Skip to main content
SpringerLink
Log in

Targeting KRAS-Mutated Gastrointestinal Malignancies with Small-Molecule Inhibitors: A New Generation of Breakthrough Therapies

  • Review Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Kirsten rat sarcoma virus (KRAS) is one of the most important and frequently mutated oncogenes in cancer and the mutational prevalence is especially high in many gastrointestinal malignancies, including colorectal cancer and pancreatic ductal adenocarcinoma. The KRAS protein is a small GTPase that functions as an “on/off” switch to activate downstream signaling, mainly through the mitogen-activated protein kinase pathway. KRAS was previously considered undruggable because of biochemical constraints; however, recent breakthroughs have enabled the development of small-molecule inhibitors of KRAS G12C. These drugs were initially approved in lung cancer and have now shown substantial clinical activity in KRAS G12C-mutated pancreatic ductal adenocarcinoma as well as colorectal cancer when combined with anti-EGFR monoclonal antibodies. Early data are encouraging for other gastrointestinal cancers as well and many other combination strategies are being investigated. Several new KRAS G12C inhibitors and novel inhibitors of other KRAS alterations have recently entered the clinic. These molecules employ a variety of innovative mechanisms and have generated intense interest. These novel drugs are especially important as KRAS G12C is rare in gastrointestinal malignancies compared with other KRAS alterations, representing potentially groundbreaking advances. Soon, the rapidly evolving landscape of novel KRAS inhibitors may substantially shift the therapeutic landscape for gastrointestinal cancers and offer meaningful survival improvements.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Hymowitz SG, Malek S. Targeting the MAPK pathway in RAS mutant cancers. Cold Spring Harb Perspect Med. 2018;8(11): a031492.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Ostrem JM, Shokat KM. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov. 2016;15(11):771–85.

    Article  PubMed  CAS  Google Scholar 

  3. Consortium APG. AACR Project GENIE: powering precision medicine through an international consortium. Cancer Discov. 2017;7(8):818–31.

    Article  Google Scholar 

  4. Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23(6):703–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. 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(10):637–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Wang H, Chi L, Yu F, Dai H, Gao C, Si X, et al. Annual review of KRAS inhibitors in 2022. Eur J Med Chem. 2023;249: 115124.

    Article  PubMed  CAS  Google Scholar 

  7. Lu S, Jang H, Nussinov R, Zhang J. The structural basis of oncogenic mutations G12, G13 and Q61 in small GTPase K-Ras4B. Sci Rep. 2016;6:21949.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531(7592):47–52.

    Article  PubMed  CAS  Google Scholar 

  10. Network CGA. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–7.

    Article  Google Scholar 

  11. Zaidi SH, Harrison TA, Phipps AI, Steinfelder R, Trinh QM, Qu C, et al. Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival. Nat Commun. 2020;11(1):3644.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Yaeger R, Chatila WK, Lipsyc MD, Hechtman JF, Cercek A, Sanchez-Vega F, et al. Clinical sequencing defines the genomic landscape of metastatic colorectal cancer. Cancer Cell. 2018;33(1):125-36.e3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Erijman A, Shifman JM. RAS/effector interactions from structural and biophysical perspective. Mini Rev Med Chem. 2016;16(5):370–5.

    Article  PubMed  CAS  Google Scholar 

  14. Glaviano A, Foo ASC, Lam HY, Yap KCH, Jacot W, Jones RH, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer. 2023;22(1):138.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. 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(22):5962–73.

    Article  PubMed  CAS  Google Scholar 

  16. Deng J, Bai X, Feng X, Ni J, Beretov J, Graham P, et al. Inhibition of PI3K/Akt/mTOR signaling pathway alleviates ovarian cancer chemoresistance through reversing epithelial-mesenchymal transition and decreasing cancer stem cell marker expression. BMC Cancer. 2019;19(1):618.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Moghadam AR, Patrad E, Tafsiri E, Peng W, Fangman B, Pluard TJ, et al. Ral signaling pathway in health and cancer. Cancer Med. 2017;6(12):2998–3013.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hunter JC, Manandhar A, Carrasco MA, Gurbani D, Gondi S, Westover KD. Biochemical and structural analysis of common cancer-associated KRAS mutations. Mol Cancer Res. 2015;13(9):1325–35.

    Article  PubMed  CAS  Google Scholar 

  19. Dias Carvalho P, Guimarães CF, Cardoso AP, Mendonça S, Costa Â, Oliveira MJ, et al. KRAS oncogenic signaling extends beyond cancer cells to orchestrate the microenvironment. Cancer Res. 2018;78(1):7–14.

