Background: Immune checkpoint inhibitors (ICIs) targeting PD-(L)1 in combination with platinum-based chemotherapy is standard first-line therapy for patients with advanced non-small cell lung cancer (NSCLC). The majority of these patients progress and there remains a high unmet medical need in the second-line setting given the limited FDA approved available therapies. The ICI plus vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI) combination, successful across several tumor types, was studied in NSCLC as a potential treatment option. Methods: The FDA identified 3 randomized trials conducted between June 2019 and August 2023, comparing the combination regimen ICI plus VEGF TKI to docetaxel in patients with advanced NSCLC who had progressed on both platinum-based chemotherapy and an ICI. All 3 trials were publicly reported to have not met their primary endpoint. Topline results for key efficacy and safety outcomes from each of the 3 trials were provided by the commercial sponsors. Results: 1317 total patients across 3 trials (LEAP-008, SAPPHIRE and CONTACT-01) were randomized to receive either an ICI plus VEGF TKI or docetaxel. The results are presented (Table). Efficacy parameters demonstrated similar results across trials between arms. There was no clear signal that the combination is more effective than single agent docetaxel. Safety parameters across trials consistently demonstrated higher rates of toxicity with the combination. Conclusions: ICI plus oral VEGF TKI combinations have not demonstrated an advantage over docetaxel in randomized trials of patients with advanced NSCLC. In 2 of the 3 trials, response rate data did not demonstrate superior efficacy compared to docetaxel. Additionally, any observed PFS benefit was small in magnitude. The relatively low efficacy, in combination with the additive toxicity of the regimen, may curtail a potential OS benefit. There remains a high unmet medical need in this patient population and further analysis is necessary to explore potential NSCLC subgroups which may derive benefit.