Pts with LS-SCLC have a modest prognosis (5-year survival rate: 25–30%) and require more effective therapies. T-cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domains (TIGIT) is a co-inhibitory immune checkpoint receptor upregulated on T-cells and natural killer cells in multiple solid tumors, which can inhibit anticancer immune responses. Dual targeting of tumors with anti-TIGIT and anti-programmed cell death protein 1 (PD-1) produces synergistic immune cell activation and enhanced antitumor activity in preclinical models. OCI is a humanized, mAb that binds TIGIT with high specificity and affinity, blocking interaction with its ligands on tumor cells. TIS is an anti-PD-1 mAb engineered to minimize binding to Fc-gamma receptors on macrophages to abrogate antibody-dependent phagocytosis, a potential resistance mechanism to anti-PD-1 therapy. AdvanTIG-204 is a phase 2, randomized, multicenter, open-label study (NCT04952597). Approximately 120 treatment-naïve pts with LS-SCLC will be randomized 1:1:1 to receive either OCI 900 mg intravenously (IV) + TIS 200 mg IV combined with cCRT for 4 cycles, followed by OCI 900 mg + TIS 200 mg (Arm A), TIS 200 mg IV combined with cCRT for 4 cycles, followed by TIS 200 mg IV (Arm B), or cCRT only for 4 cycles (Arm C). OCI and TIS will be administered once every 3 weeks for ≤ 12 months, or until disease progression, unacceptable toxicity, death or withdrawal of consent, whichever occurs first. RT start early within Cycle 1 or 2 of systemic therapy. Pts will be stratified by disease stage (I/II vs III). The primary endpoint is PFS as assessed by the investigator (RECIST v1.1) in the intent-to-treat population. Secondary endpoints include, complete response rate, overall response rate, duration of response, overall survival (all investigator-assessed), correlation of PD-L1 and TIGIT expression with efficacy endpoints, and safety. Exploratory endpoints include, but are not limited to, biomarker evaluation, health-related quality of life, and circulating tumor DNA. Study enrollment is ongoing. NCT04952597. Medical writing support for the development of this abstract, under the direction of the authors, was provided by Tamsin Grewal, MSc, of Ashfield MedComms, an Ashfield Health company, and was funded by BeiGene, Ltd. BeiGene, Ltd.