    Article  PubMed  CAS  Google Scholar 

  20. Hamarsheh S, Groß O, Brummer T, Zeiser R. Immune modulatory effects of oncogenic KRAS in cancer. Nat Commun. 2020;11(1):5439.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Jones RP, Sutton PA, Evans JP, Clifford R, McAvoy A, Lewis J, et al. Specific mutations in KRAS codon 12 are associated with worse overall survival in patients with advanced and recurrent colorectal cancer. Br J Cancer. 2017;116(7):923–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Taieb J, Le Malicot K, Shi Q, Penault-Llorca F, Bouché O, Tabernero J, et al. Prognostic value of BRAF and KRAS mutations in MSI and MSS stage III colon cancer. J Natl Cancer Inst. 2017;109(5):djw272.

  23. Koulouridi A, Karagianni M, Messaritakis I, Sfakianaki M, Voutsina A, Trypaki M, et al. Prognostic value of KRAS mutations in colorectal cancer patients. Cancers (Basel). 2022;14(14):3320.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Guo TA, Wu YC, Tan C, Jin YT, Sheng WQ, Cai SJ, et al. Clinicopathologic features and prognostic value of KRAS, NRAS and BRAF mutations and DNA mismatch repair status: a single-center retrospective study of 1,834 Chinese patients with stage I-IV colorectal cancer. Int J Cancer. 2019;145(6):1625–34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Strickler JH, Yoshino T, Stevinson K, Eichinger CS, Giannopoulou C, Rehn M, et al. Prevalence of KRAS G12C mutation and co-mutations and associated clinical outcomes in patients with colorectal cancer: a systematic literature review. Oncologist. 2023;28(11):e981–94.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(10):1626–34.

    Article  PubMed  CAS  Google Scholar 

  27. Windon AL, Loaiza-Bonilla A, Jensen CE, Randall M, Morrissette JJD, Shroff SG. A KRAS wild type mutational status confers a survival advantage in pancreatic ductal adenocarcinoma. J Gastrointest Oncol. 2018;9(1):1–10.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Tanaka M, Kunita A, Yamagishi M, Katoh H, Ishikawa S, Yamamoto H, et al. KRAS mutation in intrahepatic cholangiocarcinoma: linkage with metastasis-free survival and reduced E-cadherin expression. Liver Int. 2022;42(10):2329–40.

    Article  PubMed  CAS  Google Scholar 

  29. Zhou SL, Xin HY, Sun RQ, Zhou ZJ, Hu ZQ, Luo CB, et al. Association of KRAS variant subtypes with survival and recurrence in patients with surgically treated intrahepatic cholangiocarcinoma. JAMA Surg. 2022;157(1):59–65.

    Article  PubMed  Google Scholar 

  30. Wang JY, Xiu J, Baca Y, Arai H, Battaglin F, Kawanishi N, et al. Distinct genomic landscapes of gastroesophageal adenocarcinoma depending on PD-L1 expression identify mutations in RAS-MAPK pathway and TP53 as potential predictors of immunotherapy efficacy. Ann Oncol. 2021;32(7):906–16.

    Article  PubMed  CAS  Google Scholar 

  31. Traut TW. Physiological concentrations of purines and pyrimidines. Mol Cell Biochem. 1994;140(1):1–22.

    Article  PubMed  CAS  Google Scholar 

  32. Smyth LA, Collins I. Measuring and interpreting the selectivity of protein kinase inhibitors. J Chem Biol. 2009;2(3):131–51.

    Article  PubMed  PubMed Central  Google Scholar 

  33. John J, Sohmen R, Feuerstein J, Linke R, Wittinghofer A, Goody RS. Kinetics of interaction of nucleotides with nucleotide-free H-ras p21. Biochemistry. 1990;29(25):6058–65.

    Article  PubMed  CAS  Google Scholar 

  34. 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(7781):217–23.

    Article  PubMed  CAS  Google Scholar 

  35. Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. KRAS G12C inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, et al. The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 2020;10(1):54–71.

    Article  PubMed  CAS  Google Scholar 

  37. Ou SI, Jänne PA, Leal TA, Rybkin II, Sabari JK, Barve MA, et al. First-in-human phase I/IB dose-finding study of adagrasib (MRTX849) in patients with advanced KRAS G12C solid tumors (KRYSTAL-1). J Clin Oncol. 2022;40(23):2530–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. 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(25):2371–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC [press release]. Food and Drug Administration. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sotorasib-kras-g12c-mutated-nsclc. 28 May 2021.

  40. Jänne PA, Riely GJ, Gadgeel SM, Heist RS, Ou SI, Pacheco JM, et al. Adagrasib in non-small-cell lung cancer harboring a KRASG12C mutation. N Engl J Med. 2022;387(2):120–31.

    Article  PubMed  Google Scholar 

  41. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC [press release]. Food and Drug Administration. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-kras-g12c-mutated-nsclc. 12 Dec 2022.

