Therapeutic advances with KRASG12C inhibitors and combination strategies in non-small cell lung cancer brain metastases

Non-small cell lung cancer (NSCLC) frequently metastasizes to the brain in approximately 20–40% of cases. Mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) are common in NSCLC, with the KRASG12C variant accounting for approximately 40% of KRAS-mutant cases. Up to 40% of NSCLC patients harboring the KRASG12C mutation develop brain metastases during follow-up, and a substantial proportion present with brain metastases at diagnosis. While KRASG12C inhibitors such as sotorasib and adagrasib are approved therapies, most patients with KRASG12C mutant NSCLC experience disease progression within 5 to 6 months. Emerging KRASG12Cinhibitors, such as adagrasib, RMC-6236, and olomorasib, show intracranial activity in KRASG12C mutant NSCLC brain metastases, but adaptive resistance limits their effectiveness as monotherapies. This article examines the clinical and translational application of specific next-generation blood-brain barrier penetrant KRASG12C inhibitors, such as sotorasib, adagrasib, olomorasib, RMC-6236, and D3S-001, and their rational integration with radiation therapy, targeted therapies, and immunotherapies to overcome therapeutic resistance in patients with NSCLC brain metastases. This review summarizes recent advances aimed at enhancing intracranial tumor control and overall survival in patients with NSCLC brain metastases through the use of next-generation KRASG12C inhibitors and multimodal therapies.

Gerelateerde artikelen:

Similar content being viewed by others

Pan-tumor activity of olomorasib, a next-generation KRAS G12C inhibitor in KRAS G12C-mutant advanced solid tumors: a first-in-human study

Article Open access12 March 2026

From bench to bedside: current development and emerging trend of KRAS-targeted therapy

Article 04 December 2023

Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes

Article Open access 29 November 2021

References:

1. Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025;75:10–45.

   PubMed PubMed Central Google Scholar 

2. Fuchs J, Fruh M, Papachristofilou A, Bubendorf L, Hauptle P, Jost L, et al. Resection of isolated brain metastases in non-small cell lung cancer (NSCLC) patients–evaluation of outcome and prognostic factors: a retrospective multicenter study. PLoS One. 2021;16:e0253601.

   Article CAS PubMed PubMed Central Google Scholar 

3. Waqar SN, Samson PP, Robinson CG, Bradley J, Devarakonda S, Du L, et al. Non-small-cell lung cancer with brain metastasis at presentation. Clin Lung Cancer. 2018;19:e373–e379.

   Article PubMed PubMed Central Google Scholar 

4. Sperduto PW, Yang TJ, Beal K, Pan H, Brown PD, Bangdiwala A, et al. Estimating survival in patients with lung cancer and brain metastases: an update of the graded prognostic assessment for lung cancer using molecular markers (Lung-molGPA). JAMA Oncol. 2017;3:827–31.

   Article PubMed PubMed Central Google Scholar 

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;32:1101–10.

   Article CAS PubMed Google Scholar 

6. Huang L, Guo Z, Wang F, Fu L. KRAS mutation: from undruggable to druggable in cancer. Signal Transduct Target Ther. 2021;6:386.

   Article PubMed PubMed Central Google Scholar 

7. Liu J, Kang R, Tang D. The KRAS-G12C inhibitor: activity and resistance. Cancer Gene Ther. 2022;29:875–8.

   Article CAS PubMed Google Scholar 

8. Judd J, Abdel Karim N, Khan H, Naqash AR, Baca Y, Xiu J, et al. Characterization of KRAS mutation subtypes in non–small cell lung cancer. Mol Cancer Ther. 2021;20:2577–84.

   Article CAS PubMed PubMed Central Google Scholar 

9. Attili I, Corvaja C, Trillo Aliaga P, Del Signore E, Spitaleri G, Passaro A, et al. Dealing with KRAS G12C inhibition in non-small cell lung cancer (NSCLC)-biology, clinical results and future directions. Cancer Treat Rev. 2025;137:102957.

   Article PubMed Google Scholar 

10. Xie M, Xu X, Fan Y. KRAS-mutant non-small cell lung cancer: an emerging, promisingly treatable subgroup. Front Oncol. 2021;11:672612.

    Article CAS PubMed PubMed Central Google Scholar 

11. Abhyankar A, Dy GK. Intracranial efficacy of adagrasib in patients with KRAS G12C mutated non-small cell lung cancer (NSCLC): are results KRYSTAL clear? AME Clin Trials Rev. 2024;2:57.

