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Targeting KRASG12C in Non-Small-Cell Lung Cancer: Current Standards and Developments

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Abstract

Among the most common molecular alterations detected in non-small-cell lung cancer (NSCLC) are mutations in Kristen Rat Sarcoma viral oncogene homolog (KRAS). KRAS mutant NSCLC is a heterogenous group of diseases, different from other oncogene-driven tumors in terms of biology and response to therapies. Despite efforts to develop drugs aimed at inhibiting KRAS or its signaling pathways, KRAS had remained undruggable for decades. The discovery of a small pocket in the binding switch II region of KRASG12C has revolutionized the treatment of KRASG12C-mutated NSCLC patients. Sotorasib and adagrasib, direct KRASG12C inhibitors, have been approved by the US Food and Drug Administration (FDA) and other regulatory agencies for patients with previously treated KRASG12C-mutated NSCLC, and these advances have become practice changing. However, first-line treatment in KRASG12C-mutated NSCLC does not differ from NSCLC without actionable driver genomic alterations. Treatment with KRASG12C inhibitors is not curative and patients develop progressive disease, so understanding associated mechanisms of drug resistance is key. New KRASG12C inhibitors and several combination therapy strategies, including with immune checkpoint inhibitors, are being studied in clinical trials. The aim of this review is to explore the clinical impact of KRAS, and outline different treatment approaches, focusing on the novel treatment of KRASG12C-mutated NSCLC.

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References

  1. Leiter A, Veluswamy RR, Wisnivesky JP. The global burden of lung cancer: current status and future trends. Nat Rev Clin Oncol. 2023;20(9):624–39. https://doi.org/10.1038/s41571-023-00798-3.

    Article  PubMed  Google Scholar 

  2. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74:12–49. https://doi.org/10.3322/caac.21820.

    Article  PubMed  Google Scholar 

  3. Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS. Lung cancer. Lancet. 2021;398:535–54. https://doi.org/10.1016/S0140-6736(21)00312-3.

    Article  PubMed  Google Scholar 

  4. Nicholson AG, Tsao MS, Beasley MB, Borczuk AC, Brambilla E, Cooper WA, et al. The 2021 WHO classification of lung tumors: impact of advances since 2015. J Thorac Oncol. 2022;17:362–87. https://doi.org/10.1016/j.jtho.2021.11.003.

    Article  PubMed  Google Scholar 

  5. The Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511:543–50. https://doi.org/10.1038/nature13385.

    Article  CAS  PubMed Central  Google Scholar 

  6. Yang S-R, Schultheis AM, Yu H, Mandelker D, Ladanyi M, Büttner R. Precision medicine in non-small cell lung cancer: current applications and future directions. Semin Cancer Biol. 2022;84:184–98. https://doi.org/10.1016/j.semcancer.2020.07.009.

    Article  CAS  PubMed  Google Scholar 

  7. Díaz-Serrano A, Gella P, Jiménez E, Zugazagoitia J, Paz-Ares Rodríguez L. Targeting EGFR in lung cancer: current standards and developments. Drugs. 2018;78:893–911. https://doi.org/10.1007/s40265-018-0916-4.

    Article  CAS  PubMed  Google Scholar 

  8. Tan AC, Tan DSW. Targeted therapies for lung cancer patients with oncogenic driver molecular alterations. J Clin Oncol. 2022;40:611–25. https://doi.org/10.1200/JCO.21.01626.

    Article  CAS  PubMed  Google Scholar 

  9. Howlader N, Forjaz G, Mooradian MJ, Meza R, Kong CY, Cronin KA, et al. The effect of advances in lung-cancer treatment on population mortality. N Engl J Med. 2020;383:640–9. https://doi.org/10.1056/NEJMoa1916623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Reck M, Remon J, Hellmann MD. First-line immunotherapy for non–small-cell lung cancer. J Clin Oncol. 2022;40:586–97. https://doi.org/10.1200/JCO.21.01497.

    Article  CAS  PubMed  Google Scholar 

  11. Prior IA, Hood FE, Hartley JL. The frequency of Ras mutations in cancer. Cancer Res. 2020;80:2969–74. https://doi.org/10.1158/0008-5472.CAN-19-3682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Friedlaender A, Drilon A, Weiss GJ, Banna GL, Addeo A. KRAS as a druggable target in NSCLC: rising like a phoenix after decades of development failures. Cancer Treat Rev. 2020;85: 101978. https://doi.org/10.1016/j.ctrv.2020.101978.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Veluswamy R, Mack PC, Houldsworth J, Elkhouly E, Hirsch FR. KRAS G12C-mutant non-small cell lung cancer. J Mol Diagn. 2021;23:507–20. https://doi.org/10.1016/j.jmoldx.2021.02.002.

    Article  CAS  PubMed  Google Scholar 

  14. Gainor JF, Varghese AM, Ou S-HI, Kabraji S, Awad MM, Katayama R, Pawlak A, et al. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res. 2013;19:4273–81. https://doi.org/10.1158/1078-0432.CCR-13-0318.

    Article  CAS  PubMed  Google Scholar 

  15. Jordan EJ, Kim HR, Arcila ME, Barron D, Chakravarty D, Gao J, et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 2017;7:596–609. https://doi.org/10.1158/2159-8290.CD-16-1337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ceddia S, Landi L, Cappuzzo F. KRAS-mutant non-small-cell lung cancer: from past efforts to future challenges. Int J Mol Sci. 2022;23:9391. https://doi.org/10.3390/ijms23169391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Corral de la Fuente E, Olme do Garcia ME, Gomez Rueda A, Lage Y, Garrido P. Targeting KRAS in non-small cell lung cancer. Front Oncol. 2022;11: 792635. https://doi.org/10.3389/fonc.2021.792635.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Blair HA. Sotorasib: first approval. Drugs. 2021;81:1573–9. https://doi.org/10.1007/s40265-021-01574-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. U.S. Food and Drug Administration FDA Grants Accelerated Approval to Adagrasib for KRAS G12C-Mutated NSCLC.

  20. Timar J, Kashofer K. Molecular epidemiology and diagnostics of KRAS mutations in human cancer. Cancer Metastasis Rev. 2020;39:1029–38. https://doi.org/10.1007/s10555-020-09915-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3:11–22. https://doi.org/10.1038/nrc969.

    Article  CAS  PubMed  Google Scholar 

  22. Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: mission possible? Nat Rev Drug Discov. 2014;13:828–51. https://doi.org/10.1038/nrd4389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Garrido P, Olmedo ME, Gómez A, Paz Ares L, López-Ríos F, Rosa-Rosa JM, et al. Treating KRAS-mutant NSCLC: latest evidence and clinical consequences. Ther Adv Med Oncol. 2017;9:589–97. https://doi.org/10.1177/1758834017719829.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kranenburg O. The KRAS oncogene: past, present, and future. Biochim Biophys Acta BBA Rev Cancer. 2005;1756:81–2. https://doi.org/10.1016/j.bbcan.2005.10.001.

    Article  CAS  Google Scholar 

  25. Cox AD, Der CJ. Ras history: the saga continues. Small GTPases. 2010;1:2–27. https://doi.org/10.4161/sgtp.1.1.12178.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Weng C, Faure AJ, Escobedo A, Lehner B. The energetic and allosteric landscape for KRAS inhibition. Nature. 2023;626(7999):643–52. https://doi.org/10.1038/s41586-023-06954-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503:548–51. https://doi.org/10.1038/nature12796.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ostrem JML, Shokat KM. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov. 2016;15:771–85. https://doi.org/10.1038/nrd.2016.139.

    Article  CAS  PubMed  Google Scholar 

  29. Hillig RC, Sautier B, Schroeder J, Moosmayer D, Hilpmann A, Stegmann CM, et al. Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS–SOS1 interaction. Proc Natl Acad Sci. 2019;116:2551–60. https://doi.org/10.1073/pnas.1812963116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Moore AR, Rosenberg SC, McCormick F, Malek S. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov. 2020;19:533–52. https://doi.org/10.1038/s41573-020-0068-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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. https://doi.org/10.1016/j.annonc.2021.06.001.

