Urtecho S Berenice, Provenzano Leonardo, Spagnoletti Andrea, Bottiglieri Achille, Pircher Chiara, Massa Giacomo, Sposetti Caterina, Proto Claudia, Brambilla Marta, Occhipinti Mario, Mazzeo Laura, Beninato Teresa, Leporati Rita, Giani Claudia, Cavalli Chiara, Serino Roberta, Prina Marco Meazza, Bassetti Anna, Nasca Vincenzo, di Mauro Rosa Maria, Abate Alice, Manglaviti Sara, Dumitrascu Andra Diana, Liberti Giorgia Di, Cassano Teresa Serra, Ganzinelli Monica, Wu Sulin, Garassino Marina Chiara, de Braud Filippo G M, Russo Giuseppe Lo, Prelaj Arsela
Medical Oncology Department, Fundacion Instituto Valenciano de Oncologia (IVO).
Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Lung Cancer. 2025 Jan;199:108051. doi: 10.1016/j.lungcan.2024.108051. Epub 2024 Dec 9.
KRAS mutation the most common molecular alteration in advanced non-small cell lung cancer (NSCLC) and is associated with an unfavourable prognosis, largely due to the lack of targeted therapeutic options for the majority of the KRAS mutated isoforms. The landscape of NSCLC treatment has expanded with the introduction of immune checkpoint inhibitors (ICIs). Nonetheless, data regarding the efficacy of ICI in NSCLC patients harbouring KRAS mutations are conflicting. This study aimed to compare clinical outcomes of ICIs in advanced NSCLC with different isoforms of KRAS mutations.
A retrospective study was conducted on 143 patients with advanced NSCLC harbouring different KRAS mutation and treated with immune checkpoint inhibitors (ICI) between December 2020 and July 2022 at "Fondazione IRCCS Istituto Nazionale dei Tumori" in Milan. Log-rank and Cox Hazard methods were used for survival analysis.
We evaluated 143 patients with advanced non-small cell lung cancer (NSCLC) harboring KRAS mutations. The most common mutation was G12C (41 %), followed by G12V (23.7 %) and G12D (11.8 %). The G12C mutation was notably associated with a higher incidence of bone metastases (42 %). Immunotherapy was administered as monotherapy in 54.5 % of cases, while 69 % received it as part of a first-line combination with chemotherapy. Co-mutations were detected in 52 % of patients, with Q61 (63 %) and G12C (58 %) being the most prevalent. Among these, 24 % had STK11 co-mutations, and 29 % had TP53 co-mutations. No significant differences in overall survival (OS) or progression-free survival (PFS) were observed across different KRAS subtypes. The longest OS was seen in patients with Q61 (46.5 months), 13X (31.8 months), and G12C (28.7 months). The highest overall response rate (ORR) of 73 % was observed in the G12D group, particularly with the combination of chemoimmunotherapy, where stable disease was the most common outcome at 40 %. The median duration of response (DOR) was 7.4 months across both treatments. The longest DOR was seen in the G12V group at 10.2 months, with no significant difference between treatments. In contrast, the shortest DOR was in the G12A group, with 1.54 months in those treated with combination therapy compared to 2.57 months with single-agent therapy. Regarding co-mutations, patients with STK11 co-mutations had a higher median OS than those without (39.7 vs. 26.1 months), but this was not statistically significant (p = 1). Similarly, TP53 co-mutations were associated with a lower median OS (19.1 vs. 26.1 months, p = 0.7), though this too was not statistically significant. Importantly, bone metastases emerged as a significant adverse prognostic factor, nearly doubling the risk of mortality (HR: 2.81, p < 0.001), regardless of KRAS subtype or co-mutation status.
KRAS mutation subtypes demonstrate varying clinical outcomes. Although no statistically significant differences were observed in overall survival (OS) or progression-free survival (PFS), bone metastases were identified as a significant adverse prognostic factor, nearly doubling the risk of mortality (HR: 2.72, p < 0.001) regardless of KRAS subtype or co-mutation status. These findings underscore the importance of personalized treatment approaches tailored to the genetic profiles of patients with advanced NSCLC.
KRAS 突变是晚期非小细胞肺癌（NSCLC）中最常见的分子改变，与不良预后相关，这主要是由于大多数 KRAS 突变亚型缺乏靶向治疗选择。随着免疫检查点抑制剂（ICI）的引入，NSCLC 的治疗格局得到了扩展。然而，关于 ICI 在携带 KRAS 突变的 NSCLC 患者中的疗效数据存在矛盾。本研究旨在比较不同 KRAS 突变亚型的晚期 NSCLC 患者接受 ICI 治疗后的临床结局。
对 2020 年 12 月至 2022 年 7 月期间在米兰的“Fondazione IRCCS Istituto Nazionale dei Tumori”接受免疫检查点抑制剂（ICI）治疗的 143 例携带不同 KRAS 突变的晚期 NSCLC 患者进行了回顾性研究。采用对数秩和 Cox 风险方法进行生存分析。
我们评估了 143 例携带 KRAS 突变的晚期非小细胞肺癌（NSCLC）患者。最常见的突变是 G12C（41%），其次是 G12V（23.7%）和 G12D（11.8%）。G12C 突变与骨转移的发生率较高显著相关（42%）。54.5%的病例中免疫治疗作为单一疗法给药，而 69%的患者将其作为一线化疗联合方案的一部分接受治疗。52%的患者检测到共突变，其中 Q61（63%）和 G12C（58%）最为普遍。其中，24%的患者有 STK11 共突变，29%的患者有 TP53 共突变。不同 KRAS 亚型之间在总生存期（OS）或无进展生存期（PFS）方面未观察到显著差异。Q61（46.5 个月）、13X（31.8 个月）和 G12C（28.7 个月）的患者总生存期最长。G12D 组观察到最高的总体缓解率（ORR）为 73%，特别是在化疗免疫治疗联合方案中，疾病稳定是最常见的结局，占 40%。两种治疗方法的中位缓解持续时间（DOR）均为 7.4 个月。G12V 组的 DOR 最长，为 10.2 个月，不同治疗方法之间无显著差异。相比之下，G12A 组的 DOR 最短，联合治疗的患者为 1.54 个月，单药治疗的患者为 2.57 个月。关于共突变，有 STK11 共突变的患者中位 OS 高于无共突变的患者（39.7 个月对 26.1 个月），但这无统计学意义（p = 1）。同样，TP53 共突变与较低的中位 OS 相关（19.1 个月对 26.1 个月，p = 0.7），尽管这也无统计学意义。重要的是，无论 KRAS 亚型或共突变状态如何，骨转移均是一个显著的不良预后因素，死亡风险几乎增加一倍（HR：2.81，p < 0.001）。
KRAS 突变亚型表现出不同的临床结局。尽管在总生存期（OS）或无进展生存期（PFS）方面未观察到统计学上的显著差异，但骨转移被确定为一个显著的不良预后因素，无论 KRAS 亚型或共突变状态如何，死亡风险几乎增加一倍（HR：2.72，p < 0.001）。这些发现强调了根据晚期 NSCLC 患者的基因特征制定个性化治疗方案的重要性。
