Research progress on KRAS mutations in colorectal cancer

Abstract

The RAS gene family, responsible for signal transduction within the mitogen activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K) pathways, is frequently involved in carcinogenesis, and alterations in its member genes can be detected, with variable frequency, in a wide variety of solid and hematological cancers. These alterations may behave as prognostic-predictive biomarkers and driver mutations, making them an interesting therapeutic target. Since their discovery, many strategies have been pursued to act on their signaling pathways. Indeed, in clinical practice, KRAS, the most prominent member of the RAS gene family, represents an especially elusive target in most malignancies; pathway inhibition is carried out upstream, on the EGFR receptor, or downstream, most frequently on the BRAF/MEK/ERK cascade. Recently, clinically relevant direct RAS inhibition has been successfully achieved with the development of potent and selective covalent inhibitors of KRAS c.34G>T (p.G12C). These latest-generation drugs represent both a new and interesting tool in the therapeutic armamentarium and a symbolic end to the myth of KRAS undruggability. However, their clinical relevance and appropriate place in treatment strategies remain to be determined.

Keywords

KRAS / targeted therapies / EGFR pathway / MAPK / colorectal cancer

References

[1] Anderson GR.Rat sequences of the Kirsten and Harvey murine sarcoma virus genomes: nature, origin, and expression in rat tumor RNA.J Virol1976;17:335-51 PMCID:PMC515425

[2] Tsuchida N,Ohtsubo E.Nucleotide sequence of the oncogene encoding the p21 transforming protein of Kirsten murine sarcoma virus.Science1982;217:937-9

[3] Shimizu K,Perucho M.Isolation and preliminary characterization of the transforming gene of a human neuroblastoma cell line.Proc Natl Acad Sci U S A1983;80:383-7 PMCID:PMC393381

[4] Stratton MR,Futreal PA.The cancer genome.Nature2009;458:719-24 PMCID:PMC2821689

[5] Garraway LA.Lessons from the cancer genome.Cell2013;153:17-37

[6] Vogelstein B,Velculescu VE,Diaz LA Jr.Cancer genome landscapes.Science2013;339:1546-58 PMCID:PMC3749880

[7] Fearon ER.A genetic model for colorectal tumorigenesis.Cell1990;61:759-67

[8] Ionescu DL.New approach in the pharmacologic treatment of cancer.Rev Med Chir Soc Med Nat Iasi2004;108:509-12

[9] Vogelstein B.Cancer genes and the pathways they control.Nat Med2004;10:789-99

[10] Kinzler KW.Cancer-susceptibility genes. Gatekeepers and caretakers.Nature1997;386:761, 763

[11] Yun J,Cheong I.Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells.Science2009;325:1555-9 PMCID:PMC2820374

[12] Ying H,Lyssiotis CA.Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism.Cell2012;149:656-70 PMCID:PMC3472002

[13] Mármol I,Pradilla Dieste A,Rodriguez Yoldi MJ.Colorectal carcinoma: a general overview and future perspectives in colorectal cancer.Int J Mol Sci2017;18:197 PMCID:PMC5297828

[14] Abdulkareem FB,Richman SD.KRAS and BRAF mutations in Nigerian colorectal cancers.West Afr J Med2012; 31:198-203

[15] Hoffman SJ.Phenotypic and genotypic differences in colorectal carcinoma among Caucasians, Asians, and Hispanics lack statistical significance.Pathol Res Pract2018;214:720-6

[16] Peeters M,Taylor A.Prevalence of RAS mutations and individual variation patterns among patients with metastatic colorectal cancer: A pooled analysis of randomised controlled trials.Eur J Cancer2015;51:1704-13

[17] Project GENIE Consortium. AACR Project GENIE: Powering Precision Medicine through an International Consortium.Cancer Discov2017;7:818-31 PMCID:PMC5611790

[18] Timar J.Molecular epidemiology and diagnostics of KRAS mutations in human cancer.Cancer Metastasis Rev2020;39:1029-38 PMCID:PMC7680318

