PO.ET05.02 · 实验与分子治疗
sotorasib 联合 panitumumab 在 KRAS G12C 突变结直肠癌中的免疫和药效学效应：CodeBreaK 101 的配对活检结果
Immune and pharmacodynamic effects of sotorasib plus panitumumab in KRAS G12C-mutant colorectal cancer: Paired biopsy results from CodeBreaK 101
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：KRAS G12C 抑制剂 sotorasib 联合 panitumumab 已获批用于化疗难治性转移性结直肠癌（mCRC）。然而，其在临床样本中对肿瘤微环境（TME）的早期效应尚不十分清楚。在临床前模型中，sotorasib 强效抑制 MAPK 信号通路并促进以 CD8⁺ T 细胞浸润和 IFN-γ 活性增加为特征的促炎性 TME，提示适应性免疫参与肿瘤控制。我们考察了在接受 sotorasib 联合 panitumumab 治疗的患者（pts）中是否临床上可观察到这些药效学和免疫学效应。
方法：从 CodeBreaK 101（NCT04185883）队列 A 的 12 名患者中获得了 sotorasib 联合 panitumumab 治疗前和治疗 3-4 周后的配对活检。我们进行了全转录组 RNA 测序（n=12）、pERK 免疫组化（n=8）、使用数字病理学对 H&E 染色切片进行空间分析（n=10）以及单细胞空间转录组学（n=2）。分析主要为描述性，采用 Wilcoxon 符号秩检验和汇总统计来表征配对活检之间的差异。
结果：转录组分析揭示了 MAPK 信号通路的强效抑制，表现为 MAPK 通路活性评分中位数约降低 4 倍，且细胞周期相关基因持续下调。关键 MAPK 靶点被下调，包括 ETV4（−6.9 倍）、EPHA2（−2.8 倍）和 DUSP6（−2.0 倍），而 EPHA4 基本保持不变。pERK 免疫组化显示，在受检患者中 H 评分约降低 1.8 倍，pERK⁺ 肿瘤细胞核比例降低 2.0 倍，与有效的 MAPK 通路抑制一致。免疫激活表现为肿瘤炎症特征评分增加 1.9 倍，以及趋化因子和抗原呈递基因（CXCL9、CCL5、HLA-DPA1）的上调。对 H&E 图像的数字病理学分析显示 TME 中免疫细胞聚集增加，与 RNA-seq 数据中观察到的免疫重塑相呼应。单细胞空间分析证实了肿瘤及相关基质中存在 CXCR6⁺ CD8⁺ T 细胞和巨噬细胞来源的 CXCL10，提示细胞毒性 T 细胞的招募和激活。全面的通路分析显示，部分患者中 PI3K-AKT、HER2 和 TGFβ 信号通路上调，提示代偿性生存机制以及联合策略的潜在依据。
结论：配对活检分析揭示了强效的 MAPK 抑制和免疫重塑，为免疫 TME 在对 sotorasib 联合 panitumumab 早期反应中的作用提供了机制性见解，并凸显了 mCRC 中合理联合策略的机会。
查看英文原文 English abstract
Background: Sotorasib, a KRAS G12C inhibitor, plus panitumumab is approved for use in chemorefractory metastatic colorectal cancer (mCRC) . Yet, early effects on the tumor microenvironment (TME) in clinical samples are not well understood. In preclinical models, sotorasib potently suppresses MAPK signaling and promotes a pro-inflammatory TME characterized by CD8⁺ T cell infiltration and increased IFN-gamma activity, implicating adaptive immunity in tumor control. We investigated if these pharmacodynamic and immunologic effects are observed clinically in patients (pts) treated with sotorasib plus panitumumab.
Methods: Paired biopsies before and after 3-4 weeks of sotorasib plus panitumumab treatment were available from 12 pts in Cohort A of CodeBreaK 101 (NCT04185883). We performed whole-transcriptome RNA sequencing (n=12), pERK immunohistochemistry (n=8), spatial analysis of H&E-stained sections using digital pathology (n=10), and single-cell spatial transcriptomics (n=2). Analyses were primarily descriptive, and Wilcoxon signed-rank tests and summary statistics were used to characterize differences between paired biopsies.
Results: Transcriptomic profiling revealed robust suppression of MAPK signaling, shown by an approximate 4-fold reduction in median MAPK Pathway Activity Score with consistent downregulation of cell cycle-related genes. Key MAPK targets were downregulated, including ETV4 (−6.9-fold), EPHA2 (−2.8-fold), and DUSP6 (−2.0-fold), while EPHA4 was largely unchanged. pERK immunohistochemistry showed an approximately 1.8-fold reduction in H-score and a 2.0-fold decrease in proportion of pERK⁺ tumor nuclei among profiled pts, consistent with effective MAPK pathway inhibition. Immune activation was reflected by a 1.9-fold increase in the Tumor Inflammation Signature score and upregulation of chemokines and antigen-presentation genes (CXCL9, CCL5, HLA-DPA1). Digital pathology analysis of H&E images showed increased immune cell clustering in the TME, mirroring immune remodeling observed in RNA-seq data. Single-cell spatial confirmed presence of CXCR6⁺ CD8⁺ T cells and macrophage derived CXCL10 in the tumor and associated stroma suggesting cytotoxic T cell recruitment and activation. Comprehensive pathway analysis showed upregulation of PI3K-AKT, HER2, and TGFbeta signaling in some pts, suggesting compensatory survival mechanisms and a potential rationale for combinatorial strategies.
Conclusion: Paired biopsy analysis revealed potent MAPK inhibition and immune remodeling, providing mechanistic insight into the role of the immune TME in early response to sotorasib plus panitumumab and underscoring opportunities for rational combination strategies in mCRC.
利益披露 Disclosure
D. Hong,
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L. Mukundan,
Amgen Inc. Employment, Stock.
A. Anderson,
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D. French,
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L. Haeggblom,
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D. Lu,
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T. Masuishi,
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R. Yaeger,
Loxo@Lilly; Mirati Therapeutics; Revolution Medicines; Merck; Erasca; Parabilis Medicines; Bayer; Alterome Other, Consulting or Advisory Role.
Amgen (Inst); Boundless Bio (Inst); Daiichi Sankyo/UCB Japan (Inst); Mirati Therapeutics (Inst); Pfizer (Inst); Parabilis Medicine (Inst); Revolution Medicines (Inst); Eli Lilly (Inst) ).
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Amgen Inc. Employment, Stock.