In the last 2 years we were very happy to have seen: nivolumab, pembrolizumab and recently atezolizumab approved for non-small cell lung cancer (NSCLC). If you remember all of them are approved for second line therapy of NSCLC and pembrolizumab has been moved and approved already for first line NSCLC therapy if the tumor expresses PDL-1 immunohistochemistry staining (IHC) more than 50%. All of these agents block the interaction between the receptor PD-1 present in T lymphocytes and the ligand PDL-1 present in tumor cells and they are called “checkpoint inhibitors”. Some of them like atezolizumab block the PDL-1 ligand and the others are PD-1 inhibitors, there are no clear differences among them other than the current FDA indications. Soon we will know if there are differences in these 2 types of inhibitors among themselves regardless effectivity or toxicity. However these are not the only agents, we have more PDL-1 inhibitors in development like: avelumab (also known as MSB0010718C) that is in priority review for urothelial cancer but results from the JAVELIN trial were recently reported in December in Vienna during the 17^th International Association for the Study of Lung Cancer (IASLC) Annual Meeting showing good responses and toxicity profile similar to the other inhibitors. The same happened with another anti-PDL-1 called durvalumab that was also presented at the IASLC meeting too with similar outcomes. But not only anti PD-1/PDL-1 antibodies are considered check point inhibitors we also have to remember that we have anti-CTL4 antibodies called ipilimumab and tremelimumab; none of them are approved for lung cancer yet but the first is already commercially available for melanoma. The importance of these anti-CTL4 antibodies is in the fact that they stimulate the immune response by a different mechanism of the PD-1/PDL-1 inhibitors then the great interest from the research community in combining these 2 different type of drugs to try to enhance the immune response as already has happened successfully in melanoma where the combination of ipilimumab + nivolumab is becoming standard. Other investigators are already combining durvalumab with tremelimumab for NSCLC, the first phase I study was published in the journal “Lancet” in February 2016 where they showed a manageable tolerability profile, with antitumour activity irrespective of PD-L1 status. During World Lung IASLC conference in December 2016 the combination of ipilimumab + nivolumab was presented showing good tolerance for the patients and enhancing the immune response of single agent nivolumab and the final paper was published also in “Lancet” in January 2017.

But this story even gets better: while some pharmaceutical companies are developing similar check point inhibitors to the 2 types described (anti PD-1/PDL-1 and anti-CTL4) other companies are exploring other targets and checkpoints so there is a large list of potential candidates that can be targeted with  the hope to achieve an immune response like: A2AR, B7-H3, also called CD276, B7-H4, also called VTCN1, BTLA also called CD272, IDO, short for Indoleamine 2,3-dioxygenase; KIR, short for Killer-cell Immunoglobulin-like Receptor, LAG3, short for Lymphocyte Activation Gene-3, TIM-3, short for T-cell Immunoglobulin domain and Mucin domain 3, and VISTA (protein), Short for V-domain Ig suppressor of T cell activation, among others.

The future is very exciting these days for the possibilities that is bringing to our NSCLC patients.