[19] Palomba G,Paliogiannis P.Prognostic role of.KRAS12:1415-21 PMCID:PMC4950545

[20] Mazurenko NN,Tsyganova IV,Breder VV.The frequency and spectrum of KRAS mutations in metastatic colorectal cancer.Vopr Onkol2013;59:751-5

[21] Shen H,Hu HG.Clinical significance of K-ras and BRAF mutations in Chinese colorectal cancer patients.World J Gastroenterol2011;17:809-16 PMCID:PMC3042662

[22] Zhu XL,Zhang L.[KRAS and BRAF gene mutations in correlation with clinicopathologic features of colorectal carcinoma in Chinese].Zhonghua Bing Li Xue Za Zhi2012;41:584-9

[23] Zhang J,Yang Y.Molecular spectrum of KRAS, NRAS, BRAF and PIK3CA mutations in Chinese colorectal cancer patients: analysis of 1,110 cases.Sci Rep2015;5:18678 PMCID:PMC4687048

[24] Peng J,Poston G.The molecular heterogeneity of sporadic colorectal cancer with different tumor sites in Chinese patients.Oncotarget2017;8:49076-83 PMCID:PMC5564750

[25] Shen Y,Han X.Effectors of epidermal growth factor receptor pathway: the genetic profiling ofKRAS, BRAF, PIK3CA, NRAS mutations in colorectal cancer characteristics and personalized medicine.PLoS One2013;8:e81628 PMCID:PMC3858242

[26] Won DD,Lee IK,Jung ES.The prognostic significance of KRAS and BRAF mutation status in Korean colorectal cancer patients.BMC Cancer2017;17:403 PMCID:PMC5460473

[27] Kumar K,Giardiello F.Distinct BRAF (V600E) and KRAS mutations in high microsatellite instability sporadic colorectal cancer in African Americans.Clin Cancer Res2009;15:1155-61 PMCID:PMC2713502

[28] Kang M,Kim S.Somatic gene mutations in African Americans may predict worse outcomes in colorectal cancer.Cancer Biomark2013;13:359-66 PMCID:PMC4589188

[29] Sylvester BE,Khramtsov A.Molecular analysis of colorectal tumors within a diverse patient cohort at a single institution.Clin Cancer Res2012;18:350-9 PMCID:PMC3272273

[30] Sanchez-Ibarra HE,Gallegos-Gonzalez EY.KRAS, NRAS, and BRAF mutation prevalence, clinicopathological association, and their application in a predictive model in Mexican patients with metastatic colorectal cancer: A retrospective cohort study.PLoS One2020;15:e0235490 PMCID:PMC7337295

[31] Hobbs GA,Rossman KL.RAS isoforms and mutations in cancer at a glance.J Cell Sci2016;129:1287-92 PMCID:PMC4869631

[32] Buday L.Many faces of Ras activation.Biochim Biophys Acta2008;1786:178-87

[33] Pylayeva-Gupta Y,Bar-Sagi D.RAS oncogenes: weaving a tumorigenic web.Nat Rev Cancer2011;11:761-74 PMCID:PMC3632399

[34] Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer.Nature2012;487:330-7 PMCID:PMC3401966

[35] Kucab JE,Morganella S.A Compendium of Mutational Signatures of Environmental Agents.Cell2019;177:821-836.e16 PMCID:PMC6506336

[36] Fahrer J.Impact of DNA repair on the dose-response of colorectal cancer formation induced by dietary carcinogens.Food Chem Toxicol2017;106:583-94

[37] Hogervorst JG,Schouten LJ.Dietary acrylamide intake and the risk of colorectal cancer with specific mutations in KRAS and APC.Carcinogenesis2014;35:1032-8

[38] Imperial R,Toor OM.Comparative proteogenomic analysis of right-sided colon cancer, left-sided colon cancer and rectal cancer reveals distinct mutational profiles.Mol Cancer2018;17:177 PMCID:PMC6303985

[39] Salem ME,Goldberg RM.Molecular analyses of Left- and Right-Sided tumors in adolescents and young adults with colorectal cancer.Oncologist2020;25:404-13 PMCID:PMC7216442