  42. Fakih MG, Kopetz S, Kuboki Y, Kim TW, Munster PN, Krauss JC, et al. Sotorasib for previously treated colorectal cancers with KRAS G12C mutation (CodeBreaK100): a pre-specified analysis of a single-arm, phase 2 trial. Lancet Oncol. 2022;23(1):115–24.

    Article  PubMed  CAS  Google Scholar 

  43. Yaeger R, Weiss J, Pelster MS, Spira AI, Barve M, Ou SI, et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C. N Engl J Med. 2023;388(1):44–54.

    Article  PubMed  CAS  Google Scholar 

  44. Kopetz S, Desai J, Chan E, Hecht JR, O’Dwyer PJ, Maru D, et al. Phase II pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J Clin Oncol. 2015;33(34):4032–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Corcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012;2(3):227–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Corcoran RB, André T, Atreya CE, Schellens JHM, Yoshino T, Bendell JC, et al. Combined BRAF, EGFR, and MEK inhibition in patients with BRAFV600E-mutant colorectal cancer. Cancer Discov. 2018;8(4):428–43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019;381(17):1632–43.

    Article  PubMed  CAS  Google Scholar 

  48. Strickler JH, Satake H, George TJ, Yaeger R, Hollebecque A, Garrido-Laguna I, et al. Sotorasib in KRAS p.G12C-mutated advanced pancreatic cancer. N Engl J Med. 2023;388(1):33–43.

    Article  PubMed  CAS  Google Scholar 

  49. Bekaii-Saab TS, Yaeger R, Spira AI, Pelster MS, Sabari JK, Hafez N, et al. Adagrasib in advanced solid tumors harboring a KRAS G12C mutation. J Clin Oncol. 2023:JCO2300434.

  50. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: pancreatic adenocarcinoma (version 2.2023). 2023. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf

  51. Desai J, Han S-W, Lee J-S, Shacham-Shmueli E, Massarelli E, Cervantes A, et al. Abstract CT029: phase Ib study of GDC-6036 in combination with cetuximab in patients with colorectal cancer (CRC) with KRAS G12C mutation. Cancer Res. 2023;83(8_Suppl.):CT029-CT.

  52. 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(8):710–21.

    Article  PubMed  CAS  Google Scholar 

  53. 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(8_Suppl.):CT028-CT.

  54. Ruan D-y, Lee MA, Deng Y, Lee K-W, Millward M, Grewal JS, et al. Safety and efficacy of D-1553 in KRAS G12C-mutated colorectal cancer: results from a phase I/II study. J Clin Oncol. 2023;41(16_Suppl.):3563.

  55. 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(13_Suppl.):932.

  56. Li J, Huang J, Ba Y, Cao B, Luo S, Li W, et al. Abstract: glecirasib (JAB-21822, KRAS G12C inhibitor) monotherapy and in combination with cetuximab in patients with advanced colorectal cancer. Presented at JCA-AACR Precision Cancer Medicine International Conference, Kyoto, Japan; 30 June 2023.

  57. 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(16_Suppl.):3089.

  58. Kondo S, Yan D, Ganju V, Richardson G, Hou X, Shan J, et al. 1622P D-1553 in patients with KRAS G12C mutated advanced pancreatic cancer (pca). Ann Oncol. 2023;34:S898–9.

    Article  Google Scholar 

  59. 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.

    Article  Google Scholar 

  60. 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(16_Suppl.):9007.

  61. 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(12_Suppl.):2667.

  62. Lee A. Sotorasib: a review in KRAS G12C mutation-positive non-small cell lung cancer. Target Oncol. 2022;17(6):727–33.

    Article  PubMed  PubMed Central  Google Scholar 

  63. 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. Lancet. 2023;401(10378):733–46.

    Article  PubMed  Google Scholar 

  64. Waterhouse DM, Rothschild S, Dooms C, Mennecier B, Bozorgmehr F, Majem Tarruella M, et al. Patient-reported outcomes from the CodeBreaK 200 phase 3 trial comparing sotorasib versus docetaxel in KRAS G12C-mutated NSCLC. Presented at the European lung cancer congress, Copenhagen, Denmark; Mar 29, 2023. J Thora Onc 202318(4):S37-38. https://doi.org/10.1016/S1556-0864(23)00258-7.

  65. 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(12_Suppl.):3595.

  66. Cregg J, Nichols RJ, Yang YC, Schulze CJ, Wang Z, Dua R, et al. Abstract ND07: discovery of RMC-6291, a tri-complex KRASG12C(ON) inhibitor. Cancer Res. 2023;83(7_Suppl.):ND07-ND.

  67. NCT05462717: dose escalation and dose expansion study of RMC-6291 monotherapy in subjects with advanced KRASG12C mutant solid tumors: ClinicalTrials.gov; 2022 [updated Aug 15, 2023]. https://www.clinicaltrials.gov/study/NCT05462717. Accessed 12 Dec 2023.

