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<p>Oncogenic KRAS mutations are frequently detected in NSCLC. It remains a major challenge to target all KRAS mutants. MEK inhibitors are considered candidates for treating KRAS-mutant NSCLC; however, their easy adaptive resistance precludes further application. Here, we found that MEK inhibitor-trametinib treatment results in the feedback activation of multiple receptor tyrosine kinases (RTKs) and that treatment with the pan-RTK inhibitor anlotinib effectively inhibits the progression of KRAS-mutant NSCLC. Furthermore, we evaluated this strategy in a clinical study (NCT04967079) involving 33 advanced non-G12C KRAS-mutant NSCLC patients. The phase Ia containing 13 patients showed that the recommended phase 2 dose (RP2D) is trametinib (2 mg) plus anlotinib (8 mg), the objective response rate (ORR) is 69.2% (95% CI: 38.6-90.9), the median progression-free survival (PFS) is 6.9 months (95% CI: 3.9 to could not be evaluated), disease control rate (DCR) is 92% (95% CI: 64.0–99.8) and the rate of adverse events (AEs) ≥grade 3 is 23%. The phase Ib containing 20 patients demonstrated the high efficacy of this combinational therapy with RP2D, with the ORR at 65% (95% CI: 40.8–84.6), the median PFS is 11.5 months (95% CI: 8.3–15.5), the median overall survival (OS) is 15.5 months (95% CI: 15.5 to could not be evaluated), the DCR at 100% (95% CI: 83.2–100.0), the median duration of overall response (DoR) is 9.3 months (95% CI: 2.5–12.1), and the rate of AEs ≥ grade 3 at 35%. Overall, this study provides a potential combinational therapeutic strategy for KRAS-mutant NSCLC through the cotargeting of MEK and RTKs.</p>

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Coinhibition of the MEK/RTK pathway has high therapeutic efficacy in KRAS-mutant non-small cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月12日

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  • Jun Lu,
  • Minjuan Hu,
  • Yikai Zhao,
  • Tianqing Chu,
  • Wei Zhang,
  • Yijia Zhou,
  • Xinlei Cai,
  • Jun Wu,
  • Liang Hu,
  • Chunlei Shi,
  • Liwen Xiong,
  • Aiqin Gu,
  • Huimin Wang,
  • Yanwei Zhang,
  • Yuqing Lou,
  • Runbo Zhong,
  • Zhiqiang Gao,
  • Hongyu Liu,
  • Chao Zhou,
  • Yingli Wu,
  • Liang Zhu,
  • Hua Zhong,
  • Hongbin Ji,
  • Baohui Han

摘要

Oncogenic KRAS mutations are frequently detected in NSCLC. It remains a major challenge to target all KRAS mutants. MEK inhibitors are considered candidates for treating KRAS-mutant NSCLC; however, their easy adaptive resistance precludes further application. Here, we found that MEK inhibitor-trametinib treatment results in the feedback activation of multiple receptor tyrosine kinases (RTKs) and that treatment with the pan-RTK inhibitor anlotinib effectively inhibits the progression of KRAS-mutant NSCLC. Furthermore, we evaluated this strategy in a clinical study (NCT04967079) involving 33 advanced non-G12C KRAS-mutant NSCLC patients. The phase Ia containing 13 patients showed that the recommended phase 2 dose (RP2D) is trametinib (2 mg) plus anlotinib (8 mg), the objective response rate (ORR) is 69.2% (95% CI: 38.6-90.9), the median progression-free survival (PFS) is 6.9 months (95% CI: 3.9 to could not be evaluated), disease control rate (DCR) is 92% (95% CI: 64.0–99.8) and the rate of adverse events (AEs) ≥grade 3 is 23%. The phase Ib containing 20 patients demonstrated the high efficacy of this combinational therapy with RP2D, with the ORR at 65% (95% CI: 40.8–84.6), the median PFS is 11.5 months (95% CI: 8.3–15.5), the median overall survival (OS) is 15.5 months (95% CI: 15.5 to could not be evaluated), the DCR at 100% (95% CI: 83.2–100.0), the median duration of overall response (DoR) is 9.3 months (95% CI: 2.5–12.1), and the rate of AEs ≥ grade 3 at 35%. Overall, this study provides a potential combinational therapeutic strategy for KRAS-mutant NSCLC through the cotargeting of MEK and RTKs.