[40] Charlton ME,Greenbaum AA.KRAS testing, tumor location, and survival in patients with stage IV colorectal cancer: SEER 2010-2013.J Natl Compr Canc Netw2017;15:1484-93 PMCID:PMC7458121

[41] Gil-Raga M,Gallach S.Molecular subtypes in early colorectal cancer associated with clinical features and patient prognosis.Clin Transl Oncol2018;20:1422-9

[42] Saeed O,Fisher KW.RAS genes in colorectal carcinoma: pathogenesis, testing guidelines and treatment implications.J Clin Pathol2019;72:135-9

[43] Uprety D.KRAS: From undruggable to a druggable Cancer Target.Cancer Treat Rev2020;89:102070

[44] Gallo G,Vescio G.The prognostic value of KRAS and BRAF in stage I-III colorectal cancer. A systematic review.Ann Ital Chir2019;90:127-37.

[45] de Cuba EM,Heideman DA.Prognostic value of BRAF and KRAS mutation status in stage II and III microsatellite instable colon cancers.Int J Cancer2016;138:1139-45

[46] Eklöf V,Edin S.The prognostic role of KRAS, BRAF, PIK3CA and PTEN in colorectal cancer.Br J Cancer2013;108:2153-63 PMCID:PMC3670497

[47] Nash GM,Cohen AM.KRAS mutation and microsatellite instability: two genetic markers of early tumor development that influence the prognosis of colorectal cancer.Ann Surg Oncol2010;17:416-24 PMCID:PMC4380015

[48] Sinicrope FA,Smyrk TC.Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy.J Clin Oncol2013;31:3664-72 PMCID:PMC3789216

[49] Marco M,Choi S,Shia J.A KRAS mutation is associated with an immunosuppressive tumor microenvironment in mismatch-repair proficient colorectal cancer.J Clin Oncol2019;37:609

[50] Roth AD,Delorenzi M.Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial.J Clin Oncol2010;28:466-74

[51] Andersen SN,Breivik J.K-ras mutations and prognosis in large-bowel carcinomas.Scand J Gastroenterol1997;32:62-9

[52] Bouzourene H,Cerottini J.p53 and Ki-ras as prognostic factors for Dukes' stage B colorectal cancer.Eur J Cancer2000;36:1008-15

[53] González-Aguilera JJ,Azcoita MM.Simultaneous mutations in K-ras and TP53 are indicative of poor prognosis in sporadic colorectal cancer.Am J Clin Oncol2004;27:39-45

[54] Westra JL,Hollema H.Determination of TP53 mutation is more relevant than microsatellite instability status for the prediction of disease-free survival in adjuvant-treated stage III colon cancer patients.J Clin Oncol2005;23:5635-43

[55] Hutchins G,Handley K.Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer.J Clin Oncol2011;29:1261-70

[56] Dinu D,Panaitescu E.Prognostic significance of KRAS gene mutations in colorectal cancer--preliminary study.J Med Life2014;7:581-7. PMCID:PMC4316144

[57] Hecht JR,Neubauer MA.Lack of correlation between epidermal growth factor receptor status and response to Panitumumab monotherapy in metastatic colorectal cancer.Clin Cancer Res2010;16:2205-13

[58] Sorich MJ,Rowland A,McKinnon RA.Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials.Ann Oncol2015;26:13-21

[59] Cutsem E, Cervantes A, Nordlinger B, Arnold D; ESMO Guidelines Working Group. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol2014;25 Suppl 3:iii1-9

[60] Sepulveda AR,Allegra CJ.Molecular biomarkers for the evaluation of colorectal cancer: guideline from the american society for clinical pathology, college of american pathologists, association for molecular pathology, and the american society of clinical oncology.J Clin Oncol2017;35:1453-86

[61] Etienne-Grimaldi MC,Francoual M.K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy.Clin Cancer Res2008;14:4830-5