    Article  CAS  PubMed  Google Scholar 

  32. Stokoe D, Macdonald SG, Cadwallader K, Symons M, Hancock JF. Activation of Raf as a result of recruitment to the plasma membrane. Science. 1994;264:1463–7. https://doi.org/10.1126/science.7811320.

    Article  CAS  PubMed  Google Scholar 

  33. Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003;3:459–65. https://doi.org/10.1038/nrc1097.

    Article  CAS  PubMed  Google Scholar 

  34. Adderley H, Blackhall FH, Lindsay CR. KRAS-mutant non-small cell lung cancer: converging small molecules and immune checkpoint inhibition. EBioMedicine. 2019;41:711–6. https://doi.org/10.1016/j.ebiom.2019.02.049.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Uras IZ, Moll HP, Casanova E. Targeting KRAS mutant non-small-cell lung cancer: past, present and future. Int J Mol Sci. 2020;21:4325. https://doi.org/10.3390/ijms21124325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Dogan S, Shen R, Ang DC, Johnson ML, D’Angelo SP, Paik PK, Brzostowski EB, et al. Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin Cancer Res. 2012;18:6169–77. https://doi.org/10.1158/1078-0432.CCR-11-3265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Martin P, Leighl NB, Tsao M-S, Shepherd FA. KRAS mutations as prognostic and predictive markers in non-small cell lung cancer. J Thorac Oncol. 2013;8:530–42. https://doi.org/10.1097/JTO.0b013e318283d958.

    Article  CAS  PubMed  Google Scholar 

  38. Skoulidis F, Heymach JV. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy. Nat Rev Cancer. 2019;19:495–509. https://doi.org/10.1038/s41568-019-0179-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dearden S, Stevens J, Wu Y-L, Blowers D. Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol. 2013;24:2371–6. https://doi.org/10.1093/annonc/mdt205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Loong HH-F, Du N, Cheng C, Lin H, Guo J, Lin G, et al. KRAS G12C mutations in Asia: a landscape analysis of 11,951 Chinese tumor samples. Transl Lung Cancer Res. 2020;9:1759–69. https://doi.org/10.21037/tlcr-20-455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wu S-G, Liao W-Y, Su K-Y, Yu S-L, Huang Y-L, Yu C-J, et al. Prognostic characteristics and immunotherapy response of patients with nonsquamous NSCLC with Kras mutation in east Asian populations: a single-center cohort study in Taiwan. JTO Clin Res Rep. 2021;2: 100140. https://doi.org/10.1016/j.jtocrr.2020.100140.

    Article  PubMed  Google Scholar 

  42. Sato K, Akamatsu H, Koh Y, Ogawa K, Isa S, Ando M, et al. Differential properties of KRAS transversion and transition mutations in non-small cell lung cancer: associations with environmental factors and clinical outcomes. BMC Cancer. 2022;22:1148. https://doi.org/10.1186/s12885-022-10246-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Simanshu DK, Nissley DV, McCormick F. RAS proteins and their regulators in human disease. Cell. 2017;170:17–33. https://doi.org/10.1016/j.cell.2017.06.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wiesweg M, Kasper S, Worm K, Herold T, Reis H, Sara L, et al. Impact of RAS mutation subtype on clinical outcome—a cross-entity comparison of patients with advanced non-small cell lung cancer and colorectal cancer. Oncogene. 2019;38:2953–66. https://doi.org/10.1038/s41388-018-0634-0.

    Article  CAS  PubMed  Google Scholar 

  45. Khan I, Rhett JM, O’Bryan JP. Therapeutic targeting of RAS: new hope for drugging the “undruggable.” Biochim Biophys Acta BBA Mol Cell Res. 2020;1867: 118570. https://doi.org/10.1016/j.bbamcr.2019.118570.

    Article  CAS  Google Scholar 

  46. Yang H, Liang S-Q, Schmid RA, Peng R-W. New horizons in KRAS-mutant lung cancer: dawn after darkness. Front Oncol. 2019;9:953. https://doi.org/10.3389/fonc.2019.00953.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Renaud S, Seitlinger J, Falcoz P-E, Schaeffer M, Voegeli A-C, Legrain M, et al. Specific KRAS amino acid substitutions and EGFR mutations predict site-specific recurrence and metastasis following non-small-cell lung cancer surgery. Br J Cancer. 2016;115:346–53. https://doi.org/10.1038/bjc.2016.182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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 KRAS G12C inhibitor in KRAS G12C-mutant non-small cell lung cancer. Clin Cancer Res. 2020;26:5962–73. https://doi.org/10.1158/1078-0432.CCR-20-2077.

    Article  CAS  PubMed  Google Scholar 

  49. Redig AJ, Chambers ES, Lydon CA, Dahlberg SE, Alden RS, Janne PA. Genomic complexity in KRAS mutant non-small cell lung cancer (NSCLC) from never/light-smokers v smokers. J Clin Oncol. 2016;34:9087–9087. https://doi.org/10.1200/JCO.2016.34.15_suppl.9087.

    Article  Google Scholar 

  50. Hendriks LE, Kerr KM, Menis J, Mok TS, Nestle U, Passaro A, et al. Non-oncogene-addicted metastatic non-small-cell lung cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34:358–76. https://doi.org/10.1016/j.annonc.2022.12.013.

    Article  CAS  PubMed  Google Scholar 

  51. National Comprehensive Cancer Network, Inc. 2023 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Non-Small Cell Lung Cancer Version 3.2023—April 13, 2023.

  52. Pisapia P, Malapelle U, Troncone G. Liquid biopsy and lung cancer. Acta Cytol. 2019;63:489–96. https://doi.org/10.1159/000492710.

    Article  CAS  PubMed  Google Scholar 

  53. Nacchio M, Sgariglia R, Gristina V, Pisapia P, Pepe F, De Luca C, et al. KRAS mutations testing in non-small cell lung cancer: the role of liquid biopsy in the basal setting. J Thorac Dis. 2020;12:3836–43. https://doi.org/10.21037/jtd.2020.01.19.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Thein K, Banks K, Saam J, Raymond VM, Roszik J, Meric-Bernstam F, et al. The prevalence of KRASG12C mutations utilizing circulating tumor DNA (ctDNA) in 80,911 patients with cancer. J Clin Oncol. 2020;38:3547–3547. https://doi.org/10.1200/JCO.2020.38.15_suppl.3547.

    Article  Google Scholar 

  55. Dziadziuszko R, Li X, Anderson EC, Zer A, Corrales-Rodriguez L, Cheema P, et al. Clinicogenomic real-world data analysis of patients (Pts) with KRAS G12C-mutant advanced non-small cell lung cancer (aNSCLC) from the natural history cohort of the blood first assay screening trial (BFAST). J Clin Oncol. 2021;39:9023–9023. https://doi.org/10.1200/JCO.2021.39.15_suppl.9023.

    Article  Google Scholar 

  56. Skoulidis F, Byers LA, Diao L, Papadimitrakopoulou VA, Tong P, Izzo J, et al. Co-Occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 2015;5:860–77. https://doi.org/10.1158/2159-8290.CD-14-1236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Skoulidis F, Goldberg ME, Greenawalt DM, Hellmann MD, Awad MM, Gainor JF, et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 2018;8:822–35. https://doi.org/10.1158/2159-8290.CD-18-0099.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Riely GJ, Jordan E, Kim HR, Yu HA, Berger MF, Solit DB, et al. Association of outcomes and co-occuring genomic alterations in patients with KRAS-mutant non-small cell lung cancer. J Clin Oncol. 2016;34:9019–9019. https://doi.org/10.1200/JCO.2016.34.15_suppl.9019.

    Article  Google Scholar 

  59. El Osta B, Behera M, Kim S, Berry LD, Sica G, Pillai RN, et al. characteristics and outcomes of patients with metastatic KRAS-mutant lung adenocarcinomas: the lung cancer mutation consortium experience. J Thorac Oncol. 2019;14:876–89. https://doi.org/10.1016/j.jtho.2019.01.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kiat Hon Lim T, Skoulidis F, Kerr KM, Ahn M-J, Kapp JR, Soares FA, et al. KRAS G12C in advanced NSCLC: prevalence, co-mutations, and testing. Lung Cancer. 2023;184: 107293. https://doi.org/10.1016/j.lungcan.2023.107293.