  68. Patel S, Bhhatarai B, Calses P, Erlanson D, Everley R, Fong S, et al. Abstract 1142: discovery of FMC-376 a novel orally bioavailable inhibitor of activated KRASG12C. Cancer Res. 2023;83(7_Suppl.):1142.

  69. 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(7):1633–43.

  70. Ryan MB, Coker O, Sorokin A, Fella K, Barnes H, Wong E, et al. KRASG12C-independent feedback activation of wildtype RAS constrains KRASG12C inhibitor efficacy. Cell Rep. 2022;39(12): 110993.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. 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(25):2382–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. 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(8):1913–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Zhang Y, Weinberg RA. Epithelial-to-mesenchymal transition in cancer: complexity and opportunities. Front Med. 2018;12(4):361–73.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Singh A, Greninger P, Rhodes D, Koopman L, Violette S, Bardeesy N, et al. A gene expression signature associated with “K-Ras addiction” reveals regulators of EMT and tumor cell survival. Cancer Cell. 2009;15(6):489–500.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Kuboki Y, Yaeger R, Fakih M, Strickler J, Masuishi T, Kim E, et al. Abstract 45MO: Sotorasib in combination with panitumumab in refractory KRAS G12C-mutated colorectal cancer: safety and efficacy for phase Ib full expansion cohort. Ann Oncol. 2022;33:S1445-1446

  76. Xu RH, Xu Y, Yan D, Munster P, Ruan D, Deng Y, et al. 550O Safety and efficacy of D-1553 in combination with cetuximab in KRAS G12C mutated colorectal cancer (CRC): a phase II study. Ann Oncol. 2023;34:S410–1.

    Article  Google Scholar 

  77. Yaeger R, Mezzadra R, Sinopoli J, Bian Y, Marasco M, Kaplun E, et al. Molecular characterization of acquired resistance to KRASG12C–EGFR inhibition in colorectal cancer. Cancer Discov. 2023;13(1):41–55.

    Article  PubMed  CAS  Google Scholar 

  78. Hong DS, Kuboki Y, Yaeger R, Strickler JH, Masuishi T, Langer C, et al. Abstract 2308: biomarkers of acquired resistance to sotorasib (soto) plus panitumumab (pani) in chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC). Cancer Res. 2023;83(7_Suppl.):2308.

  79. Paez D, Meriggi F, Cremolini C, Folprecht G, Korantzis I, Chan E, et al. Abstract 437TiP trial in progress: a phase III global study of sotorasib, a specific KRAS G12C inhibitor, in combination with panitumumab versus investigator’s choice in chemorefractory metastatic colorectal cancer (CodeBreaK 300). Ann Oncol. 2022;33:S734. https://doi.org/10.1016/j.annonc.2022.07.575.

  80. Pietrantonio F, Salvatore L, Esaki T DPM, D. Paez 5 JT, M.V. Karamouzis , E. Ruiz TWK, et al. Abstract LBA10: sotorasib plus panitumumab versus standard-of-care for chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC): CodeBreak 300 phase III study. Ann Oncol. 2023;34:S1266. https://doi.org/10.1016/j.annonc.2023.20.016.

  81. Fakih MG, Salvatore L, Esaki T, Modest DP, Lopez-Bravo DP, Taieb J, et al. Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C. N Engl J Med. 2023; 389:2125-39. https://doi.org/10.1056/NEJMoa2308795.

  82. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369(11):1023–34.

    Article  PubMed  CAS  Google Scholar 

  83. Hong DS, Kuboki Y, Strickler JH, Fakih M, Houssiau H, Price TJ, et al. Sotorasib (Soto) plus panitumumab (Pmab) and FOLFIRI for previously treated KRAS G12C-mutated metastatic colorectal cancer (mCRC): CodeBreaK 101 phase 1b safety and efficacy. J Clin Oncol. 2023;41(16_Suppl.):3513.

  84. NCT05722327: phase I trial of adagrasib (MRTX849) in combination with cetuximab and irinotecan in patients with colorectal cancer: ClinicalTrials.gov; 2023 [updated Jun 15, 2023]. https://www.clinicaltrials.gov/study/NCT05722327. Accessed 12 Dec 2023.

  85. NCT04929223: a study evaluating the safety and efficacy of targeted therapies in subpopulations of patients with metastatic colorectal cancer (INTRINSIC): ClinicalTrials.gov; 2021 [updated June 22, 2023]. https://www.clinicaltrials.gov/study/NCT04929223. Accessed 12 Dec 2023.

  86. Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19(5):603–15.

    Article  PubMed  CAS  Google Scholar 

  87. 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(12_Suppl.):P05-1-P-1.

  88. 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(4_Suppl.):TPS214-TPS.

