Background: Immune checkpoint inhibitors have led to durable remissions for some patients with advanced malignancies, including NSCLC; however, only a minority of patients benefit. The field of oncology is addressing this via the development of novel therapies, combinations and identification of biomarkers to select patients most likely to derive clinical benefit. ICOS, a novel therapeutic target, is a costimulatory molecule upregulated on activated T cells. Vopratelimab is an investigational IgG1 ICOS agonist monoclonal antibody that results in activation and proliferation of primed CD4 T effector cells. The preliminary efficacy of vopratelimab +/- nivolumab was assessed in the phase 1/2 ICONIC study in which durable responses were observed in a subset of patients who demonstrated on treatment emergence of peripheral ICOS hi CD4 T effector cells. Patients with peripheral ICOS hi CD4 T cells achieved significantly greater clinical benefit than patients whose CD4 T cells remained ICOS lo. An RNA based tumor inflammation signature (TIS) comprised of 18 genes associated with immune cell infiltration was previously identified as a predictive biomarker of response to anti-PD-1 therapy (Ayers et al, 2017); it was also associated with ICOS hi CD4 T cell emergence in ICONIC (ASCO-SITC 2020). The pre-treatment tumor TIS score, coupled with a specific threshold established by Jounce, referred to as TIS^vopra, was predictive of ICOS hi CD4 T cell emergence. TIS^vopra positive patients had improved RECIST response, PFS, and OS compared to those with a TIS^vopra negative score. Therefore, we hypothesize that patient selection by TIS^vopra will identify those who will display emergence of ICOS hi CD4 T cell populations and importantly, improved clinical outcomes when treated with vopratelimab in combination with JTX-4014 (a novel PD-1 inhibitor in development by Jounce) vs JTX-4014 alone. Methods: This Phase 2 open-label multicenter study is investigating JTX-4014 alone and in combination with vopratelimab in TIS^vopra selected patients with metastatic NSCLC after one prior platinum-containing regimen (NCT04549025). Patients must be PD-1/L1 inhibitor naïve and negative for activating EGFR mutations. TIS^vopra eligibility is determined using RNA isolated from a tumor sample. Eligible patients will be randomized to receive either JTX-4014 as monotherapy or in combination with one of two dose levels of vopratelimab. The primary endpoint is mean percent change from baseline tumor size of all measurable existing and new lesions averaged over 9 and 18 weeks. Secondary endpoints include ORR and PFS according to RECIST v1.1, OS, safety, and association of baseline TIS score with clinical outcomes. The study has a target enrollment goal of approximately 75 patients; the first patient was dosed October 2020. Clinical trial information: NCT04549025