    Article Google Scholar 

12. Punekar SR, Velcheti V, Neel BG, Wong KK. The current state of the art and future trends in RAS-targeted cancer therapies. Nat Rev Clin Oncol. 2022;19:637–55.

    Article CAS PubMed PubMed Central Google Scholar 

13. Cui W, Franchini F, Alexander M, Officer A, Wong HL, M IJ, et al. Real-world outcomes in KRAS G12C mutation-positive non-small cell lung cancer. Lung Cancer. 2020;146:310–7.

    Article PubMed Google Scholar 

14. Lamberti G, Aizer A, Ricciuti B, Alessi JV, Pecci F, Tseng SC, et al. Incidence of brain metastases and preliminary evidence of intracranial activity with sotorasib in patients with KRAS(G12C)-mutant non-small-cell lung cancer. JCO Precis Oncol. 2023;7:e2200621.

    Article PubMed PubMed Central Google Scholar 

15. Vassella E, Kashani E, Zens P, Kundig A, Fung C, Scherz A, et al. Mutational profiles of primary pulmonary adenocarcinoma and paired brain metastases disclose the importance of KRAS mutations. Eur J Cancer. 2021;159:227–36.

    Article CAS PubMed Google Scholar 

16. Sabari JK, Velcheti V, Shimizu K, Strickland MR, Heist RS, Singh M, et al. Activity of adagrasib (MRTX849) in brain metastases: preclinical models and clinical data from patients with KRASG12C-mutant non-small cell lung cancer. Clin Cancer Res. 2022;28:3318–28.

    Article CAS PubMed PubMed Central Google Scholar 

17. Nassar AH, Adib E, Kwiatkowski DJ. Distribution of KRAS (G12C) somatic mutations across race, sex, and cancer type. N Engl J Med. 2021;384:185–7.

    Article PubMed Google Scholar 

18. Parikh NR, Likhacheva A, Pinnix C, Allen PK, Prabhu SS, Guha-Thakurta N, et al. Prognostic significance of EGFR and KRAS mutations in NSCLC patients with brain metastases treated with radiosurgery(dagger). J Radiosurgery SBRT. 2015;3:171–8.

    Google Scholar 

19. Chour A, Toffart AC, Berton E, Duruisseaux M. Mechanisms of resistance to KRASG12C inhibitors in KRASG12C-mutated non-small cell lung cancer. Front Oncol. 2024;14:1328728.

    Article CAS PubMed PubMed Central Google Scholar 

20. Kim D, Xue JY, Lito P. Targeting KRAS(G12C): from inhibitory mechanism to modulation of antitumor effects in patients. Cell. 2020;183:850–9.

    Article CAS PubMed PubMed Central Google Scholar 

21. Rosell R, Codony-Servat J, Gonzalez J, Santarpia M, Jain A, Shivamallu C, et al. KRAS G12C-mutant driven non-small cell lung cancer (NSCLC). Crit Rev Oncol Hematol. 2024;195:104228.

    Article PubMed Google Scholar 

22. Zhou Y, Kuang Y, Wang C, Yu Y, Pan L, Hu X. Impact of KRAS mutation on the tumor microenvironment in colorectal cancer. Int J Biol Sci. 2024;20:1947–64.

    Article CAS PubMed PubMed Central Google Scholar 

23. Xu M, Zhao X, Wen T, Qu X. Unveiling the role of KRAS in tumor immune microenvironment. Biomed Pharmacother. 2024;171:116058.

    Article CAS PubMed Google Scholar 

24. Chi A, Komaki R. Treatment of brain metastasis from lung cancer. Cancers. 2010;2:2100–37.

    Article CAS PubMed PubMed Central Google Scholar 

25. Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS, Wolf J, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. 2021;384:2371–81.

    Article CAS PubMed PubMed Central Google Scholar 

26. de Langen AJ, Johnson ML, Mazieres J, Dingemans AC, Mountzios G, Pless M, et al. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS(G12C) mutation: a randomised, open-label, phase 3 trial. Lancet. 2023;401:733–46.

    Article PubMed Google Scholar 

27. Janne PA, Riely GJ, Gadgeel SM, Heist RS, Ou SI, Pacheco JM, et al. Adagrasib in non-small-cell lung cancer harboring a KRAS(G12C) mutation. N Engl J Med. 2022;387:120–31.