[62] Thierry AR,Mollevi C.Clinical utility of circulating DNA analysis for rapid detection of actionable mutations to select metastatic colorectal patients for anti-EGFR treatment.Ann Oncol2017;28:2149-59

[63] Schmiegel W,Dooley S.Blood-based detection of RAS mutations to guide anti-EGFR therapy in colorectal cancer patients: concordance of results from circulating tumor DNA and tissue-based RAS testing.Mol Oncol2017;11:208-19 PMCID:PMC5527457

[64] Snyder M,Almhanna K.Impact of Primary Tumor Location on First-line Bevacizumab or Cetuximab in Metastatic Colorectal Cancer.Rev Recent Clin Trials2018;13:139-49

[65] Guinney J,Wang X.The consensus molecular subtypes of colorectal cancer.Nat Med2015;21:1350-6 PMCID:PMC4636487

[66] Goldberg RM,Wainberg ZA.Optimising the use of cetuximab in the continuum of care for patients with metastatic colorectal cancer.ESMO Open2018;3:e000353 PMCID:PMC5950648

[67] Siravegna G,Buscarino M.Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients.Nat Med2015;21:795-801 PMCID:PMC4868598

[68] Rossini D,Conca E.Liquid biopsy allows predicting benefit from rechallenge with cetuximab(cet)+irinotecan(iri) in RAS/BRAF wild-type mCRC patients(pts) with resistance to 1st-line cet+iri: final results and translational analyses of the CRICKET study by GONO.Ann Oncol2018;29:v102

[69] Gazzaniga P,Nicolazzo C,Cortesi E.ctDNA might expand therapeutic options for second line treatment of KRAS mutant mCRC.Ann Oncol2017;28:v586

[70] Gazzaniga P,Urbano F.Second line EGFR-inhibitors in RAS mutant metastatic colorectal cancer: the plasma RAS wild type “window of opportunity”.Ann Oncol2018;29:viii183-4

[71] Henry J,Parseghian CM.NeoRAS: Incidence of RAS reversion from RAS mutated to RAS wild type.JCO2020;38:180

[72] Antoniotti C,Corallo S,Falcone A.Circulating tumor DNA analysis in colorectal cancer: from dream to reality.JCO Precision Oncology2019;(3):1-14

[73] Laurent-Puig P,Normand C.Clinical relevance of KRAS-mutated subclones detected with picodroplet digital PCR in advanced colorectal cancer treated with anti-EGFR therapy.Clin Cancer Res2015;21:1087-97

[74] Jacobs B,Pomella V.Abstract 940: Analytical and clinical validation of the IdyllaTM ctKRAS and ctNRAS-BRAF liquid biopsy tests identifies mCRC patient groups with high and low ctDNA shedding. In: Clinical Research (Excluding Clinical Trials).Cancer Res2018;78(13 Supplement):940

[75] Diehl F,Choti MA.Circulating mutant DNA to assess tumor dynamics.Nat Med2008;14:985-90 PMCID:PMC2820391

[76] Diaz LA Jr.Liquid biopsies: genotyping circulating tumor DNA.J Clin Oncol2014;32:579-86 PMCID:PMC4820760

[77] Hamada T,Nishihara R.Molecular pathological epidemiology: new developing frontiers of big data science to study etiologies and pathogenesis.J Gastroenterol2017;52,265-75. PMCID:PMC5325774

[78] Ogino S,Hamada T,Nishihara R.Insights into Pathogenic Interactions Among Environment, Host, and Tumor at the Crossroads of Molecular Pathology and Epidemiology.Annu Rev Pathol2019;14,83-103. PMCID:PMC6345592

[79] Song N,Cho S,Oh JH.Evaluation of gene-environment interactions for colorectal cancer susceptibility loci using case-only and case-control designs.BMC Cancer2019;19:1231 PMCID:PMC6918639

[80] Cook JH,Gulhan DC,Haigis KM.The origins and genetic interactions of KRAS mutations are allele- and tissue-specific.Nat Commun2021;12:1808 PMCID:PMC7985210

[81] Degirmenci U,Hu J.Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy.Cells2020;9:198 PMCID:PMC7017232

