New advances in the clinical management of RAS and BRAF mutant colorectal cancer patients

References

• Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013;49(6):1374–1403.
   PubMed Web of Science ®Google Scholar
• Fang JY, Richardson BC. The MAPK signaling pathways and colorectal cancer. Lancet Oncol. 2005;6(5):322–327.
   PubMed Web of Science ®Google Scholar
• The Cancer Genome Atlas Network (326 collaborators). Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330‐7.
   Web of Science ®Google Scholar
• Rimbert J, Tachon G, Junca A, et al. Association between clinicopathological characteristics and RAS mutation in colorectal cancer. Mod Pathol. 2018;31(3):517‐26.
   PubMed Web of Science ®Google Scholar
• Domingo E, Ramamoorthy R, Oukrif D, et al. Use of multivariate analysis to suggest a new molecular classification of colorectal cancer. J Pathol. 2013;229(3):441‐8.
   PubMed Web of Science ®Google Scholar
• Morris V, Kopetz S. Clinical biomarkers in colorectal cancer. Clin Adv Hematol Oncol. 2013;11(12):768–776.
   PubMedGoogle Scholar
• Clarke CN, Kopetz ES. BRAF mutant colorectal cancer as a distinct subset of colorectal cancer: clinical characteristics, clinical behavior, and response to targeted therapies. J Gastrointest Oncol. 2015;6(6):660–667.
   PubMed Web of Science ®Google Scholar
• Bos JL, Fearon ER, Hamilton SR, et al. Prevalence of ras gene mutations in human colorectal cancers. Nature. 1987;327(6120):293‐7.
   PubMed Web of Science ®Google Scholar
• Rajagopalan H, Bardelli A, Lengauer C, et al. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature. 2002;418(6901):934.
   PubMed Web of Science ®Google Scholar
• Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003;3(6):459‐65.
   PubMed Web of Science ®Google Scholar
• Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–954.
   PubMed Web of Science ®Google Scholar
• Taieb J, Lapeyre-Prost A, Laurent Puig P, et al. Exploring the best treatment options for BRAF-mutant metastatic colon cancer. Br J Cancer. 2019;121(6):434‐42.
   Web of Science ®Google Scholar
• Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350–1356.
   PubMed Web of Science ®Google Scholar
• Gonsalves WI, Mahoney MR, Sargent DJ, et al. Patient and tumor characteristics and BRAF and KRAS mutations in colon cancer, NCCTG/Alliance N0147. J Natl Cancer Inst. 2014;106(7):dju106.
   PubMedGoogle Scholar
• Lipsyc M, Yaeger R. Impact of somatic mutations on patterns of metastasis in colorectal cancer. J Gastrointest Oncol. 2015;6(6):645‐9.
   PubMed Web of Science ®Google Scholar
• Morkel M, Riemer P, Bläker H, et al. Similar but different: distinct roles for KRAS and BRAF oncogenes in colorectal cancer development and therapy resistance. Oncotarget. 2015;6(25):20785‐800.
   PubMedGoogle Scholar
• Li X, Huang Y, Jiang J, et al. ERK-dependent threonine phosphorylation of EGF receptor modulates receptor downregulation and signaling. Cell Signal. 2008;20(11):2145–2155.
   PubMed Web of Science ®Google Scholar
• Sun C, Hobor S, Bertotti A, et al. Intrinsic resistance to MEK inhibition in KRAS mutant lung and colon cancer through transcriptional induction of ERBB3. Cell Rep. 2014;7(1):86‐93.
   Web of Science ®Google Scholar
• Fritsche-Guenther R, Witzel F, Sieber A, et al. Strong negative feedback from Erk to Raf confers robustness to MAPK signalling. Mol Syst Biol. 2011;7(1):489.
   PubMedGoogle Scholar
• Lito P, Rosen N, Solit DB. Tumor adaptation and resistance to RAF inhibitors. Nat Med. 2013;19(11):1401‐9.
   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.
   PubMed Web of Science ®Google Scholar
• Montagut C, Tsui DW, Diaz LA Jr. Detection of somatic RAS mutations in circulating tumor DNA from metastatic colorectal cancer patients: are we ready for clinical use? Ann Oncol. 2018;29(5):1083–1084.
   PubMed Web of Science ®Google Scholar
• Thierry AR, Mouliere F, El Messaoudi S, et al. Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA. Nat Med. 2014;20(4):430–435.
   PubMed Web of Science ®Google Scholar
• Vidal J, Muinelo L, Dalmases A, et al. Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients. Ann Oncol. 2017;28(6):1325–1332.