    Article CAS PubMed Google Scholar 

28. Negrao MV, Araujo HA, Lamberti G, Cooper AJ, Akhave NS, Zhou T, et al. Comutations and KRASG12C inhibitor efficacy in advanced NSCLC. Cancer Discov. 2023;13:1556–71.

    Article CAS PubMed PubMed Central Google Scholar 

29. Armon S, Hofman P, Ilie M. Perspectives and issues in the assessment of SMARCA4 deficiency in the management of lung cancer patients. Cells. 2021;10:1920.

30. Satoh H, Moriguchi T, Takai J, Ebina M, Yamamoto M. Nrf2 prevents initiation but accelerates progression through the Kras signaling pathway during lung carcinogenesis. Cancer Res. 2013;73:4158–68.

    Article CAS PubMed Google Scholar 

31. Ji H, Ramsey MR, Hayes DN, Fan C, McNamara K, Kozlowski P, et al. LKB1 modulates lung cancer differentiation and metastasis. Nature. 2007;448:807–10.

    Article CAS PubMed Google Scholar 

32. Zhao N, Wilkerson MD, Shah U, Yin X, Wang A, Hayward MC, et al. Alterations of LKB1 and KRAS and risk of brain metastasis: comprehensive characterization by mutation analysis, copy number, and gene expression in non-small-cell lung carcinoma. Lung Cancer. 2014;86:255–61.

    Article PubMed PubMed Central Google Scholar 

33. Manolakos P, Boccuto L, Ivankovic DS. A critical review of the impact of SMARCA4 mutations on survival outcomes in non-small cell lung cancer. J Pers Med. 2024;14:684.

34. Morshed RA, Nguyen MP, Cummins DD, Saggi S, Young JS, Haddad AF, et al. CDKN2A/B co-deletion is associated with increased risk of local and distant intracranial recurrence after surgical resection of brain metastases. Neurooncol Adv. 2023;5:vdad007.

    PubMed PubMed Central Google Scholar 

35. Skakodub A, Walch H, Tringale KR, Eichholz J, Imber BS, Vasudevan HN, et al. Genomic analysis and clinical correlations of non-small cell lung cancer brain metastasis. Nat Commun. 2023;14:4980.

    Article CAS PubMed PubMed Central Google Scholar 

36. Schuster K, Venkateswaran N, Rabellino A, Girard L, Pena-Llopis S, Scaglioni PP. Nullifying the CDKN2AB locus promotes mutant K-ras lung tumorigenesis. Mol Cancer Res. 2014;12:912–23.

    Article CAS PubMed PubMed Central Google Scholar 

37. Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, et al. The KRAS(G12C) inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 2020;10:54–71.

    Article CAS PubMed Google Scholar 

38. Tang M, Wu Y, Bai X, Lu Y. KRAS(G12C) inhibitors in non-small cell lung cancer: a review. Onco Targets Ther. 2024;17:683–95.

    Article CAS PubMed PubMed Central Google Scholar 

39. Jiang J, Jiang L, Maldonato BJ, Wang Y, Holderfield M, Aronchik I, et al. Translational and therapeutic evaluation of RAS-GTP inhibition by RMC-6236 in RAS-driven cancers. Cancer Discov. 2024;14:994–1017.

    Article CAS PubMed PubMed Central Google Scholar 

40. Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575:217–23.

    Article CAS PubMed Google Scholar 

41. Nakajima EC, Drezner N, Li X, Mishra-Kalyani PS, Liu Y, Zhao H, et al. FDA approval summary: sotorasib for KRAS G12C-mutated metastatic NSCLC. Clin Cancer Res. 2022;28:1482–6.

    Article CAS PubMed PubMed Central Google Scholar 

42. Lebouille-Veldman AB, Taros TN, Nawabi NLA, Mekary RA, Peng L, Phillips J. Brief report on the efficacy of sotorasib in KRAS-mutated NSCLC patients with brain metastases. Lung Cancer. 2024;187:107425.

    Article CAS PubMed Google Scholar 

43. Ramalingam S, Skoulidis F, Govindan R, Velcheti V, Li B, Besse B, et al. P52.03 efficacy of sotorasib in KRAS p. G12C-mutated NSCLC with stable brain metastases: a post-hoc analysis of CodeBreaK 100. J Thorac Oncol. 2021;16:S1123.