[82] Khan I,O'Bryan JP.Therapeutic targeting of RAS: New hope for drugging the "undruggable".Biochim Biophys Acta Mol Cell Res2020;1867:118570 PMCID:PMC6937383

[83] LoRusso PM.One step at a Time - Clinical Evidence that KRAS is indeed druggable.N Engl J Med2020;383:1277-8

[84] Ross SJ,Hanson LL.Targeting KRAS-dependent tumors with AZD4785, a high-affinity therapeutic antisense oligonucleotide inhibitor of KRAS.Sci Transl Med2017;9:eaal5253

[85] Gray GD,Hebel D,Pow-Sang JM.Antisense DNA inhibition of tumor growth induced by c-Ha-ras oncogene in nude mice.Cancer Res1993;53:577-580

[86] Cunningham CC,Geary RS.A Phase I trial of h-ras antisense oligonucleotide ISIS 2503 administered as a continuous intravenous infusion in patients with advanced carcinoma.Cancer2001;92:1265-71

[87] Marshall JL,Johnson MD.A phase II trial of ISIS 3521 in patients with metastatic colorectal cancer.Clin Colorectal Cancer2004;4:268-74

[88] Alberts SR,Erlichman C.Gemcitabine and ISIS-2503 for patients with locally advanced or metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II trial.J Clin Oncol2004;22:4944-50

[89] Adjei AA,Bruzek L.Phase II study of the farnesyl transferase inhibitor R115777 in patients with advanced non-small-cell lung cancer.J Clin Oncol2003;21:1760-6

[90] Gajewski TF,Niedzwiecki D.Cancer and Leukemia Group BPhase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104).J Transl Med2012;10:246 PMCID:PMC3543225

[91] Rao S,de Gramont A.Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer.J Clin Oncol2004;22:3950-7

[92] Luger S,Paietta E.Tipifarnib as maintenance therapy in Acute Myeloid Leukemia (AML) improves survival in a subgroup of patients with high risk disease. Results of the phase III intergroup trial E2902.Blood2015;126:1308

[93] Sharma S,Kelsen DP.A phase II trial of farnesyl protein transferase inhibitor SCH 66336, given by twice-daily oral administration, in patients with metastatic colorectal cancer refractory to 5-fluorouracil and irinotecan.Ann Oncol2002;13:1067-71

[94] Winquist E,Chi KN.A multinomial Phase II study of lonafarnib (SCH 66336) in patients with refractory urothelial cancer.Urol Oncol2005;23:143-9

[95] Kim ES,Fossella FV.Phase II study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in patients with taxane-refractory/resistant nonsmall cell lung carcinoma.Cancer2005;104:561-9

[96] Ho A,Haddad R. Preliminary results from a phase 2 trial of tipifarnib in squamous cell carcinomas (SCCs) with HRAS mutations. Abstract PR08: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA, 2019.

[97] Karasic TB,Sebti SM.A Phase I Study of GGTI-2418 (Geranylgeranyl Transferase I Inhibitor) in Patients with Advanced Solid Tumors.Target Oncol2019;14:613-8 PMCID:PMC7771543

[98] Peterson YK,Weinbaum CA.A novel protein geranylgeranyltransferase-I inhibitor with high potency, selectivity, and cellular activity.J Biol Chem2006;281:12445-50

[99] Lobell RB,Buser CA.Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein transferase type-I.Mol Cancer Ther2002;1:747-58

[100] Wahlstrom AM,Liu M.Inactivating Icmt ameliorates K-RAS-induced myeloproliferative disease.Blood2008;112:1357-65 PMCID:PMC2515151

[101] Bergman JA,Song J,Gibbs RA.S-Farnesyl-Thiopropionic Acid (FTPA) Triazoles as Potent Inhibitors of Isoprenylcysteine Carboxyl Methyltransferase.ACS Med Chem Lett2012;3:15-9 PMCID:PMC3387282

