A Study of Atezolizumab Compared With a Single-Agent Chemotherapy in Treatment Naïve Participants With Locally Advanced or Recurrent or Metastatic Non-Small Cell Lung Cancer Who Are Deemed Unsuitable For Platinum-Doublet Chemotherapy

Phase 3

Completed

Conditions: Non-Small Cell Lung Cancer

Interventions: Drug: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody
Drug: Vinorelbine
Drug: Gemcitabine

Registration Number: NCT03191786

Lead Sponsor: Hoffmann-La Roche

Brief Summary: This Phase III, global, multicenter, open-label, randomized, controlled study will evaluate the efficacy and safety of atezolizumab (an anti-programmed death-ligand 1 \[anti-PD-L1\] antibody) compared with a single agent chemotherapy regimen by investigator choice (vinorelbine or gemcitabine) in treatment-naïve participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) who are deemed unsuitable for any platinum-doublet chemotherapy due to poor performance status (Eastern Cooperative Oncology Group \[ECOG\] performance status of 2-3).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 453

Inclusion Criteria

Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC as per the American Joint Committee on Cancer (AJCC) 7th edition
No sensitizing epidermal growth factor receptor (EGFR) mutation (L858R or exon 19 deletions) or anaplastic lymphoma kinase (ALK) fusion oncogene detected
No prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC as per the AJCC 7th edition
Life expectancy greater than or equal to (>/=) 8 weeks
Deemed unsuitable by the investigator for any platinum-doublet chemotherapy due to poor performance status (ECOG performance status of 2-3). However, participants >= 70 years of age who have an ECOG PS of 0 or 1 may be included due to: a) substantial comorbidities; b) contraindication(s) for any platinum-doublet chemotherapy
Representative formalin-fixed paraffin-embedded (FPPE) tumor tissue block obtained during course of disease (archival tissue) or at screening
Participants with treated, asymptomatic central nervous system (CNS) metastases are eligible, provided they meet all of the following criteria: Measurable disease outside CNS; Only supratentorial and cerebellar metastases allowed; No ongoing requirement for corticosteroids as therapy for CNS disease; No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to randomization; No evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study
Adequate hematologic and end organ function
Female participants of childbearing potential randomized to the atezolizumab treatment arm agree to use protocol defined methods of contraception

Exclusion Criteria

Cancer-Specific Exclusion Criteria:

Participants younger than 70 years who have an ECOG performance status of 0 or 1
Active or untreated CNS metastases as determined by computed tomography (CT) or magnetic resonance imaging (MRI) evaluation of the brain during screening and prior radiographic assessments
Uncontrolled tumor-related pain
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
Uncontrolled or symptomatic hyerpcalcemia (ionized calcium > 1.5 mmol/L or calcium >12 mg/dL or corrected serum calcium >ULN)
History of other malignancy within 5 years prior to screening, with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 (v4.0) Grade 3 or higher toxicities due to any prior therapy (example [e.g.], radiotherapy) (excluding alopecia), which have not shown improvement and are strictly considered to interfere with current study medication
Participants who have received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy, or chemoradiotherapy with curative intent for non-metastatic disease must have experienced a treatment-free interval of at least 6 months from randomization since the last chemotherapy, radiotherapy, or chemoradiotherapy

General Medical Exclusion Criteria:

History of autoimmune disease except autoimmune-related hypothyroidism and controlled Type I diabetes mellitus
History of idiopathic pulmonary fibrosis (IPF), organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis
Known positivity for human immunodeficiency virus (HIV)
Known active hepatitis B or hepatitis C
Active tuberculosis
Severe infections within 4 weeks prior to randomization
Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), myocardial infarction within 3 months prior to randomization, unstable arrhythmias, or unstable angina
Major surgical procedure other than for diagnosis within 4 weeks prior to randomization or anticipation of need for a major surgical procedure during the course of the study
Prior allogeneic bone marrow transplantation or solid organ transplant
Participants with an illness or condition that may interfere with capacity or compliance with the study protocol, as per investigator's judgment
Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 28 days prior to randomization

Exclusion Criteria Related to Atezolizumab:

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
Oral or IV antibiotic treatment
Administration of a live, attenuated vaccine within 4 weeks before randomization or anticipation that such a live attenuated vaccine will be required during the study
Prior treatment with cluster of differentiation 137 (CD137) agonists or immune checkpoint blockade therapies, anti-programmed death-1 (anti-PD-1), and anti-PD-L1 therapeutic antibodies
Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to randomization
Treatment with systemic corticosteroids or other immunosuppressive medications
Participants not willing to stop treatment with traditional herbal medicines

