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<p>Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced clear cell renal cell carcinoma (ccRCC), but the biomarkers predicting benefits from ICI-based therapies over conventional VEGFR/mTOR inhibitors remain incompletely elucidated. In this study, we analyzed clinical, mutational, and/or transcriptomic data of multiple cohorts, including five clinical trials (JAVELIN Renal 101 [<i>n</i> = 885], IMmotion151 [<i>n</i> = 715], and CheckMate-009/010/025 [<i>n</i> = 1006]), two prognostic cohorts (TCGA-KIRC, <i>n</i> = 537; ICGC, <i>n</i> = 475). Pharmacogenomic analysis was conducted using the cancer cell line encyclopedia (CCLE) database. Our results revealed that only <i>NF1/2</i> mutations exhibited a consistent relationship with benefits from ICI-based therapies over VEGFR/mTOR inhibitors among all the common mutations in the JAVELIN Renal 101, IMmotion151, and CheckMate-009/010/025 trials (pooled estimate of interaction effect, <i>P</i> = 0.028). In the multivariable models, ICI benefits were higher in the <i>NF1/2</i>-mutant group compared with the <i>NF1/2</i>-wildtype group (avelumab plus axitinib vs. sunitinib: HR<sub>mut</sub> = 0.35/HR<sub>wildtype</sub> = 0.64; atezolizumab plus bevacizumab vs. sunitinib: HR<sub>mut</sub> = 0.55/HR<sub>wildtype</sub> = 0.82; nivolumab vs. everolimus: HR<sub>mut</sub> = 0.17/HR<sub>wildtype</sub> = 0.73). <i>NF1/2</i> mutations were associated with greater expression of the genes related to FGFR rather than VEGFR or PI3K-AKT-mTOR in advanced ccRCCs and higher sensitivity to FGFR inhibitors instead of VEGFR/PI3K-AKT-mTOR inhibitors in ccRCC cell lines. Compared with the <i>NF1/2</i>-wildtype advanced ccRCCs, those with mutated <i>NF1/2</i> had an inferior prognosis (HR = 2.53). This tendency was not changed by everolimus (HR = 2.66), but was abrogated slightly by sunitinib (HR = 1.59) and considerably by ICI-based therapies, including nivolumab monotherapy (HR = 1.12), atezolizumab plus bevacizumab (HR = 1.10), and avelumab plus axitinib (HR = 0.69). Overall, our findings suggest that <i>NF1/2</i> mutations can serve as predictive biomarkers for favorable benefits from ICI-based treatments over VEGFR/mTOR inhibitors in advanced ccRCCs.</p>

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NF1/2 mutations predict favorable benefit from immune checkpoint inhibitor-based therapies over VEGFR/mTOR inhibitors in clear cell renal cell carcinoma

  • 期刊论文

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  • 发表日期：

    2026年1月17日

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  • Yi Sun,
  • Qiang Cheng,
  • Qiaoxia Zhou,
  • Yu Xu,
  • Guoqiang Wang,
  • Chunwei Xu,
  • Wenxian Wang,
  • Shangli Cai,
  • Wenzheng Chen

摘要

Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced clear cell renal cell carcinoma (ccRCC), but the biomarkers predicting benefits from ICI-based therapies over conventional VEGFR/mTOR inhibitors remain incompletely elucidated. In this study, we analyzed clinical, mutational, and/or transcriptomic data of multiple cohorts, including five clinical trials (JAVELIN Renal 101 [n = 885], IMmotion151 [n = 715], and CheckMate-009/010/025 [n = 1006]), two prognostic cohorts (TCGA-KIRC, n = 537; ICGC, n = 475). Pharmacogenomic analysis was conducted using the cancer cell line encyclopedia (CCLE) database. Our results revealed that only NF1/2 mutations exhibited a consistent relationship with benefits from ICI-based therapies over VEGFR/mTOR inhibitors among all the common mutations in the JAVELIN Renal 101, IMmotion151, and CheckMate-009/010/025 trials (pooled estimate of interaction effect, P = 0.028). In the multivariable models, ICI benefits were higher in the NF1/2-mutant group compared with the NF1/2-wildtype group (avelumab plus axitinib vs. sunitinib: HRmut = 0.35/HRwildtype = 0.64; atezolizumab plus bevacizumab vs. sunitinib: HRmut = 0.55/HRwildtype = 0.82; nivolumab vs. everolimus: HRmut = 0.17/HRwildtype = 0.73). NF1/2 mutations were associated with greater expression of the genes related to FGFR rather than VEGFR or PI3K-AKT-mTOR in advanced ccRCCs and higher sensitivity to FGFR inhibitors instead of VEGFR/PI3K-AKT-mTOR inhibitors in ccRCC cell lines. Compared with the NF1/2-wildtype advanced ccRCCs, those with mutated NF1/2 had an inferior prognosis (HR = 2.53). This tendency was not changed by everolimus (HR = 2.66), but was abrogated slightly by sunitinib (HR = 1.59) and considerably by ICI-based therapies, including nivolumab monotherapy (HR = 1.12), atezolizumab plus bevacizumab (HR = 1.10), and avelumab plus axitinib (HR = 0.69). Overall, our findings suggest that NF1/2 mutations can serve as predictive biomarkers for favorable benefits from ICI-based treatments over VEGFR/mTOR inhibitors in advanced ccRCCs.