    Article  CAS  Google Scholar 

  61. Goulding RE, Chenoweth M, Carter GC, Boye ME, Sheffield KM, John WJ, et al. KRAS Mutation as a prognostic factor and predictive factor in advanced/metastatic non-small cell lung cancer: a systematic literature review and meta-analysis. Cancer Treat Res Commun. 2020;24: 100200. https://doi.org/10.1016/j.ctarc.2020.100200.

    Article  PubMed  Google Scholar 

  62. Ihle NT, Byers LA, Kim ES, Saintigny P, Lee JJ, Blumenschein GR, et al. Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome. JNCI J Natl Cancer Inst. 2012;104:228–39. https://doi.org/10.1093/jnci/djr523.

    Article  CAS  PubMed  Google Scholar 

  63. Christensen JG, Olson P, Briere T, Wiel C, Bergo MO. Targeting Krasg12c-mutant cancer with a mutation-specific inhibitor. J Intern Med. 2020;288:183–91. https://doi.org/10.1111/joim.13057.

    Article  CAS  PubMed  Google Scholar 

  64. Kuang S, Lau SCM, Sharma K, Lee J, Ryan MI, Schmid S, et al. Impact of KRAS mutational variant on response to immunotherapy in metastatic NSCLC. J Clin Oncol. 2021;39: e21127. https://doi.org/10.1200/JCO.2021.39.15_suppl.e21127.

    Article  Google Scholar 

  65. Kim ES, Kies MS, Fossella FV, Glisson BS, Zaknoen S, Statkevich P, et al. Phase II study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in patients with taxane-refractory/resistant nonsmall cell lung carcinoma. Cancer. 2005;104:561–9. https://doi.org/10.1002/cncr.21188.

    Article  CAS  PubMed  Google Scholar 

  66. Adjei AA, Mauer A, Bruzek L, Marks RS, Hillman S, Geyer S, et al. Phase II study of the farnesyl transferase inhibitor R115777 in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2003;21:1760–6. https://doi.org/10.1200/JCO.2003.09.075.

    Article  CAS  PubMed  Google Scholar 

  67. Riely GJ, Johnson ML, Medina C, Rizvi NA, Miller VA, Kris MG, et al. A phase II trial of salirasib in patients with lung adenocarcinomas with KRAS mutations. J Thorac Oncol. 2011;6:1435–7. https://doi.org/10.1097/JTO.0b013e318223c099.

    Article  PubMed  Google Scholar 

  68. Papke B, Der CJ. Drugging RAS: know the enemy. Science. 2017;355:1158–63. https://doi.org/10.1126/science.aam7622.

    Article  CAS  PubMed  Google Scholar 

  69. Yuan TL, Amzallag A, Bagni R, Yi M, Afghani S, Burgan W, et al. Differential effector engagement by oncogenic KRAS. Cell Rep. 2018;22:1889–902. https://doi.org/10.1016/j.celrep.2018.01.051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Jänne PA, Van Den Heuvel MM, Barlesi F, Cobo M, Mazieres J, Crinò L, et al. selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer: the SELECT-1 randomized clinical trial. JAMA. 1844;2017:317. https://doi.org/10.1001/jama.2017.3438.

    Article  CAS  Google Scholar 

  71. Blumenschein GR, Smit EF, Planchard D, Kim D-W, 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). Ann Oncol. 2015;26:894–901. https://doi.org/10.1093/annonc/mdv072.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Paz-Ares L, Hirsh V, Zhang L, De Marinis F, Yang JC-H, Wakelee HA, et al. Monotherapy administration of sorafenib in patients with non-small cell lung cancer (MISSION) trial. J Thorac Oncol. 2015;10:1745–53. https://doi.org/10.1097/JTO.0000000000000693.

    Article  CAS  PubMed  Google Scholar 

  73. Vansteenkiste JF, Canon J-L, De Braud F, Grossi F, De Pas T, Gray JE, et al. Safety and efficacy of buparlisib (BKM120) in patients with PI3K pathway-activated non-small cell lung cancer. J Thorac Oncol. 2015;10:1319–27. https://doi.org/10.1097/JTO.0000000000000607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Falchook G, Patel M, Infante J, Arkenau H-T, Dean E, Brenner A, et al. Abstract CT153: first in human study of the first-in-class fatty acid synthase (FASN) inhibitor TVB-2640. Cancer Res. 2017;77:CT153. https://doi.org/10.1158/1538-7445.AM2017-CT153.

    Article  Google Scholar 

  75. Puyol M, Martín A, Dubus P, Mulero F, Pizcueta P, Khan G, et al. A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell. 2010;18:63–73. https://doi.org/10.1016/j.ccr.2010.05.025.

    Article  CAS  PubMed  Google Scholar 

  76. Lou K, Steri V, Ge AY, Hwang YC, Yogodzinski CH, Shkedi AR, et al. KRASG12C inhibition produces a driver-limited state revealing collateral dependencies. Sci Signal. 2019;12: eaaw9450. https://doi.org/10.1126/scisignal.aaw9450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Goldman JW, Mazieres J, Barlesi F, Dragnev KH, Koczywas M, Göskel T, et al. A randomized phase III study of abemaciclib versus erlotinib in patients with stage IV non-small cell lung cancer with a detectable KRAS mutation who failed prior platinum-based therapy: JUNIPER. Front Oncol. 2020;10: 578756. https://doi.org/10.3389/fonc.2020.578756.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Edelman MJ, Redman MW, Albain KS, McGary EC, Rafique NM, Petro D, et al. SWOG S1400C (NCT02154490)—a phase II study of palbociclib for previously treated cell cycle gene alteration-positive patients with stage IV squamous cell lung cancer (lung-MAP substudy). J Thorac Oncol. 2019;14:1853–9. https://doi.org/10.1016/j.jtho.2019.06.027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Riely GJ, Brahmer JR, Planchard D, Crinò L, Doebele RC, Mas Lopez LA, et al. A randomized discontinuation phase II trial of ridaforolimus in non-small cell lung cancer (NSCLC) patients with KRAS mutations. J Clin Oncol. 2012;30:7531–7531. https://doi.org/10.1200/jco.2012.30.15_suppl.7531.

    Article  Google Scholar 

  80. Ou SI, Koczywas M, Ulahannan S, Janne P, Pacheco J, Burris H, et al. A12 the SHP2 inhibitor RMC-4630 in patients with KRAS-mutant non-small cell lung cancer: preliminary evaluation of a first-in-man phase 1 clinical trial. J Thorac Oncol. 2020;15:S15–6. https://doi.org/10.1016/j.jtho.2019.12.041.

    Article  Google Scholar 

  81. Spoerner M, Herrmann C, Vetter IR, Kalbitzer HR, Wittinghofer A. Dynamic properties of the Ras switch I region and its importance for binding to effectors. Proc Natl Acad Sci. 2001;98:4944–9. https://doi.org/10.1073/pnas.081441398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Gysin S, Salt M, Young A, McCormick F. Therapeutic strategies for targeting Ras proteins. Genes Cancer. 2011;2:359–72. https://doi.org/10.1177/1947601911412376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Tomasini P, Walia P, Labbe C, Jao K, Leighl NB. Targeting the KRAS pathway in non-small cell lung cancer. Oncologist. 2016;21:1450–60. https://doi.org/10.1634/theoncologist.2015-0084.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lietman CD, Johnson ML, McCormick F, Lindsay CR. More to the RAS story: KRASG12C inhibition, resistance mechanisms, and moving beyond KRASG12C. Am Soc Clin Oncol Educ Book. 2022;2022:205–17. https://doi.org/10.1200/EDBK_351333.

    Article  Google Scholar 

  85. 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. https://doi.org/10.1038/s41586-019-1694-1.

