lung-page
In NSCLC, RAS tightens its GRIP in more ways than one

In NSCLC

It is time to look closer

at the grip of RAS

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HOW PREVALENT ARE RAS MUTATIONS IN NSCLC?
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RAS mutations are the most common oncogenic driver in NSCLC1*

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  • In NSCLC, KRAS is the most commonly mutated isoform in the RAS gene family2
  • KRAS mutations occur in ~30% of NSCLC, which is about double the prevalence of EGFR mutations, the next most common genetic driver in NSCLC1*
  • KRAS mutations are typically mutually exclusive of other known driver mutations in NSCLC2
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Common driver mutations in NSCLC1†

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†Prevalence varies between different datasets and studies.
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Although RAS mutations are the most common oncogenic driver in NSCLC, RAS-targeted therapies remain limited1,3

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*Prevalence varies by region. In the United States and Europe, KRAS mutations are the most frequent driver of NSCLC, whereas in Asia, EGFR mutations are the most common driver mutations.4
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WHY IS IT IMPORTANT TO IDENTIFY SPECIFIC RAS MUTATIONS IN NSCLC?
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Not all RAS mutations are the same in NSCLC5

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  • KRAS G12V, G12D, and G12A account for ~40% of all RAS mutations in NSCLC6
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RAS mutations in NSCLC6‡

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‡Numbers are approximate.
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§Other includes additional codon 12, codon 13, and codon 61 mutations.6
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  • KRAS G12D is associated with less favorable responses to immunotherapy8,11
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  • KRAS G12V generally resembles KRAS G12C in biological features and responses to immunotherapy, but displays more variability7,13-15
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With new potential approaches to targeting RAS on the horizon, your patient's specific RAS mutation matters

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WHAT IS THE ROLE OF RAS(ON) IN DRIVING NSCLC?
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Excessive RAS(ON) signaling promotes the development and progression of RAS-driven cancers16,17

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  • RAS proteins regulate cell growth by switching between the active RAS(ON) and inactive RAS(OFF) states16
  • RAS(ON) promotes cell growth and survival in response to growth signals16,18
  • When RAS is mutated, it remains mostly in the ON state, resulting in overactive RAS signaling and uncontrolled cell growth16
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Targeting oncogenic RAS(ON), a key driver of NSCLC, represents a critical unmet need16,17

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WHAT ARE THE UNMET NEEDS IN RAS-MUTATED NSCLC?
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Although advances have been made, challenges in treating RAS-driven NSCLC persist3,5

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RAS-driven NSCLC tumors are often characterized by rapid tumor growth and cancer spread1,19

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  • RAS-driven NSCLC confers worse treatment outcomes than wild-type RAS NSCLC20,21
  • Patients with KRAS G12D–mutated NSCLC typically have less favorable response to current
standard-of-care treatments, compared with patients with KRAS G12C or G12V mutations8,11
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Currently, there is no approved RAS-targeted treatment for many patients with RAS-mutated NSCLC3,6

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About 60% of patients with RAS-mutated NSCLC have non–KRAS G12C tumors, including G12D, G12V, or G12A, and are therefore ineligible for approved RAS-targeted therapies.3,6
Chemotherapy and immunotherapy are the current standards of care for the majority of patients with RAS-mutated NSCLC, but do not target the mutation likely driving the disease.1,18,22
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Explore potential approaches to targeting more of the RAS mutations that drive NSCLC