  89. NCT05358249: platform study of JDQ443 in combinations in patients with advanced solid tumors harboring the KRAS G12C mutation (KontRASt-03): ClinicalTrials.gov; 2022 [updated Aug 30, 2023]. https://www.clinicaltrials.gov/study/NCT05358249. Accessed 12 Dec 2023.

  90. Coma S, Chowdhury S, Dilly J, Musteanu M, Barbacid M, Aguirre AJ, et al. Abstract 402: dual RAF/MEK inhibitor VS-6766 enhances antitumor efficacy of KRAS G12C inhibitors through vertical inhibition of RAS, RAF and MEK. Cancer Res. 2022;82(12_Suppl.):402.

  91. NCT05074810: phase 1/2 study of avutometinib (VS-6766) + sotorasib in G12C NSCLC patients (RAMP203): ClinicalTrials.gov; 2022 [updated Aug 2, 2023]. https://www.clinicaltrials.gov/study/NCT05074810. Accessed 12 Dec 2023.

  92. NCT05375994: study of avutometinib (VS-6766) + adagrasib in KRAS G12C NSCLC patients (RAMP204): ClinicalTrials.gov; 2022 [updated Jul 7, 2023]. https://www.clinicaltrials.gov/study/NCT05375994. Accessed 12 Dec 2023.

  93. Liu C, Lu H, Wang H, Loo A, Zhang X, Yang G, et al. Combinations with allosteric SHP2 inhibitor TNO155 to block receptor tyrosine kinase signaling. Clin Cancer Res. 2021;27(1):342–54.

    Article  PubMed  CAS  Google Scholar 

  94. 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(9):S8.

    Article  Google Scholar 

  95. 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.

    Article  Google Scholar 

  96. LaMarche MJ, Acker M, Argintaru A, Bauer D, Boisclair J, Chan H, et al. Identification of TNO155, an allosteric SHP2 inhibitor for the treatment of cancer. J Med Chem. 2020;63(22):13578–94.

    Article  PubMed  CAS  Google Scholar 

  97. NCT04185883: Sotorasib activity in subjects with advanced solid tumors with KRAS p.G12C mutation (CodeBreak 101): ClinicalTrials.gov; 2019 [updated Aug 14, 2023]. https://www.clinicaltrials.gov/study/NCT04185883. Accessed 12 Dec 2023.

  98. 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(3_Suppl.):TPS146-TPS.

  99. Stice JP, Donovan S, Sun Y, Kohl N, Czako B, Mseeh F, et al. Abstract P207: BBP-398, a potent, small molecule inhibitor of SHP2, enhances the response of established NSCLC xenografts to KRASG12C and mutEGFR inhibitors. Mol Cancer Ther. 2021;20(12_Suppl.):P207-P.

  100. Drilon AE, Johnson ML, Gadgeel SM, Nepert D, Feng G, Golmakani M, et al. A first-in-human, phase 1 study of the SHP2 inhibitor PF-07284892 as monotherapy and in combination with different targeted therapies in oncogene-driven, treatment-resistant solid tumors. J Clin Oncol. 2023;41(16_Suppl.):3020.

  101. Williams B, Taylor A, Orozco O, Owen C, Kelley E, Lescarbeau A, et al. Abstract 3327: Discovery and characterization of the potent, allosteric SHP2 inhibitor GDC-1971 for the treatment of RTK/RAS driven tumors. Cancer Res. 2022;82(12_Suppl.):3327.

  102. 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(1):142–57.

    Article  PubMed  CAS  Google Scholar 

  103. Thatikonda V, Lu H, Jurado S, Kostyrko K, Bristow CA, Bosch K, et al. Combined KRAS G12C and SOS1 inhibition enhances and extends the anti-tumor response in KRAS G12C-driven cancers by addressing intrinsic and acquired resistance. bioRxiv [Preprint]. 2023 Jan 23:2023.01.23.525210. https://doi.org/10.1101/2023.01.23.525210.

  104. 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(13_Suppl.):CT210-CT. https://doi.org/10.1158/1538-7445.am2021-ct210.

  105. Tang Q, Chen Y, Li X, Long S, Shi Y, Yu Y, et al. The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers. Front Immunol. 2022;13: 964442.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. O’Neil BH, Wallmark JM, Lorente D, Elez E, Raimbourg J, Gomez-Roca C, et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced colorectal carcinoma. PLoS ONE. 2017;12(12): e0189848.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Ott PA, Bang Y-J, Piha-Paul SA, Razak ARA, Bennouna J, Soria J-C, et al. T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J Clin Oncol. 2019;37(4):318–27.

    Article  PubMed  Google Scholar 

  108. Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398(10294):27–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Sun JM, Shen L, Shah MA, Enzinger P, Adenis A, Doi T, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021;398(10302):759–71.

    Article  PubMed  CAS  Google Scholar 

  110. Oh D-Y, He AR, Qin S, Chen L-T, Okusaka T, Vogel A, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid. 2022;1(8). https://doi.org/10.1056/EVIDoa2200015.