    Article Google Scholar 

44. Negrao MV, Spira AI, Heist RS, Janne PA, Pacheco JM, Weiss J, et al. Intracranial efficacy of adagrasib in patients from the KRYSTAL-1 trial with KRAS(G12C)-mutated non-small-cell lung cancer who have untreated CNS metastases. J Clin Oncol. 2023;41:4472–7.

    Article CAS PubMed PubMed Central Google Scholar 

45. Peng S-B, Si C, Zhang Y, Van Horn RD, Lin X, Gong X, et al. Abstract 1259: preclinical characterization of LY3537982, a novel, highly selective and potent KRAS-G12C inhibitor. Cancer Res. 2021;81:1259.

    Article Google Scholar 

46. Heist RS, Koyama T, Murciano-Goroff YR, Hollebecque A, Cassier PA, Han J-Y, et al. Pan-tumor activity of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in patients with KRAS G12C-mutant advanced solid tumors. J Clin Oncol. 2024;42:3007.

    Article Google Scholar 

47. Nigro P, Pompilio G, Capogrossi MC. Cyclophilin A: a key player for human disease. Cell Death Dis. 2013;4:e888.

    Article CAS PubMed PubMed Central Google Scholar 

48. Lamb YN. Fulzerasib: first approval. Drugs. 2024;84:1665–71.

    Article CAS PubMed Google Scholar 

49. Zhou Q, Yang N, Zhao M, Huang D, Zhao J, Yu Y, et al. Potent covalent irreversible inhibitor of KRAS G12C IBI351 in patients with advanced solid tumors: first-in-human phase I study. Eur J Cancer. 2024;212:114337.

    Article CAS PubMed Google Scholar 

50. Zhou Q, Meng X, Sun L, Huang D, Yang N, Yu Y, et al. Efficacy and safety of KRASG12C inhibitor IBI351 monotherapy in patients with advanced NSCLC: results from a phase 2 pivotal study. J Thorac Oncol. 2024;19:1630–9.

    Article CAS PubMed Google Scholar 

51. Gregorc V, Gonzalez-Cao M, Salvagni S, Koumarianou A, Gil-Bazo I, Maio M, et al. KROCUS: a phase II study investigating the efficacy and safety of fulzerasib (GFH925) in combination with cetuximab in patients with previously untreated advanced KRAS G12C mutated NSCLC. J Clin Oncol. 2024;42:LBA8511.

52. Zhou Q, Yang N, Zhao J, Zhao M, Yu Y, Yuan Y. et al. Phase I study of IBI351 (GFH925) monotherapy in patients with advanced solid tumors: Updated results of the phase I study. Cancer Res. 2023;83:CT030.

    Article Google Scholar 

53. Li Z, Song Z, Zhao Y, Wang P, Jiang L, Gong Y, et al. D-1553 (Garsorasib), a potent and selective inhibitor of KRAS(G12C) in Patients With NSCLC: phase 1 study results. J Thorac Oncol. 2023;18:940–51.

    Article CAS PubMed Google Scholar 

54. Li Z, Dang X, Huang D, Jin S, Li W, Shi J, et al. Garsorasib in patients with KRAS(G12C)-mutated non-small-cell lung cancer in China: an open-label, multicentre, single-arm, phase 2 trial. Lancet Respir Med. 2024;12:589–98.

    Article CAS PubMed Google Scholar 

55. Batrash F, Kutmah M, Zhang J. The current landscape of using direct inhibitors to target KRAS(G12C)-mutated NSCLC. Exp Hematol Oncol. 2023;12:93.

    Article CAS PubMed PubMed Central Google Scholar 

56. Waizenegger IC, Lu H, Thamer C, Savarese F, Gerlach D, Rudolph D, et al. Abstract 2667: Trial in progress: phase 1 study of BI 1823911, an irreversible KRASG12C inhibitor targeting KRAS in its GDP-loaded state, as monotherapy and in combination with the pan-KRAS SOS1 inhibitor BI 1701963 in solid tumors expressing KRASG12C mutation. Cancer Res. 2022;82:2667.

    Article Google Scholar 

57. Zhang F, Wang B, Wu M, Zhang L, Ji M. Current status of KRAS G12C inhibitors in NSCLC and the potential for combination with anti-PD-(L)1 therapy: a systematic review. Front Immunol. 2025;16:1509173.

