Elena Garralda, Charles W. Abbott, Alma Calahorro, Oriol Mirallas, Jason Pugh, Ana Belén Moreno-Cárdenas, Kathleen C. Keough, Vladimir Galvao, G. Alonso, A. Mel Olano, María Vieito, A. Oberoi, Julia Lostes, Alberto Hernando‐Calvo, Irene Braña, G. Pretelli, Belén Ortega, Carlota Arenillas, Natalia Czerniak, Fábio C. P. Navarro, Bailiang Li, Rachel Marty Pyke, Neeraja Ravi, Christina Zatse, Francesco Grussu, M.Á. Heredero Sanz, Cristina Viaplana, Kira Raskina, José Jimenez, Roberta Fasani, Patricia Casbas-Hernández, Ezoglin Oflazoglu, Darren Hodgson, Jorge S. Reis‐Filho, Enriqueta Felip, Elena Élez, Eva Muñoz‐Couselo, Rodrigo Dienstmann, Josep Tabernero, Raquel Pérez-López, Paolo Nucíforo, Richard Chen, Sean Michael Boyle, Rodrigo A. Toledo
PURPOSE: Prior studies have suggested the biomarker potential of plasma-derived ctDNA in patients with cancer treated with immune checkpoint inhibitors. This study investigated the ability of ctDNA to predict progression-free and overall survival in a cohort of patients with advanced cancer treated with immunotherapies. EXPERIMENTAL DESIGN: In order to characterize the potential role of ultrasensitive ctDNA detection in the management of these patients, we have performed tumor whole-genome sequencing-informed, ultrasensitive ctDNA analysis-tracking approximately 1,800 tumor-specific mutations per patient-in a retrospective cohort (n = 136) and a prospective validation cohort (n = 66) across 24 cancer types treated with immune checkpoint inhibitors alone or in combination with bispecific antibodies or immune cell engagers. RESULTS: Analyzing 1,455 longitudinal samples, we found that ctDNA molecular response measured as early as 3 weeks after treatment initiation correlated with improved progression-free and overall survival, whereas ctDNA clearance at any time strongly correlated with radiologic response and prolonged survival. Additionally, ctDNA dynamics distinguished true progression from pseudoprogression and predicted outcomes in patients receiving continued immunotherapy beyond initial progression. CONCLUSIONS: This study highlights the broader applicability of ultrasensitive ctDNA as a biomarker across cancer types and immunotherapy modalities.