Dynamic changes of circulating tumor DNA predict clinical outcome in patients with advanced non-small-cell lung cancer treated with immune checkpoint inhibitors

Sabrina Weber, Paul van der Leest, Hylke C. Donker, Thomas Schlange, Wim Timens, Menno Tamminga, Samantha O. Hasenleithner, Ricarda Graf, Tina Moser, Benjamin Spiegl, Marie Laure Yaspo, Leon W.M.M. Terstappen, Grigory Sidorenkov, T. Jeroen Hiltermann, Michael R. Speicher, Ed Schuuring, Ellen Heitzer*, Harry J.M. Groen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

35 Citations (Scopus)
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PURPOSE Immune checkpoint inhibitors (ICIs) are increasingly being used in non-small-cell lung cancer (NSCLC), yet biomarkers predicting their benefit are lacking. We evaluated if on-treatment changes of circulating tumor DNA (ctDNA) from ICI start (t0) to after two cycles (t1) assessed with a commercial panel could identify patients with NSCLC who would benefit from ICI. PATIENTS AND METHODS The molecular ctDNA response was evaluated as a predictor of radiographic tumor response and long-term survival benefit of ICI. To maximize the yield of ctDNA detection, de novo mutation calling was performed. Furthermore, the impact of clonal hematopoiesis (CH)-related variants as a source of biologic noise was investigated. RESULTS After correction for CH-related variants, which were detected in 75 patients (44.9%), ctDNA was detected in 152 of 167 (91.0%) patients. We observed only a fair agreement of the molecular and radiographic response, which was even more impaired by the inclusion of CH-related variants. After exclusion of those, a ≥ 50% molecular response improved progression-free survival (10 v 2 months; hazard ratio [HR], 0.55; 95% CI, 0.39 to 0.77; P =.0011) and overall survival (18.4 v 5.9 months; HR, 0.44; 95% CI, 0.31 to 0.62; P,.0001) compared with patients not achieving this end point. After adjusting for clinical variables, ctDNA response and STK11/KEAP1 mutations (HR, 2.08; 95% CI, 1.4 to 3.0; P,.001) remained independent predictors for overall survival, irrespective of programmed death ligand-1 expression. A landmark survival analysis at 2 months (n = 129) provided similar results. CONCLUSION On-treatment changes of ctDNA in plasma reveal predictive information for long-term clinical benefit in ICI-treated patients with NSCLC. A broader NSCLC patient coverage through de novo mutation calling and the use of a variant call set excluding CH-related variants improved the classification of molecular responders, but had no significant impact on survival.

Original languageEnglish
Pages (from-to)1540-1553
Number of pages14
JournalJCO Precision Oncology
Publication statusPublished - 29 Sept 2021


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