    Article CAS PubMed PubMed Central Google Scholar 

58. Heymach J, Kotecki N, Prenen H, Alonso G, Lindsay C, Barve M, et al. 665P First-in-human, phase Ia/b, dose-escalation/expansion study of KRAS G12C inhibitor BI 1823911, as monotherapy and combined with anticancer therapies, in patients (pts) with advanced or metastatic solid tumours harbouring a KRAS G12C mutation. Ann Oncol. 2023;34:S468.

    Article Google Scholar 

59. Savarese F, Gollner A, Rudolph D, Lipp J, Popow J, Hofmann MH, et al. In vitro and in vivo characterization of BI 1823911-a novel KRASG12C selective small molecule inhibitor. Cancer Res. 2021;81:1271.

    Article Google Scholar 

60. Duma N, Sanchez L, Miranda C, Glisch C, Abu-Ihweij K, Zhang S, et al. Prognostic factors for brain metastasis in non-small cell lung cancer (NSCLC): A single Institution's experience for over 10 years. J Clin Oncol. 2015;33:e19062–e19062.

    Article Google Scholar 

61. Sayama H, Marcantonio D, Nagashima T, Shimazaki M, Minematsu T, Apgar JF, et al. Virtual clinical trial simulations for a novel KRAS(G12C) inhibitor (ASP2453) in non-small cell lung cancer. CPT Pharmacomet Syst Pharmacol. 2021;10:864–77.

    Article CAS Google Scholar 

62. Sacher A, LoRusso P, Patel MR, Miller WH Jr., Garralda E, Forster MD, et al. Single-agent divarasib (GDC-6036) in solid tumors with a KRAS G12C mutation. N Engl J Med. 2023;389:710–21.

    Article CAS PubMed Google Scholar 

63. Skoulidis F, Cuppens K, Sacher AG, Velcheti V, Lee DH, Lin MT, et al. Krascendo-170 Lung: a phase Ib/II study of divarasib + pembrolizumab ± platinum-based chemotherapy and pemetrexed in untreated KRAS G12C+advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2024;42:TPS8651.

    Article Google Scholar 

64. Zhang J, Lim SM, Yu MR, Chen C, Wang J, Wang W, et al. D3S-001, a KRAS G12C Inhibitor with rapid target engagement kinetics, overcomes nucleotide cycling, and demonstrates robust preclinical and clinical activities. Cancer Discov. 2024;14:1675–98.

    Article CAS PubMed PubMed Central Google Scholar 

65. Paisana E, Cascao R, Alvoeiro M, Felix F, Martins G, Guerreiro C, et al. Immunotherapy in lung cancer brain metastases. NPJ Precis Oncol. 2025;9:130.

    Article PubMed PubMed Central Google Scholar 

66. Akhave NS, Biter AB, Hong DS. Mechanisms of resistance to KRAS(G12C)-targeted therapy. Cancer Discov. 2021;11:1345–52.

    Article CAS PubMed PubMed Central Google Scholar 

67. Koga T, Suda K, Fujino T, Ohara S, Hamada A, Nishino M, et al. KRAS secondary mutations that confer acquired resistance to KRAS G12C inhibitors, sotorasib and adagrasib, and overcoming strategies: insights from in vitro experiments. J Thorac Oncol. 2021;16:1321–32.

    Article CAS PubMed Google Scholar 

68. Awad MM, Liu S, Rybkin II, Arbour KC, Dilly J, Zhu VW, et al. Acquired resistance to KRAS(G12C) inhibition in cancer. N Engl J Med. 2021;384:2382–93.

    Article CAS PubMed PubMed Central Google Scholar 

69. Tanaka N, Lin JJ, Li C, Ryan MB, Zhang J, Kiedrowski LA, et al. Clinical acquired resistance to KRAS(G12C) inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation. Cancer Discov. 2021;11:1913–22.

    Article CAS PubMed PubMed Central Google Scholar 

70. Ash LJ, Busia-Bourdain O, Okpattah D, Kamel A, Liberchuk A, Wolfe AL. KRAS: biology, inhibition, and mechanisms of inhibitor resistance. Curr Oncol. 2024;31:2024–46.

