Research Spotlight: A longitudinal circulating tumor DNA-based model associated with survival in metastatic non-small-cell lung cancer

Kansara, M., et al. Molecular Oncology. 2022, DOI 10.1002/1878-0261.13349


There is an urgent need to identify biomarkers of early response that can accurately predict the benefit of immune checkpoint inhibitors (ICI) for cancer patients. Despite the clinical potential of immunotherapy treatment to improve patient survival, to date, only a minority of patients experience long-term benefit from treatment.

Robust, predictive biomarkers are needed to monitor patients’ response to immunotherapy [1] utility across cancer types [2]. High tissue PD-L1 expression, microsatellite instability-high (MSI-H), or tumor mutational burden-high (TMB-H) are biomarkers that, when present before treatment in certain tumor types, increase the likelihood of immunotherapy clinical benefit [3-6]. However, they are static assessments and not reflective of changes that may occur while patients undergo treatment.

Circulating tumor DNA (ctDNA) has emerged as a potential biomarker that can be measured longitudinally to meet this clinical unmet need and may detect changes in tumor burden in real time.

Study Details:

Patients receiving two ICIs, durvalumab and tremelimumab, were evaluated at baseline using a clinical trial assay version of FoundationOne®CDx, a tissue-based comprehensive genomic profiling test, to identifyvariants for the design of FoundationOne®Tracker, a tissue-informed personalized ctDNA-monitoring assay for detecting molecular responses for patients across a variety of tumor types. [7, 8]

ctDNA was assessed at baseline and at 4 and/or 8 weeks into treatment. Correlations between ctDNA changes to treatment response and overall survival (OS) were made to assess potential clinical benefit. As early as 4 weeks after treatment, decline in ctDNA from baseline predicted improved OS, a finding which was also seen through Week 8. ctDNA decreases at week 4 or through week 8 were the only significant biomarkers for survival benefit in this heterogeneous cohort of cancer histologies, including other known immunotherapy biomarkers like MSI-H, TMB, and tumor and immune PD-L1 immunohistochemistry. ctDNA changes on treatment were also able to support and refine objective measures of tumor response to therapy. In two patients with complete response, ctDNA clearance, or complete removal of ctDNA, preceded any response by scan, exhibiting a median lead time of 11.5 months, a potential advantage in the use of ctDNA for assessment.

Why this matters:

ctDNA response monitoring is emerging as a dynamic, personalized biomarker method that may predict survival outcomes in patients with diverse solid tumor histologies and add important data to help with evaluation of patient response to treatment. In this study, a reduction in ctDNA as early as 4 weeks into immunotherapy treatment was a predictor for long-term survival benefit. In addition, ctDNA dynamics were able to refine and, in some cases, precede radiographic response assessments, especially in cases of mixed or unevaluable radiologic response to treatment. Compared with the use of standard immune biomarkers like PD-L1, TMB-H, and MSI-H, which are assessed before treatment, longitudinal assessment of ctDNA dynamics provides an accessible view into tumor response to therapy.

With additional research and prospective evaluation, this approach could be extended to enable clinicians to adapt therapy based on ctDNA dynamics. For example, in the context of a rise in ctDNA on therapy, therapy intensification (e.g. dose, frequency) or a change in line of therapy could be considered, whereas a decrease or clearance in ctDNA may enable a lessening or stopping of treatment. In both cases, this could allow patients to avoid the medical and financial toxicities associated with ineffective or unnecessary treatment.

Molecular response, as measured by ctDNA change from baseline, is complementary to imaging-based response assessment and represents an important emerging tool for assessing drug effect in the development of new therapeutics and predictive biomarkers as well as for use in a standard-of-care setting.

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This study was partially funded by Foundation Medicine.


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November 29, 2022