    Article  CAS  PubMed  Google Scholar 

  86. Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383:1207–17. https://doi.org/10.1056/NEJMoa1917239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 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. https://doi.org/10.1056/NEJMoa2103695.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. US Food and Drug Administration FDA Approves First Targeted Therapy for Lung Cancer Mutation Previously Considered Resistant to Drug Therapy.

  89. European Medicines Agency European Medicines Agency Approves Sotorasib.

  90. Dy GK, Govindan R, Velcheti V, Falchook GS, Italiano A, Wolf J, Sacher AG, et al. Abstract CT008: long-term outcomes with sotorasib in pretreated KRASp.G12C-mutated NSCLC: 2-year analysis of CodeBreaK100. Cancer Res. 2022;82:CT008. https://doi.org/10.1158/1538-7445.AM2022-CT008.

    Article  Google Scholar 

  91. Dy GK, Govindan R, Velcheti V, Falchook GS, Italiano A, Wolf J, et al. Long-term outcomes and molecular correlates of sotorasib efficacy in patients with pretreated KRAS G12C-mutated non-small-cell lung cancer: 2-year analysis of CodeBreaK 100. J Clin Oncol. 2023. https://doi.org/10.1200/JCO.22.02524.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Hochmair MJ, Vermaelen K, Mountzios G, Carcereny E, Dooms C, Lee S-H, et al. VP4-2023: sotorasib 960 mg versus 240 mg in pretreated KRAS G12C advanced NSCLC. Ann Oncol. 2023. https://doi.org/10.1016/j.annonc.2023.10.790.

    Article  Google Scholar 

  93. De Langen AJ, Johnson ML, Mazieres J, Dingemans A-MC, Mountzios G, Pless M, et al. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial. Lancet. 2023;401:733–46. https://doi.org/10.1016/S0140-6736(23)00221-0.

    Article  PubMed  Google Scholar 

  94. Dingemans A-MC, Syrigos K, Livi L, Paulus A, Kim S-W, Chen Y, et al. Intracranial efficacy of sotorasib versus docetaxel in pretreated KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC): practice-informing data from a global, phase 3, randomized, controlled trial (RCT). J Clin Oncol. 2023;41:LBA9016. https://doi.org/10.1200/JCO.2023.41.17_suppl.LBA9016.

    Article  Google Scholar 

  95. Skoulidis F, De Langen A, Paz-Ares LG, Mountzios GS, Curioni-Fontecedro A, Couraud S, Janssens A, et al. Biomarker subgroup analyses of CodeBreaK 200, a phase 3 trial of sotorasib versus (vs) docetaxel in patients (Pts) with pretreated KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2023;41:9008–9008. https://doi.org/10.1200/JCO.2023.41.16_suppl.9008.

    Article  Google Scholar 

  96. Arbour KC, Khurana M, Dai T, Skoulidis F. Trial in progress: a phase 2 study of sotorasib as first-line treatment in patients with stage IV non-small cell lung cancer (NSCLC) whose tumors harbor a KRAS p.G12C mutation (CodeBreaK 201). J Clin Oncol. 2022;40:TPS9150. https://doi.org/10.1200/JCO.2022.40.16_suppl.TPS9150.

    Article  Google Scholar 

  97. Clarke JM, Felip E, Li BT, Ruffinelli JC, Garrido P, Zugazagoitia J, et al. MA06.05 CodeBreaK 101: safety and efficacy of sotorasib with carboplatin and pemetrexed in KRAS G12C-mutated advanced NSCLC. J Thorac Oncol. 2023;18:S118–9. https://doi.org/10.1016/j.jtho.2023.09.153.

    Article  Google Scholar 

  98. Sakata S, Akamatsu H, Azuma K, Uemura T, Tsuchiya-Kawano Y, Yoshioka H, et al. The primary endpoint analysis of SCARLET study: a single-arm, phase II study of sotorasib plus carboplatin-pemetrexed in patients with advanced non-squamous, non-small cell lung cancer with KRAS G12C mutation (WJOG14821L). J Clin Oncol. 2023;41:9006–9006. https://doi.org/10.1200/JCO.2023.41.16_suppl.9006.

    Article  Google Scholar 

  99. Padda SK, Redman MW, Gerber DE, Stinchcombe T, Waqar SN, Leal T, et al. ECOG-ACRIN LUNG-MAP S1900E substudy: a phase II study of sotorasib in participants (Pts) with previously treated stage IV or recurrent KRAS G12C mutant non-squamous (non-Sq) non-small cell lung cancer (NSCLC). J Clin Oncol. 2023;41:TPS9143. https://doi.org/10.1200/JCO.2023.41.16_suppl.TPS9143.

    Article  Google Scholar 

  100. Govindan R, Awad MM, Gadgeel SM, Pachter JA, Patrick G, Denis LJ. A phase 1/2 study of VS-6766 (RAF/MEK clamp) in combination with sotorasib (G12C inhibitor) in patients with KRAS G12C mutant non-small cell lung cancer (NSCLC) (RAMP 203). J Clin Oncol. 2022;40:TPS9148. https://doi.org/10.1200/JCO.2022.40.16_suppl.TPS9148.

    Article  Google Scholar 

  101. Falchook G, Li BT, Marrone KA, Bestvina CM, Langer CJ, Krauss JC, et al. OA03.03 sotorasib in combination with RMC-4630, a SHP2 inhibitor, in KRAS p.G12C-mutated NSCLC and other solid tumors. J Thorac Oncol. 2022;17:S8. https://doi.org/10.1016/j.jtho.2022.07.022.

    Article  Google Scholar 

  102. Hong DS, Yaeger R, Kuboki Y, Masuishi T, Barve MA, Falchook GS, et al. A Phase 1b study of sotorasib, a specific and irreversible KRASG12C inhibitor, in combination with other anticancer therapies in advanced colorectal cancer (CRC) and other solid tumors (CodeBreaK 101). J Clin Oncol. 2022;40:TPS214. https://doi.org/10.1200/JCO.2022.40.4_suppl.TPS214.

    Article  Google Scholar 

  103. Fell JB, Fischer JP, Baer BR, Ballard J, Blake JF, Bouhana K, et al. Discovery of tetrahydropyridopyrimidines as irreversible covalent inhibitors of KRAS-G12C with in vivo activity. ACS Med Chem Lett. 2018;9:1230–4. https://doi.org/10.1021/acsmedchemlett.8b00382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Gabizon R, London N. Hitting KRAS when it’s down. J Med Chem. 2020;63:6677–8. https://doi.org/10.1021/acs.jmedchem.0c00785.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Jänne PA, Riely GJ, Gadgeel SM, Heist RS, Ou S-HI, Pacheco JM, et al. Adagrasib in non-small-cell lung cancer harboring a KRASG12C mutation. N Engl J Med. 2022;387:120–31. https://doi.org/10.1056/NEJMoa2204619.

    Article  PubMed  Google Scholar 

  106. Negrao MV, Spira AI, Heist RS, Jänne PA, Pacheco JM, Weiss J, et al. Intracranial efficacy of adagrasib in patients from the KRYSTAL-1 trial with KRASG12C-mutated non-small-cell lung cancer who have untreated CNS metastases. J Clin Oncol. 2023. https://doi.org/10.1200/JCO.23.00046.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Mok TSK, Lawler WE, Shum MK, Dakhil SR, Spira AI, Barlesi F, et al. KRYSTAL-12: a randomized phase 3 study of adagrasib (MRTX849) versus docetaxel in patients (pts) with previously treated non-small-cell lung cancer (NSCLC) with KRASG12C mutation. J Clin Oncol. 2021;39:TPS9129. https://doi.org/10.1200/JCO.2021.39.15_suppl.TPS9129.

    Article  Google Scholar 

  108. Sabari JK, Park H, Tolcher AW, Ou S-HI, Garon EB, George B, et al. KRYSTAL-2: a phase I/II trial of adagrasib (MRTX849) in combination with TNO155 in patients with advanced solid tumors with KRAS G12C mutation. J Clin Oncol. 2021;39:TPS146. https://doi.org/10.1200/JCO.2021.39.3_suppl.TPS146.

