There have been many studies of ctDNA clearance (or relapse) with cancer immunotherapy. Here is a 940-patient meta-study in TKI treated NSCLC, part of the Friends of Cancer Research (FOCR) portfoilio.
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Andrews et al. publish a 940-patient meta-analysis of TKI-treated lung cancer (total of 8 studies). Clearance of ctDNA is correlated with overall survival, with a hazard ratio of 2.12 (p<.0001).
- See post at Linked In here.
- See longer summary at FOCR here.
- See Andrews et al. 2025 here - open access.
- See more about the FOCR ctDNA portfolio - here.
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See the abstract and "translational relevance," from the article. Below these sections directly from the authors, I also provide an AI summary and ten AI "key takeaways" for policy experts, clinicians, and invstors.
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ctDNA Clearance as an Early Indicator of Improved Clinical Outcomes in Advanced NSCLC Treated with TKI: Findings from an Aggregate Analysis of Eight Clinical Trials - Andrews et al, 2025, Clinical Cancer Research.
Authors:
Purpose:
Circulating tumor DNA (ctDNA) holds promise as an early endpoint to predict overall survival (OS). The creation and structured interrogation of aggregated datasets inform the hypothesis that ctDNA is reasonably likely to predict treatment benefit. Friends of Cancer Research convened a diverse working group to establish and implement an analysis plan assessing patient-level associations between changes in ctDNA levels with OS and progression-free survival (PFS).
Experimental Design:
The aggregate dataset included eight clinical trials representing 940 patients with biomarker-positive advanced non–small cell lung cancer treated with tyrosine kinase inhibitors. Detection of baseline and on-treatment ctDNA was assessed for associations with OS and PFS. Additionally, combinations of ctDNA detection and RECIST measurements up to 10 weeks on treatment were considered.
Results:
Patients with detected ctDNA at baseline that became nondetected on treatment (“clearance”) experienced improved OS compared with patients with persistently detected ctDNA (adjusted HR = 2.12, P < 0.001).
This pattern was also seen in the subset of patients with stable disease as measured by RECIST within 10 weeks of treatment initiation (adjusted HR = 4.15, P < 0.001). Results were similar for PFS.
Conclusions:
In patients with oncogene-driven advanced non–small cell lung cancer treated with tyrosine kinase inhibitors, ctDNA clearance within 10 weeks of treatment initiation was associated with improved OS and PFS. These patient-level results support the growing evidence that demonstrates a change in ctDNA levels during treatment is associated with clinical benefit. Future prospective trials should include predefined thresholds of molecular response to advance the utility of ctDNA as an early endpoint.
Authors:
Translational Relevance
ctDNA holds promise as an early endpoint in solid tumor oncology trials; however, patient- and trial-level meta-analyses demonstrating associations between changes in ctDNA and long-term outcomes, such as overall survival and progression-free survival, are necessary before ctDNA can be used in regulatory decision-making. A patient-level aggregate analysis of eight previously completed clinical trials of patients with advanced non–small cell lung cancer treated with tyrosine kinase inhibitors showed that clearance of ctDNA was associated with improved overall survival and progression-free survival compared with those who had persistently detected ctDNA. Additional work is necessary to establish ctDNA as an early endpoint, but this study supports the growing body of evidence that decreased ctDNA levels are associated with improved outcomes.
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AI CORNER [Direct AI Output - vet any details before quoting]
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Summary and Commentary
This multi-trial patient-level analysis—led by the Friends of Cancer Research ctMoniTR collaboration—marks a significant step in validating circulating tumor DNA (ctDNA) clearance as a promising early surrogate endpoint for overall survival (OS) and progression-free survival (PFS) in patients with advanced non–small cell lung cancer (aNSCLC) receiving tyrosine kinase inhibitors (TKIs).
Drawing on de-identified data from eight clinical trials involving 940 patients with oncogene-driven aNSCLC (e.g., EGFR, ALK, RET, MET alterations), the study demonstrated that ctDNA clearance within 10 weeks of treatment initiation was strongly associated with improved OS and PFS, even after adjusting for confounding clinical variables.