    Article PubMed PubMed Central Google Scholar 

71. Lee C, Yi J, Park J, Ahn B, Won YW, Jeon J, et al. Hedgehog signalling is involved in acquired resistance to KRAS(G12C) inhibitors in lung cancer cells. Cell Death Dis. 2024;15:56.

    Article CAS PubMed PubMed Central Google Scholar 

72. Morimoto K, Yamada T, Hirai S, Katayama Y, Fukui S, Sawada R, et al. AXL signal mediates adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutant tumor cells. Cancer Lett. 2024;587:216692.

    Article CAS PubMed Google Scholar 

73. Ning W, Marti TM, Dorn P, Peng RW. Non-genetic adaptive resistance to KRAS(G12C) inhibition: EMT is not the only culprit. Front Oncol. 2022;12:1004669.

    Article CAS PubMed PubMed Central Google Scholar 

74. Lietman CD, Johnson ML, McCormick F, Lindsay CR. More to the RAS Story: KRAS(G12C) inhibition, resistance mechanisms, and moving beyond KRAS(G12C). Am Soc Clin Oncol Educ Book. 2022;42:1–13.

    PubMed Google Scholar 

75. Adachi Y, Ito K, Hayashi Y, Kimura R, Tan TZ, Yamaguchi R, et al. Epithelial-to-mesenchymal transition is a cause of both intrinsic and acquired resistance to the KRAS G12C inhibitor in KRAS G12C-mutant non-small cell lung cancer. Clin Cancer Res. 2020;26:5962–73.

    Article CAS PubMed Google Scholar 

76. Shih DJH, Nayyar N, Bihun I, Dagogo-Jack I, Gill CM, Aquilanti E, et al. Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma. Nat Genet. 2020;52:371–7.

    Article CAS PubMed PubMed Central Google Scholar 

77. Migliarese C, Sadeh Y, Torrini C, Turna Demir F, Nayyar N, Yamazawa E, et al. Combination therapy of adagrasib and abemaciclib in non-small cell lung cancer brain metastasis models, genomically characterized by KRAS-G12C and homozygous loss of CDKN2A. Acta Neuropathol Commun. 2025;13:88.

    Article CAS PubMed PubMed Central Google Scholar 

78. Liu L, Hong S, Zhang V, Gilmer T. Abstract 4394: Identification of molecular determinants of response to GSK1120212B, a potent and selective MEK inhibitor, as a single agent and in combination in RAS/RAF mutant non-small cell lung carcinoma cells. Cancer Res. 2011;71:4394.

    Article Google Scholar 

79. Blumenschein GR Jr., Smit EF, Planchard D, Kim DW, Cadranel J, De Pas T, et al. A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC). dagger Ann Oncol. 2015;26:894–901.

    Article Google Scholar 

80. Ramalingam S, Fakih M, Strickler J, Govindan R, Li BT, Goldberg S, et al. Abstract P05-01: A phase 1b study evaluating the safety and efficacy of sotorasib, a KRASG12C inhibitor, in combination with trametinib, a MEK inhibitor, in KRAS p.G12C-Mutated Solid Tumors. Mol Cancer Ther. 2021;20:P05-01.

    Article Google Scholar 

81. Negrao M, Cassier P, Solomon B, Schuler M, Rohrberg K, Cresta S, et al. MA06.03 KontRASt-01: preliminary safety and efficacy of JDQ443+ TNO155 in patients with advanced, KRAS G12C-mutated solid tumors. J Thorac Oncol. 2023;18:S117–S118.

    Article Google Scholar 

82. Anastasiou P, Moore C, Rana S, Tomaschko M, Pillsbury CE, de Castro A, et al. Combining RAS(ON) G12C-selective inhibitor with SHP2 inhibition sensitises lung tumours to immune checkpoint blockade. Nat Commun. 2024;15:8146.

    Article CAS PubMed PubMed Central Google Scholar 

83. Laurent PA, Milic M, Quevrin C, Meziani L, Liu W, Morel D, et al. KRAS(G12C) inhibition using MRTX1257: a novel radio-sensitizing partner. J Transl Med. 2023;21:773.

    Article CAS PubMed PubMed Central Google Scholar 

84. Jia X, Liu M, Cheng Z. Sotorasib as first-line therapy in patients with advanced non-small cell lung cancer with KRAS gene mutations combined with brain metastases: a case report. AME Case Rep. 2024;8:48.

