TY - JOUR
T1 - Dynamic changes of circulating tumor DNA predict clinical outcome in patients with advanced non-small-cell lung cancer treated with immune checkpoint inhibitors
AU - Weber, Sabrina
AU - van der Leest, Paul
AU - Donker, Hylke C.
AU - Schlange, Thomas
AU - Timens, Wim
AU - Tamminga, Menno
AU - Hasenleithner, Samantha O.
AU - Graf, Ricarda
AU - Moser, Tina
AU - Spiegl, Benjamin
AU - Yaspo, Marie Laure
AU - Terstappen, Leon W.M.M.
AU - Sidorenkov, Grigory
AU - Hiltermann, T. Jeroen
AU - Speicher, Michael R.
AU - Schuuring, Ed
AU - Heitzer, Ellen
AU - Groen, Harry J.M.
N1 - Funding Information:
Supported by CANCER-ID, a European consortium supported by Europe’s Innovative Medicines Initiative (IMI) under grant agreement no. 115749; the Austrian Federal Ministry for Digital and Economic Affairs (Christian Doppler Research Fund for Liquid Biopsies for Early Detection of Cancer); and Roche.
Publisher Copyright:
© 2021 by American Society of Clinical Oncology
PY - 2021/9/29
Y1 - 2021/9/29
N2 - 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.
AB - 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.
KW - 2022 OA procedure
UR - http://www.scopus.com/inward/record.url?scp=85119040223&partnerID=8YFLogxK
U2 - 10.1200/PO.21.00182
DO - 10.1200/PO.21.00182
M3 - Article
AN - SCOPUS:85119040223
SN - 2473-4284
VL - 5
SP - 1540
EP - 1553
JO - JCO Precision Oncology
JF - JCO Precision Oncology
ER -
