Changes in Circulating Tumor DNA Reflect Clinical Benefit Across Multiple Studies of Patients With Non-Small-Cell Lung Cancer Treated With Immune Checkpoint Inhibitors

• Published in: JCO precision oncology Vol. 6; p. e2100372
• Main Authors: Vega, Diana Merino, Nishimura, Katherine K, Zariffa, Névine, Thompson, Jeffrey C, Hoering, Antje, Cilento, Vanessa, Rosenthal, Adam, Anagnostou, Valsamo, Baden, Jonathan, Beaver, Julia A, Chaudhuri, Aadel A, Chudova, Darya, Fine, Alexander D, Fiore, Joseph, Hodge, Rachel, Hodgson, Darren, Hunkapiller, Nathan, Klass, Daniel M, Kobie, Julie, Peña, Carol, Pennello, Gene, Peterman, Neil, Philip, Reena, Quinn, Katie J, Raben, David, Rosner, Gary L, Sausen, Mark, Tezcan, Ayse, Xia, Qi, Yi, Jing, Young, Amanda G, Stewart, Mark D, Carpenter, Erica L, Aggarwal, Charu, Allen, Jeff
• Format: Journal Article
• Language: English
• Published: United States 01-08-2022
• Subjects: Antineoplastic Agents, Immunological - therapeutic use; Biomarkers, Tumor - genetics; Carcinoma, Non-Small-Cell Lung - drug therapy; Circulating Tumor DNA - genetics; Clinical Trials as Topic; Humans; Immune Checkpoint Inhibitors - pharmacology; Lung Neoplasms - drug therapy; Prognosis
• ISSN: 2473-4284
• DOI: 10.1200/PO.21.00372

As immune checkpoint inhibitors (ICI) become increasingly used in frontline settings, identifying early indicators of response is needed. Recent studies suggest a role for circulating tumor DNA (ctDNA) in monitoring response to ICI, but uncertainty exists in the generalizability of these studies. Here, the role of ctDNA for monitoring response to ICI is assessed through a standardized approach by assessing clinical trial data from five independent studies.
Patient-level clinical and ctDNA data were pooled and harmonized from 200 patients across five independent clinical trials investigating the treatment of patients with non-small-cell lung cancer with programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1)-directed monotherapy or in combination with chemotherapy. CtDNA levels were measured using different ctDNA assays across the studies. Maximum variant allele frequencies were calculated using all somatic tumor-derived variants in each unique patient sample to correlate ctDNA changes with overall survival (OS) and progression-free survival (PFS).
We observed strong associations between reductions in ctDNA levels from on-treatment liquid biopsies with improved OS (OS; hazard ratio, 2.28; 95% CI, 1.62 to 3.20;
< .001) and PFS (PFS; hazard ratio 1.76; 95% CI, 1.31 to 2.36;
< .001). Changes in the maximum variant allele frequencies ctDNA values showed strong association across different outcomes.
In this pooled analysis of five independent clinical trials, consistent and robust associations between reductions in ctDNA and outcomes were found across multiple end points assessed in patients with non-small-cell lung cancer treated with an ICI. Additional tumor types, stages, and drug classes should be included in future analyses to further validate this. CtDNA may serve as an important tool in clinical development and an early indicator of treatment benefit.