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.