Exclusion Criteria Related to Chemotherapy:

Known sensitivity and contraindications to the 2 comparative chemotherapy agents (that is [i.e.] vinorelbine, oral or intravenous, and gemcitabine, intravenous)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Atezolizumab	Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody	Participants will receive atezolizumab 1200 milligrams (mg) intravenous (IV) infusion on Day 1 of each 21-day cycle until loss of clinical benefit, unacceptable toxicity, participant or physician decision to discontinue, or death.
Single Agent Chemotherapy (Vinorelbine or Gemcitabine)	Vinorelbine	Participants will receive single agent chemotherapy; either vinorelbine oral or IV, or gemcitabine IV, according to the label based on investigator's choice.
Single Agent Chemotherapy (Vinorelbine or Gemcitabine)	Gemcitabine	Participants will receive single agent chemotherapy; either vinorelbine oral or IV, or gemcitabine IV, according to the label based on investigator's choice.

Primary Outcome Measures

Name	Time	Method
Overall Survival (OS)	From randomization up to death from any cause (up to approximately 55 months)	OS was defined as the time between the date of randomization and the date of death due to any cause. Kaplan-Meier (KM) estimates were used to calculate median.

Secondary Outcome Measures

Name	Time	Method
OS Rates at the 6, 12, 18, 24-Months Timepoints	6, 12, 18 and 24 months	OS was defined as the time between the date of randomization and the date of death due to any cause. OS rate at 6, 12, 18 and 24 months were estimated for each treatment arm using Kaplan Meier methodology. Percentages were rounded off to the nearest decimal point.
Percentage of Participants With Objective Response, as Determined by the Investigator Using Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1)	From randomization to the first occurence of disease progression or death from any cause, whichever occurs first (up to approximately 55 months)	Objective response rate (ORR)=best overall response (BOR) of either complete response (CR)/partial response (PR), as determined by investigator with use of RECIST v1.1. CR= disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in short axis to \<10 millimeters (mm). PR=at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. A minimum interval of 6 weeks (42 days) was considered for stable disease (SD) to be assigned as BOR, i.e. in case the single response is SD, PR or CR, this single response must have been assessed no less than 6 weeks (at least 42 days) after start date of study treatment. SD=neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the diameters while in the study. Percentages were rounded off to the nearest decimal point.
Progression-Free Survival (PFS), as Determined by the Investigator Using RECIST v1.1	From randomization to the first occurence of disease progression or death from any cause, whichever occurs first (up to approximately 55 months)	PFS was defined as the time from randomization to the first documented disease progression as determined by the investigator with the use of RECIST v1.1 or death from any cause, whichever occurs first. Progressive disease (PD) was defined as at least 20% increase in the sum of diameters of lesions, taking as reference the smallest sum during the study (nadir), including baseline. KM estimates were used to calculate median.
Duration of Response (DOR), as Determined by the Investigator Using RECIST v1.1	Time from the first occurrence of a documented objective response to the time of disease progression or death from any cause, whichever occurs first (up to approximately 55 months)	DOR was defined as the time from the first tumor assessment that supports the participants' objective response (CR or PR, whichever is first reported) to documented disease progression as determined by the investigator according to RECIST v1.1 or death from any cause, whichever occurs first, among participants who have a best overall response as CR or PR. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a 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 20% increase in the sum of diameters of lesions, taking as reference the smallest sum during the study (nadir), including baseline. KM estimates were used to calculate median.
Percentage of Participants With At Least One Adverse Event (AE)	Baseline up to 90 days after last dose of atezolizumab (approximately 62 months)	An AE was any untoward medical occurrence in participant administered a pharmaceutical product \& regardless of causal relationship with this treatment. An AE can therefore be any unfavorable \& unintended sign (including an abnormal laboratory finding), symptom/disease temporally associated with use of investigational product, whether or not considered related to investigational product. AEs were reported based on the National Cancer Institute Common Terminology Criteria for AEs, version 4.0 (NCI-CTCAE, v4.0).
Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC-QLQ-C30) Score	Baseline, Day 1 of each treatment cycle up to 30 days after last dose (up to approximately 55 months) (Cycle length = 21 days)	EORTC QLQ-C30 consists of 30 questions that assess 5 aspects of patient functioning (physical, emotional, role, cognitive, and social), 3 symptom scales (fatigue, nausea and vomiting, pain), global health/quality of life, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). It was scored according to EORTC scoring manual (Fayers et al. 2001). All EORTC scales \& single-item measures are linearly transformed so that each score has a range of 0-100. A high score for a functional/global health status scale represents a high/healthy level of functioning/HRQoL (Health-Related Quality of Life); however a high score for a symptom scale represents a high level of symptomatology or problems. A ≥10-point change in the symptoms subscale score was perceived by participants as clinically significant (Osoba et al. 1998). A positive change from baseline=improvement \& negative change from baseline indicated worsening.