   PubMed Web of Science ®Google Scholar
• Grasselli J, Elez E, Caratù G, et al. Concordance of blood- and tumor-based detection of RAS mutations to guide anti-EGFR therapy in metastatic colorectal cancer. Ann Oncol. 2017;28(6):1294–1301.
   PubMed Web of Science ®Google Scholar
• Andreyev HJ, Norman AR, Cunningham D, et al. Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study. J Natl Cancer Inst. 1998;90(9):675‐84.
   PubMedGoogle Scholar
• Andreyev HJ, Norman AR, Cunningham D, et al. Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study. Br J Cancer. 2001;85(5):692–696.
   PubMed Web of Science ®Google Scholar
• Taieb J, Zaanan A, Le Malicot K, et al. Prognostic effect of BRAF and KRAS mutations in patients with stage III colon cancer treated with leucovorin, fluorouracil, and oxaliplatin with or without cetuximab: A post hoc analysis of the PETACC-8 trial. JAMA Oncol. 2016;2(5):643‐53.
   Web of Science ®Google Scholar
• Yoon HH, Tougeron D, Shi Q, et al. KRAS codon 12 and 13 mutations in relation to disease-free survival in BRAF-wild-type stage III colon cancers from an adjuvant chemotherapy trial (N0147 alliance). Clin Cancer Res. 2014;20(11):3033‐43.
   Web of Science ®Google Scholar
• Taieb J, Le Malicot K, Shi Q, et al. Prognostic value of BRAF and KRAS mutations in MSI and MSS stage III colon cancer. J Natl Cancer Inst. 2016;109(5):djw272.
   Google Scholar
• Dienstmann R, Mason MJ, Sinicrope FA, et al. Prediction of overall survival in stage II and III colon cancer beyond TNM system: a retrospective, pooled biomarker study. Ann Oncol. 2017;28(5):1023‐31.
   Web of Science ®Google Scholar
• Ogino S, Meyerhardt JA, Irahara N, et al. KRAS mutation in stage III colon cancer and clinical outcome following intergroup trial CALGB 89803. Clin Cancer Res. 2009;15(23):7322‐9.
   Web of Science ®Google Scholar
• Roth AD, Tejpar S, Delorenzi M, et al. 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 Oncol. 2010;28(3):466‐74.
   Web of Science ®Google Scholar
• Gavin PG, Colangelo LH, Fumagalli D, et al. Mutation profiling and microsatellite instability in stage II and III colon cancer: an assessment of their prognostic and oxaliplatin predictive value. Clin Cancer Res. 2012;18(23):6531‐41.
   PubMed Web of Science ®Google Scholar
• Taieb J, Balogoun R, Le Malicot K, et al. Adjuvant FOLFOX ± cetuximab in full RAS and BRAF wildtype stage III colon cancer patients. Ann Oncol. 2017;28(4):824‐30.
   Web of Science ®Google Scholar
• Labianca R, Nordlinger B, Beretta GD, et al. Early colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(Suppl 6):vi64‐vi72.
   Google Scholar
• National Comprehensive Cancer Network. Colon Cancer (Version 3.0). http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. cited 2020 Jun 13
   Google Scholar
• Etienne-Grimaldi MC, Formento JL, Francoual M, et al. K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy. Clin Cancer Res. 2008;14(15):4830‐5.
   PubMed Web of Science ®Google Scholar
• Bokemeyer C, Bondarenko I, Hartmann JT, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011;22(7):1535–1546.
   PubMed Web of Science ®Google Scholar
• Qiu LX, Mao C, Zhang J, et al. Predictive and prognostic value of KRAS mutations in metastatic colorectal cancer patients treated with cetuximab: a meta-analysis of 22 studies. Eur J Cancer. 2010;46(15):2781‐7.
   Web of Science ®Google Scholar
• Petrelli F, Coinu A, Cabiddu M, et al. KRAS as prognostic biomarker in metastatic colorectal cancer patients treated with bevacizumab: a pooled analysis of 12 published trials. Med Oncol. 2013;30(3):650.
   PubMed Web of Science ®Google Scholar
• Stintzing S, Miller-Phillips L, Modest DP, et al. Impact of BRAF and RAS mutations on first-line efficacy of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab: analysis of the FIRE-3 (AIO KRK-0306) study. Eur J Cancer. 2017;79:50‐60.
