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Evaluating Circulating Tumor DNA Clearance as an Early Intermediate End Point Predicting Clinical Benefit in Metastatic Nonsquamous NSCLC After First-Line Chemoimmunotherapy

Year: 2025

Type: article

Abstract: Introduction: In the first-line (1L) NSCLC setting, overall survival (OS) as a trial end point is increasingly challenging due to longer survival and confounding from novel later-line therapies. This study aims to evaluate whether circulating tumor DNA (ctDNA) clearance (alone or with radiographic response) is a reliable early surrogate end point for progression-free survival (PFS) and OS in 1L NSCLC studies. Methods: Data from a phase III trial (IMpower150) of patients with untreated metastatic nonsquamous NSCLC were used. ctDNA clearance, unconfirmed radiographic response, and confirmed radiographic response at approximately 6 months after treatment were evaluated as surrogates for PFS and OS. The meta-analytic approaches were used. The data were randomly split into four cohorts, treating each as an independent "trial" to simulate a multi-trial meta-analysis. This process was repeated 50 times for statistical robustness. Results: = 0.34-0.41). Conclusion: ctDNA decline is associated with improved survival outcomes in a clear dose-response manner. ctDNA clearance and radiologic response provide complementary prognostic information, and combining these end points (ctDNA_CL + Resp) can further improve prediction of PFS and OS. This combination also enhanced the correlation between treatment effects on the early end points and PFS/OS at the trial level. However, their overall ability to predict treatment effects at the trial level remained modest for both PFS and OS, likely due to the limited data from a single study. Further validation in larger, multi-trial data sets is needed to establish ctDNA clearance as a reliable early surrogate end point in first-line NSCLC.

Source: JTO Clinical and Research Reports

DOI: 10.1016/j.jtocrr.2025.100907

Authors: Min Yuan, Haolun Ding, Weiwei Zhuang, Yaning Yang, Xu Steven Xu

Institutions: Anhui Medical University, University of Science and Technology of China, Genmab (United States)

Language: English

Topic: Lung Cancer Treatments and Mutations

Subfield: Pulmonary and Respiratory Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,000