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Background <p>Dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (<i>VEGF</i>) pathways may improve outcomes in metastatic <i>EGFR</i>-mutant NSCLC, but VEGF inhibitors are not universally effective. We evaluated the impact of VEGFA and VEGFR2 expressions on EGFR-TKI outcomes.</p> Methods <p><i>EGFR</i>-mutant NSCLC patients from the National Cancer Center Hospital, were retrospectively analysed. The early-stage cohort comprised stage I–IIIA patients (1997–2019). The advanced-stage cohort included metastatic patients (2018–2022). VEGFA/VEGFR2 expressions were dichotomised by median transcripts per million.</p> Results <p>Among 447 early-stage patients (median age 66), high VEGFA was associated with smoking, <i>TP53</i> co-mutation, higher Brinkman Index, and higher tumour mutation burden (all <i>p</i> &lt; 0.01). High VEGFA predicted shorter relapse-free survival (HR 2.10, 95% CI 1.63–2.71, <i>p</i> &lt; 0.01) and overall survival (HR 2.07, 95% CI 1.46–2.95, <i>p</i> &lt; 0.01). VEGFR2 expression showed no prognostic impact. In 146 relapsed patients receiving first-line EGFR-TKIs, high VEGFA was linked to shorter progression-free survival (PFS) overall (HR 1.70,95%CI 1.13-2.56, <i>p</i> = 0.009), particularly for first/second-generation EGFR-TKIs (HR 1.66,95%CI 1.08-2.54 <i>p</i> = 0.023), but not for osimertinib (<i>p</i> = 0.491). In 60 advanced-stage patients on osimertinib, PFS was unaffected by VEGFA (<i>p</i> = 0.102).</p> Conclusions <p>High VEGFA is associated with aggressive biology and inferior outcomes, correlating with shorter PFS for first/second-generation EGFR-TKIs but not for osimertinib.</p> <p></p>

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Role of VEGFA/VEGFR2 signaling in predicting clinical outcomes of EGFR-TKI treatment in EGFR-mutant non-small cell lung cancer

  • 期刊论文

  • 发表日期：

    2026年6月2日

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  • Ryoko Inaba Higashiyama,
  • Tatsuya Yoshida,
  • Kouya Shiraishi,
  • Jun Miyakoshi,
  • Masahiro Torasawa,
  • Masayuki Shirasawa,
  • Ken Masuda,
  • Yuki Shinno,
  • Yuji Matsumoto,
  • Yusuke Okuma,
  • Yukihiro Yoshida,
  • Yasushi Goto,
  • Hidehito Horinouchi,
  • Takaaki Tuchida,
  • Ryuji Hamamoto,
  • Noboru Yamamoto,
  • Shun-ichi Watanabe,
  • Yasushi Yatabe,
  • Takashi Kohno,
  • Yuichiro Ohe

摘要

Background

Dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways may improve outcomes in metastatic EGFR-mutant NSCLC, but VEGF inhibitors are not universally effective. We evaluated the impact of VEGFA and VEGFR2 expressions on EGFR-TKI outcomes.

Methods

EGFR-mutant NSCLC patients from the National Cancer Center Hospital, were retrospectively analysed. The early-stage cohort comprised stage I–IIIA patients (1997–2019). The advanced-stage cohort included metastatic patients (2018–2022). VEGFA/VEGFR2 expressions were dichotomised by median transcripts per million.

Results

Among 447 early-stage patients (median age 66), high VEGFA was associated with smoking, TP53 co-mutation, higher Brinkman Index, and higher tumour mutation burden (all p < 0.01). High VEGFA predicted shorter relapse-free survival (HR 2.10, 95% CI 1.63–2.71, p < 0.01) and overall survival (HR 2.07, 95% CI 1.46–2.95, p < 0.01). VEGFR2 expression showed no prognostic impact. In 146 relapsed patients receiving first-line EGFR-TKIs, high VEGFA was linked to shorter progression-free survival (PFS) overall (HR 1.70,95%CI 1.13-2.56, p = 0.009), particularly for first/second-generation EGFR-TKIs (HR 1.66,95%CI 1.08-2.54 p = 0.023), but not for osimertinib (p = 0.491). In 60 advanced-stage patients on osimertinib, PFS was unaffected by VEGFA (p = 0.102).

Conclusions

High VEGFA is associated with aggressive biology and inferior outcomes, correlating with shorter PFS for first/second-generation EGFR-TKIs but not for osimertinib.