Among patients with oncogene-driven advanced NSCLC who were treated with TKIs, ctDNA clearance was associated with improved survival end points.
Among patients with oncogene-driven advanced non–small cell lung cancer (NSCLC) who were treated with tyrosine kinase inhibitors (TKIs), improved survival end points were associated with circulating tumor DNA (ctDNA) clearance within 10 weeks of treatment initiation, according to findings published in AACR Journals.
This means that patients undergoing TKI treatment for their lung cancer, which is driven by genetic mutations that promote cancer growth, and who had no detectable ctDNA in their blood within 10 weeks of starting treatment, had improved overall survival (OS) and progression-free survival (PFS) outcomes.
“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 end point,” Dr. Hillary S. Andrews, first study author, and co-authors wrote in their research.
Tyrosine kinase inhibitors (TKIs): a class of targeted cancer drugs used to treat tumors with those mutations.
Circulating tumor DNA (ctDNA): fragments of DNA from cancer cells that are released into the bloodstream.
ctDNA clearance: when these DNA fragments are no longer detectable in blood tests, suggesting a response to treatment.
Andrews is the director of Regulatory and Research Partnerships at Friends of Cancer Research, a non-profit organization located in Washington, D.C.
It is important to note, according to the authors' research, that clinical trial end points, such as OS and PFS, represent information about the safety and effectiveness of therapies under investigation. However, investigators are also looking for additional early reliable end points to best predict the likelihood of clinical benefit in patients, aiming to fulfill unmet medical needs in the cancer therapy space.
ctDNA has emerged as a novel biomarker which holds a lot of potential as an early end point to predict OS for patients and can be assessed through a blood draw. In turn, this can potentially allow for earlier measurement of molecular response that is less invasive for patients, and can be performed earlier and more frequently than other types of response assessments.
Investigators are continuing to investigate the connection between ctDNA — which are fragments of DNA from cancer cells that are released into the bloodstream, according to The University of Texas MD Anderson Cancer Center’s website — change and clinical outcomes like OS and PFS. Ongoing research has showed an association between ctDNA change and long-term clinical outcomes across various cancer types; however, these outcomes have not been comprehensively evaluated in aggregate patient-level datasets, according to the journal.
In order to better asses this association, investigators launched the Friends of Cancer Research ctDNA for Monitoring Treatment Response (ctMoniTR) project.
“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 PFS,” investigators wrote.
Each cohort was defined either as a treatment arm from a randomized controlled trial or as patients from a single-arm trial. Only TKI-treated patients were included; those receiving chemotherapy were excluded.
Inclusion criteria for patients required participants to have biomarker-positive advanced NSCLC treated with the corresponding TKI, as well as have information consisting of RECIST v1.1 assessments, survival data, a baseline ctDNA sample within 14 days and at least one on-treatment ctDNA sample. Additional criteria included defining the 10-week on-treatment window, relevant clinical covariates for multivariable analysis, outcomes of interest and minimum cohort sizes for training and test sets.
The primary ctDNA endpoint was the change in variant allele frequency from baseline to up to 10 weeks post-index. For patients with multiple samples within this window, the lowest variant allele frequency or a non-detectable result was used.
Data from eight clinical trials comprising 1,590 patients with biomarker-positive advanced NSCLC treated with TKIs were reviewed; however, once the 10-week post-index sample window was selected, 940 patients were analyzed.
Among patients with baseline ctDNA that became undetectable on treatment (“clearance”), OS was significantly improved compared with those who had persistent ctDNA. This association persisted in the subgroup with stable disease within 10 weeks of treatment initiation and, notably, similar patterns were observed for PFS.
The analysis confirmed that patients with never-detected ctDNA had the most favorable OS and PFS outcomes. Among those with detectable ctDNA at baseline, clearance was associated with significantly improved OS and PFS compared with persistent detection. Findings were consistent across training and test sets.
“The FDA emphasizes the importance of patient-level meta-analyses to support the validation of ctDNA as an early endpoint for regulatory decision-making,” the study investigators wrote in their research. “Findings herein provide a patient-level aggregate analysis demonstrating an association between ctDNA clearance and improved OS. However, additional work is necessary to establish ctDNA as a reliable clinical and regulatory tool. Future studies should include prospectively defined analyses to evaluate changes in ctDNA levels and associations with long-term clinical outcomes.”
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