Targeting KRAS^G12C-Mutated Advanced Colorectal Cancer: Research and Clinical Developments

References

• Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757–1765. doi:10.1056/NEJMoa0804385
   PubMed Web of Science ®Google Scholar
• Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(10):1626–1634. doi:10.1200/JCO.2007.14.7116
   PubMed Web of Science ®Google Scholar
• Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27(8):1386–1422. doi:10.1093/annonc/mdw235
   PubMed Web of Science ®Google Scholar
• Sanchez-Vega F, Mina M, Armenia J, et al. Oncogenic signaling pathways in the cancer genome atlas. Cell. 2018;173(2):321–337.e10. doi:10.1016/j.cell.2018.03.035
   PubMed Web of Science ®Google Scholar
• Ou SHI, Sokol ES, Madison R, et al. Comprehensive pan-cancer analysis of KRAS genomic alterations (GA) including potentially targetable subsets. Ann Oncol. 2019;30:v26. doi:10.1093/annonc/mdz239.003
   Web of Science ®Google Scholar
• Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A. Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract. 2009;205(12):858–862. doi:10.1016/j.prp.2009.07.010
   PubMed Web of Science ®Google Scholar
• Ouerhani S, Elgaaied ABA. The mutational spectrum of HRAS, KRAS, NRAS and FGFR3 genes in bladder cancer. Cancer Biomark. 2011;10(6):259–266. doi:10.3233/CBM-2012-0254
   PubMed Web of Science ®Google Scholar
• Henry JT, Coker O, Chowdhury S, et al. Comprehensive clinical and molecular characterization of KRAS G12C-mutant colorectal cancer. JCO Precis Oncol. 2021;5:PO.20.00256. doi:10.1200/PO.20.00256
   PubMed Web of Science ®Google Scholar
• Muñoz-Maldonado C, Zimmer Y, Medová M. A comparative analysis of individual RAS mutations in cancer biology. Front Oncol. 2019;9:1088. doi:10.3389/fonc.2019.01088
   PubMed Web of Science ®Google Scholar
• Khan AQ, Kuttikrishnan S, Siveen KS, et al. RAS-mediated oncogenic signaling pathways in human malignancies. Semin Cancer Biol. 2019;54:1–13. doi:10.1016/j.semcancer.2018.03.001
   PubMed Web of Science ®Google Scholar
• McCormick F. Targeting KRAS directly. Annu Rev Cancer Biol. 2018;2(1):81–90. doi:10.1146/annurev-cancerbio-050216-122010
   Google Scholar
• Patricelli MP, Janes MR, Li LS, et al. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov. 2016;6(3):316–329. doi:10.1158/2159-8290.CD-15-1105
   PubMed Web of Science ®Google Scholar
• Lito P, Solomon M, Li LS, Hansen R, Rosen N. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science. 2016;351(6273):604–608. doi:10.1126/science.aad6204
   PubMed Web of Science ®Google Scholar
• 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):548–551. doi:10.1038/nature12796
   PubMed Web of Science ®Google Scholar
• Fell JB, Fischer JP, Baer BR, et al. Identification of the clinical development candidate MRTX849, a covalent KRASG12C inhibitor for the treatment of cancer. J Med Chem. 2020;63(13):6679–6693. doi:10.1021/acs.jmedchem.9b02052
   PubMed Web of Science ®Google Scholar
• Janes MR, Zhang J, Li LS, et al. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell. 2018;172(3):578–589.e17. doi:10.1016/j.cell.2018.01.006
   PubMed Web of Science ®Google Scholar
• Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575(7781):217–223. doi:10.1038/s41586-019-1694-1
   PubMed Web of Science ®Google Scholar
