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Background <p>Combination regimens of immunotherapy and chemotherapy have become the standard treatment for HER2-negative advanced gastric cancer (AGC). Here, we evaluate the therapeutic efficacy of first-line treatment regimens across different PD-L1 expression, circulating tumor DNA (ctDNA) and T-cell receptor (TCR).</p> Methods <p>This study retrospectively recruited 245 patients with AGC. 55 blood samples from 20 patients were prospectively collected before immunotherapy, after two cycles of treatment, and during disease progression.</p> Results <p>In the CPS &lt; 5 cohort, chemotherapy + PD-1 inhibitor + anti-angiogenic treatment showed a higher progression-free survival (PFS). In the CPS ≥ 5 cohort, chemotherapy + PD-1 inhibitor improved median PFS (<i>p</i> = 0.04) and ORR (<i>p</i> = 0.014) over chemotherapy alone. ctDNA analysis revealed that at various time points, patients in the short-PFS group exhibited significantly elevated maxVAF and ctDNA levels. Post-treatment, ctDNA levels decreased in 50% of patients in the long-PFS group, whereas only 25% in the short-PFS group. The short-PFS group had a lower TCR clone count, while no significantly different in the diversity of the TCR repertoire compared with long-PFS groups.</p> Conclusions <p>These findings suggest the different efficacy of first-line treatment regimens across varying levels of PD-L1 expression, and the molecular characteristics of patients with long-term benefits from immunotherapy.</p>

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Exploration of the benefits and resistance mechanisms of immunotherapy based on PD-L1 expression, circulating tumor DNA and T-cell receptor profiles in advanced gastric cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月19日

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  • Miaomiao Gou,
  • Niansong Qian,
  • Yong Zhang,
  • Bingfa Yan,
  • Zhikuan Wang,
  • Guanghai Dai

摘要

Background

Combination regimens of immunotherapy and chemotherapy have become the standard treatment for HER2-negative advanced gastric cancer (AGC). Here, we evaluate the therapeutic efficacy of first-line treatment regimens across different PD-L1 expression, circulating tumor DNA (ctDNA) and T-cell receptor (TCR).

Methods

This study retrospectively recruited 245 patients with AGC. 55 blood samples from 20 patients were prospectively collected before immunotherapy, after two cycles of treatment, and during disease progression.

Results

In the CPS < 5 cohort, chemotherapy + PD-1 inhibitor + anti-angiogenic treatment showed a higher progression-free survival (PFS). In the CPS ≥ 5 cohort, chemotherapy + PD-1 inhibitor improved median PFS (p = 0.04) and ORR (p = 0.014) over chemotherapy alone. ctDNA analysis revealed that at various time points, patients in the short-PFS group exhibited significantly elevated maxVAF and ctDNA levels. Post-treatment, ctDNA levels decreased in 50% of patients in the long-PFS group, whereas only 25% in the short-PFS group. The short-PFS group had a lower TCR clone count, while no significantly different in the diversity of the TCR repertoire compared with long-PFS groups.

Conclusions

These findings suggest the different efficacy of first-line treatment regimens across varying levels of PD-L1 expression, and the molecular characteristics of patients with long-term benefits from immunotherapy.