Abstract LB120: Driver-specific MRD strategy associated with pathological response and predicted recurrence in stage III driver-mutant NSCLC receiving neoadjuvant treatment

Abstract Background: Postoperative driver gene-specific circulating tumor DNA (ctDNA) monitoring stratifies recurrence risk in resectable stage III driver-mutant NSCLC (NCT06443684). Whether driver-specific ctDNA MRD can evaluate neoadjuvant response and predict recurrence in stage III driver-mutant NSCLC remains to be defined. Methods: From 2022 to 2025, 203 resectable stage III NSCLC patients with tissue-confirmed driver mutations were prospectively enrolled at 14 centers in China (NCT06443684). Peripheral blood was collected before neoadjuvant therapy, preoperatively, 3 days and 1 month after surgery, and every 3 months until investigator-confirmed recurrence. ctDNA was analyzed using a 10-gene driver panel (LC10). This analysis focused on peri-neoadjuvant ctDNA dynamics and clinical outcomes among 82 patients who received neoadjuvant therapy followed by surgery. Results: Among the 82 neoadjuvant-treated patients, regimens included chemo-immunotherapy (57. 3%), TKI (3rd-EGFR TKI/2nd or 3rd-ALK TKI, 39. 0%), and chemotherapy alone (3. 7%). Post-neoadjuvant ctDNA positivity was associated with a significantly lower MPR rate versus ctDNA negativity (0% vs 42. 3%, p=0. 004), whereas baseline ctDNA status was not associated with MPR (16. 7% vs 21. 2%). Post-neoadjuvant ctDNA molecular residual level (hGE/mL) positively correlated with residual viable tumor cells (R=0. 332, p=0. 009). Post-neoadjuvant ctDNA-positive patients had significantly shorter event-free survival (median EFS 11. 4 vs 23. 8 months; HR=8. 82; p=0. 009). For non-MPR patients, post-neoadjuvant negative ctDNA status also indicated favorable prognosis (median EFS 23. 8 vs 4. 7 months; HR=5. 80; p=0. 054). Compared with other regimens, neoadjuvant TKI was associated with a lower post-treatment ctDNA residual rate (0% vs 15. 3%; p=0. 05). Patients with persistent ctDNA positivity (baseline→post-neoadjuvant) had the shortest EFS (median 4. 7 months), followed by negative→positive (23. 8 months), while positive to negative and persistent negative ctDNA indicated disease free status (log-rank p0. 001). Conclusions: A driver-specific ctDNA MRD strategy provides a practical tool for neoadjuvant efficacy assessment and postoperative recurrence risk stratification for stage III driver-mutant NSCLC patients. Citation Format: Jian Hu, Xiao Teng, Ziming Li, Yu Qi, Feng Li, Qixun Chen, Changbin Zhu, Xing Li, Shun Lu. Driver-specific MRD strategy associated with pathological response and predicted recurrence in stage III driver-mutant NSCLC receiving neoadjuvant treatment abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB120.