Baseline levels and dynamic changes of cfDNA, tumor fraction and mutations to anticipate the clinical course of small cell lung cancer (SCLC) patients treated with first-line atezolizumab and chemotherapy: an hypothesis generating study (CATS/ML43257)

Background: Atezolizumab (A) plus carboplatin-etoposide (CE) represents the new first-line treatment in extensive stage (ES)-Small Cell Lung Cancer (SCLC) patients. This study aims at identifying the association of baseline and dynamic changes of cfDNA, Tumor Fraction (TF) and variant allele frequency (VAF) of tumor-related mutations with median (m) overall (OS) and progression free survival (PFS) in SCLC patients treated with ACE. Materials and methods: This is a single-center prospective exploratory study including treatment-naive ES-SCLC patients eligible to first-line ACE. Liquid biopsies were longitudinally collected at baseline (T0), after cycle 1 (T1) and 2 (T2), at disease progression (T3). cfDNA Next Generation Sequencing (NGS) analysis was performed; genomic profiles and TF were inferred from shallow WGS (sWGS). Results: Thirty-two patients were included; mPFS and mOS were 5.19 and 7.96 months, respectively. Higher T0 cfDNA (HR 1.44, 95% CI 1.17-1.77, p = 0.0006) and VAF (HR 2.6, 95% CI 1.36-4.93, p = 0.0039) were associated with risk of death; higher T0 cfDNA (HR 1.29, 95% CI 1.08-1.54, p = 0.0049), TF (HR 1.97, 95% CI 1.02-3.82, p = 0.044) and VAF (HR 2.32, 95% CI 1.22-4.42, p = 0.01) were predictors of risk of PD. Among the dynamic changes in the biomarkers under investigation, the association of 10-unit increase of VAF T0-T1 and T0-T2 with OS (HR 1.38, 95% CI 1.01-1.88, p = 0.043; HR 1.56, 95% CI 1.21-2.16, p = 0.008) and PFS (HR 1.69, 95% CI 1.18-2.43, p = 0.004; HR 1.81, 95% CI 1.22-2.70, p = 0.003) was estimated. Conclusion: T0 and dynamic changes of cfDNA, TF and VAF may help physicians to stratify ES-SCLC patients receiving first-line ACE and to anticipate the clinical course of the disease.