• Hallin J, Engstrom LD, Hargis L, 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. doi:10.1158/2159-8290.CD-19-1167
   PubMed Web of Science ®Google Scholar
• Fakih M, O’Neil B, Price TJ, et al. Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRAS G12C inhibitor, in advanced solid tumors. J Clin Oncol. 2019;37(15_suppl):3003. doi:10.1200/JCO.2019.37.15_suppl.3003
   Web of Science ®Google Scholar
• Fakih M, Desai J, Kuboki Y, et al. CodeBreak 100: activity of AMG 510, a novel small molecule inhibitor of KRAS G12C, in patients with advanced colorectal cancer. J Clin Oncol. 2020;38(15_suppl):4018. doi:10.1200/JCO.2020.38.15_suppl.4018
   Web of Science ®Google Scholar
• Hong DS, Kuo J, Sacher AG, et al. CodeBreak 100: Phase I study of AMG 510, a novel KRAS G12C inhibitor, in patients (pts) with advanced solid tumors other than non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). J Clin Oncol. 2020;38(15_suppl):3511. doi:10.1200/JCO.2020.38.15_suppl.3511
   Google Scholar
• Hong DS, Fakih MG, Strickler JH, et al. KRAS G12C inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207–1217. doi:10.1056/NEJMoa1917239
   PubMed Web of Science ®Google Scholar
• Jänne P, Rybkin II, Spira A, et al. KRYSTAL-1: activity and safety of adagrasib (MRTX849) in advanced/ metastatic Non–Small-Cell Lung Cancer (NSCLC) harboring KRAS G12C mutation. Eur J Cancer. 2020;138(Suppl2):S1–2.
   PubMedGoogle Scholar
• NCT03600883. A Phase 1/2, study evaluating the safety, tolerability, PK, and efficacy of sotorasib (AMG 510) in Subjects with solid tumors with a specific KRAS mutation (CodeBreaK 100). Available from: https://clinicaltrials.gov/ct2/show/NCT03600883. Accessed April 5, 2022.
   Google Scholar
• Fakih MG, Kopetz S, Kuboki Y, et al. Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial. Lancet Oncol. 2022;23(1):115–124. doi:10.1016/S1470-2045(21)00605-7
   PubMed Web of Science ®Google Scholar
• Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. 2021;384(25):2371–2381. doi:10.1056/NEJMoa2103695
   PubMed Web of Science ®Google Scholar
• NCT03785249. Phase 1/2 study of MRTX849 in patients with cancer having a KRAS G12C mutation KRYSTAL-1. Available from: https://clinicaltrials.gov/ct2/show/NCT03785249. Accessed April 5, 2022.
   Google Scholar
• Ou SHI, Jänne PA, Leal TA, 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. doi:10.1200/JCO.21.02752
   Web of Science ®Google Scholar
• Weiss J, Yaeger RD, Johnson ML, et al. LBA6 KRYSTAL-1: adagrasib (MRTX849) as monotherapy or combined with cetuximab (Cetux) in patients (Pts) with colorectal cancer (CRC) harboring a KRASG12C mutation. Ann Oncol. 2021;32:S1294. doi:10.1016/j.annonc.2021.08.2093
   PubMed Web of Science ®Google Scholar
• Corral de la Fuente E, Olmedo Garcia ME, Gomez Rueda A, Lage Y, Garrido P. Targeting KRAS in Non-Small Cell Lung Cancer. Front Oncol. 2022;11:792635. doi:10.3389/fonc.2021.792635
   PubMed Web of Science ®Google Scholar
• Lanman BA, Allen JR, Allen JG, et al. Discovery of a covalent inhibitor of KRASG12C (AMG 510) for the treatment of solid tumors. J Med Chem. 2020;63(1):52–65. doi:10.1021/acs.jmedchem.9b01180
   PubMed Web of Science ®Google Scholar
• Goebel L, Müller MP, Goody RS, Rauh D. KRasG12C inhibitors in clinical trials: a short historical perspective. RSC Med Chem. 2020;11(7):760–770. doi:10.1039/D0MD00096E
   PubMedGoogle Scholar