   PubMed Web of Science ®Google Scholar
• Tosi F, Magni E, Amatu A, et al. Effect of KRAS and BRAF mutations on survival of metastatic colorectal cancer after liver resection: A systematic review and meta-analysis. Clin Colorectal Cancer. 2017;16(3):e153–63.
   PubMed Web of Science ®Google Scholar
• Tsilimigras DI, Ntanasis-Stathopoulos I, Bagante F, et al. Clinical significance and prognostic relevance of KRAS, BRAF, PI3K and TP53 genetic mutation analysis for resectable and unresectable colorectal liver metastases: A systematic review of the current evidence. Surg Oncol. 2018;27(2):280‐8.
   Web of Science ®Google Scholar
• Li S, Balmain A, Counter CM. A model for RAS mutation patterns in cancers: finding the sweet spot. Nat Rev Cancer. 2018;18(12):767–777.
   PubMed Web of Science ®Google Scholar
• Modest DP, Ricard I, Heinemann V, et al. Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group. Ann Oncol. 2016;27(9):1746–1753.
   PubMed Web of Science ®Google Scholar
• Schirripa M, Nappo F, Cremolini C, et al. KRAS G12C Metastatic Colorectal Cancer: specific Features of a New Emerging Target Population [published online ahead of print, article in press]. Clin Colorectal Cancer. 2020;S1533–0028(20):30067.
   Google Scholar
• Farina-Sarasqueta A, van Lijnschoten G, Moerland E, et al. The BRAF V600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients. Ann Oncol. 2010;21(12):2396–2402.
   PubMed Web of Science ®Google Scholar
• Morris V, Overman MJ, Jiang ZQ, et al. Progression-free survival remains poor over sequential lines of systemic therapy in patients with BRAF-mutated colorectal cancer. Clin Colorectal Cancer. 2014;13(3):164–171.
   PubMed Web of Science ®Google Scholar
• Cremolini C, Di Bartolomeo M, Amatu A, et al. BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis. Ann Oncol. 2015;26(10):2092–2097.
   PubMed Web of Science ®Google Scholar
• Shimada Y, Tajima Y, Nagahashi M, et al. Clinical significance of BRAF non-V600E mutations in colorectal cancer: a retrospective study of two institutions. J Surg Res. 2018;232:72–81.
   PubMed Web of Science ®Google Scholar
• Bond CE, Whitehall VLJ. How the BRAF V600E mutation defines a distinct subgroup of colorectal cancer: molecular and clinical implications. Gastroenterol Res Pract. 2018;2018:1–14. [ Article ID 9250757].
   PubMed Web of Science ®Google Scholar
• Tran B, Kopetz S, Tie J, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 2011;117(20):4623–4632.
   PubMed Web of Science ®Google Scholar
• Lochhead P, Kuchiba A, Imamura Y, et al. Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. J Natl Cancer Inst. 2013;105(15):1151–1156.
   PubMedGoogle Scholar
• Lièvre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66(8):3992‐5.
   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):1626‐34.
   PubMed Web of Science ®Google Scholar
• Peeters M, Oliner KS, Price TJ, et al. Analysis of KRAS/NRAS mutations in a phase iii study of panitumumab with FOLFIRI compared with FOLFIRI alone as second-line treatment for metastatic colorectal cancer. Clin Cancer Res. 2015;21(24):5469‐79.
   Web of Science ®Google Scholar
• Seymour MT, Brown SR, Middleton G, et al. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol. 2013;14(8):749‐59.
   Web of Science ®Google Scholar
• De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11(8):753‐62.
   PubMed Web of Science ®Google Scholar
• Van Cutsem E, Lenz HJ, Köhne CH, et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015;33(7):692‐700.
   Web of Science ®Google Scholar
• Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369(11):1023‐34.
   Web of Science ®Google Scholar
• Richman SD, Seymour MT, Chambers P, et al. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol. 2009;27(35):5931‐7.
   Web of Science ®Google Scholar
• Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015;16(13):1306–1315.
   PubMed Web of Science ®Google Scholar
• Vacante M, Borzì AM, Basile F, et al. Biomarkers in colorectal cancer: current clinical utility and future perspectives. World J Clin Cases. 2018;6(15):869‐81.
   PubMed Web of Science ®Google Scholar
• Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26(35):5705–5712.
   PubMed Web of Science ®Google Scholar
• Loupakis F, Ruzzo A, Cremolini C, et al. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer. 2009;101(4):715–721.
   PubMed Web of Science ®Google Scholar
• Pietrantonio F, Petrelli F, Coinu A, et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur J Cancer. 2015;51(5):587–594.