    Article  Google Scholar 

  109. Riely GJ, Ou S-HI, Rybkin I, Spira A, Papadopoulos K, Sabari JK, et al. 99O_PR KRYSTAL-1: activity and preliminary pharmacodynamic (PD) analysis of adagrasib (MRTX849) in patients (Pts) with advanced non-small cell lung cancer (NSCLC) harboring KRASG12C mutation. J Thorac Oncol. 2021;16:S751–2. https://doi.org/10.1016/S1556-0864(21)01941-9.

    Article  Google Scholar 

  110. Purkey H. Abstract ND11: discovery of GDC-6036, a clinical stage treatment for KRAS G12C-positive cancers. Cancer Res. 2022;82:ND11. https://doi.org/10.1158/1538-7445.AM2022-ND11.

    Article  Google Scholar 

  111. Sacher A, LoRusso P, Patel MR, Miller WH, 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. https://doi.org/10.1056/NEJMoa2303810.

    Article  CAS  PubMed  Google Scholar 

  112. Shi Z, Weng J, Fan X, Wang E, Zhu Q, Tao L, et al. Abstract 932: discovery of D-1553, a novel and selective KRas-G12C inhibitor with potent anti-tumor activity in a broad spectrum of tumor cell lines and xenograft models. Cancer Res. 2021;81:932–932. https://doi.org/10.1158/1538-7445.AM2021-932.

    Article  Google Scholar 

  113. Li Z, Song Z, Zhao Y, Wang P, Jiang L, Gong Y, et al. D-1553 (garsorasib), a potent and selective inhibitor of KRASG12C in patients with NSCLC: phase 1 study results. J Thorac Oncol. 2023. https://doi.org/10.1016/j.jtho.2023.03.015.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Li J, Zhao J, Cao B, Fang J, Li X, Wang M, et al. A phase I/II study of first-in-human trial of JAB-21822 (KRAS G12C inhibitor) in advanced solid tumors. J Clin Oncol. 2022;40:3089–3089. https://doi.org/10.1200/JCO.2022.40.16_suppl.3089.

    Article  Google Scholar 

  115. Wang J, Zhao J, Zhong J, Li X, Fang J, Yu Y, et al. 653O glecirasib (KRAS G12C inhibitor) in combination with JAB-3312 (SHP2 inhibitor) in patients with KRAS p.G12C mutated solid tumors. Ann Oncol. 2023;34:S459. https://doi.org/10.1016/j.annonc.2023.09.1839.

    Article  Google Scholar 

  116. Brachmann SM, Weiss A, Guthy DA, Beyer K, Voshol J, Maira M, et al. Abstract P124: JDQ443, a covalent irreversible inhibitor of KRAS G12C, exhibits a novel binding mode and demonstrates potent anti-tumor activity and favorable pharmacokinetic properties in preclinical models. Mol Cancer Ther. 2021;20:P124–P124. https://doi.org/10.1158/1535-7163.TARG-21-P124.

    Article  Google Scholar 

  117. Lorthiois E, Gerspacher M, Beyer KS, Vaupel A, Leblanc C, Stringer R, et al. JDQ443, a structurally novel, pyrazole-based, covalent inhibitor of KRAS G12C for the treatment of solid tumors. J Med Chem. 2022;65:16173–203. https://doi.org/10.1021/acs.jmedchem.2c01438.

    Article  CAS  PubMed  Google Scholar 

  118. Tan DS, Shimizu T, Solomon B, Heist RS, Schuler M, Luken MJDM, et al. Abstract CT033: KontRASt-01: a phase Ib/II, dose-escalation study of JDQ443 in patients (Pts) with advanced, KRAS G12C-mutated solid tumors. Cancer Res. 2022;82:CT033. https://doi.org/10.1158/1538-7445.AM2022-CT033.

    Article  Google Scholar 

  119. Cassier PA, Dooms CA, Gazzah A, Felip E, Steeghs N, Rohrberg KS, et al. KontRASt-01 update: safety and efficacy of JDQ443 in KRAS G12C-mutated solid tumors including non-small cell lung cancer (NSCLC). J Clin Oncol. 2023;41:9007–9007. https://doi.org/10.1200/JCO.2023.41.16_suppl.9007.

    Article  Google Scholar 

  120. Lindsay CR, Veluswamy R, Castro G, Tan DS-W, Caparica R, Glaser S, et al. A phase II trial of JDQ443 in KRAS G12C-mutated NSCLC with PD-L1 expression <1% or PD-L1 expression ≥1% and an STK11 co-mutation. J Clin Oncol. 2023;41:9158. https://doi.org/10.1200/JCO.2023.41.16_suppl.TPS9158.

    Article  Google Scholar 

  121. Cappuzzo F, Castro G, Kang J-H, Wu Y-L, Brustugun OT, Cheema PK, et al. KontRASt-02: a phase III trial investigating the efficacy and safety of the KRAS G12C inhibitor JDQ443 vs docetaxel in patients with previously treated, locally advanced or metastatic, KRAS G12C-mutated NSCLC. J Clin Oncol. 2023;41:TPS9144. https://doi.org/10.1200/JCO.2023.41.16_suppl.TPS9144.

    Article  Google Scholar 

  122. 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;81:1259–1259. https://doi.org/10.1158/1538-7445.AM2021-1259.

    Article  Google Scholar 

  123. Murciano-Goroff YR, Heist RS, Kuboki Y, Koyama T, Ammakkanavar NR, Hollebecque A, et al. Abstract CT028: a first-in-human phase 1 study of LY3537982, a highly selective and potent KRAS G12C inhibitor in patients with KRAS G12C-mutant advanced solid tumors. Cancer Res. 2023;83:CT028. https://doi.org/10.1158/1538-7445.AM2023-CT028.

    Article  Google Scholar 

  124. Savarese F, Gollner A, Rudolph D, Lipp J, Popow J, Hofmann MH, et al. Abstract 1271: in vitro and in vivo characterization of BI 1823911—a novel KRASG12C selective small molecule inhibitor. Cancer Res. 2021;81:1271. https://doi.org/10.1158/1538-7445.AM2021-1271.

    Article  Google Scholar 

  125. Garralda E, Oberoi A, Koyama T, Schoeffski P, Ascierto PA, Lin C-C, et al. 695P a phase I/Ib study evaluating the safety and tolerability of NIZ985 alone and in combination with spartalizumab (Anti-PD-1) in patients (Pts) with solid tumors or lymphoma. Ann Oncol. 2023;34:S484. https://doi.org/10.1016/j.annonc.2023.09.1881.

    Article  Google Scholar 

  126. Zhou Q, Yang N, Zhao J, Dong X, Wang H, Yuan Y, et al. Phase I dose-escalation study of IBI351 (GFH925) monotherapy in patients with advanced solid tumors. J Clin Oncol. 2022;40:3110–3110. https://doi.org/10.1200/JCO.2022.40.16_suppl.3110.

    Article  Google Scholar 

  127. Zhang J, Wu W, Xu Y, Qian Y, Xia Y, Lu J, et al. Preclinical characterization of D3S-001, a highly potent, selective, and differentiated covalent inhibitor of KRAS G12C. J Clin Oncol. 2022;40:e15102–e15102. https://doi.org/10.1200/JCO.2022.40.16_suppl.e15102.

    Article  Google Scholar 

  128. Liu R, Qu X, Yang N, Chai X, Xu J. First-in-human study of ZG19018, targeting KRAS G12C, as monotherapy in patients with advanced solid tumors. J Clin Oncol. 2023;41:e15127–e15127. https://doi.org/10.1200/JCO.2023.41.16_suppl.e15127.

    Article  Google Scholar 

  129. Zhang Y, Zhou L, Gong Y, Huang M, Tang M, Liu Y, et al. Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of GEC255, a novel KRAS G12C inhibitor, in advanced solid tumors. J Clin Oncol. 2023;41:9112–9112. https://doi.org/10.1200/JCO.2023.41.16_suppl.9112.

