Herbst 2020.

Study characteristics
Methods	Study design: randomised open‐label parallel controlled, phase 3 trial Study setting: multicentre trial, 191 planned study locations Country: 19 countries USA, Brazil, China, France, UK, Germany, Greece, Hungry, Italy, Poland, Romania, Russia, Serbia, Spain, Ukraine ,Japan, Korea, Thailand,Turkey) Publication: abstract
Participants	572 participants Inclusion criteria Histologically or cytologically confirmed, Stage IV non‐squamous or squamous NSCLC No prior treatment for Stage IV non‐squamous or squamous NSCLC. Participant known to have a sensitising mutation in the epidermal growth factor receptor (EGFR) gene or an anaplastic lymphoma kinase (ALK) fusion oncogene are excluded from the study Tumour PD‐L1 expression as determined by immunohistochemistry (IHC) assay of archival tumour tissue or tissue obtained at screening. Only people with PD‐L1 expression ≥1% on tumour cells (TC) or immune cells (IC) were included. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) Adequate haematological and end‐organ function Exclusion criteria Known sensitising mutation in the EGFR gene or ALK fusion oncogene Active or untreated central nervous system (CNS) metastases as determined by Computed Tomography (CT) or magnetic resonance imaging (MRI) evaluation Malignancies other than NSCLC within 5 years prior to randomisation, 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, organising 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 for Human Immunodeficiency Virus (HIV) Active hepatitis B or hepatitis C Prior treatment with cluster of differentiation (CD) 137 agonists or immune checkpoint blockade therapies, anti PD1, and anti‐PD‐L1 therapeutic antibody Severe infection within 4 weeks prior to randomisation Significant history of cardiovascular disease Participants characteristics Number randomised: 554 Atezolizumab group N = 277. Age < 65 years, n (%): 143, (51.6). Male sex n (%): 196 (70.8); ECOG performance n (%): 0: 97 (35); never smoked 37 (13.4. Histology: non‐squamous n (%) = 192 (69.3) Chemotherapy group: N = 277. Age < 65 years n (%): 134, (48.4). Male sex n (%): 193 (69.7); ECOG performance n (%): 0: 102 (36.8); never smoked 35 (12.6). Histology: non‐squamous n (%) = 193 (69.7)
Interventions	Intervention: atezolizumab, other names: MPDL3280A, RO5541267 Atezolizumab 1200 milligram (mg), intravenous infusion every 21 days until loss of clinical benefit (as assessed by the investigator), unacceptable toxicity, or death (maximum up to approximately 58 months). Comparators: (Carboplatin/Cisplatin) + (Pemetrexed/ Gemcitabine) Participants with non‐squamous NSCLC will receive chemotherapy with pemetrexed in combination with either cisplatin or carboplatin (per investigator discretion) on Day 1 of each 21‐day cycle for 4 or 6 cycles as per local standard of care, followed by maintenance therapy with pemetrexed alone as per local standard of care until disease progression (per RECIST v1.1), unacceptable toxicity, or death (maximum up to approximately 58 months). Participants with squamous NSCLC will receive chemotherapy with gemcitabine on Days 1 and 8 of each 21‐day cycle in combination with either cisplatin or carboplatin on Day 1 of each 21‐day cycle for 4 or 6 cycles as per local standard of care, followed by best supportive care as per local standard of care until disease progression, unacceptable toxicity, or death (maximum up to approximately 58 months).
Outcomes	Primary outcome measures Overall survival (OS): time frame: from randomisation to death from any cause (maximum up to approximately 58 months) in PD‐L1 positive (tumour cell (TC) or immune cell score (IC) ≥ 1%) The primary endpoint was tested hierarchically in the following subgroups: PD‐L1 ≥50% on TC or IC (TC3 or IC3); PD‐L1 ≥5% on TC or IC (TC 2/3 or IC 2/3); and PD‐L1≥1% on TC or IC (TC1/2/3 or IC1/2/3). Secondary outcome measures :Progression‐free Survival (PFS): time frame: from randomisation to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 58 months) Percentage of participants with objective response (ORR): time frame: every 6 weeks for 48 weeks following day 1, thereafter every 9 weeks after completion of the week 48 tumour assessment, regardless of treatment delays, until radiographic disease progression (maximum up to approximately 58 months) ] Duration of Response (DOR):time frame: from the first occurrence of a complete response (CR) or partial response (PR), whichever occurs first, until the first date that progressive disease or death is documented, whichever occurs first (up to approximately 58 months) Percentage of participants who are alive at 1 and 2 Years, time frame: 1 and 2 years Time to deterioration (TTD) in patient‐reported Lung Cancer Symptoms Score as assessed by the Symptoms in Lung Cancer (SILC) Scale Symptom Score (time frame: Baseline up to approximately 58 months) Change From Baseline in patient‐reported Lung Cancer Symptoms Score as Assessed by the SILC Scale Symptom Score (time frame: baseline up to approximately 58 months) TTD as assessed using European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire‐Core (EORTC QLQ‐C30) (time frame: baseline up to approximately 58 months) TTD as assessed using EORTC QLQ Supplementary Lung Cancer Module (EORTC QLQ‐LC13) (time frame: baseline up to approximately 58 months) OS in participants with PD‐L1 expression (time frame: from randomisation to death from any cause (maximum up to approximately 58 months) Investigator‐assessed PFS in participants with PD‐L1 expression according to RECIST v1.1 (time frame: from randomisation to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 58 months) OS in participants with blood Tumour Mutational Burden (bTMB) (time frame: from randomisation to death from any cause (maximum up to approximately 58 months) Investigator‐assessed PFS in participants with bTMB according to RECIST v1.1 (time frame: from randomisation to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 58 months)
Notes	Sponsorship source: Roche ClinicalTrials.gov Identifier: NCT02409342 Study protocol: not published Other notes: Cross‐over during the trial was not permitted
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation number was obtained by a web‐based response system
Allocation concealment (selection bias)	Low risk	Central allocation was performed. Study sites obtained participants randomisation number and treatment assignment from interactive voice or web‐based response system
Blinding of participants and personnel (performance bias) All outcomes	Low risk	No blinding it is an open‐label study design. However, the absence of blinding unlikely influenced results of the primary outcome (OS).
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Primary endpoint (overall survival) was not influenced by the absence of blinding assessment
Incomplete outcome data (attrition bias) All outcomes	Low risk	Outcome reported as intention to treat (ITT) population. No drop outs
Selective reporting (reporting bias)	Low risk	Protocol was available and all outcomes were reported.
Other bias	Unclear risk	Some authors declared conflicts of interest related to the present study or received personal fees from pharmaceutical companies conducting the trial.