# 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)

## TL;DR

This study explores how baseline and changing levels of cfDNA, tumor fraction, and mutations can predict outcomes in lung cancer patients treated with a new therapy.

## Contribution

The study identifies baseline and dynamic biomarker changes as potential predictors of survival in small cell lung cancer patients treated with atezolizumab and chemotherapy.

## Key findings

- Higher baseline cfDNA and variant allele frequency (VAF) are associated with increased risk of death in SCLC patients.
- Dynamic increases in VAF over time are linked to worse overall and progression-free survival outcomes.
- Baseline tumor fraction (TF) and cfDNA levels are predictive of disease progression in patients receiving first-line treatment.

## Abstract

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.

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).

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.

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.

The online version contains supplementary material available at 10.1186/s13046-025-03434-3.