Adagrasib, an irreversible, selective KRASG12C inhibitor, may be an effective treatment in KRASG12C-mutated colorectal cancer, particularly when combined with an anti-EGFR antibody. In this analysis of the KRYSTAL-1 trial, patients with previously treated KRASG12C-mutated unresectable or metastatic colorectal cancer received adagrasib (600 mg twice daily) plus cetuximab. The primary endpoint was objective response rate (ORR) by blinded independent central review. Ninety-four patients received adagrasib plus cetuximab. With a median follow-up of 11.9 months, ORR was 34.0%, disease control rate was 85.1%, and median duration of response was 5.8 months (95% confidence interval [CI], 4.2–7.6). Median progression-free survival was 6.9 months (95% CI, 5.7–7.4) and median overall survival was 15.9 months (95% CI, 11.8–18.8). Treatment-related adverse events (TRAEs) occurred in all patients; grade 3–4 in 27.7% and no grade 5. No TRAEs led to adagrasib discontinuation. Exploratory analyses suggest circulating tumor DNA may identify features of response and acquired resistance. Significance: Adagrasib plus cetuximab demonstrates promising clinical activity and tolerable safety in heavily pretreated patients with unresectable or metastatic KRASG12C-mutated colorectal cancer. These data support a potential new standard of care and highlight the significance of testing and identification of KRASG12C mutations in patients with colorectal cancer.

中文翻译：

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阿达格拉西联合西妥昔单抗治疗 KRASG12C 突变的转移性结直肠癌患者的疗效和安全性

Adagrasib 是一种不可逆的选择性 KRASG12C 抑制剂，可能是 KRASG12C 突变结直肠癌的有效治疗方法，特别是与抗 EGFR 抗体联合使用时。在 KRYSTAL-1 试验的这项分析中，先前接受过治疗的 KRASG12C 突变的不可切除或转移性结直肠癌患者接受阿达拉西（600 毫克，每日两次）加西妥昔单抗治疗。主要终点是通过盲法独立中央审查得出的客观缓解率（ORR）。 94 名患者接受阿达格拉西加西妥昔单抗治疗。中位随访时间为 11.9 个月，ORR 为 34.0%，疾病控制率为 85.1%，中位缓解持续时间为 5.8 个月（95% 置信区间 [CI]，4.2-7.6）。中位无进展生存期为 6.9 个月（95% CI，5.7-7.4），中位总生存期为 15.9 个月（95% CI，11.8-18.8）。所有患者均发生治疗相关不良事件（TRAE）； 27.7% 为 3-4 级，没有 5 级。没有 TRAE 导致阿达格拉西停药。探索性分析表明循环肿瘤 DNA 可以识别反应和获得​​性耐药的特征。意义：Adagrasib 联合西妥昔单抗在接受过多次治疗的不可切除或转移性 KRASG12C 突变结直肠癌患者中表现出良好的临床活性和可耐受的安全性。这些数据支持潜在的新护理标准，并强调了测试和鉴定结直肠癌患者 KRASG12C 突变的重要性。