Background: Checkpoint inhibitor immunotherapy (CPI) offers durable, immune-mediated, anti-tumor responses to a subset of patients (pts) with advanced non-small cell lung cancer (NSCLC), but not all derive meaningful benefit. Two clinical unmet needs where CPI has fallen short include EGFR-mutated NSCLC, where CPI is minimally effective, and NSCLC with intrinsic or acquired resistance to currently available CPI. Novel combination strategies have shown promise. Two agents that have demonstrated synergy with the anti-PD-L1 CPI atezolizumab in NSCLC are bevacizumab, a vascular endothelial growth factor (VEGF)-blocking antibody, and tiragolumab, a T-cell immunoglobulin and ITIM domain (TIGIT) immune checkpoint-blocking antibody. This multi-cohort phase II trial seeks to evaluate the efficacy of tiragolumab with atezolizumab plus bevacizumab in 2 CPI-resistant cohorts - EGFR-wild type, CPI-refractory advanced NSCLC (cohort A) and EGFR-mutated, CPI-naïve advanced NSCLC (cohort B) - incorporating novel genomic and immunologic analyses to deliver mechanistic insight into the biology of CPI-resistance in NSCLC. Methods: This open-label, phase II study has two cohorts. Cohort A includes pts with advanced PD-L1+ (TPS ≥ 1%), EGFR/ALK/ROS1 wild type NSCLC with progression on prior anti-PD(L)1-based CPI therapy. Cohort B includes pts with targeted therapy-refractory EGFR-mutated NSCLC who are CPI-naïve. Pts must have measurable disease and those with symptomatic and/or untreated brain metastases are excluded. Pts in both arms will receive tiragolumab 600mg IV with atezolizumab 1200mg IV and bevacizumab 15mg/kg IV every 3 weeks until progressive disease or unacceptable toxicity. The primary efficacy endpoint will be assessed separately in each cohort by investigator-assessed objective response rate (ORR) according to RECIST v1.1. Each cohort utilizes a Simon 2-stage design in which a null ORR of 4% is tested against a one-sided alternative of 20%. A sample size of 21 pts/cohort provides 80% power with a one-sided type 1 error rate of 5% to determine a true ORR of 20%. Secondary efficacy endpoints include: duration of response, progression-free survival (PFS), 6-month PFS, overall survival. Blood and tumor specimens will be acquired pre- and on-treatment. Correlative analyses to illuminate the biology of CPI resistance will include multiplex imaging mass cytometry of tumor tissue. In addition, whole exome sequencing, T-cell receptor sequencing, and MANAFEST neoantigen prediction will be used to identify neoantigen-specific T-cells and track these temporally (during/post treatment) and spatially (across biologic compartments). The study is activated and both cohorts are accruing simultaneously with enrollment ongoing. Clinical trial information: NCT04958811.