   PubMed Web of Science ®Google Scholar
• Rowland A, Dias MM, Wiese MD, et al. Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer. Br J Cancer. 2015;112(12):1888‐94.
   PubMed Web of Science ®Google Scholar
• O’Bryan JP. Pharmacological targeting of RAS: recent success with direct inhibitors. Pharmacol Res. 2019;139:503‐11.
   PubMed Web of Science ®Google Scholar
• Ryan MB, Corcoran RB. Therapeutic strategies to target RAS-mutant cancers. Nat Rev Clin Oncol. 2018;15(11):709‐20.
   PubMed Web of Science ®Google Scholar
• Zimmermann G, Papke B, Ismail S, et al. Small molecule inhibition of the KRAS-PDEdelta interaction impairs oncogenic KRAS signalling. Nature. 2013;497(7451):638–642.
   PubMed Web of Science ®Google Scholar
• Papke B, Murarka S, Vogel HA, et al. Identification of pyrazolopyridazinones as PDEdelta inhibitors. Nat Commun. 2016;7(1):11360.
   PubMedGoogle Scholar
• Infante JR, Fecher LA, Falchook GS, et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13(8):773–781.
   PubMed Web of Science ®Google Scholar
• Bedard PL, Tabernero J, Janku F, et al. A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors. Clin Cancer Res. 2015;21(4):730‐8.
   PubMed Web of Science ®Google Scholar
• Tolcher AW, Patnaik A, Papadopoulos KP, et al. Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. Cancer Chemother Pharmacol. 2015;75(1):183‐9.
   PubMed Web of Science ®Google Scholar
• Tolcher AW, Kurzrock R, Valero V, et al. Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors. Cancer Chemother Pharmacol. 2020;85(4):673‐83.
   PubMed Web of Science ®Google Scholar
• Bennouna J, Lang I, Valladares-Ayerbes M, et al. A Phase II, open-label, randomised study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens. Invest New Drugs. 2011;29(5):1021‐8.
   PubMed Web of Science ®Google Scholar
• Hochster HS, Uboha N, Messersmith W, et al. Phase II study of selumetinib (AZD6244, ARRY-142886) plus irinotecan as second-line therapy in patients with K-RAS mutated colorectal cancer. Cancer Chemother Pharmacol. 2015;75(1):17‐23.
   PubMed Web of Science ®Google Scholar
• Deming DA, Cavalcante LL, Lubner SJ, et al. A phase I study of selumetinib (AZD6244/ARRY-142866), a MEK1/2 inhibitor, in combination with cetuximab in refractory solid tumors and KRAS mutant colorectal cancer. Invest New Drugs. 2016;34(2):168‐75.
   PubMed Web of Science ®Google Scholar
• Tolcher AW, Khan K, Ong M, et al. Antitumor activity in RAS-driven tumors by blocking AKT and MEK. Clin Cancer Res. 2015;21(4):739‐48.
   Web of Science ®Google Scholar
• Krishnamurthy A, Dasari A, Noonan AM, et al. Phase Ib results of the rational combination of selumetinib and cyclosporin A in advanced solid tumors with an expansion cohort in metastatic colorectal cancer. Cancer Res. 2018;78(18):5398‐407.
   Web of Science ®Google Scholar
• Rosen LS, LoRusso P, Ma WW, et al. A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors. Invest New Drugs. 2016;34(5):604‐13.
   PubMed Web of Science ®Google Scholar
• Lieu CH, Hidalgo M, Berlin JD, et al. A phase Ib dose-escalation study of the safety, tolerability, and pharmacokinetics of cobimetinib and duligotuzumab in patients with previously treated locally advanced or metastatic cancers with mutant KRAS. Oncologist. 2017;22(9):1024‐e89.
   PubMed Web of Science ®Google Scholar
• Hellmann MD, Kim TW, Lee CB, et al. Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors. Ann Oncol. 2019;30(7):1134‐42.
   Web of Science ®Google Scholar
• Eng C, Kim TW, Bendell J, et al. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2019;20(6):849‐61.
   PubMed Web of Science ®Google Scholar
• Bendell JC, Javle M, Bekaii-Saab TS, et al. A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor. Br J Cancer. 2017;116(5):575‐83.
   PubMed Web of Science ®Google Scholar
• Cho M, Gong J, Frankel P, et al. A phase I clinical trial of binimetinib in combination with FOLFOX in patients with advanced metastatic colorectal cancer who failed prior standard therapy. Oncotarget. 2017;8(45):79750–79760.