• Koga T, Suda K, Fujino T, et al. KRAS secondary mutations that confer acquired resistance to KRAS G12C inhibitors, sotorasib and adagrasib, and overcoming strategies: insights from in vitro experiments. J Thorac Oncol. 2021;16(8):1321–1332. doi:10.1016/j.jtho.2021.04.015
   PubMed Web of Science ®Google Scholar
• Zhang SS, Nagasaka M. Spotlight on Sotorasib (AMG 510) for KRAS G12C positive Non-Small Cell Lung Cancer. Lung Cancer. 2021;12:115–122. doi:10.2147/LCTT.S334623
   PubMed Web of Science ®Google Scholar
• Zhao Y, Murciano-Goroff YR, Xue JY, et al. Diverse alterations associated with resistance to KRAS(G12C) inhibition. Nature. 2021;599(7886):679–683. doi:10.1038/s41586-021-04065-2
   PubMed Web of Science ®Google Scholar
• Xue JY, Zhao Y, Aronowitz J, et al. Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition. Nature. 2020;577(7790):421–425. doi:10.1038/s41586-019-1884-x
   PubMed Web of Science ®Google Scholar
• Awad MM, Liu S, Rybkin II, et al. Acquired resistance to KRAS G12C inhibition in cancer. N Engl J Med. 2021;384(25):2382–2393. doi:10.1056/NEJMoa2105281
   PubMed Web of Science ®Google Scholar
• NCT04185883. Sotorasib activity in subjects with advanced solid tumors with KRAS p.G12C mutation (CodeBreak 101). Available from: https://www.clinicaltrials.gov/ct2/show/NCT04185883. Accessed April 5, 2022.
   Google Scholar
• Tsai YS, Woodcock MG, Azam SH, et al. Rapid idiosyncratic mechanisms of clinical resistance to KRAS G12C inhibition. J Clin Invest. 2022;132(4):e155523. doi:10.1172/JCI155523
   PubMed Web of Science ®Google Scholar
• Robert C, Grob JJ, Stroyakovskiy D, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019;381(7):626–636. doi:10.1056/NEJMoa1904059
   PubMed Web of Science ®Google Scholar
• Planchard D, Besse B, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016;17(7):984–993. doi:10.1016/S1470-2045(16)30146-2
   PubMed Web of Science ®Google Scholar
• Corcoran RB, André T, Atreya CE, et al. Combined BRAF, EGFR, and MEK inhibition in patients with BRAFV600E-mutant colorectal cancer. Cancer Discov. 2018;8(4):428–443. doi:10.1158/2159-8290.CD-17-1226
   PubMed Web of Science ®Google Scholar
• Planchard D, Smit EF, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017;18(10):1307–1316. doi:10.1016/S1470-2045(17)30679-4
   PubMed Web of Science ®Google Scholar
• Dunnett-Kane V, Nicola P, Blackhall F, Lindsay C. Mechanisms of resistance to KRASG12C inhibitors. Cancers. 2021;13(1):E151. doi:10.3390/cancers13010151
   PubMed Web of Science ®Google Scholar
• Singh A, Greninger P, Rhodes D, 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. doi:10.1016/j.ccr.2009.03.022
   PubMed Web of Science ®Google Scholar
• Amodio V, Yaeger R, Arcella P, et al. EGFR blockade reverts resistance to KRAS G12C inhibition in colorectal cancer. Cancer Discov. 2020;10(8):1129–1139. doi:10.1158/2159-8290.CD-20-0187
   PubMed Web of Science ®Google Scholar
• Lee S, Jeong W, Cho Y, et al. β‐Catenin‐ RAS interaction serves as a molecular switch for RAS degradation via GSK 3β. EMBO Rep. 2018;19:12. doi:10.15252/embr.201846060
   Web of Science ®Google Scholar
• Kopetz S, Desai J, Chan E, et al. Phase II pilot study of Vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J Clin Oncol. 2015;33(34):4032–4038. doi:10.1200/JCO.2015.63.2497
   PubMed Web of Science ®Google Scholar