  111. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894–905.

    Article  PubMed  CAS  Google Scholar 

  112. Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1(8):EVIDoa2100070.

  113. Ott PA, Piha-Paul SA, Munster P, Pishvaian MJ, van Brummelen EMJ, Cohen RB, et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Ann Oncol. 2017;28(5):1036–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Morris VK, Salem ME, Nimeiri H, Iqbal S, Singh P, Ciombor K, et al. Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(4):446–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Janne P, Smit E, de Marinis F, Laskin J, Gomez D, Gadgell S, et al. Abstract 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. Presented at ESMO Immuno-Oncology Congress, Geneva, Switzerland. Immuno-Onc and Tech. 2022;15:100360

  116. Li B, Falchook G, Durm G, Burns T, Skoulidis F, Ramalingam S, et al. Abstract 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(9):S10-11. https://doi.org/10.1016/j.jtho.2022.07.025.

  117. NCT05848843: a phase I study of adagrasib and durvalumab for treatment of advanced non-small cell lung cancers and gastro-intestinal cancers harboring KRAS G12C mutations: ClinicalTrials.gov; 2023 [updated May 10, 2023]. https://www.clinicaltrials.gov/study/NCT05848843. Accessed 12 Dec 2023.

  118. NCT06039384: a study of INCB099280 in combination with adagrasib in adults with advanced solid tumors harboring a KRASG12C mutation: ClinicalTrials.gov; 2023 [updated Sep 15, 2023]. https://www.clinicaltrials.gov/study/NCT06039384. Accessed 12 Dec 2023.

  119. Hallin J, Bowcut V, Calinisan A, Briere DM, Hargis L, Engstrom LD, et al. Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor. Nat Med. 2022;28(10):2171–82.

    Article  PubMed  CAS  Google Scholar 

  120. Nagashima T, Yoshinari T, Nishizono Y, Tasaki M, Inamura K, Ishioka H, et al. Abstract 5735: novel KRAS G12D degrader ASP3082 demonstrates in vivo, dose-dependent KRAS degradation, KRAS pathway inhibition, and antitumor efficacy in multiple KRAS G12D-mutated cancer models. Cancer Res. 2023;83(7_Suppl.):5735.

  121. Tolcher AW, Park W, Wang JS, Spira AI, Janne PA, Lee H-J, et al. Trial in progress: a phase 1, first-in-human, open-label, multicenter, dose-escalation and dose-expansion study of ASP3082 in patients with previously treated advanced solid tumors and KRAS G12D mutations. J Clin Oncol. 2023;41(4_Suppl.):TPS764-TPS.

  122. NCT05533463: phase I study of HRS-4642 in patients with advanced solid tumors harboring KRAS G12D mutation: ClinicalTrials.gov; 2022 [updated Oct 25, 2022]. https://www.clinicaltrials.gov/study/NCT05533463. Accessed 12 Dec 2023.

  123. Zhou C, Li W, Song Z, Zhang Y, Huang D, Yang Z, et al. LBA33 A first-in-human phase I study of a novel KRAS G12D inhibitor HRS-4642 in patients with advanced solid tumors harboring KRAS G12D mutation. Ann Oncol. 2023;34:S1273.

    Article  Google Scholar 

  124. NCT06040541: study of RMC-9805 in participants with KRASG12D-mutant solid tumors: ClinicalTrials.gov; 2023 [updated Sep 15, 2023]. https://www.clinicaltrials.gov/study/NCT06040541. Accessed 12 Dec 2023.

  125. Kemp SB, Cheng N, Markosyan N, Sor R, Kim IK, Hallin J, et al. Efficacy of a small-molecule inhibitor of KrasG12D in immunocompetent models of pancreatic cancer. Cancer Discov. 2023;13(2):298–311.

    Article  PubMed  CAS  Google Scholar 

  126. Bery N, Miller A, Rabbitts T. A potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS. Nat Commun. 2020;11(1):3233.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Escher TE, Satchell KJF. RAS degraders: the new frontier for RAS-driven cancers. Mol Ther. 2023;31(7):1904–19.

    Article  PubMed  CAS  Google Scholar 

  128. Jiang L, Menard M, Weller C, Wang Z, Burnett L, Aronchik I, et al. Abstract 526: RMC-9805, a first-in-class, mutant-selective, covalent and oral KRASG12D(ON) inhibitor that induces apoptosis and drives tumor regression in preclinical models of KRASG12D cancers. Cancer Res. 2023;83(7_Suppl.):526.

  129. Menard MJ, Chow C, Chen K, Blaj C, Shifrin NT, Courtney H, et al. Abstract 3475: RMC-9805, a first-in-class, mutant-selective, covalent and orally bioavailable KRASG12D(ON) inhibitor, promotes cancer-associated neoantigen recognition and synergizes with immunotherapy in preclinical models. Cancer Res. 2023;83(7_Suppl.):3475.

