Document Type
Journal Article
Publication Title
ESMO Open
Volume
8
Issue
6
PubMed ID
37995426
Publisher
Elsevier
School
School of Medical and Health Sciences / Centre for Precision Health / School of Science
RAS ID
62221
Funders
Oncomine Clinical Research Grant from Thermo Fisher Scientific / Fiona Stanley Hospital / Lung Foundation Australia-Ellen Yates Memorial Grant in Aid for Lung Cancer Research / International Lung Cancer Foundation / Cancer Council of Western Australia
Abstract
Background: The circulating T-cell receptor (TCR) repertoire is a dynamic representation of overall immune responses in an individual. Materials and methods: We prospectively collected baseline blood from patients treated with first-line pembrolizumab monotherapy or in combination with chemotherapy. TCR repertoire metrics were correlated with clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS) and immune-related adverse events (irAEs). We built a logistic regression classifier by fitting all four TCR- repertoire metrics to the immune checkpoint inhibitor (ICI) CBR data. In the subsequent receiver operating characteristic (ROC) analysis of the resulting logistic regression model probabilities, the best cut-off value was selected to maximise sensitivity to predict CBR to ICI. Results: We observed an association between reduced number of unique clones and CBR among patients treated with pembrolizumab monotherapy (cohort 1) [risk ratio = 2.86, 95% confidence interval (CI) 1.04-8.73, P = 0.039]. For patients treated with pembrolizumab plus chemotherapy (cohort 2), increased number of unique clones [hazard ratio (HR) = 2.96, 95% CI 1.28-6.88, P = 0.012] and Shannon diversity (HR = 2.73, 95% CI 1.08-6.87, P = 0.033), and reduced evenness (HR = 0.43, 95% CI 0.21-0.90, P = 0.025) and convergence (HR = 0.41, 95% CI 0.19-0.90, P = 0.027) were associated with improved PFS, while only an increased number of unique clones (HR = 4.62, 95% CI 1.52-14.02, P = 0.007) were associated with improved OS. Logistic regression models combining the TCR repertoire metrics improved the prediction of CBR (cohorts 1 and 2) and were strongly associated with PFS (cohort 1, HR = 0.38, 95% CI 0.19-0.78, P = 0.009) and OS (cohort 2, HR = 0.20, 95% CI 0.05-0.76, P < 0.0001). Reduced TCR conversion was associated with increased frequency of irAEs needing systemic steroid treatment. Conclusion: Combined pre-treatment circulating TCR metrics might serve as a predictive biomarker for clinical outcomes among patients with advanced non-small-cell lung cancer treated with pembrolizumab alone or in combination with chemotherapy.
DOI
10.1016/j.esmoop.2023.102066
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Comments
Abed, A., Beasley, A. B., Reid, A. L., Law, N., Calapre, L., Millward, M., . . . Gray, E. S. (2023). Circulating pre-treatment t-cell receptor repertoire as a predictive biomarker in advanced or metastatic non-small-cell lung cancer patients treated with pembrolizumab alone or in combination with chemotherapy. ESMO Open, 8(6), article 102066. https://doi.org/10.1016/j.esmoop.2023.102066