Background: Combination strategies to improve the efficacy of single agent immune checkpoint inhibitors (ICIs) are increasingly being explored, with one strategy being the addition of vascular endothelial growth factor (VEGF) inhibition. Having shown promise in the treatment of hepatocellular carcinoma and renal cell carcinoma, NCT03583086 is a multi-institutional, phase I/II study of combination vorolanib and nivolumab in both naïve and refractory thoracic tumors that progressed on at least one prior line of platinum-based chemotherapy. Though structurally similar to the tyrosine kinase inhibitor, sunitinib, vorolanib was designed to have a more favorable safety profile with comparable efficacy. Here we present safety data across all cohorts and interim efficacy analyses of the SCLC and NSCLC with primary resistance to ICI-based therapy cohorts, both of which have now completed enrolment. Methods: The maximum tolerated dose determined in phase I was vorolanib 200mg daily and nivolumab 240mg q2 weeks. Phase II uses a two-stage MinMax design across 5 cohorts with objective response rate (ORR) as the primary endpoint: NSCLC (ICI naïve, primary refractory, and acquired resistance), SCLC, and thymic carcinoma. Primary refractory is defined as radiographic progression of disease within 12 weeks of ICI initiation. Results: As of January 2021, 75 patients have been enrolled across all cohorts. Stage 1 of the SCLC and primary refractory NSCLC cohorts have completed accrual at 18 and 15 patients, respectively. In the SCLC cohort, disease-control rate (DCR) was 7% and no objective responses were achieved among 14 evaluable patients. In the primary refractory NSCLC cohort, DCR was 57% and ORR 7% (1 partial response) among 14 evaluable patients. A total of 140 treatment-related adverse events (TRAEs) have been reported, 13 (9%) were grade 3 and there were no grade 4/5 events. Fatigue (9%), nausea (6%), diarrhea (6%), ALT elevation (5%), and AST elevation (5%) were the most common all grade TRAEs. The most common grade 3 TRAEs were ALT elevation and hypertension. Conclusions: This therapeutic strategy of nivolumab plus vorolanib appears to be a well-tolerated combination with a manageable safety profile. Adding VEGF inhibition may offer additional disease control in the setting of NSCLC with primary resistance to ICIs, but neither the SCLC or primary refractory NSCLC cohorts achieved the pre-determined target number of objective responses for progression to stage 2 of the study. Enrolment in the other 3 cohorts as well as exploratory correlatives are ongoing. Clinical trial information: NCT03583086