[102] Lau HY,Guo D.An improved isoprenylcysteine carboxylmethyltransferase inhibitor induces cancer cell death and attenuates tumor growth in vivo.Cancer Biol Ther2014;15:1280-91 PMCID:PMC4128870

[103] Wang M,Tan W.Inhibition of isoprenylcysteine carboxylmethyltransferase induces autophagic-dependent apoptosis and impairs tumor growth.Oncogene2010;29:4959-70

[104] Llovet JM,Mazzaferro V.SHARP Investigators Study GroupSorafenib in advanced hepatocellular carcinoma.N Engl J Med2008;359:378-90

[105] Escudier B,Stadler WM.TARGET Study GroupSorafenib in advanced clear-cell renal-cell carcinoma.N Engl J Med2007;356:125-34

[106] Brose MS,Jarzab B.Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial.Lancet2014;384:319-28 PMCID:PMC4366116

[107] Wilhelm SM,Tang L.BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis.Cancer Res2004;64:7099-109

[108] Hauschild A,Demidov LV.Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial.Lancet2012;380:358-65

[109] Subbiah V,Wainberg ZA.Dabrafenib and trametinib treatment in patients with locally advanced or Metastatic BRAF V600-mutant anaplastic thyroid cancer.J Clin Oncol2018;36:7-13 PMCID:PMC5791845

[110] in multiple nonmelanoma cancers with BRAF V600 mutations; Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer.N Engl J Med2018;379:1585

[111] Kopetz S,Yaeger R.Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer.N Engl J Med2019;381:1632-43

[112] Pickles OJ,Tee L,Middleton GW.Paradox breaker BRAF inhibitors have comparable potency and MAPK pathway reactivation to encorafenib in BRAF mutant colorectal cancer.Oncotarget2020;11:3188-97 PMCID:PMC7456617

[113] Poulikakos PI,Bollag G,Rosen N.RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF.Nature2010;464:427-30 PMCID:PMC3178447

[114] Heidorn SJ,Whittaker S.Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF.Cell2010;140:209-21 PMCID:PMC2872605

[115] Wang L,Huijberts S.An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential.Cell2018;173:1413-1425.e14

[116] Seghers AC,Lebbé C.Successful rechallenge in two patients with BRAF-V600-mutant melanoma who experienced previous progression during treatment with a selective BRAF inhibitor.Melanoma Res2012;22:466-72

[117] Cheng Y.Current Development Status of MEK Inhibitors.Molecules2017;22:1551 PMCID:PMC6151813

[118] Amodio V,Arcella P.EGFR Blockade Reverts Resistance to KRAS^G12C Inhibition in Colorectal Cancer.Cancer Discov2020;10:1129-39 PMCID:PMC7416460

[119] Hong DS,Strickler JH.KRAS^G12C Inhibition with Sotorasib in Advanced Solid Tumors.N Engl J Med2020;383:1207-17 PMCID:PMC7571518

[120] AMG 510 (pINN) Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101). Available from: https://clinicaltrials.gov/ct2/show/NCT04185883. [Last accessed on 23 Feb 2021]

[121] Jänne PA,Spira AI.KRYSTAL-1: activity and safety of adagrasib (MRTX849) in advanced/metastatic Non-Small-Cell Lung Cancer (NSCLC) harboring KRAS G12C mutation.Eur J Cancer2020;138:S1-2

[122] Johnson ML,Barve M.KRYSTAL-1: activity and safety of adagrasib (MRTX849) in patients with Colorectal Cancer (CRC) and other solid tumors harboring a KRAS G12C mutation.Eur J Cancer2020;138:S2

[123] Phase 2 Trial of MRTX849 Plus Pembrolizumab for NSCLC With KRAS G12C Mutation KRYSTAL-7. Available from: https://clinicaltrials.gov/ct2/show/NCT04613596. [Last accessed on 23 Feb 2021]

[124] Sabari JK,Tolcher AW.KRYSTAL-2: a phase I/II trial of adagrasib (MRTX849) in combination with TNO155 in patients with advanced solid tumors with KRAS G12C mutation.JCO2021;39:TPS146