Background: Stage IV NSCLC patients who are never-smokers or with EGFR-mutated tumors generally do not benefit from single-agent immunotherapy. Retrospective subgroup analyses from recent phase III trials suggest that immunotherapy-chemotherapy +/- VEGF inhibition may overcome resistance to PD-L1 inhibitors in these patients, however prospective research on this is needed. This trial will examine a patient population with stage IV non-squamous disease who either have tumors that possess an EGFR exon 19 or 21 mutation or who are never-smoker wild-types, to determine whether the PD-L1 inhibitor atezolizumab in combination with pemetrexed, carboplatin, and bevacizumab can improve outcomes. Methods: This is a randomized, phase II, multi-center, open-label trial to assess pemetrexed/carboplatin and bevacizumab +/- atezolizumab in 117 subjects with stage IV non-squamous NSCLC. Randomization will be 2:1 favoring the + atezolizumab arm. Patients are stratified by EGFR mutation status (i.e. EGFR exon 19 or 21 vs. never-smoker wild-type). Never-smoker wild-type is defined as smoking < 100 cigarettes in a lifetime and without any EGFR mutation or ALK or ROS1 rearrangement. Patients with EGFR exon 19 or 21 mutated tumors must have progression of disease or intolerance of treatment with one or more prior TKIs. Primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), overall response rate, duration of response, and time to response. Primary objective is to compare PFS between arms. Secondary objectives include a safety analysis in all treated subjects, and comparisons of PFS and OS between arms for the patient subset with EGFR-mutated tumors. Correlative studies include interrogating flow cytometry-based peripheral blood biomarkers, examining the role of desmoplasia in local tumor immunosuppression, and assessing the contribution of estrogen metabolites to tumorigenesis. This study opened in August 2019 with 2 patients enrolled at the time of submission. Twenty U.S. sites through the NCCN are participating. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Genentech, Inc. Clinical trial information: NCT03786692.