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Learn more

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ALK=anaplastic lymphoma kinase; BRAF=B-Raf proto-oncogene, serine/threonine kinase; EGFR=epidermal growth factor receptor; ERBB2=erythroblastic oncogene B receptor tyrosine kinase 2; HER2=human epidermal growth factor receptor 2; KRAS=Kirsten rat sarcoma; MET=mesenchymal-epithelial transition; NRG1=neuregulin 1; NSCLC=non-small cell lung cancer; NTRK=neurotrophic tyrosine receptor kinase; PD-L1=programmed death-ligand 1; RAS=rat sarcoma; RET=ret proto-oncogene protein; ROS1=ROS proto-oncogene 1, receptor tyrosine kinase.
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References: 1. Spagnuolo A, Maione P, Gridelli C. The treatment of advanced non-small cell lung cancer harboring KRAS mutation: a new class of drugs for an old target—a narrative review. Transl Lung Cancer Res. 2022;11(6):1199-1216. doi:10.21037/tlcr-21-948 2. Reita D, Pabst L, Pencreach E, et al. Direct targeting KRAS mutation in non-small cell lung cancer: focus on resistance. Cancers (Basel). 2022;14(5):1321. doi:10.3390/cancers14051321 3. Frisch A, Martin E, Kim SY, Riess JW, Sen T, Karim N. KRAS mutated NSCLC: past, present, and future directions in a rapidly evolving landscape. Oncologist. 2025;30(6):oyaf153. doi:10.1093/oncolo/oyaf153 4. Laguna JC, García-Pardo M, Alessi J, et al. Geographic differences in lung cancer: focus on carcinogens, genetic predisposition, and molecular epidemiology. Ther Adv Med Oncol. 2024;16:17588359241231260. doi:10.1177/17588359241231260 5. Reck M, Carbone DP, Garassino M, Barlesi F. Targeting KRAS in non-small-cell lung cancer: recent progress and new approaches. Ann Oncol. 2021;32(9):1101-1110. doi:10.1016/j.annonc.2021.06.001 6. Data on file. Revolution Medicines, Inc.; 2025. 7. Sun L, Zhou Y, Handorf EA, Borghaei H, Bauman J, Aggarwal C. Brief report: not created equal: survival differences by KRAS mutation subtype in NSCLC treated with immunotherapy. JTO Clin Res Rep. 2024;6(1):100755. doi:10.1016/j.jtocrr.2024.100755 8. Ricciuti B, Alessi JV, Elkrief A, et al. Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRASG12D-mutated non-small-cell lung cancer. Ann Oncol. 2022;33(10):1029-1040. doi:10.1016/ j.annonc.2022.07.005 9. Di Federico A, Hong L, Elkrief A, et al. Lung adenocarcinomas with mucinous histology: clinical, genomic, and immune microenvironment characterization and outcomes to immunotherapy-based treatments and KRASG12C inhibitors. Ann Oncol. 2025;36(3):297-308. doi:10.1016/j.annonc.2024.11.014 10. Shim HS, Kenudson M, Zheng Z, et al. Unique genetic and survival characteristics of invasive mucinous adenocarcinoma of the lung. J Thorac Oncol. 2015;10(8):1156-1162. doi:10.1097/JTO.0000000000000579 11. Zhao R, Shu Y, Xu W, et al. The efficacy of immunotherapy in non-small cell lung cancer with KRAS mutation: a systematic review and meta-analysis. Cancer Cell Int. 2024;24(1):361. doi:10.1186/s12935-024-03498-9 12. Gu G, Liu C, Zhu X, et al. Clinical characteristics of KRAS mutation subtypes in non-small cell lung cancer population in Xinjiang, China, and their impact on the prognosis of immunotherapy. J Cancer Res Clin Oncol. 2024;150(9):413. doi:10.1007/s00432-024-05932-x 13. Tamiya Y, Matsumoto S, Zenke Y, et al. Large-scale clinico-genomic profile of non-small cell lung cancer with KRAS G12C: results from LC-SCRUM-Asia study. Lung Cancer. 2023;176:103-111. doi:10.1016/j.lungcan.2022.12.019 14. Zhao D, Li H, Mambetsariev I, et al. Clinical and molecular features of KRAS-mutated lung cancer patients treated with immune checkpoint inhibitors. Cancers (Basel). 2022;14(19):4933. doi:10.3390/cancers14194933 15. Eklund EA, Sayin SI, Jonsson JS, et al. Monotherapy with immune checkpoint blockade improves survival outcomes in KRAS-mutant but not KRAS wild-type metastatic lung adenocarcinoma: validation from an extended Swedish cohort. JTO Clin Res Rep. 2025;6(10):100880. doi:10.1016/j.jtocrr.2025.100880 16. Lokhandwala J, Smalley TB, Tran TH. Structural perspectives on recent breakthrough efforts toward direct drugging of RAS and acquired resistance. Front Oncol. 2024;14:1394702. doi:10.3389/fonc.2024.1394702 17. Jiang J, Jiang L, Maldonato BJ, et al. Translational and therapeutic evaluation of RAS-GTP inhibition by RMC-6236 in RAS-driven cancers. Cancer Discov. 2024;14(6):994-1017. doi: 10.1158/2159-8290.CD-24-0027 18. Ghazali N, Garassino MC, Leighl NB, Bestvina CM. Immunotherapy in advanced, KRAS G12C-mutant non-small-cell lung cancer: current strategies and future directions. Ther Adv Med Oncol. 2025;17:17588359251323985. doi:10.1177/17588359251323985 19. Uniyal P, Kashyap VK, Behl T, Parashar D, Rawat R. KRAS mutations in cancer: understanding signaling pathways to immune regulation and the potential of immunotherapy. Cancers (Basel). 2025;17(5):785. doi:10.3390/cancers17050785 20. Huang HT, Huang DDR. Beyond PACIFIC: rethinking consolidation in molecularly defined stage III NSCLC. J Thorac Oncol. 2026;21(6):103658. doi:10.1016/j.jtho.2026.103658 21. Eklund EA, Wiel C, Fagman H, et al. KRAS mutations impact clinical outcome in metastatic non-small cell lung cancer. Cancers (Basel). 2022;14(9):2063. doi:10.3390/cancers14092063 22. Bailly C, Thuru X, Quesnel B. Combined cytotoxic chemotherapy and immunotherapy of cancer: modern times. NAR Cancer. 2020;2(1):zcaa002. doi:10.1093/narcan/zcaa002
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