ArticleClinical cancer research : an official journal of the American Association for Cancer Research2025
Impact of Co-mutations and Transcriptional Signatures in Non-Small Cell Lung Cancer Patients Treated with Adagrasib in the KRYSTAL-1 Trial.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03785249 (A Phase 1/2 Multiple Expansion Cohort Trial of MRTX849 in Patients With Advanced Solid Tumors With KRAS G12C Mutation KRYSTAL-1), which is not on this map. Cited by 21 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase 1/2 Multiple Expansion Cohort Trial of MRTX849 in Patients With Advanced Solid Tumors With KRAS G12C Mutation KRYSTAL-1
Who cites it
21 citing papers in PubMed.
- Axitinib plus Avelumab in Recurrent/Metastatic Adenoid Cystic Carcinoma: Biomarker Analysis and Updated Results of the Phase II Trial.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Trial
- Review
- Molecular insights and therapeutic implications for the tumor suppressor role of LKB1 in non-small cell lung cancer.Cancer letters · 2026Review
- The Role of KRAS in Non-Small Cell Lung Cancer: From Molecular Background to Precision Medicine.International journal of molecular sciences · 2026Review
- Targeting non-small cell lung cancer: Molecular mechanisms and clinical studies (Review).Oncology letters · 2026Review
- HNF4α controls growth, identity, and KRAS inhibitor response in invasive mucinous adenocarcinoma of the lung.The Journal of clinical investigation · 2026Article
- Study of the blood-brain barrier-penetrating KRAS G12C inhibitor JMKX1899 in KRAS G12C-mutated NSCLC with brain metastases.Journal of the National Cancer Center · 2026Article
- Advances in translational lung cancer research in 2025: a narrative review.Translational lung cancer research · 2026Review
- Review
- Characterization and therapeutic suppression of KEAP1-NRF2-driven resistance to KRAS inhibitors in pancreatic and lung cancer.bioRxiv : the preprint server for biology · 2026Article
- Advances in targeting KRAS mutations: A promising approach for the treatment of non‑small cell lung cancer (Review).Oncology reports · 2026Review
- KRAS mutated lung adenocarcinoma responds to pan-ERBB and Aurora kinase inhibitors.NPJ precision oncology · 2026Article
- Wise as a Serpent and Gentle as a Dove: Pharmacological Targeting of NRF2/KEAP1 Pathway from Treasure Trove of Mother Nature.Drug design, development and therapy · 2026Review
- Integrative Analysis of Glycosylation-Related Genes Reveals Prognostic Subtypes, Immune Evasion, and Therapeutic Vulnerabilities in Lung Adenocarcinoma.Oncology research · 2026Article
- [Advances in Diagnosis and Targeted Therapy of KRASG12C Mutant Non-small Cell Lung Cancer].Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2025Review
- Genetic drivers of tumor microenvironment and immunotherapy resistance in non-small cell lung cancer: the role ofJournal for immunotherapy of cancer · 2025Review
- Targeting LKB1/STK11-mutant cancer: distinct metabolism, microenvironment, and therapeutic resistance.Trends in pharmacological sciences · 2025Review
- Article
- Review
- Response and Resistance to RAS Inhibition in Cancer.Cancer discovery · 2025Review
Corrections and comments
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Authors and funding
22 authors.
Funding
Abstract
purposeKRAS inhibitors are revolutionizing the treatment of non-small cell lung cancer (NSCLC), but clinico-genomic determinants of treatment efficacy warrant continued exploration. EXPERIMENTAL
designPatients 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.
resultsKEAP1 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).
conclusionsKEAP1, 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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