  130. Kessler D, Gmachl M, Mantoulidis A, Martin LJ, Zoephel A, Mayer M, et al. Drugging an undruggable pocket on KRAS. Proc Natl Acad Sci USA. 2019;116(32):15823–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Brooun A, Bae JH, Cheng H, Li P, Lin B, Fagan P, et al. Abstract 54: Non-clinical identification and characterization of KRAS G12D inhibitors. Presented at the 34th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Barcelona, Spain. Eur J Cancer. 2022;174S1:S19.

  132. Bianca J Lee, Jim Cregg, Zhe Chen, Kyle Seamon, Anne Edwards, Andre Eriksson, et al. Abstract: selective inhibition of the active state of KRASG12V with the non-covalent, tri-complex inhibitor RMC-5127. In: AACR-NCI-EORTC international conference; 13 Oct 2023; Boston (MA).

  133. Schulze CJ, Cregg J, Seamon KJ, Yang YC, Wang Z, Garrenton LS, et al. Abstract 3598: a first-in-class tri-complex KRASG13C(ON) inhibitor validates therapeutic targeting of KRASG13Cand drives tumor regressions in preclinical models. Cancer Res. 2022;82(12_Suppl.):3598.

  134. Yang YC, Thompson S, Montgomery D, Quiñones AJ, Wei X, Madej B, et al. Abstract 1598: RM-046, a first-in-class, mutant-selective, and oral KRASQ61H(ON) inhibitor that drives tumor regression in preclinical models and validates KRASQ61H as a therapeutic target. Cancer Res. 2023;83(7_Suppl.):1598.

  135. NCT05379985: evaluation of RMC-6236 in subjects with advanced solid tumors harboring specific mutations in KRAS: ClinicalTrials.gov; 2022 [updated Dec 27, 2022]. https://www.clinicaltrials.gov/study/NCT05379985. Accessed 12 Dec 2023.

  136. Koltun ES, Rice MA, Gustafson WC, Wilds D, Jiang J, Lee BJ, et al. Abstract 3597: direct targeting of KRASG12X mutant cancers with RMC-6236, a first-in-class, RAS-selective, orally bioavailable, tri-complex RASMULTI(ON) inhibitor. Cancer Res. 2022;82(12_Suppl.):3597.

  137. Arbour KC, Punekar S, Garrido-Laguna I, Hong DS, Wolpin B, Pelster MS, et al. Abstract 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.

  138. Wasko UN, Sastra SA, Palermo CF, Wildes D, Singh M, Olive KP. Abstract 1725: preclinical evaluation of RM-042, an orally bioavailable inhibitor of GTP-RAS, in models of pancreatic ductal adenocarcinoma. Cancer Res. 2023;83(7_Suppl.):1725. https://doi.org/10.1158/1538-7445.am2023-1725.

  139. 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(7968):160–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Corcoran RB. A single inhibitor for all KRAS mutations. Nat Cancer. 2023;4(8):1060–2.

    Article  PubMed  CAS  Google Scholar 

  141. Tran E, Robbins PF, Lu YC, Prickett TD, Gartner JJ, Jia L, et al. T-cell transfer therapy targeting mutant KRAS in cancer. N Engl J Med. 2016;375(23):2255–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Leidner R, Sanjuan Silva N, Huang H, Sprott D, Zheng C, Shih YP, et al. Neoantigen T-cell receptor gene therapy in pancreatic cancer. N Engl J Med. 2022;386(22):2112–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Pant S, Furqan M, Abdul-Karim RM, Chung V, Devoe CE, Johnson ML, et al. First-in-human phase 1 trial of ELI-002 immunotherapy as treatment for subjects with Kirsten rat sarcoma (KRAS)-mutated pancreatic ductal adenocarcinoma and other solid tumors. J Clin Oncol. 2022;40(16_Suppl.):TPS2701-TPS.

  144. Haldar SD, Heumann TR, Berg M, Ferguson A, Lim SJ, Wang H, et al. A phase I study of a mutant KRAS-targeted long peptide vaccine combined with ipilimumab/nivolumab in resected pancreatic cancer and MMR-proficient metastatic colorectal cancer. J Clin Oncol. 2023;41(4_Suppl.):TPS814-TPS.

  145. Surana R, LeBleu VS, Lee JJ, Smaglo BG, Zhao D, Lee MS, et al. Phase I study of mesenchymal stem cell (MSC)-derived exosomes with KRASG12D siRNA in patients with metastatic pancreatic cancer harboring a KRASG12D mutation. J Clin Oncol 2022;40(4_Suppl.):TPS633-TPS.