Key Novel Contributions
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Cross-Trial Patient-Level Evidence:
Unlike prior single-trial reports, this is among the first studies to aggregate and harmonize patient-level data from multiple pharma-sponsored trials across different assay platforms (NGS and ddPCR), enhancing the generalizability of the findings. -
Stratified Prognosis by ctDNA Status:
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Patients with persistently detected ctDNA had the worst outcomes (OS HR = 6.25 vs. ctDNA never detected).
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Patients with ctDNA clearance (D to ND) showed significantly better survival than those with persistent ctDNA (OS HR = 2.12, P < 0.001).
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Patients with undetectable ctDNA at both timepoints had the best prognosis—a reminder that pretreatment ctDNA status is also prognostic.
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ctDNA Surpasses Early RECIST:
While early RECIST-based radiographic response was not strongly associated with long-term outcomes, ctDNA clearance added predictive value even among patients with stable disease (SD) by imaging. Notably, among SD patients, persistent ctDNA detection conferred a 4.15-fold higher risk of death compared to those with ctDNA clearance. -
Implications for Trial Design and Drug Development:
The study supports incorporating early molecular response metrics—specifically ctDNA clearance—as supplementary endpoints in clinical trials. This may be especially impactful in settings with ambiguous imaging findings (e.g., SD or non-measurable disease) and for informing early go/no-go decisions.
Limitations and Future Direction
The analysis is retrospective and exploratory, and while it adjusts for multiple variables, it is not designed to establish causality. Assay heterogeneity and variable sampling schedules across trials add complexity, underscoring the need for:
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Standardized ctDNA assays and response thresholds
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Prospective validation of ctDNA-based surrogate endpoints
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Regulatory consensus on how ctDNA can support accelerated approval frameworks
Conclusion
This rigorous, multi-trial patient-level analysis adds momentum to the use of ctDNA clearance as a molecular response biomarker in NSCLC. By showing a robust association with survival outcomes, independent of radiographic response, the study contributes critical evidence toward positioning ctDNA as a regulatory-grade early endpoint—potentially transforming the pace and precision of oncology drug development.
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SIDEBAR - TEN POINTS
Here is a sidebar-style list of ten key takeaways from the study, categorized by audience—policy/coverage, clinical oncology, investors, and general science insights.
📌 Sidebar: 10 Key Takeaways from the FOCR ctDNA Clearance Study
🏛️ For Policy & Coverage Stakeholders
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Regulatory Readiness: This large, multi-trial analysis supports ctDNA clearance as a reasonably likely surrogate for survival outcomes—aligning with FDA guidance for accelerated approval in solid tumors.
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Coverage Implications: If ctDNA clearance becomes a validated early endpoint, payors may face increasing pressure to cover serial liquid biopsy testing—not just for mutation detection, but for on-treatment response monitoring.
🩺 For Clinical Oncologists
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ctDNA vs. Imaging: ctDNA clearance at 10 weeks outperformed early RECIST response in predicting OS and PFS, especially in patients with stable disease—suggesting it could refine treatment decisions.
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Prognostic Stratification: Even among partial responders or SD patients by imaging, ctDNA status stratified prognosis, offering an early molecular readout of benefit vs. futility.
💼 For Investors in Oncology Diagnostics & Therapeutics
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Market Opportunity: The study creates a compelling clinical use case for repeat liquid biopsy platforms, particularly in TKI-treated NSCLC—an early and growing segment of precision oncology.
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Differentiation Signal: Diagnostics firms with sensitive and reproducible ctDNA quantification capabilities (NGS or ddPCR) may benefit from emerging demand for treatment-response monitoring tools.
🔬 General Scientific Highlights
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Broad Applicability: The analysis includes patients treated with EGFR-, ALK-, MET-, and RET-targeted TKIs, suggesting platform-agnostic utility across oncogene-driven NSCLC.
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ctDNA Clearance = Survival Signal: Among patients with detectable ctDNA at baseline, clearance within 10 weeks led to a 2-fold improvement in OS vs. persistent detection (HR 2.12, P < 0.001).
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Independence from RECIST: ctDNA clearance and RECIST response had low redundancy—the former added predictive value even when imaging was ambiguous.
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Step Toward Standardization: This study pushes the field toward harmonizing ctDNA assays and response definitions, a necessary precursor to regulatory validation and routine clinical use.
