Related Experiment Video
Updated: Jun 2, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Impact of Co-mutations and Transcriptional Signatures in Non-Small Cell Lung Cancer Patients Treated with Adagrasib
Marcelo V Negrao1, Alvaro G Paula1, David Molkentine1
1Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston, Texas.
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.
Insights
Keap1, Stk11, and Nrf2 mutations impact adagrasib efficacy in KRASG12C-mutant non-small cell lung cancer. Genomic profiling can guide treatment selection for improved patient outcomes.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- KRAS inhibitors are transforming non-small cell lung cancer (NSCLC) treatment.
- Understanding clinico-genomic factors influencing KRAS inhibitor efficacy is crucial.
- Adagrasib is an emerging targeted therapy for KRASG12C-mutant NSCLC.
Purpose of the Study:
- To explore clinico-genomic determinants of adagrasib efficacy in KRASG12C-mutant NSCLC.
- To investigate the impact of KEAP1, STK11, and NRF2 status on treatment outcomes.
- To evaluate combination therapies for resistant NSCLC models.
Main Methods:
- Analysis of patients with advanced KRASG12C-mutant NSCLC treated with adagrasib (KRYSTAL-1 trial).
- Pretreatment next-generation sequencing for gene expression profiling using HTG EdgeSeq.
- In vitro and in vivo sensitivity analyses and combination drug screens in NSCLC cell lines and xenografts.
Main Results:
- KEAP1 and STK11 mutations were associated with significantly shorter progression-free survival (PFS) and overall survival (OS) with adagrasib.
- Patients with wild-type KEAP1 and STK11 (KEAP1WT/STK11WT) showed significantly longer PFS and OS.
- High NRF2 signaling correlated with poorer outcomes, while KEAP1WT/STK11WT/NRF2LOW status identified patients with superior survival.
Conclusions:
- KEAP1, STK11, and NRF2 genomic status are key predictors of adagrasib response in KRASG12C-mutant NSCLC.
- Genomic profiling, including mutational and non-mutational features, can inform treatment selection for these patients.
- Combination therapy with mTOR inhibitors showed promise in models with co-occurring STK11 and KEAP1 mutations.
More Related Videos
11:15Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
09:38Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
Published on: June 26, 2019
