Abstract 110: Clinical utility of landmark ctDNA molecular response as an early indicator of immunotherapy outcomes in lung cancer.

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Abstract Background: Circulating tumor DNA (ctDNA) analyses are informative as an early indicator of immunotherapy response in advanced non-small cell lung cancer (NSCLC), however the clinical role of ctDNA molecular response requires further validation. Methods: As part of a prospective clinical protocol (NCT05995821), we performed ctDNA (n=328) and matched white blood cell DNA (WBC; n=109) targeted 521 fixed gene panel next-generation sequencing (Elio Plasma Complete) from 109 patients with advanced/metastatic NSCLC who received anti-PD-(L)1 as monotherapy or in combination with chemotherapy. Following variant cellular origin resolution, landmark molecular response (mR) was defined as undetectable ctDNA within 3-9 weeks of treatment initiation. For a subset of patients (n=34), whole-exome sequencing of baseline tumors was performed and used in benchmarking ctDNA detection and therapy response assessment. Results: Among 2,818 plasma variants, 23% were clonal haematopoiesis-related, which confounded the interpretation of driver gene associations with clinical outcomes and assessment of molecular responses. Implementing a tumor-naïve WBC DNA-informed approach increased the number of evaluable cases while maintaining the overall accuracy of landmark ctDNA molecular responses. Pre-treatment ctDNA burden but not blood tumor mutation burden, predicted survival. Overall, 77 patients were evaluable for landmark molecular response assessment; of these, 29 patients (38%) attained a mR. Landmark evaluation of molecular response enabled evaluation of all cases, was highly specific (92%), and achieved a higher sensitivity (66%) compared to clearance or ctDNA reduction from baseline (sensitivity 59%). In predicting landmark progression-free survival (PFS) at 6 months (durable clinical benefit, DCB), the tumor-agnostic WBC-informed approach strikes a balance between sensitivity (71.4%) and specificity (100%) compared to plasma-only (sensitivity=14.3%, specificity=100%) or tumor-informed (sensitivity=78.6%, specificity=71.4%) approaches. A significant enrichment in landmark ctDNA mR was noted among patients with DCB with immunotherapy (p=2.5e-05) and chemo-immunotherapy (p=0.02). Patients in the landmark mR group attained longer PFS (p=1.6e-06) and overall survival (p=2.5e-05) compared to those with molecular progression. The association between landmark molecular response and survival remained significant (PFS and OS, P < 0.001) after accounting for clinical covariates, line of therapy, and baseline ctDNA levels. Conclusions: Our findings indicate that landmark ctDNA molecular response at 3-9 weeks on treatment provides a real-time and accurate approach for monitoring immunotherapy clinical outcomes. Although not currently validated for regulatory use, these findings demonstrate the potential utility of ctDNA as an early endpoint in clinical trials. Citation Format: Jaime Wehr, Noushin Niknafs, Lavanya Sivapalan, Archana Balan, Gavin Pereira, Samira Hosseini-Nami, Iiasha Beadles, Aliyah Pabani, Kristen Marrone, Qing K. Li, Joseph Christopher Murray, Mark Sausen, Bryan Chesnick, Lorenzo Rinaldi, Christine L. Hann, Susan Combs Scott, Josephine Feliciano, Vincent K. Lam, Benjamin Levy, Patrick M. Forde, Julie R. Brahmer, Valsamo (Elsa) Anagnostou. Clinical utility of landmark ctDNA molecular response as an early indicator of immunotherapy outcomes in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 110.

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