Negrao Marcelo V, Paula Alvaro G, Molkentine David, Hover Laura, Nilsson Monique, Vokes Natalie, Engstrom Lars, Calinisan Andrew, Briere David M, Waters Laura, Hallin Jill, Diao Lixia, Altan Mehmet, Blumenschein George R, Skoulidis Ferdinandos, Wang Jing, Kopetz Scott E, Hong David S, Gibbons Don L, Olson Peter, Christensen James G, Heymach John V
Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston, Texas.
Monoceros Biosystems, San Diego, California.
Clin Cancer Res. 2025 Mar 17;31(6):1069-1081. doi: 10.1158/1078-0432.CCR-24-2310.
KRAS inhibitors are revolutionizing the treatment of non-small cell lung cancer (NSCLC), but clinico-genomic determinants of treatment efficacy warrant continued exploration.
Patients with advanced KRASG12C-mutant NSCLC treated with adagrasib [KRYSTAL-1 (NCT03785249)] were included in the analysis. Pretreatment next-generation sequencing data were collected per protocol. HTG EdgeSeq Transcriptome Panel was used for gene expression profiling. Clinical endpoints included objective response, progression-free survival (PFS), and overall survival (OS). KRASG12C-mutant NSCLC cell lines and xenograft models were used for sensitivity analyses and combination drug screens.
KEAP1 MUT and STK11MUT were associated with shorter survival to adagrasib [KEAP1: PFS 4.1 vs. 9.9 months, HR 2.7, P < 0.01; OS 5.4 vs. 19.0 months, HR 3.6, P < 0.01; STK11: PFS 4.2 vs. 11.0 months, HR 2.2, P < 0.01; OS 9.8 months vs. not reached (NR), HR 2.6, P < 0.01]. KEAP1WT/STK11WT status identified adagrasib-treated patients with significantly longer PFS (16.9 months) and OS (NR). Preclinical analyses further validate the association between KEAP1 loss of function and adagrasib resistance. Adagrasib and mTOR inhibitor combinations produced higher treatment efficacy in NSCLC models harboring STK11 and KEAP1 co-mutations. NRF2HIGH signaling was associated with shorter survival to adagrasib (PFS: 4.2 vs. 8.4 months, HR 2.0, P = 0.02; OS: 6.5 vs. 19.0 months, HR 2.8, P < 0.01) even in patients with KEAP1WT NSCLC. KEAP1WT/STK11WT/NRF2LOW status identified patients-32%-with longer survival to adagrasib (PFS 12.0 vs. 4.2 months, HR 0.2, P < 0.01; OS NR vs. 8.0 months, HR 0.1, P < 0.01).
KEAP1, STK11, and NRF2 status define patients with KRASG12C-mutant NSCLC with markedly distinct outcomes to adagrasib. These results further support the use of genomic features-mutational and nonmutational-for the treatment selection of patients with KRASG12C-mutant NSCLC.
KRAS抑制剂正在彻底改变非小细胞肺癌（NSCLC）的治疗方式，但治疗疗效的临床基因组决定因素仍需持续探索。
分析接受阿达格拉西布治疗的晚期KRASG12C突变型NSCLC患者[KRYSTAL-1（NCT03785249）]。按照方案收集治疗前的二代测序数据。使用HTG EdgeSeq转录组分析试剂盒进行基因表达谱分析。临床终点包括客观缓解、无进展生存期（PFS）和总生存期（OS）。使用KRASG12C突变型NSCLC细胞系和异种移植模型进行敏感性分析和联合药物筛选。
KEAP1突变（KEAP1 MUT）和STK11突变（STK11MUT）与接受阿达格拉西布治疗后的生存期缩短相关[KEAP1：PFS 4.1个月对9.9个月，HR 2.7，P<0.01；OS 5.4个月对19.0个月，HR 3.6，P<0.01；STK11：PFS 4.2个月对11.0个月，HR 2.2，P<0.01；OS 9.8个月对未达到（NR），HR 2.6，P<0.01]。KEAP1野生型/STK11野生型（KEAP1WT/STK11WT）状态表明接受阿达格拉西布治疗的患者PFS（16.9个月）和OS（NR）显著更长。临床前分析进一步验证了KEAP1功能丧失与阿达格拉西布耐药之间的关联。在同时存在STK11和KEAP1共突变的NSCLC模型中，阿达格拉西布与mTOR抑制剂联合使用产生了更高的治疗疗效。即使在KEAP1野生型NSCLC患者中，NRF2高表达信号也与接受阿达格拉西布治疗后的生存期缩短相关（PFS：4.2个月对8.4个月，HR 2.0，P = 0.02；OS：6.5个月对19.0个月，HR 2.8，P<0.01）。KEAP1WT/STK11WT/NRF2低表达（KEAP1WT/STK11WT/NRF2LOW）状态确定了32%的患者接受阿达格拉西布治疗后的生存期更长（PFS 12.0个月对4.2个月，HR 0.2，P<0.01；OS NR对8.0个月，HR 0.1，P<0.01）。
KEAP1、STK11和NRF2状态可明确KRASG12C突变型NSCLC患者接受阿达格拉西布治疗后的显著不同结局。这些结果进一步支持利用基因组特征——突变和非突变特征——来选择KRASG12C突变型NSCLC患者的治疗方案。