Change From Baseline in EORTC QLQ Supplementary Lung Cancer Module 13 (EORTC QLQ-LC13) Score	Baseline, Day 1 of each treatment cycle up to 30 days after last dose (up to approximately 55 months) (Cycle length = 21 days)	The EORTC QLQ-LC13 module incorporates one multiple item scale to assess dyspnea and a series of single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. The EORTC QLQ-LC13 was scored according to the EORTC scoring manual (Fayers et al. 2001). All EORTC scales and single-item measures are linearly transformed so that each score has a range of 0-100. A high score for a functional/global health status scale represents a high or healthy level of functioning/HRQoL (Health-Related Quality of Life); however, a high score for a symptom scale or item represents a high level of symptomatology or problems. A≥10-point change in the symptoms subscale score was perceived by participants as clinically significant (Osoba et al. 1998). A positive change from baseline indicates improvement and negative change from baseline indicated worsening.
Time to Deterioration (TTD) in Patient-Reported Lung Cancer Symptoms as Assessed by EORTC QLQ-C30 Score	From baseline up to approximately 55 months	TTD with use of the EORTC was defined as the time from randomization to the first confirmed clinically meaningful deterioration in EORTC symptom scores. Confirmed clinically meaningful deterioration in lung cancer symptoms was defined as a = 10-point increase above baseline in a symptom score that must be held for at least two consecutive assessments or an initial = 10-point increase above baseline followed by either (a) death within 6 weeks from the last assessment through Week 48 or (b) death within 9 weeks from the last assessment from Week 48 thereafter. A = 10-point change in the EORTC scale score was perceived by participants as clinically significant (Osoba et al. 1998).
TTD in Patient-Reported Lung Cancer Symptoms As Assessed by EORTC QLQ-LC13 Score	From baseline up to approximately 55 months	TTD with use of the EORTC was defined as the time from randomization to the first confirmed clinically meaningful deterioration in EORTC symptom scores. Confirmed clinically meaningful deterioration in lung cancer symptoms was defined as a = 10-point increase above baseline in a symptom score that must be held for at least two consecutive assessments or an initial = 10-point increase above baseline followed by either (a) death within 6 weeks from the last assessment through Week 48 or (b) death within 9 weeks from the last assessment from Week 48 thereafter. A = 10-point change in the EORTC scale score was perceived by participants as clinically significant.
OS in Participants With Programmed Death-Ligand 1 (PD-L1) Positive Status	From randomization up to death from any cause (up to approximately 55 months)	OS was defined as the time between the date of randomization and the date of death due to any cause. OS was assessed in participants whose tumors express PD-L1 protein (i.e., tumor cell (TC) ≥1%) as measured by PD-L1 SP263 immunohistochemistry (IHC) assay. KM estimates were used to calculate the median.
PFS as Determined by the Investigator Using RECIST v1.1 in Participants With PD-L1 Positive Status	From randomization to the first occurence of disease progression or death from any cause, whichever occurs first (up to approximately 55 months)	PFS was defined as the time from randomization to the first documented disease progression as determined by the investigator with the use of RECIST v1.1 or death from any cause, whichever occurs first. PD was defined as at least 20% increase in the sum of diameters of lesions, taking as reference the smallest sum during the study (nadir), including baseline. Investigator-assessed PFS was assessed in participants whose tumors express PD-L1 protein as measured by PD-L1 SP263 IHC assay. KM estimates were used to calculate the median.

Trial Locations

Locations (91): LungenClinic Großhansdorf GmbH; Klinische Forschung
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Großhansdorf, Germany
Fundación CENIT para la Investigación en Neurociencias
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Buenos Aires, Argentina
Hospital Privado de Comunidad
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Mar del Plata, Argentina
Clinica Viedma S.A.
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Viedma, Argentina
UZ Brussel
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Brussel, Belgium
Grand Hôpital de Charleroi Notre Dame
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Charleroi, Belgium
UZ Leuven Gasthuisberg
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Leuven, Belgium
Hospital Nossa Senhora da Conceicao
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Porto Alegre, RS, Brazil
Hospital Sao Lucas - PUCRS
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Porto Alegre, RS, Brazil
Instituto do Cancer do Estado de Sao Paulo - ICESP
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Sao Paulo, SP, Brazil
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LungenClinic Großhansdorf GmbH; Klinische Forschung
🇩🇪Großhansdorf, Germany