    Article PubMed PubMed Central Google Scholar 

85. Zheng Y, Liu Y, Zhang F, Su C, Chen X, Zhang M, et al. Radiation combined with KRAS-MEK inhibitors enhances anticancer immunity in KRAS-mutated tumor models. Transl Res. 2023;252:79–90.

    Article CAS PubMed Google Scholar 

86. Lee K, Choi YJ, Kim JS, Kim DS, Lee SY, Shin BK, et al. Association between PD-L1 expression and initial brain metastasis in patients with non-small cell lung cancer and its clinical implications. Thorac Cancer. 2021;12:2143–50.

    Article CAS PubMed PubMed Central Google Scholar 

87. Sabari JK, Spira AI, Heist RS, Janne PA, Pacheco JM, Weiss J. et al, Activity of adagrasib (MRTX849) in patients with KRASG12C-mutated NSCLC and active, untreated CNS metastases in the KRYSTAL-1 trial. J Clin Oncol. 2022;40:LBA9009.

    Article Google Scholar 

88. Tripathi P, Soni R, Antra, Tandon V. Pixantrone confers radiosensitization in KRAS-mutated cancer cells by suppression of radiation-induced prosurvival pathways. Free Radic Biol Med. 2022;190:351–62.

    Article CAS PubMed Google Scholar 

89. Sad K, Parashar P, Tripathi P, Hungyo H, Sistla R, Soni R, et al. Prochlorperazine enhances radiosensitivity of non-small cell lung carcinoma by stabilizing GDP-bound mutant KRAS conformation. Free Radic Biol Med. 2021;177:299–312.

    Article CAS PubMed Google Scholar 

90. Ma X, Sloman DL, Duggal R, Anderson KD, Ballard JE, Bharathan I, et al. Discovery of MK-1084: an orally bioavailable and low-dose KRAS(G12C) inhibitor. J Med Chem. 2024;67:11024–52.

    Article CAS PubMed Google Scholar 

91. Shi Z, Weng J, Niu H, Yang H, Liu R, Weng Y, et al. D-1553: a novel KRAS(G12C) inhibitor with potent and selective cellular and in vivo antitumor activity. Cancer Sci. 2023;114:2951–60.

    Article CAS PubMed PubMed Central Google Scholar 

92. Li A, Li S, Wang P, Dang C, Fan X, Chen M, et al. Design, structure optimization, and preclinical characterization of JAB-21822, a covalent inhibitor of KRAS(G12C). J Med Chem. 2025;68:2422–36.

    Article CAS PubMed Google Scholar 

93. Schulze CJ, Seamon KJ, Zhao Y, Yang YC, Cregg J, Kim D, et al. Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS. Science. 2023;381:794–9.

    Article CAS PubMed PubMed Central Google Scholar 

94. Cheema PK, Banerji SO, Blais N, Chu QS, Juergens RA, Leighl NB, et al. Canadian consensus recommendations on the management of KRAS G12C-mutated NSCLC. Curr Oncol. 2023;30:6473–96.

    Article PubMed PubMed Central Google Scholar 

95. Ganguly A, Yoo E. Sotorasib: a KRAS(G12C) inhibitor for non-small cell lung cancer. Trends Pharmacol Sci. 2022;43:536–7.

    Article CAS PubMed PubMed Central Google Scholar 

96. Tian H, Yang Z, He J. Adagrasib: a landmark in the KRAS(G12C)-mutated NSCLC. MedComm. 2022;3:e190 (2020).

    Article PubMed PubMed Central Google Scholar 

97. Araujo HA, Pechuan-Jorge X, Zhou T, Do MT, Hu X, Rojas Álvarez FR, et al. Mechanisms of response and tolerance to active RAS inhibition in KRAS-mutant non-small cell lung cancer. Cancer Discov. 2024;14:2183–208.

    Article CAS PubMed PubMed Central Google Scholar 

98. Wasko UN, Jiang J, Dalton TC, Curiel-Garcia A, Edwards AC, Wang Y, et al. Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer. Nature. 2024;629:927–36.

    Article CAS PubMed PubMed Central Google Scholar 

99. Cho BC, Lu S, Lee MA, Song Z, Park JJ, Lim SM, et al. D3S-001 in advanced solid tumors with KRAS(G12C) mutations: a phase 1 trial. Nat Med. 2025;31:2768–77.

    Article CAS PubMed Google Scholar