American Society for Transplantation and Cell Therapy (ASTCT) Consensus Grading Scale

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.

Time frame: Up to approximately 57 months

Serum Concentration of Tiragolumab at Specified Timepoints

Time frame: 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

Time frame: 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

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: 30 mins-EOI on Day 1 of Cycle 1 (1 Cycle=21 days)

Minimum Plasma Concentration (Cmin) of Tiragolumab

Time frame: Pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12, 16 (1 Cycle=21 days)

Cmax of Atezolizumab

Time frame: 30 mins-EOI on Day 1 of Cycle 1 (1 Cycle= 21 days)

Cmin of Atezolizumab

Time frame: 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

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.

Time frame: Up to approximately 32.3 months