Analysis of the association between adverse events and outcome in patients receiving a programmed death protein-1 or programmed death ligand-1 antibody

Since their discovery, new immunotherapies have demonstrated their ability to induce durable tumor responses, which have significantly improved long-term survival in patients with different types of metastatic disease. Among the most effective strategies of cancer immunotherapy, the use of monoclonal antibodies against inhibitory immune checkpoint molecules affecting T-cell activation, such as protein death-1 (PD-1) and protein death ligand-1 (PD-L1), represents one of the main investigation areas in cancer research today (1). Despite the significant benefit that checkpoint inhibitors have represented for metastatic patients, these therapies can promote the activation of autoreactive T-cells resulting in profound inflammatory and unique immune-related adverse events which may be life-threatening and can cause a reduction of the optimal medication dose or treatment discontinuation (2). Although these complications may represent an important impediment for the success of checkpoint blocking therapies, there is a need to understand if the development of autoimmune adverse events may be related with the activation of the immune system and subsequent patient outcome. In their recent article, Maher et al. evaluate the relationship between the development of adverse events and patient outcome, in terms of response and overall survival, among 1,747 patients with metastatic or locally advanced urothelial cancer who received an anti-PE-1/PD-L1 inhibitor in seven clinical trials that led to product approval by the FDA (3). Provided that systemic corticosteroids could cause immunosuppression and interfere the immune response, they also ask if the use of these substances would affect the duration response. The authors find that patients who respond to PD-1/ PD-L1 blocking antibodies are more likely to report a related adverse event of special interest (AESI) or related immune-mediated adverse event (imAE) regardless the duration of treatment. They also find that the use of systemic corticosteroids neither appear to affect the chances of developing a response nor duration of response. As the authors observe, both the duration of observation for AESIs/imAEs and the ability of clinicians involved in cancer patients care to correctly identify which adverse events are actually caused by the use of PD-1/PD-L1 inhibitors represent limiting factors for this type of study which justify the need to develop clinical guides and updated training that allow for the correct definition and management of AESIs/ imAEs related to the corresponding drug. The authors also highlight the existence of significant differences in the percentage of responding patients with a related AESI/imAE, which leaves an open-ended question Editorial Commentary