Introduction

The KRAS p.G12C mutation, prevalent in non–small-cell lung cancer (NSCLC), has only recently become a viable target. Here we present results of the largest retrospective observational study analyzing KRAS p.G12C in patients with advanced NSCLC.

Materials and Methods

Adults with advanced NSCLC (All Advanced NSCLC cohort) and subcohorts with different mutation profiles (KRAS p.G12C [G12C] and KRAS/EGFR/ALK wild type [Triple WT]) diagnosed January 2011 to March 2019 were selected from a US clinico-genomic database; treatment-related characteristics, molecular profiles, real-world overall (rwOS) and progression-free survival (rwPFS) were analyzed.

Results

Demographics were similar across cohorts, with more smokers and nonsquamous cell carcinoma histology in the G12C cohort. KRAS p.G12C was nearly mutually exclusive (≤1.2 %) with known actionable driver mutations, but non-driver co-mutations were common (STK11, 21.5 %; KEAP1, 7.0 %; TP53, 48.0 %). Among G12C patients, 20 % had no documentation of receiving systemic therapy. Across treated G12C patients, 67 % received immune checkpoint inhibitors; first-line usage increased from 0% (2014) to 81 % (2019). Among G12C patients, median (95 % CI) rwOS was 12.0 (9.6–15.3), 9.5 (8.1–13.1), and 6.7 (5.9–10.7) months after first, second, and third line of therapy, respectively; median (95 % CI) rwPFS was 5.0 (4.4–5.8), 4.0 (2.8–5.3), and 3.1 (2.4–4.3) months. Outcomes for the G12C subcohort were similar to those for all patients (All Advanced NSCLC cohort). Mutations in STK11/KEAP1 were associated with poorer survival across all cohorts.

Conclusion

The poor outcomes associated with KRAS p.G12C mutated advanced NSCLC indicate an unmet need for more effective novel treatments.

中文翻译：

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KRAS p.G12C突变或野生型晚期非小细胞肺癌自然病程的回顾性观察研究

介绍

在非小细胞肺癌 (NSCLC) 中普遍存在的KRAS p.G12C 突变最近才成为一个可行的靶点。在这里，我们展示了分析晚期 NSCLC 患者中KRAS p.G12C的最大回顾性观察研究的结果。

材料和方法

2011 年 1 月至 2019 年 3 月诊断的晚期 NSCLC 成人（所有晚期 NSCLC 队列）和具有不同突变谱（KRAS p.G12C [G12C] 和KRAS/EGFR/ALK野生型 [Triple WT]）的亚队列选自美国临床-基因组数据库；分析了治疗相关特征、分子特征、真实世界总体 (rwOS) 和无进展生存期 (rwPFS)。

结果

各队列的人口统计学相似，G12C 队列中有更多的吸烟者和非鳞状细胞癌组织学。KRAS p.G12C 与已知的可操作驱动突变几乎相互排斥（≤1.2%），但非驱动共突变很常见（STK11，21.5 %；KEAP1，7.0 %；TP53, 48.0%)。在 G12C 患者中，20% 没有接受全身治疗的记录。在接受治疗的 G12C 患者中，67% 接受了免疫检查点抑制剂；一线使用率从 0%（2014 年）增加到 81%（2019 年）。在 G12C 患者中，一线、二线和三线治疗后的中位 (95% CI) rwOS 分别为 12.0 (9.6–15.3)、9.5 (8.1–13.1) 和 6.7 (5.9–10.7) 个月；中位 (95% CI) rwPFS 为 5.0 (4.4–5.8)、4.0 (2.8–5.3) 和 3.1 (2.4–4.3) 个月。G12C 亚组的结果与所有患者（所有晚期 NSCLC 队列）的结果相似。STK11/KEAP1 的突变与所有队列中较差的存活率相关。

结论

与KRAS p.G12C 突变的晚期 NSCLC相关的不良结果表明对更有效的新疗法的需求未得到满足。