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<p>Molecular determinants of KRAS(G12C)inhibitor efficacy in <i>KRAS</i><sup><i>G12C</i></sup>-mutated non-small-cell lung cancer (NSCLC) remain poorly characterized. Here we report one of the largest integrated analyses to date of sotorasib clinical efficacy biomarkers from the phase 2 CodeBreaK 100 and phase 3 CodeBreaK 200 studies. We reveal differential sotorasib activity and relative benefit compared to docetaxel across <i>KRAS</i><sup><i>G12C</i></sup>-mutated NSCLC co-mutational subsets and transcriptional subtypes. We also identify low expression of <i>TTF1</i> and <i>KEAP1</i> co-mutations/NRF2 activation as major determinants of sotorasib anti-tumor efficacy and adverse prognostic features. Exploratory analyses highlight potential tumor cell-extrinsic contributors to sotorasib anti-tumor activity and suggest that early on-treatment clearance of <i>KRAS</i><sup><i>G12C</i></sup>- circulating tumor DNA may refine clinical response prediction algorithms. Our findings advance precision medicine for patients with <i>KRAS</i><sup><i>G12C</i></sup>-mutated NSCLC and establish a framework for patient stratification and selection for treatment intensification with rationally applied therapeutic combinations.</p>

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Molecular determinants of sotorasib clinical efficacy in KRASG12C-mutated non-small-cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月28日

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  • Ferdinandos Skoulidis,
  • Bob T. Li,
  • Adrianus Johannes de Langen,
  • David S. Hong,
  • Herve Lena,
  • Juergen Wolf,
  • Grace K. Dy,
  • Alessandra Curioni Fontecedro,
  • Pascale Tomasini,
  • Vamsidhar Velcheti,
  • Anthonie J. van der Wekken,
  • Christophe Dooms,
  • Luis Paz-Ares Rodriguez,
  • Giannis Mountzios,
  • Adrian Sacher,
  • Ernest Nadal,
  • Sebastien Couraud,
  • Sang-We Kim,
  • Kenneth O’Byrne,
  • Danilo Rocco,
  • Ryo Toyozawa,
  • Izabela Chmielewska,
  • Colin R. Lindsay,
  • Antreas Hindoyan,
  • Lata Mukundan,
  • Tomasz Wilmanski,
  • Abraham Anderson,
  • Christine Ardito-Abraham,
  • Amrita Pati,
  • Anita Reddy,
  • Bhakti Mehta,
  • Martin Schuler

摘要

Molecular determinants of KRAS(G12C)inhibitor efficacy in KRASG12C-mutated non-small-cell lung cancer (NSCLC) remain poorly characterized. Here we report one of the largest integrated analyses to date of sotorasib clinical efficacy biomarkers from the phase 2 CodeBreaK 100 and phase 3 CodeBreaK 200 studies. We reveal differential sotorasib activity and relative benefit compared to docetaxel across KRASG12C-mutated NSCLC co-mutational subsets and transcriptional subtypes. We also identify low expression of TTF1 and KEAP1 co-mutations/NRF2 activation as major determinants of sotorasib anti-tumor efficacy and adverse prognostic features. Exploratory analyses highlight potential tumor cell-extrinsic contributors to sotorasib anti-tumor activity and suggest that early on-treatment clearance of KRASG12C- circulating tumor DNA may refine clinical response prediction algorithms. Our findings advance precision medicine for patients with KRASG12C-mutated NSCLC and establish a framework for patient stratification and selection for treatment intensification with rationally applied therapeutic combinations.