    Article  Google Scholar 

  130. Rojas C, Lugowska I, Juergens R, Sacher A, Weindler S, Sendur MAN, et al. 663P safety and preliminary efficacy of the KRAS G12C inhibitor MK-1084 in solid tumors and in combination with pembrolizumab in NSCLC. Ann Oncol. 2023;34:S466–7. https://doi.org/10.1016/j.annonc.2023.09.1849.

    Article  Google Scholar 

  131. Sacher A, Patel MR, Miller WH, Desai J, Garralda E, Bowyer S, et al. OA03.04 phase I A study to evaluate GDC-6036 monotherapy in patients with non-small cell lung cancer (NSCLC) with KRAS G12C mutation. J Thorac Oncol. 2022;17:S8–9. https://doi.org/10.1016/j.jtho.2022.07.023.

    Article  Google Scholar 

  132. Rosen JC, Sacher A, Tsao M-S. Direct GDP-KRASG12C inhibitors and mechanisms of resistance: the tip of the iceberg. Ther Adv Med Oncol. 2023;15:175883592311601. https://doi.org/10.1177/17588359231160141.

    Article  CAS  Google Scholar 

  133. Awad MM, Liu S, Rybkin II, Arbour KC, Dilly J, Zhu VW, et al. Acquired resistance to KRASG12C inhibition in cancer. N Engl J Med. 2021;384:2382–93. https://doi.org/10.1056/NEJMoa2105281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Li BT, Velcheti V, Price TJ, Hong DS, Fakih M, Kim D-W, et al. Largest evaluation of acquired resistance to sotorasib in KRAS p.G12C-mutated non-small cell lung cancer (NSCLC) and colorectal cancer (CRC): plasma biomarker analysis of CodeBreaK100. J Clin Oncol. 2022;40:102–102. https://doi.org/10.1200/JCO.2022.40.16_suppl.102.

    Article  Google Scholar 

  135. Punekar SR, Velcheti V, Neel BG, Wong K-K. The current state of the art and future trends in RAS-targeted cancer therapies. Nat Rev Clin Oncol. 2022;19:637–55. https://doi.org/10.1038/s41571-022-00671-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Tsai YS, Woodcock MG, Azam SH, Thorne LB, Kanchi KL, Parker JS, et al. Idiosyncratic mechanisms of clinical resistance to KRAS G12C inhibition. J Clin Investig. 2022;132: e155523. https://doi.org/10.1172/JCI155523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Santana-Codina N, Chandhoke AS, Yu Q, Małachowska B, Kuljanin M, Gikandi A, et al. Defining and targeting adaptations to oncogenic KRASG12C inhibition using quantitative temporal proteomics. Cell Rep. 2020;30:4584-4599.e4. https://doi.org/10.1016/j.celrep.2020.03.021.

    Article  CAS  PubMed  Google Scholar 

  138. Nichols RJ, Cregg J, Schulze CJ, Wang Z, Yang K, Jiang J, et al. Abstract 1261: a next generation tri-complex KRASG12C(ON) inhibitor directly targets the active, GTP-bound state of mutant RAS and may overcome resistance to KRASG12C(OFF) inhibition. Cancer Res. 2021;81:1261–1261. https://doi.org/10.1158/1538-7445.AM2021-1261.

    Article  Google Scholar 

  139. Nichols R, Schulze C, Bermingham A, Choy T, Cregg J, Kiss G, et al. A06 tri-complex inhibitors of the oncogenic, GTP-bound form of KRASG12C overcome RTK-mediated escape mechanisms and drive tumor regressions in preclinical models of NSCLC. J Thorac Oncol. 2020;15:S13–4. https://doi.org/10.1016/j.jtho.2019.12.035.

    Article  Google Scholar 

  140. Nichols RJ, Yang YC, Cregg J, Schulze CJ, Wang Z, Dua R, et al. Abstract 3595: RMC-6291, a next-generation tri-complex KRASG12C(ON) inhibitor, outperforms KRASG12C(OFF) inhibitors in preclinical models of KRASG12C cancers. Cancer Res. 2022;82:3595–3595. https://doi.org/10.1158/1538-7445.AM2022-3595.

    Article  Google Scholar 

  141. Lindsay CR, Garassino MC, Nadal E, Öhrling K, Scheffler M, Mazières J. On Target: rational approaches to KRAS Inhibition for treatment of non-small cell lung carcinoma. Lung Cancer. 2021;160:152–65. https://doi.org/10.1016/j.lungcan.2021.07.005.

    Article  CAS  PubMed  Google Scholar 

  142. Wang X, Allen S, Blake JF, Bowcut V, Briere DM, Calinisan A, et al. Identification of MRTX1133, a noncovalent, potent, and selective KRAS G12D inhibitor. J Med Chem. 2022;65:3123–33. https://doi.org/10.1021/acs.jmedchem.1c01688.

    Article  CAS  PubMed  Google Scholar 

  143. Knox JE, Jiang J, Burnett GL, Liu Y, Weller CE, Wang Z, et al. Abstract 3596: RM-036, a first-in-class, orally-bioavailable, tri-complex covalent KRASG12D(ON) inhibitor, drives profound anti-tumor activity in KRASG12D mutant tumor models. Cancer Res. 2022;82:3596–3596. https://doi.org/10.1158/1538-7445.AM2022-3596.

    Article  Google Scholar 

  144. Kessler D, Gmachl M, Mantoulidis A, Martin LJ, Zoephel A, Mayer M, et al. Drugging an undruggable pocket on KRAS. Proc Natl Acad Sci. 2019;116:15823–9. https://doi.org/10.1073/pnas.1904529116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Popow J, Farnaby W, Gollner A, Kofink C, Fischer G, Wurm M, et al. Targeting cancer with small molecule pan-KRAS degraders; pharmacology and toxicology; 2023.

  146. Kim D, Herdeis L, Rudolph D, Zhao Y, Böttcher J, Vides A, et al. Pan-KRAS inhibitor disables oncogenic signalling and tumour growth. Nature. 2023;619:160–6. https://doi.org/10.1038/s41586-023-06123-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Corcoran RB. A single inhibitor for All KRAS mutations. Nat Cancer. 2023;4:1060–2. https://doi.org/10.1038/s43018-023-00615-x.

    Article  CAS  PubMed  Google Scholar 

  148. Arbour KC, Punekar S, Garrido-Laguna I, Hong DS, Wolpin B, Pelster MS, et al. 652O preliminary clinical activity of RMC-6236, a first-in-class, RAS-selective, tri-complex RAS-MULTI(ON) inhibitor in patients with KRAS mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). Ann Oncol. 2023;34:S458. https://doi.org/10.1016/j.annonc.2023.09.1838.

    Article  Google Scholar 

  149. Gumusay O, Vitiello PP, Wabl C, Corcoran RB, Bardelli A, Rugo HS. Strategic combinations to prevent and overcome resistance to targeted therapies in oncology. Am Soc Clin Oncol Educ Book. 2020. https://doi.org/10.1200/EDBK_280845.

    Article  PubMed  Google Scholar 

  150. Drosten M, Barbacid M. Targeting KRAS mutant lung cancer: light at the end of the tunnel. Mol Oncol. 2022;16:1057–71. https://doi.org/10.1002/1878-0261.13168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Jiang L, Xu W, Chen Y, Zhang Y. SHP2 inhibitor specifically suppresses the stemness of KRAS-mutant non-small cell lung cancer cells. Artif Cells Nanomedicine Biotechnol. 2019;47:3231–8. https://doi.org/10.1080/21691401.2019.1646748.

    Article  CAS  Google Scholar 

  152. Fedele C, Li S, Teng KW, Foster CJR, Peng D, Ran H, et al. SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling. J Exp Med. 2021;218: e20201414. https://doi.org/10.1084/jem.20201414.

    Article  CAS  PubMed  Google Scholar 

  153. Yaeger R, Solit DB. Overcoming adaptive resistance to KRAS inhibitors through vertical pathway targeting. Clin Cancer Res. 2020;26:1538–40. https://doi.org/10.1158/1078-0432.CCR-19-4060.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Johnson ML, Langdon R, Ellison D, Spira A, Amin H, Castine M, et al. 76TiP RMC-4630 and sotorasib for advanced KRASG12C NSCLC after failure of prior standard therapies: a phase II trial. Ann Oncol. 2022;33:S66–7. https://doi.org/10.1016/j.annonc.2022.02.085.

