Defining Resistance to Treatment with Anti-PD-1/PD-L1 Immunotherapy

When designing and conducting clinical trials, establishing a consensus on how the results will be analyzed and interpreted is vital to guiding future research and patient treatment decisions. This importance extends to immunotherapy and the broader field of cancer research, where there is a need to develop appropriate guidelines for the evaluation of different treatments with respect to clinical definitions of patient resistance or response.

As highlighted in the Cancer Research Institute (CRI) Anna-Maria Kellen Clinical Accelerator annual PD-1/PD-L1 trial landscape analysis, thousands of oncology clinical trials explore the use of PD-1/PD-L1 inhibitors alone or in combination with other anti-cancer agents to treat advanced cancers. The number of trials has outpaced the understanding of the biological response to checkpoint inhibitors and the knowledge of which patients are ultimately deriving true benefit. It is thus difficult to understand when a patient has failed PD-1/PD-L1 treatment due to the lack of a consensus definition surrounding therapeutic resistance (a patient’s resistance to the treatment). The ability to successfully evaluate different treatments requires the standardization and harmonization of the clinical definitions for resistance and responses to treatment.

In order to address this unmet need, the Society for Immunotherapy of Cancer (SITC) convened experts from academia, industry, and government to define PD-1/PD-L1 resistance via three categories: primary resistance, secondary resistance, and progression after treatment discontinuation. Vanessa M. Lucey, Ph.D, MBA, director of the Anna-Maria Kellen Clinical Accelerator, represented CRI in this endeavor, which collectively defined each resistance classification, timeframes that delineate each resistance type, and methods to confirm resistance.

Additional CRI scientists involved in this effort included lead clinical investigator and former CRI fellow Margaret K. Callahan, MD (Memorial Sloan Kettering Cancer Center); CRI Scientific Advisory Committee member and member of our prostate cancer platform study drug selection committee Charles G. Drake, MD, PhD (Columbia University Irving Medical Center); and CRI-sponsored investigators Dung T. Le, MD (Johns Hopkins Sidney Kimmel Comprehensive Cancer Center), Janis M. Taube, MD, M.Sc. (Johns Hopkins University School of Medicine), and Suzanne L. Topalian, MD (Bloomberg~Kimmel Institute for Cancer Immunotherapy). 

This work was published in the Journal for Immunotherapy of Cancer in April 2020 and is now available to the larger scientific community.

SITC and CRI hope that this information will better guide the design and analysis of future clinical trials involving PD-1/PD-L1 inhibitors, and ultimately improve patient outcomes.