  146. Douglass J, Hsiue EH, Mog BJ, Hwang MS, DiNapoli SR, Pearlman AH, et al. Bispecific antibodies targeting mutant RAS neoantigens. Sci Immunol. 2021;6(57):eabd5515.

  147. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2(5):561–6.

    Article  PubMed  CAS  Google Scholar 

  148. Pant S, Yaeger R, Spira AI, Pelster M, Sabari JK, Hafez N, et al. KRYSTAL-1: activity and safety of adagrasib (MRTX849) in patients with advanced solid tumors harboring a KRASG12C mutation. J Clin Oncol. 2023;41(36_Suppl.):425082.

  149. NCT05634525: phase Ib trial of the KRASG12C inhibitor adagrasib (MRTX849) in KRAS G12C mutant metastatic pancreatic cancer patients: ClinicalTrials.gov; 2023 [updated May 3, 2023]. https://www.clinicaltrials.gov/study/NCT05634525. Accessed 12 Dec 2023.

  150. NCT05578092: a phase 1/2 study of MRTX0902 in solid tumors with mutations in the KRAS MAPK pathway: ClinicalTrials.gov; 2022 [updated Aug 21, 2023. https://www.clinicaltrials.gov/study/NCT05578092. Accessed 12 Dec 2023.

  151. NCT05480865: SHP2 inhibitor BBP-398 in combination with sotorasib in patients with advanced solid tumors and a KRAS-G12C mutation (Argonaut): ClinicalTrials.gov; 2022 [updated Aug 18, 2023. https://www.clinicaltrials.gov/study/NCT05480865. Accessed 12 Dec 2023.

  152. NCT06008288: a study of JAB-21822 in patients with KRAS p.G12C mutated pancreatic cancer: ClinicalTrials.gov; 2023 [updated Aug 23, 2023]. https://www.clznicaltrials.gov/study/NCT06008288. Accessed 12 Dec 2023.

  153. NCT05288205: phase 1/2a study of JAB-21822 plus JAB-3312 in patients with advanced solid tumors harboring KRAS p.G12C mutation: ClinicalTrials.gov; 2022 [updated June 30, 2022]. https://www.clinicaltrials.gov/study/NCT05288205?term=NCT05288205&rank=1. Accessed 12 Dec 2023.

  154. NCT04006301: first-in-human study of JNJ-74699157 in participants with tumors harboring the KRAS G12C mutation: ClinicalTrials.gov; 2019 [updated Nov 6, 2020]. https://www.clinicaltrials.gov/study/NCT04006301. Accessed 12 Dec 2023.

  155. Janne P, Bigot F, Papadopoulos K, Eberst L, Sommerhalder D, Lebellec L, et al. Abstract: preliminary safety and anti-tumor activity of RMC-6291, a first-in-class, tri-complex KRASG12C(ON) inhibitor, in patients with or without prior KRASG12C(OFF) inhibitor treatment. AACR-NCI-EORTC International Conference; 13 Oct 2023; Boston (MA).

  156. NCT05737706: study of MRTX1133 in patients with advanced solid tumors harboring a KRAS G12D mutation: ClinicalTrials.gov; 2023 [updated Aug 28, 2023]. https://www.clinicaltrials.gov/study/NCT05737706. Accessed 12 Dec 2023.

Download references

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA, 02114, USA

    Bennett A. Caughey

  2. Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC, USA

    John H. Strickler

Authors
  1. Bennett A. Caughey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John H. Strickler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bennett A. Caughey.

Ethics declarations

Funding

No external funding was received for the preparation of this article.

Conflict of interest

Bennett A. Caughey has received honoraria from Foundation Medicine, Inc. John H. Strickler has received grant/research support from AbbVie, Amgen, AStar D3, Bayer, Beigene, Curegenix, Daiichi-Sankyo, Eli Lilly, Erasca, Gossamer Bio, Leap Therapeutics, Nektar, Roche/Genentech, Seagen, and Silverback Therapeutics; and consulting fees from or serving in an advisory role to AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Daiichi-Sankyo, Eli Lilly, G3 Therapeutics, GSK, Natera, Pfizer, Pionyr Immunotherapeutics, Roche/Genentech, Seagen, Silverback Therapeutics, Takeda, and Viatris.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and material

All data were derived from publicly available sources at Project Genie Public Cohort 13.1, available at genie.cbioportal.org.

Code availability

Not applicable.

Author contributions

BAC and JHS both contributed to all areas of the manuscript, including conception and design, assembly and collection of data, and manuscript writing. Both authors gave final approval to the manuscript.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 219 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Caughey, B.A., Strickler, J.H. Targeting KRAS-Mutated Gastrointestinal Malignancies with Small-Molecule Inhibitors: A New Generation of Breakthrough Therapies. Drugs 84, 27–44 (2024). https://doi.org/10.1007/s40265-023-01980-8

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-023-01980-8

Search

Navigation