    Article  Google Scholar 

  155. Brana I, Shapiro G, Johnson ML, Yu HA, Robbrecht D, Tan DS-W, et al. Initial results from a dose finding study of TNO155, a SHP2 inhibitor, in adults with advanced solid tumors. J Clin Oncol. 2021;39:3005–3005. https://doi.org/10.1200/JCO.2021.39.15_suppl.3005.

    Article  Google Scholar 

  156. Dunnett-Kane V, Nicola P, Blackhall F, Lindsay C. Mechanisms of resistance to KRASG12C inhibitors. Cancers. 2021;13:151. https://doi.org/10.3390/cancers13010151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Drilon A, Sharma MR, Johnson ML, Yap TA, Gadgeel S, Nepert D, et al. SHP2 inhibition sensitizes diverse oncogene-addicted solid tumors to re-treatment with targeted therapy. Cancer Discov. 2023;13:1789–801. https://doi.org/10.1158/2159-8290.CD-23-0361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Hofmann MH, Gmachl M, Ramharter J, Savarese F, Gerlach D, Marszalek JR, et al. BI-3406, a potent and selective SOS1–KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition. Cancer Discov. 2021;11:142–57. https://doi.org/10.1158/2159-8290.CD-20-0142.

    Article  CAS  PubMed  Google Scholar 

  159. Hofmann MH, Lu H, Duenzinger U, Gerlach D, Trapani F, Machado AA, et al. Abstract CT210: trial in process: phase 1 studies of BI 1701963, a SOS1::KRAS inhibitor, in combination with MEK inhibitors, irreversible KRASG12C inhibitors or irinotecan. Cancer Res. 2021;81:CT210. https://doi.org/10.1158/1538-7445.AM2021-CT210.

    Article  Google Scholar 

  160. Johnson ML, Gort E, Pant S, Lolkema MP, Sebastian M, Scheffler M, et al. 524P A phase I, open-label, dose-escalation trial of BI 1701963 in patients (Pts) with KRAS mutated solid tumours: a snapshot analysis. Ann Oncol. 2021;32:S591–2. https://doi.org/10.1016/j.annonc.2021.08.1046.

    Article  Google Scholar 

  161. 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. https://doi.org/10.1158/1535-7163.TARG-21-P05-01.

    Article  Google Scholar 

  162. Ryan MB, Fece De La Cruz F, Phat S, Myers DT, Wong E, Shahzade HA, et al. Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition. Clin Cancer Res. 2020;26:1633–43. https://doi.org/10.1158/1078-0432.CCR-19-3523.

    Article  CAS  PubMed  Google Scholar 

  163. Spira AI, Riely GJ, Gadgeel SM, Heist RS, Ou S-HI, Pacheco JM, et al. KRYSTAL-1: activity and safety of adagrasib (MRTX849) in patients with advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRAS G12C mutation. J Clin Oncol. 2022;40:9002–9002. https://doi.org/10.1200/JCO.2022.40.16_suppl.9002.

    Article  Google Scholar 

  164. Gandara D, Marrone K, Govindan R, Skoulidis F, Durm G, Clarke J, et al. Abstract P05–02: a phase 1b study evaluating the combination of sotorasib, a KRASG12C inhibitor, and afatinib, a pan-ErbB tyrosine kinase inhibitor, in advanced KRAS p.G12C mutated non-small cell lung cancer (NSCLC). Mol Cancer Ther. 2021;20:P05-02. https://doi.org/10.1158/1535-7163.TARG-21-P05-02.

    Article  Google Scholar 

  165. Camidge DR, Reuss JE, Spira AI, Janne PA, Rehman M, Pachter JA, et al. A phase 2 study of VS-6766 (RAF/MEK Clamp) RAMP 202, as a single agent and in combination with defactinib (FAK inhibitor) in recurrent KRAS mutant (Mt) and BRAF Mt non-small cell lung cancer (NSCLC). J Clin Oncol. 2022;40:TPS9147. https://doi.org/10.1200/JCO.2022.40.16_suppl.TPS9147.

    Article  Google Scholar 

  166. Misale S, Fatherree JP, Cortez E, Li C, Bilton S, Timonina D, et al. KRAS G12C NSCLC models are sensitive to direct targeting of KRAS in combination with PI3K inhibition. Clin Cancer Res. 2019;25:796–807. https://doi.org/10.1158/1078-0432.CCR-18-0368.

    Article  CAS  PubMed  Google Scholar 

  167. Dong Z-Y, Zhong W-Z, Zhang X-C, Su J, Xie Z, Liu S-Y, et al. Potential predictive value of TP53 and KRAS mutation status for response to PD-1 blockade immunotherapy in lung adenocarcinoma. Clin Cancer Res. 2017;23:3012–24. https://doi.org/10.1158/1078-0432.CCR-16-2554.

    Article  CAS  PubMed  Google Scholar 

  168. Liu C, Zheng S, Jin R, Wang X, Wang F, Zang R, et al. The superior efficacy of anti-PD-1/PD-L1 immunotherapy in KRAS-mutant non-small cell lung cancer that correlates with an inflammatory phenotype and increased immunogenicity. Cancer Lett. 2020;470:95–105. https://doi.org/10.1016/j.canlet.2019.10.027.

    Article  CAS  PubMed  Google Scholar 

  169. Torralvo J, Friedlaender A, Achard V, Addeo A. The activity of immune checkpoint inhibition in KRAS mutated non-small cell lung cancer: a single centre experience. Cancer Genom Proteom. 2019;16:577–82. https://doi.org/10.21873/cgp.20160.

    Article  CAS  Google Scholar 

  170. Herbst RS, Lopes G, Kowalski DM, Kasahara K, Wu Y-L, De Castro G, et al. LBA4 association of KRAS mutational status with response to pembrolizumab monotherapy given as first-line therapy for PD-L1-positive advanced non-squamous NSCLC in keynote-042. Ann Oncol. 2019;30:xi63–4. https://doi.org/10.1093/annonc/mdz453.001.

    Article  Google Scholar 

  171. Sun L, Hsu M, Cohen RB, Langer CJ, Mamtani R, Aggarwal C. Association between KRAS variant status and outcomes with first-line immune checkpoint inhibitor-based therapy in patients with advanced non–small-cell lung cancer. JAMA Oncol. 2021;7:937. https://doi.org/10.1001/jamaoncol.2021.0546.

    Article  PubMed  PubMed Central  Google Scholar 

  172. Marinelli D, Mazzotta M, Scalera S, Terrenato I, Sperati F, D’Ambrosio L, et al. KEAP1-driven co-mutations in lung adenocarcinoma unresponsive to immunotherapy despite high tumor mutational burden. Ann Oncol. 2020;31:1746–54. https://doi.org/10.1016/j.annonc.2020.08.2105.

    Article  CAS  PubMed  Google Scholar 

  173. Briere DM, Li S, Calinisan A, Sudhakar N, Aranda R, Hargis L, et al. The KRASG12C inhibitor MRTX849 reconditions the tumor immune microenvironment and sensitizes tumors to checkpoint inhibitor therapy. Mol Cancer Ther. 2021;20:975–85. https://doi.org/10.1158/1535-7163.MCT-20-0462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Li BT, Falchook GS, Durm GA, Burns TF, Skoulidis F, Ramalingam SS, et al. OA03.06 CodeBreaK 100/101: first report of safety/efficacy of sotorasib in combination with pembrolizumab or atezolizumab in advanced KRAS p.G12C NSCLC. J Thorac Oncol. 2022;17:S10–1. https://doi.org/10.1016/j.jtho.2022.07.025.

    Article  Google Scholar 

  175. Jänne PA, Smit EF, De Marinis F, Laskin J, Gomez MD, Gadgeel S, et al. LBA4 preliminary safety and efficacy of adagrasib with pembrolizumab in treatment-naïve patients with advanced non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. Immuno-Oncol Technol. 2022;16: 100360. https://doi.org/10.1016/j.iotech.2022.100360.