• Van Cutsem E, Huijberts S, Grothey A, et al. Binimetinib, Encorafenib, and Cetuximab triplet therapy for patients with BRAF V600E–mutant metastatic colorectal cancer: safety Lead-in results from the Phase III BEACON colorectal cancer study. J Clin Oncol. 2019;37(17):1460–1469. doi:10.1200/JCO.18.02459
   PubMed Web of Science ®Google Scholar
• Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019;381(17):1632–1643. doi:10.1056/NEJMoa1908075
   PubMed Web of Science ®Google Scholar
• Hong DS, Morris VK, El Osta B, et al. Phase IB study of Vemurafenib in combination with Irinotecan and Cetuximab in patients with metastatic colorectal cancer with BRAFV600E mutation. Cancer Discov. 2016;6(12):1352–1365. doi:10.1158/2159-8290.CD-16-0050
   PubMed Web of Science ®Google Scholar
• Kopetz S, Guthrie KA, Morris VK, et al. Randomized trial of Irinotecan and Cetuximab with or without Vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406). J Clin Oncol. 2021;39(4):285–294. doi:10.1200/JCO.20.01994
   PubMed Web of Science ®Google Scholar
• Fakih M, Falchook GS, Hong DS, et al. 434P CodeBreaK 101 subprotocol H: phase Ib study evaluating combination of sotorasib (Soto), a KRASG12C inhibitor, and panitumumab (PMab), an EGFR inhibitor, in advanced KRAS p.G12C-mutated colorectal cancer (CRC). Ann Oncol. 2021;32:S551. doi:10.1016/j.annonc.2021.08.955
   Web of Science ®Google Scholar
• Pfeiffer P, Qvortrup C. KRASG12C inhibition in colorectal cancer. Lancet Oncol. 2022;23(1):10–11. doi:10.1016/S1470-2045(21)00652-5
   PubMed Web of Science ®Google Scholar
• Ramalingam S, Fakih M, Strickler J, et al. Abstract P05-01: a phase 1b study evaluating the safety and efficacy of sotorasib, a KRAS G12C inhibitor, in combination with trametinib, a MEK inhibitor, in KRAS p.G12C-mutated solid tumors. In: Oral Presentations - Late-Breaking Proffered Abstracts. American Association for Cancer Research; 2021. doi:10.1158/1535-7163.TARG-21-P05-01
   Google Scholar
• Santana-Codina N, Chandhoke AS, Yu Q, et al. Defining and targeting adaptations to oncogenic KRASG12C inhibition using quantitative temporal proteomics. Cell Rep. 2020;30(13):4584–4599.e4. doi:10.1016/j.celrep.2020.03.021
   PubMed Web of Science ®Google Scholar
• Lou K, Steri V, Ge AY, et al. KRASG12C inhibition produces a driver-limited state revealing collateral dependencies. Sci Signal. 2019;12(583):eaaw9450. doi:10.1126/scisignal.aaw9450
   PubMed Web of Science ®Google Scholar
• Molina-Arcas M, Moore C, Rana S, et al. Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. Sci Transl Med. 2019;11(510):eaaw7999. doi:10.1126/scitranslmed.aaw7999
   PubMed Web of Science ®Google Scholar
• Huang Y, Wang J, Cao F, et al. SHP2 associates with nuclear localization of STAT3: significance in progression and prognosis of colorectal cancer. Sci Rep. 2017;7(1):17597. doi:10.1038/s41598-017-17604-7
   PubMed Web of Science ®Google Scholar
• Fedele C, Li S, Teng KW, et al. SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling. J Exp Med. 2021;218(1):e20201414. doi:10.1084/jem.20201414
   PubMed Web of Science ®Google Scholar
• Ou SI, Koczywas M, Ulahannan S, 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(2):S15–S16. doi:10.1016/j.jtho.2019.12.041
   PubMed Web of Science ®Google Scholar
