TY - JOUR
T1 - Early Changes in Circulating Cell-Free KRAS G12C Predict Response to Adagrasib in KRAS Mutant Non-Small Cell Lung Cancer Patients
AU - Paweletz, Cloud P.
AU - Heavey, Grace A.
AU - Kuang, Yanan
AU - Durlacher, Emily
AU - Kheoh, Thian
AU - Chao, Richard C.
AU - Spira, Alexander I.
AU - Leventakos, Konstantinos
AU - Johnson, Melissa L.
AU - Ou, Sai Hong Ignatius
AU - Riely, Gregory J.
AU - Anderes, Kenna
AU - Yang, Wenjing
AU - Christensen, James G.
AU - Jänne, Pasi A.
N1 - Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2023/8/15
Y1 - 2023/8/15
N2 - Purpose: Non-invasive monitoring of circulating tumor DNA (ctDNA) has the potential to be a readily available measure for early prediction of clinical response. Here, we report on early ctDNA changes of KRAS G12C in a Phase 2 trial of adagrasib in patients with advanced, KRAS G12C-mutant lung cancer. Experimental Design: We performed serial droplet digital PCR (ddPCR) and plasma NGS on 60 KRAS G12C-mutant patients with lung cancer that participated in cohort A of the KRYSTAL-1 clinical trial. We analyzed the change in ctDNA at 2 specific intervals: Between cycles 1 and 2 and at cycle 4. Changes in ctDNA were compared with clinical and radiographic response. Results: We found that, in general, a maximal response in KRAS G12C ctDNA levels could be observed during the initial approximately 3-week treatment period, well before the first scan at approximately 6 weeks. 35 patients (89.7%) exhibited a decrease in KRAS G12C cfDNA >90% and 33 patients (84.6%) achieved complete clearance by cycle 2. Patients with complete ctDNA clearance at cycle 2 showed an improved objective response rate (ORR) compared with patients with incomplete ctDNA clearance (60.6% vs. 33.3%). Furthermore, complete ctDNA clearance at cycle 4 was associated with an improved overall survival (14.7 vs. 5.4 months) and progression-free survival (HR, 0.3). Conclusions: These results support using early plasma response of KRAS G12C assessed at approximately 3 weeks to anticipate the likelihood of a favorable objective clinical response.
AB - Purpose: Non-invasive monitoring of circulating tumor DNA (ctDNA) has the potential to be a readily available measure for early prediction of clinical response. Here, we report on early ctDNA changes of KRAS G12C in a Phase 2 trial of adagrasib in patients with advanced, KRAS G12C-mutant lung cancer. Experimental Design: We performed serial droplet digital PCR (ddPCR) and plasma NGS on 60 KRAS G12C-mutant patients with lung cancer that participated in cohort A of the KRYSTAL-1 clinical trial. We analyzed the change in ctDNA at 2 specific intervals: Between cycles 1 and 2 and at cycle 4. Changes in ctDNA were compared with clinical and radiographic response. Results: We found that, in general, a maximal response in KRAS G12C ctDNA levels could be observed during the initial approximately 3-week treatment period, well before the first scan at approximately 6 weeks. 35 patients (89.7%) exhibited a decrease in KRAS G12C cfDNA >90% and 33 patients (84.6%) achieved complete clearance by cycle 2. Patients with complete ctDNA clearance at cycle 2 showed an improved objective response rate (ORR) compared with patients with incomplete ctDNA clearance (60.6% vs. 33.3%). Furthermore, complete ctDNA clearance at cycle 4 was associated with an improved overall survival (14.7 vs. 5.4 months) and progression-free survival (HR, 0.3). Conclusions: These results support using early plasma response of KRAS G12C assessed at approximately 3 weeks to anticipate the likelihood of a favorable objective clinical response.
UR - http://www.scopus.com/inward/record.url?scp=85168222922&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85168222922&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-23-0795
DO - 10.1158/1078-0432.CCR-23-0795
M3 - Article
C2 - 37279096
AN - SCOPUS:85168222922
SN - 1078-0432
VL - 29
SP - 3074
EP - 3080
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -