A Study of Carboplatin Plus Etoposide With or Without Atezolizumab in Participants With Untreated Extensive-Stage (ES) Small Cell Lung Cancer (SCLC)

Phase 3

Completed

Conditions: Small Cell Lung Carcinoma

Interventions: Drug: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody
Drug: Carboplatin
Drug: Placebo
Drug: Etoposide

Registration Number: NCT02763579

Lead Sponsor: Hoffmann-La Roche

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 503

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Atezolizumab + Carboplatin + Etoposide	Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody	Participants 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.
Placebo + Carboplatin + Etoposide	Placebo	Participants 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.
Atezolizumab + Carboplatin + Etoposide	Etoposide	Participants 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.
Placebo + Carboplatin + Etoposide	Carboplatin	Participants 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.
Atezolizumab + Carboplatin + Etoposide	Carboplatin	Participants 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.
Placebo + Carboplatin + Etoposide	Etoposide	Participants 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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
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.
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.
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.
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.
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 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.
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 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.

Trial Locations

Locations (114): Florida Cancer Specialists - Fort Myers (Broadway)
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Fort Myers, Florida, United States
Florida Hospital
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Orlando, Florida, United States
Florida Cancer Specialists.
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Saint Petersburg, Florida, United States
Northwest Georgia Oncology Centers PC - Marietta
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Marietta, Georgia, United States
Rush University Medical Center
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Chicago, Illinois, United States
Illinois Cancer Care
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Peoria, Illinois, United States
Cancer Treatment Centers of America - Midwestern Regional Medical Center
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Zion, Illinois, United States
Louisville Oncology
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Louisville, Kentucky, United States
New England Cancer Specialists
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Scarborough, Maine, United States
Weinberg CA Inst Franklin Sq
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Baltimore, Maryland, United States
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Florida Cancer Specialists - Fort Myers (Broadway)
🇺🇸Fort Myers, Florida, United States