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Background Many patients with non–small-cell lung cancer (NSCLC) treated with immunotherapy experience immune-related adverse events (irAEs). Patients with metastatic NSCLC who receive checkpoint inhibitors (CPI) and experience irAEs generally receive fewer cycles of CPI without decreased efficacy. However, the association between irAEs and efficacy outcomes in patients with locally advanced NSCLC treated with curative intent with CPI after chemoradiation has never been reported. Here we report a retrospective analysis of the association between irAEs and efficacy outcomes from the Hoosier Cancer Research Network (HCRN) LUN 14-179 single-arm phase 2 trial of consolidation pembrolizumab after chemoradiation in patients with stage III NSCLC. Patients and Methods A total of 92 eligible patients were enrolled from March 2015 to November 2016. Demographics, disease characteristics, and number of pembrolizumab cycles received were reported in patients with and without irAEs. Chi-square test was used for comparisons for categorical variables and Wilcoxon test for continuous variables. The Kaplan-Meier method was used to analyze time to metastatic disease or death (TMDD), progression-free survival (PFS), and overall survival (OS). A log-rank test was used to compare groups. Results Any grade irAEs occurred in 55.4% of patients. There was no significant difference in number of pembrolizumab cycles received, TMDD, OS, or PFS in patients with and without irAEs. Patients who discontinued pembrolizumab early because of irAEs received significantly fewer cycles of pembrolizumab (5 vs 15, P = .0016) without a significant difference in TMDD, PFS, or OS. Similarly, patients who received immunosuppressive therapy received fewer numbers of cycles of pembrolizumab (4 vs 16, P Conclusion irAEs due to pembrolizumab, regardless of grade or number of irAEs, were not associated with decreased efficacy outcomes. Furthermore, early discontinuation of pembrolizumab because of irAEs and/or treatment of irAEs with immunosuppressive therapy was not associated with a decrease in treatment efficacy.

The treatment of advanced non-small-lung cancer (NSCLC) has steadily evolved over the past 2 decades, and current therapy includes chemoimmunotherapy or targeted therapy with tyrosine kinase inhibitors (TKIs). Angiogenesis inhibitors were first approved in the mid-2000s in combination with chemotherapy for the treatment of NSCLC. The addition of anti-angiogenics to chemotherapy resulted in modest increases in survival when median overall survival was less than 1 year. More recently, the use of anti-angiogenics has fallen out of favor with the advent of checkpoint inhibitors and never-before-seen durable long-term responses. However, we postulate that there is still an important role for anti-angiogenics in this era of targeted therapy and checkpoint inhibitors in the treatment of NSCLC. Preclinical studies have shown that combination blockade of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways leads to synergistic antitumor effects. These results have been replicated in the clinical setting in patients who harbor EGFR mutations, with VEGF inhibitor-TKI dual therapy leading to impressive survival outcomes. Similarly, combination treatment with checkpoint inhibitors and VEGF inhibitors have led to unprecedented survival outcomes in both advanced renal cell cancer as well as NSCLC. In this review, we explore the evolution of anti-angiogenic therapy in advanced NSCLC and discuss the clinical efficacy of angiogenesis inhibitors in combination with chemotherapy, TKI therapy, and checkpoint inhibitors.