Early ctDNA Dynamics Inform First-Line Therapy in Patients with Extensive-Stage Small Cell Lung Cancer

Abstract Purpose: Small cell lung cancer (SCLC) is an aggressive malignancy with a poor prognosis despite initial treatment responses. This study evaluates ctDNA for monitoring disease and assessing the efficacy of first-line therapy in patients with extensive-stage SCLC (1L ES-SCLC). Experimental Design: In the TAZMAN trial, 31 patients with 1L ES-SCLC received standard treatment with durvalumab and etoposide plus carboplatin or cisplatin. We analyzed 228 plasma samples from 27 of 31 patients using a liquid biopsy approach to detect somatic mutations and copy-number aberrations, while also accounting for clonal hematopoiesis mutations. Results: Baseline ctDNA analysis detected somatic alterations in 96.3% of patients, primarily in genes like TP53 and RB1. ctDNA dynamics during early treatment showed significant reductions in variant allele frequency, confirming early but short-lived chemosensitivity. Reduction of ctDNA below the limit of detection of the assay during induction predicted patients with longer treatment duration, surpassing imaging in distinguishing these patients. ctDNA changes often anticipated disease relapse before conventional imaging, suggesting ctDNA as a more sensitive treatment efficacy marker. Conclusions: The study shows that early ctDNA dynamics can provide valuable insights into treatment efficacy and potential molecular relapse in 1L ES-SCLC. ctDNA can enhance treatment monitoring and potentially guide the discontinuation of ineffective therapies. Larger studies with extended next-generation sequencing panels are needed to fully understand the potential of ctDNA in SCLC management from diagnosis to treatment and recurrence surveillance.