The famous words of wisdom by Marcus Aurelius, “The impediment to action advances action. What stands in the way becomes the way,” a great metaphor for how immune-checkpoint inhibitors are becoming the main approach in tackling the current challenges in cancer therapy. Evolving from being a major impediment, to the main path forward, Immune checkpoints are hopefully a means by which a curative treatment to cancer can be achieved. At the same time, in this case not all roads lead to Rome! So the main questions become - Which marker should be followed to get to your destination, how do you get there faster, and how do you follow the path with the least resistance, in this case the lowest toxicity possible?
The immune system has a complex and very selective approach to distinguish between “self” and “foreign”, thereby attacking only the foreign invaders while leaving the normal cells alone. This unique ability to maintain a balancing act is brought about by molecules known as “checkpoints” or “impediments”, which immune cells need to overcome in order to initiate an immune response.
Tumor cells exploit these checkpoints to block attack by immune cells and we now realize that over the past few decades, this cellular masking has been the reason for the failure of immune-mediated therapy in Oncology.
In the last few years, therapies have been developed that remove these blockades with initial efforts focused on 2 main targets CTLA4 and the receptor/ligand pair of PD1/PDL1. These efforts have scored impressive results recently, particularly in patients with non–small cell lung cancer (NSCLC), metastatic melanoma, Hodgkin lymphoma and bladder cancer, and are showing promise in clinical trials involving patients with many other types of cancer. Unfortunately, except in HL, characterized by high and widespread PD-L1 amplification and overexpression, where the response rate is as high as >60%, the ORR in other indications has been more modest around 15-to 30%. Therefore major efforts have been focussed on selecting the responder patient population to optimize treatment regimens.
The examination of PD-L1 levels was an obvious prognostic biomarker to analyze in such selection processes. However, PD-L1 expression measured by immunohistochemistry in patients is not necessarily a strong prognostic marker in patients. While in general all efficacy parameters for both Nivulomab and Pembrozulimab are higher in PD-L1 positive patients, a substantial % of PDL1 negative patients (10% for Pembrozulimab in NSCLC) are still responders. This has led to the contracdictory situation where Pembrozulimab is approved only in PD-L1+ patients while Nivulomab is approved in all patients. Moreover, the criteria used to define the PD-L1 status of a tumor differs vastly: for nivolumab, the cut off used is 1% to 5% of positive cells in a biopsy while pembrolizumab has a much wider range of 1% to 50%, while that for atezolizumab (anti-PD-L1) it is 1% to 10%. It is not clear what is the correct cut-off and whether measurements in biopsies are truly optimal, as they might represent a snapshot in time, especially given the data that both efficacy can be related to positivity in both the tumor cells as in the immune infiltrate whose status and amount can change with the progression of the disease and the treatment previously received. Further complications are added by the evidence that these markers might have different levels of predictivity in different tumor types. It is understandable therefore, that the FDA convened a public workshop to discuss these issues and has mandated a comparison of the different PD-L1 diagnostics