Abstract CT175: ctDNA clearance as a prognostic biomarker in ES-SCLC: Insights from the LUMINANCE phase IIIb study

Abstract Immune checkpoint inhibitors combined with chemotherapy have become the first-line standard of care for extensive-stage small cell lung cancer (ES-SCLC), yet durable responses remain limited. In the LUMINANCE Phase IIIb study —a single-arm, multi-center international trial evaluating first-line durvalumab plus platinum-etoposide in ES-SCLC— we assessed circulating tumor DNA (ctDNA) clearance as a dynamic biomarker to predict survival outcomes and recurrence risk. We utilized a tumor-agnostic, methylation-based ctDNA assay (GRAIL) to assess ctDNA detection and clearance longitudinally in 148 patients. All patients had detectable ctDNA at baseline (C1D1), with gradual decrease in ctDNA detection suggesting treatment benefit (88.9% detection rate at C2 and 46% detection rate at start of maintenance period (Mtx start)). The highest clearance rates were observed at the start of Mtx (53.6%). ctDNA clearance from baseline was associated with significant overall survival (OS) benefit (C2 p = 0.0017; Mtx start p < 0.0001; Tumor Assesment 1 (TA1) p = 0.001), as well as progression-free survival (PFS) benefit (C2 p < 0.0001; Mtx start p < 0.0001; and TA1 p = 0.00026). Patients who achieved sustained ctDNA clearance from baseline through C2 and start of Mtx experienced the most favorable survival outcomes (median OS (mOS) not reached; mPFS 19.4 months). Those with late clearance (ctDNA-positive at C2 but cleared by Mtx start) had intermediate benefit (mOS 20.8 months; mPFS 7.9 months), while patients who never cleared ctDNA showed the poorest outcomes (mOS 11.0 months; mPFS 6.0 months). Overall, differences in ctDNA clearance timing were strongly associated with both OS (p = 0.00014) and PFS (p < 0.0001). When incorporating an additional timepoint coinciding with tumor assessment during Mtx (TA1), early and sustained ctDNA clearance during induction and Mtx phases continued to predict the most favorable survival (mOS and mPFS not reached). Patients who initially cleared ctDNA but became positive at TA1 (relapsed) demonstrated intermediate benefit (mOS 24.2 months; mPFS 8.5 months) compared to the never-cleared group (mOS 11.0 months; mPFS 6.0 months). Additionally, ctDNA dynamics aligned closely with longitudinal tumor assessments and clinical response. This study shows that ctDNA clearance, assessed using a tumor-agnostic methylation assay, may predict prognosis in patients with ES-SCLC receiving first-line durvalumab with platinum-etoposide. Patterns of clearance over time are strongly linked to OS and PFS, highlighting ctDNA clearance as a meaningful biomarker. Changes in ctDNA status during treatment may serve as a surrogate for response and survival outcomes. ctDNA may complement other biomarker strategies to guide precision therapy, disease monitoring, and understanding of resistance mechanisms in ES-SCLC. Citation Format: Gozde Kar, Mingchao Xie, Niels Reinmuth, Filippo de Marinis, Mustafa Özgüroğlu, Natasha B. Leighl, Ugochinyere Emeribe, Natalia Donner, Yashaswi Shrestha. ctDNA clearance as a prognostic biomarker in ES-SCLC: Insights from the LUMINANCE phase IIIb study [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(8_Suppl):Abstract nr CT175.