    Article  Google Scholar 

  176. Gadgeel S, Jänne PA, Spira AI, Ou S-HI, Heist RS, et al. MA06.04 KRYSTAL-1: two-year follow-up of adagrasib (MRTX849) monotherapy in patients with advanced/metastatic KRASG12C-mutated NSCLC. J Thorac Oncol. 2023;18:S118. https://doi.org/10.1016/j.jtho.2023.09.152.

    Article  Google Scholar 

  177. Garassino MC, Theelen WSME, Jotte R, Laskin J, De Marinis F, Aguado C, et al. LBA65 KRYSTAL-7: efficacy and safety of adagrasib with pembrolizumab in patients with treatment-naïve, advanced non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. Ann Oncol. 2023;34:S1309–10. https://doi.org/10.1016/j.annonc.2023.10.066.

    Article  Google Scholar 

  178. Carlisle JW, Harvey RD. Tyrosine kinase inhibitors, antibody-drug conjugates, and proteolysis-targeting chimeras: the pharmacology of cutting-edge lung cancer therapies. Am Soc Clin Oncol Educ Book. 2021. https://doi.org/10.1200/EDBK_320667.

    Article  PubMed  Google Scholar 

  179. Li JW, Zheng G, Kaye FJ, Wu L. PROTAC therapy as a new targeted therapy for lung cancer. Mol Ther. 2023;31:647–56. https://doi.org/10.1016/j.ymthe.2022.11.011.

    Article  CAS  PubMed  Google Scholar 

  180. Bond MJ, Chu L, Nalawansha DA, Li K, Crews CM. Targeted degradation of oncogenic KRAS G12C by VHL-recruiting PROTACs. ACS Cent Sci. 2020;6:1367–75. https://doi.org/10.1021/acscentsci.0c00411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Bery N, Miller A, Rabbitts T. A Potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS. Nat Commun. 2020;11:3233. https://doi.org/10.1038/s41467-020-17022-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Zeng M, Xiong Y, Safaee N, Nowak RP, Donovan KA, Yuan CJ, et al. Exploring targeted degradation strategy for oncogenic KRASG12C. Cell Chem Biol. 2020;27:19-31.e6. https://doi.org/10.1016/j.chembiol.2019.12.006.

    Article  CAS  PubMed  Google Scholar 

  183. Burslem GM, Crews CM. Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell. 2020;181:102–14. https://doi.org/10.1016/j.cell.2019.11.031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Khan S, Wiegand J, Zhang P, Hu W, Thummuri D, Budamagunta V, et al. BCL-XL PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRASG12C-mutated cancers. J Hematol Oncol. 2022;15:23. https://doi.org/10.1186/s13045-022-01241-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Lahiri A, Maji A, Potdar PD, Singh N, Parikh P, Bisht B, et al. Lung cancer immunotherapy: progress, pitfalls, and promises. Mol Cancer. 2023;22:40. https://doi.org/10.1186/s12943-023-01740-y.

    Article  PubMed  PubMed Central  Google Scholar 

  186. Olson DJ, Odunsi K. Adoptive cell therapy for nonhematologic solid tumors. J Clin Oncol. 2023;41:3397–407. https://doi.org/10.1200/JCO.22.01618.

    Article  CAS  PubMed  Google Scholar 

  187. Dillard P, Casey N, Pollmann S, Vernhoff P, Gaudernack G, Kvalheim G, et al. Targeting KRAS mutations with HLA class II-restricted TCRs for the treatment of solid tumors. OncoImmunology. 2021;10:1936757. https://doi.org/10.1080/2162402X.2021.1936757.

    Article  PubMed  PubMed Central  Google Scholar 

  188. Chatani PD, Yang JC. Mutated RAS: targeting the “untargetable” with T cells. Clin Cancer Res. 2020;26:537–44. https://doi.org/10.1158/1078-0432.CCR-19-2138.

    Article  CAS  PubMed  Google Scholar 

  189. Xiao B-F, Zhang J-T, Zhu Y-G, Cui X-R, Lu Z-M, Yu B-T, et al. Chimeric antigen receptor T-cell therapy in lung cancer: potential and challenges. Front Immunol. 2021;12: 782775. https://doi.org/10.3389/fimmu.2021.782775.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Chen L, Chen F, Li J, Pu Y, Yang C, Wang Y, Lei Y, Huang Y. CAR-T cell therapy for lung cancer: potential and perspective. Thorac Cancer. 2022;13:889–99. https://doi.org/10.1111/1759-7714.14375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Tran E, Robbins PF, Lu Y-C, Prickett TD, Gartner JJ, Jia L, et al. T-cell transfer therapy targeting mutant KRAS in cancer. N Engl J Med. 2016;375:2255–62. https://doi.org/10.1056/NEJMoa1609279.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Tsimberidou A-M, Van Morris K, Vo HH, Eck S, Lin Y-F, Rivas JM, et al. T-cell receptor-based therapy: an innovative therapeutic approach for solid tumors. J Hematol Oncol. 2021;14:102. https://doi.org/10.1186/s13045-021-01115-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Kutzler MA, Weiner DB. DNA vaccines: ready for prime time? Nat Rev Genet. 2008;9:776–88. https://doi.org/10.1038/nrg2432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Chaft JE, Litvak A, Arcila ME, Patel P, D’Angelo SP, Krug LM, et al. Phase II study of the GI-4000 KRAS vaccine after curative therapy in patients with stage I–III lung adenocarcinoma harboring a KRAS G12C, G12D, or G12V mutation. Clin Lung Cancer. 2014;15:405–10. https://doi.org/10.1016/j.cllc.2014.06.002.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain

    Javier Torres-Jiménez, Javier Baena Espinar, Helena Bote de Cabo, María Zurera Berjaga, Jorge Esteban-Villarrubia, Jon Zugazagoitia Fraile & Luis Paz-Ares

  2. Lung Cancer Group, Clinical Research Program, CNIO (Centro Nacional de Investigaciones Oncológicas) and Instituto de Investigación i+12, Madrid, Spain

    Jon Zugazagoitia Fraile & Luis Paz-Ares

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  1. Javier Torres-Jiménez
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Javier Torres-Jiménez, Helena Bote de Cabo, María Zurera Berjaba, and Jorge Esteban-Villarrubia declare that they have no conflicts of interest that might be relevant to the contents of this article. Javier Baena Espinar reports personal fees from Astra Zeneca, personal fees from Roche, personal fees from BMS, personal fees from Lilly and non-financial support from MSD, outside the submitted work; Jon Zugazagoitia has served as a consultant for Sanofi, Astra Zeneca, BMS, Roche, Pfizer, Novartis, and Guardant Health. He reports speakers’ honoraria from Sanofi, Takeda, BMS, Pfizer, Roche, Astra Zeneca, NanoString and Guardant Health. He reports travel honoraria from Sanofi, Takeda, BMS, Pfizer, Roche, Astra Zeneca, and NanoString. He has received research support/funds from BMS, Astra Zeneca, and Roche. Luis Paz-Ares has served as a consultant for Lilly, MSD, Roche, Pharmamar, Merck, Astra Zeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati, GSK, Janssen, Takeda, Daichii Sankyo. He reports speakers’ honoraria from Astra Zeneca, Janssen, Merck, Mirati.

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No datasets were generated during the current study. The datasets analyzed during the current study are available from the corresponding author on reasonable request.

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Construction of the review was performed by Javier Torres-Jiménez, Javier Baena Espinar, Helena Bote de Cabo, María Zurera Berjaba, and Jorge Esteban Villarrubia. Review was performed by Jon Zugazagoita and Luis Paz-Ares. All authors contributed to the article and approved the submitted version.

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Torres-Jiménez, J., Espinar, J.B., de Cabo, H.B. et al. Targeting KRASG12C in Non-Small-Cell Lung Cancer: Current Standards and Developments. Drugs (2024). https://doi.org/10.1007/s40265-024-02030-7

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