Biomarkers are critical for the personalization of therapy in oncology. It is quite clear that all therapies, no matter how potent, will require some personalization to reach their maximum effect. We have been working on personalizing targeted therapy for almost 20 years and now have perhaps 10 to 15 molecular targets in lung cancer and other tumors for which we have drugs that can be used to treat tumors addicted to those targets. However, immunotherapy is still in its infancy, and it behooves us to now spend the time to develop the biomarkers to target immunotherapy in a more personalized way for greater effect and less toxicity.
The main article in this publication very nicely discusses the development of biomarkers and how they have been used in targeted therapy and immunotherapy. Of course, for targeted therapy, biomarker development requires gene sequencing, often using next-generation processes to identify mutations, deletions, and rearrangements. For immunotherapy, one must also look at the mutational status and tumor mutational burden that has been shown to correlate with progression-free survival. However, it is my prediction that we will also need to do immune profiling to examine the different cells of the immune system; this can lead to a better understanding of how immunotherapies can work more effectively.
At this point, it is evident that targeted therapies, although active, lead to treatment resistance. Therefore, biomarkers of sensitivity and resistance are critical in this setting, and in the case of oral tyrosine kinase inhibitors, biomarkers will be used to help us figure out who will benefit most from which drug and which class. Of course, performing biopsies after treatment resistance is critical for determining the next steps of treatment.
In lung cancer, we are seeing that immunotherapies work wonderfully in 20% of patients. However, for the remaining 80% to reap benefit, we will need to conduct studies of both genetics and immune profiling of the different regulatory cells in the immune microenvironment to better understand the regulation of this process. I am quite intrigued by recent work evaluating tumor-infiltrating lymphocytes, as it will be critical to look at these cells to help us determine which compartments are best suited for which drugs.
Oncology is a field that has always grown with new drug development. We are in a perfect storm right now in that we have drugs that target addicted driver pathways as well as the immune system. We also have other options, such as the modalities of radiation, chemotherapy, and supportive care. Determining how to use these drugs and options in the right sequence or combination is going to be critical. It will be essential to use biomarkers as described within the main article to try to identify the right drug or drug combinations in the right order for each patient. Our goal is to maximize efficacy and minimize any toxicities that we may observe.
Using biomarkers to determine the sequence of therapies is certainly important because good patient care and treatment management are critical to maintaining the best quality of life for our patients. In lung cancer, I believe a multisystem approach, using a large model—including markers such as tumor microenvironment, tumor mutational burden, regulatory T-cells, and epigenetics—will be needed, perhaps using artificial intelligence and advanced learning models to best determine how this should be done.