Background: Over 40,000 patients in the US/year are diagnosed with stage III NSCLC, but only ~25% will be cured by standard chemoradiation (CRT). Combining checkpoint inhibition through PD-L1 blockade with CRT may attenuate tumor related immunosuppression via depletion of Tregs and clonal expansion of effector T-cells, thereby improving tumor immunogenicity. Responses to immunotherapy seem to be higher in patients with significant cytoreduction, such as with radiation (RT). Further, CRT may reveal otherwise hidden antigens that can present additional targets to the reconstituting immune system. Whether anti-PD-L1 therapy before CRT will further improve outcomes in this setting is unknown. Methods: This phase II single arm Alliance Foundation Trials study (AFT-16, NCT03102242) will evaluate safety and efficacy of atezolizumab before and after definitive CRT. 63 patients with stage III NSCLC, PS 0-1, no active autoimmune disease and no underlying organ dysfunction will be enrolled at 15 US Alliance sites. Treatment consists of 4 cycles of neoadjuvant atezolizumab 1200 mg IV q 21 days with restaging after cycles 2 and 4. Non-progressing patients undergo carboplatin and paclitaxel (C/P) weekly with 60 Gy RT followed by 2 cycles of C/P consolidation followed by atezolizumab to complete one year of therapy. The primary endpoint of this pilot study is disease control rate (CR+PR+SD) after neoadjuvant atezolizumab. Secondary endpoints include ORR, PFS and OS, safety and QoL assessed by the EORTC QLQ-30. Correlatives include the role of PD-L1 and tumor mutation burden as predictive biomarkers. Tumor tissue will be obtained at study entry, and plasma and immune cells will be isolated at study entry, post neoadjuvant atezolizumab, post CRT, during adjuvant atezolizumab and at study end. Additional potential predictive biomarkers will be to define how atezolizumab affects the proportions of immunologic subtypes and immune activation using flow cytometry and T cell receptor immunophenotyping, multiplex immunohistochemistry and cytokine analysis. The trial was activated on 11/1/17. As of 2/13/18, the trial has been opened at 4 centers and 8 patients have been enrolled. Clinical trial information: NCT03102242