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

Abstract

PURPOSE 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. PATIENTS AND METHODS 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). RESULTS 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; P < .001) and PFS (PFS; hazard ratio 1.76; 95% CI, 1.31 to 2.36; P < .001). Changes in the maximum variant allele frequencies ctDNA values showed strong association across different outcomes. CONCLUSION 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.

Regulatory implications of ctDNA in immuno-oncology for solid tumors

“…4 The Friends of Cancer Research initiative, 'ctDNA for Monitoring Treatment Response (ctMoniTR) project' is an example of a pooled analysis demonstrating patientlevel correlation between changes in ctDNA and longterm clinical outcomes, and is discussed further in the next section of this review. 53 However, to date, there have been no trial-level meta-analyses evaluating the association between ctDNA and long-term survival outcomes.…”

“…59 In addition, Friends of Cancer Research initiated a public-private partnership entitled 'ctDNA for Monitoring Treatment Response (ctMoniTR) project'. 53 This project aligned methodologies to analyze ctDNA from smaller lung cancer immune checkpoint inhibitor clinical trials to assess whether decreases in the variant allele frequencies of ctDNA would predict longer term outcomes in the larger pooled dataset. Disparate clinical trials with different ctDNA time points, collection sampling schedules, and methods were successfully pooled, and associations were still observed between reduction in ctDNA and OS, PFS, and ORR.…”

Liquid biopsy approaches to capture tumor evolution and clinical outcomes during cancer immunotherapy

“…Prospective testing in the clinical trial setting remains key to fully demonstrate the clinical utility of liquid biopsies for cancer immunotherapy and identify the clinical settings where ctDNA molecular responses are the most informative. To this end, we would like to highlight several national and international initiatives led by the Friends of Cancer Research, 106 BloodPAC, 138 the Foundation for the National Institutes of Health, 139 European Society for Medical Oncology (ESMO), 140 American Society of Clinical Oncology (ASCO), 141 the International Association of Liquid Biopsy, 142 International Association for the Study of Lung Cancer (IASLC), 143 the International Quality Network for Pathology, the European Cancer Patient Coalition and the European federation of Pharmaceutical Industries and Associations 144 that aim to tackle clinical, analytical, and technical challenges and through standardization and harmonization efforts and consensus guidelines enable the integration of liquid biopsies in precision immuno-oncology. We strongly believe that the future practice of precision immuno-oncology includes liquid biopsy approaches to enable making the earliest best decisions with precision for the increasing number of individuals receiving cancer immunotherapy.…”

The potential clinical utility of cell-free DNA for gastric cancer patients treated with nivolumab monotherapy

“…We found a signi cant PFS improvement in patients with decreased ΔbTMB but not in patients with ΔmaxVAF, suggesting a potential utility of ΔbTMB as an on-treatment biomarker for PFS. Dynamics of bTMB, as well as maxVAF, have been found to be correlated with treatment response and prolonged survival [38][39][40][41][42][43][44] , given that both bTMB and maxVAF innately re ect tumor burden 43,45 ; however, there are few studies comparing the utility of maxVAF and bTMB dynamics for predicting the treatment e cacy of ICI 46 . A recent study demonstrated correlation with outcomes for cancer patients treated with ICI, including those with gastrointestinal cancers, was observed for maxVAF changes, but not for bTMB changes 46 .…”