As clinicians have increasing amount of checkpoint inhibitors to select from in the treatment of advanced stage NSCLC patients, it will be important to understand potential differences in efficacy and toxicity profiles of these agents. in response rate between PD-1 (19%) and PD-L1 (18.6%) inhibitors, p=0.17. The incidence of overall adverse events (AEs) was comparable between PD-1 and PD-L1 inhibitors (64% (CI 63-66%) versus 66% (CI 65-69%), p=0.8). Fatigue is the most frequently reported AE with both classes. Patients treated with PD-1 inhibitors have a slightly increased rate of immune related AEs (IRAEs) (16 (CI 14-17%) versus 11% (CI 10-13%), p=0.07) and pneumonitis (4% (CI 3-5) versus 2% (CI 1-3), p=0.01) compared to patients who received PD-1 inhibitors. Conclusions In this systematic review involving 5,744 patients, the toxicity and efficacy profiles of PD-1 and PD-L1 inhibitors in NSCLC patients are similar. Keywords: Immune checkpoint inhibitors, NSCLC, adverse events, immune Peptide M related adverse events Introduction Immune checkpoint inhibition Peptide M is an effective treatment strategy in multiple tumor types, including non-small cell lung cancer (NSCLC). The immune checkpoint Programmed Death 1 (PD-1) receptor is expressed on activated T cells and binds to its ligands PD-L1 and PD-L2 to limit T cell activation and prevent autoimmunity in peripheral tissues1. Activation of the PD-1 pathway MYL2 induces T cell exhaustion, which is necessary to prevent continued immune activation following successful removal of cells carrying the antigen of interest2. Several tumors overexpress PD-L1 and evade detection by T cells, which leads to immune tolerance of the tumor. Overexpression of PD-L1 is also associated with more aggressive phenotypes and poor outcomes in NSCLC3-7. Monoclonal antibodies against PD-1 and PD-L1 have emerged as effective therapies in patients with advanced NSCLC. These agents have been shown to be tolerated well and exert anti-cancer effects even in patients who have failed multiple prior lines of therapy. The PD-1 inhibitors nivolumab and pembrolizumab and the PD-L1 inhibitor atezolizumab are superior to docetaxel in the salvage setting with improved survival outcomes and toxicity8-11. More recently, pembrolizumab was shown to be superior to platinum doublet chemotherapy in treatment na?ve metastatic NSCLC patients with high tumoral PD-L1 expression, resulting in a major shift in treatment paradigm12. Peptide M The immune checkpoint inhibitors have unique mechanism-based toxicities compared to cytotoxic chemotherapy. Inhibition of the PD-1 pathway can lead to autoimmune toxicities, some of which can be severe and even fatal reactions13, 14_ENREF_14. Lung cancer patients are particularly more vulnerable for toxicities given the older age of the patient population and presence of co-morbid conditions. Of particular interest in NSCLC patients is the development of autoimmune pneumonitis, which led to a few treatment-related deaths in early phase studies of these agents15-17. As clinicians have increasing number of checkpoint inhibitors to choose from in the treatment of advanced stage NSCLC patients, it will be important to understand potential differences in efficacy and toxicity profiles of these agents. There has been speculation that since monoclonal antibodies Peptide M against PD-L1 still allow for the interaction of PD-1 with its other ligand PD-L2, this could lead to less blockade of the negative inhibitory signal and result in reduced autoimmunity. Whether this can also have implications on the efficacy of the individual agents is not known. Given that it is highly unlikely for comparative clinical trials to be conducted to compare the check point inhibitors against one another, there is an urgent need to understand key differences in efficacy and toxicity Peptide M between the various immune checkpoint inhibitors. In particular, comparison of PD-1 versus PD-L1 inhibitors is of immense clinical interest. Therefore, we conducted a systematic review of clinical trials to evaluate differences in toxicity profiles between PD-1 and PD-L1 inhibitors used as monotherapy in NSCLC. Methods Search Strategy A comprehensive and methodical search of the literature.