• Stice JP, Donovan S, Sun Y, et al. Abstract P207: BBP-398, a potent, small molecule inhibitor of SHP2, enhances the response of established NSCLC xenografts to KRAS G12C and mutEGFR inhibitors. In: Poster Presentations - Proffered Abstracts. American Association for Cancer Research; 2021:P207–P207. doi:10.1158/1535-7163.TARG-21-P207
   Google Scholar
• Liu C, Lu H, Wang H, et al. Combinations with allosteric SHP2 inhibitor TNO155 to block receptor tyrosine kinase signaling. Clin Cancer Res. 2021;27(1):342–354. doi:10.1158/1078-0432.CCR-20-2718
   PubMed Web of Science ®Google Scholar
• Lee JW, Kim S, Yang C, Burtness B. Abstract P078: aurora A kinase inhibition with VIC-1911 overcomes intrinsic and acquired resistance to KRAS G12C inhibition in KRAS(G12C) -mutated lung cancer. In: Poster Presentations - Proffered Abstracts. American Association for Cancer Research; 2021:P078–P078. doi:10.1158/1535-7163.TARG-21-P078
   Google Scholar
• Nichols RJ, Cregg J, Schulze CJ, 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(13_Supplement):1261. doi:10.1158/1538-7445.AM2021-1261
   Web of Science ®Google Scholar
• NCT04793958. Phase 3 study of MRTX849 with Cetuximab vs Chemotherapy in patients with advanced colorectal Cancer with KRAS G12C mutation (KRYSTAL-10). Available from: https://clinicaltrials.gov/ct2/show/NCT04793958. Accessed April 5, 2022.
   Google Scholar
• NCT05198934. Sotorasib and panitumumab versus investigator’s choice for participants with Kirsten Rat Sarcoma (KRAS) p.G12C mutation (CodeBreak 300). Available from: https://clinicaltrials.gov/ct2/show/NCT05198934. Accessed April 5, 2022.
   Google Scholar
• NCT04303780. Study to compare AMG 510 “Proposed INN Sotorasib” with docetaxel in non small cell lung cancer (NSCLC) (CodeBreak 200). Available from: https://www.clinicaltrials.gov/ct2/show/NCT04303780. Accessed April 5, 2022.
   Google Scholar
• NCT04933695. A study of Sotorasib (AMG 510) in participants with stage IV NSCLC whose tumors harbor a KRAS p.G12C mutation in need of first-line treatment (CodeBreaK201). Available from: https://clinicaltrials.gov/ct2/show/NCT04933695. Accessed April 5, 2022.
   Google Scholar
• NCT05118854. A Phase II study of Neoadjuvant Sotorasib in combination with Cisplatin or Carboplatin and pemetrexed for surgically resectable stage IIA-IIIB non-squamous Non-Small Cell Lung Cancer With a KRAS p.G12C mutation. Available from: https://clinicaltrials.gov/ct2/show/NCT05118854. Accessed April 5, 2022.
   Google Scholar
• Wang X, Allen S, Blake JF, et al. Identification of MRTX1133, a noncovalent, potent, and selective KRASG12D inhibitor. J Med Chem. 2022;65(4):3123–3133. doi:10.1021/acs.jmedchem.1c01688
   PubMed Web of Science ®Google Scholar
• Gustafson WC, Wildes D, Rice MA, et al. Direct targeting of RAS in pancreatic ductal adenocarcinoma with RMC-6236, a first-in-class, RAS-selective, orally bioavailable, tri-complex RAS MULTI (ON) inhibitor. J Clin Oncol. 2022;40(4_suppl):591. doi:10.1200/JCO.2022.40.4_suppl.591
   Web of Science ®Google Scholar
• Gort E, Johnson ML, Hwang JJ, et al. A Phase I, open-label, dose-escalation trial of BI 1701963 as monotherapy and in combination with trametinib in patients with KRAS mutated advanced or metastatic solid tumors. J Clin Oncol. 2020;38(15_suppl):TPS3651–TPS3651. doi:10.1200/JCO.2020.38.15_suppl.TPS3651
   Web of Science ®Google Scholar