Nabet and Esfahani et al. established a method to accurately predict early in treatment which patients with lung cancer (NSCLC) benefit from PD-1 checkpoint blockade. The researchers developed a multiparameter response classifier (DIREct-ON), including the pre-treatment markers, normalized circulating tumor (ct) DNA-based blood TMB, and circulating CD8+ T cells, as well as early on-treatment ctDNA dynamics. Although each marker had predictive value individually, there was little correlation between them, and combining all parameters resulted in the prediction of durable clinical benefit with 94% sensitivity and 89% specificity.
Contributed by Maartje Wouters
ABSTRACT: Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we demonstrate that pre-treatment circulating tumor DNA (ctDNA) and peripheral CD8 T cell levels are independently associated with DCB. We further show that ctDNA dynamics after a single infusion can aid in identification of patients who will achieve DCB. Integrating these determinants, we developed and validated an entirely noninvasive multiparameter assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA-On-treatment) that robustly predicts which patients will achieve DCB with higher accuracy than any individual feature. Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICIs.
Author Info: (1) Department of Radiation Oncology, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA. (2) Division of Oncology, Departmen
Author Info: (1) Department of Radiation Oncology, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA. (2) Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, CA, USA. (3) Department of Radiation Oncology, Stanford University, Stanford, CA, USA; Program in Cancer Biology, Stanford University, Stanford, CA, USA. (4) Department of Radiation Oncology, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA. (5) Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Stanford Cancer Institute, Stanford University, Stanford, CA, USA. (7) Department of Radiation Oncology, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. (8) Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, CA, USA. (9) Department of Pathology, Stanford University, Stanford, CA, USA. (10) Department of Radiation Oncology, Stanford University, Stanford, CA, USA. (11) Department of Radiation Oncology, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea. (12) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell School of Medicine, New York, NY, USA; Parker Institute for Cancer Immunotherapy at MSK, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (14) Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Department of Medicine, VA Palo Alto Health Care System, Palo Alto, CA, USA. (15) Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (16) Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA; Department of Biomedical Data Science, Stanford University, Stanford, CA, USA. (17) Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell School of Medicine, New York, NY, USA; Parker Institute for Cancer Immunotherapy at MSK, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: hellmanm@mskcc.org. (18) Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA. Electronic address: arasha@stanford.edu. (19) Department of Radiation Oncology, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA. Electronic address: diehn@stanford.edu.
