Impact of Co-mutations and Transcriptional Signatures in Non-Small Cell Lung Cancer Patients Treated with Adagrasib in the KRYSTAL-1 Trial.

IF 10 1区医学 Q1 ONCOLOGY Clinical Cancer Research Pub Date : 2025-03-17 DOI:10.1158/1078-0432.CCR-24-2310

Marcelo V Negrao, Alvaro G Paula, David Molkentine, Laura Hover, Monique Nilsson, Natalie Vokes, Lars Engstrom, Andrew Calinisan, David M Briere, Laura Waters, Jill Hallin, Lixia Diao, Mehmet Altan, George R Blumenschein, Ferdinandos Skoulidis, Jing Wang, Scott E Kopetz, David S Hong, Don L Gibbons, Peter Olson, James G Christensen, John V Heymach

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Abstract

Purpose: KRAS inhibitors are revolutionizing the treatment of non-small cell lung cancer (NSCLC), but clinico-genomic determinants of treatment efficacy warrant continued exploration.

Experimental design: 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.

Results: 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).

Conclusions: 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.

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KRYSTAL-1试验中阿达格拉西治疗的非小细胞肺癌患者共突变和转录特征的影响

背景：KRAS抑制剂正在彻底改变NSCLC的治疗，但治疗效果的临床基因组决定因素仍需继续探索：分析对象包括接受阿达拉西布（KRYSTAL-1-NCT03785249）治疗的晚期 KRASG12C 突变 NSCLC 患者。按照方案收集治疗前的 NGS 数据。HTG EdgeSeq Transcriptome Panel 用于基因表达谱分析。临床终点包括客观反应、无进展生存期和总生存期。KRASG12C 突变 NSCLC 细胞系和异种移植模型用于敏感性分析和联合用药筛选：结果：KEAP1MUT和STK11MUT与阿达格拉西的生存期缩短有关（KEAP1：PFS 4.1m vs 9.9m，HR 2.7，p结论：KEAP1、STK11和STK11MUT与阿达格拉西的生存期缩短有关：KEAP1、STK11和NRF2状态决定了KRASG12C突变NSCLC患者对阿达拉西布的治疗结果明显不同。这些结果进一步支持利用基因组特征（突变和非突变）来选择 KRASG12C 突变 NSCLC 患者的治疗方案。

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来源期刊

Clinical Cancer Research 医学-肿瘤学

CiteScore

20.10

自引率

1.70%

发文量

1207

审稿时长

2.1 months

期刊介绍： Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.