The Complexities and Art of Interpreting Biomarkers and Response to Immune Checkpoint Inhibitors

Source: Cancer Network, May 2023

A function of immune checkpoint inhibitors, such as PD-1 and PD-L1 inhibitors, is to allow normal tissues to coexist with the immune system and avoid triggering a destructive response. When PD-1 (found on T cells) is bound to PD-L1 (found on normal tissue), it dampens T-cell activation. It is now recognized that tumors can also express PD-L1, gaining the ability to escape detection and be allowed to proliferate. Thus, the role of PD-L1 as a biomarker has emerged, and there is interest in the therapeutic opportunity to block the PD-1/PD-L1 interaction.

In 2014, pembrolizumab (Keytruda) was the first PD-1 inhibitor to receive FDA approval for use in melanoma. This was further expanded in 2017 and 2020 to tumors with microsatellite instability–high status and tumor mutational burden (TMB) greater than 10 mut/Mb, respectively. Since then, other PD-1/PD-L1 inhibitors have been approved in various diseases, such as nivolumab (Opdivo), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi). When a response is seen, it tends to be durable and prolonged. Regarding immune-related adverse effects, they can affect any organ system and lead to reactions such as rash, diarrhea, endocrinopathies, musculoskeletal pain, pneumonitis, and more.

The authors of “Biomarkers for Response to Anti–PD-1/ PD-L1 Immune Checkpoint Inhibitors: A Large Meta-Analysis” performed a comprehensive review of 100 studies, encompassing approximately 18,000 patients to address the role of 9 predictive biomarkers across tumor types. With a large data set available to conduct robust statistical analysis, their findings suggest that TMB, PD-L1 immunohistochemistry (IHC), and multiplex IHC/immunofluorescence were sensitive in predicting response across all tumor types, although the authors acknowledge heterogeneity in study design and limited study size. Some of the complexities and nuances may pertain to the assay and clinical interpretation of immune therapies.