   PubMedGoogle Scholar
• Bardia A, Gounder M, Rodon J, et al. Phase Ib study of combination therapy with MEK inhibitor binimetinib and phosphatidylinositol 3-kinase inhibitor buparlisib in patients with advanced solid tumors with RAS/RAF alterations. Oncologist. 2020;25(1):e160‐9.
   Web of Science ®Google Scholar
• Juric D, Soria JC, Sharma S, et al. A phase 1b dose-escalation study of BYL719 plus binimetinib (MEK162) in patients with selected advanced solid tumors. J Clin Oncol. 2014;32(15):9051. suppl.
   Web of Science ®Google Scholar
• Awada A, Delord JP, Houéde N et al. Safety and recommended phase II dose (RP2D) of the selective oral MEK1/2 inhibitor pimasertib (MSC1936369B/AS703026): results of a phase I trial. 24th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Dublin, Ireland. November 9 (2012).
   Google Scholar
• Macarulla T, Cervantes A, Tabernero J, et al. Phase I study of FOLFIRI plus pimasertib as second-line treatment for KRAS-mutated metastatic colorectal cancer. Br J Cancer. 2015;112(12):1874‐81.
   PubMed Web of Science ®Google Scholar
• Mita M, Fu S, Piha-Paul SA, et al. Phase I trial of MEK 1/2 inhibitor pimasertib combined with mTOR inhibitor temsirolimus in patients with advanced solid tumors. Invest New Drugs. 2017;35(5):616‐26.
   PubMed Web of Science ®Google Scholar
• Schram AM, Gandhi L, Mita MM, et al. A phase Ib dose-escalation and expansion study of the oral MEK inhibitor pimasertib and PI3K/MTOR inhibitor voxtalisib in patients with advanced solid tumors. Br J Cancer. 2018;119(12):1471‐6.
   PubMed Web of Science ®Google Scholar
• Weekes CD, Von Hoff DD, Adjei AA, et al. Multicenter phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86–9766 in patients with advanced cancer. Clin Cancer Res. 2013;19(5):1232‐43.
   PubMed Web of Science ®Google Scholar
• Ramanathan RK, Von Hoff DD, Eskens F, et al. Phase Ib trial of the PI3K inhibitor copanlisib combined with the allosteric MEK inhibitor refametinib in patients with advanced cancer. Target Oncol. 2020;15(2):163‐74.
   PubMed Web of Science ®Google Scholar
• Adjei AA, Richards DA, El-Khoueiry A, et al. A phase I study of the safety, pharmacokinetics, and pharmacodynamics of combination therapy with refametinib plus sorafenib in patients with advanced cancer. Clin Cancer Res. 2016;22(10):2368‐76.
   PubMed Web of Science ®Google Scholar
• Leijen S, Middleton MR, Tresca P, et al. Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors. Clin Cancer Res. 2012;18(17):4794‐805.
   PubMed Web of Science ®Google Scholar
• Zimmer L, Barlesi F, Martinez-Garcia M, et al. Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655) in selected patients with advanced cancer with RAS-RAF mutations. Clin Cancer Res. 2014;20(16):4251‐61.
   PubMed Web of Science ®Google Scholar
• Adjei AA, LoRusso P, Ribas A, et al. A phase I dose-escalation study of TAK-733, an investigational oral MEK inhibitor, in patients with advanced solid tumors. Invest New Drugs. 2017;35(1):47‐58.
   PubMed Web of Science ®Google Scholar
• Lorusso PM, Adjei AA, Varterasian M, et al. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol. 2005;23(23):5281‐93.
   Web of Science ®Google Scholar
• Rinehart J, Adjei AA, Lorusso PM, et al. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol. 2004;22(22):4456‐62.
   PubMed Web of Science ®Google Scholar
• LoRusso PM, Krishnamurthi SS, Rinehart JJ, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clin Cancer Res. 2010;16(6):1924‐37.
   Web of Science ®Google Scholar
• Wainberg ZA, Alsina M, Soares HP, et al. A Multi-Arm Phase I Study of the PI3K/mTOR Inhibitors PF-04691502 and Gedatolisib (PF-05212384) plus Irinotecan or the MEK Inhibitor PD-0325901 in Advanced Cancer. Target Oncol. 2017;12(6):775‐85.
   PubMed Web of Science ®Google Scholar
• van Geel RMJM, van Brummelen EMJ, Eskens FALM, et al. Phase 1 study of the pan-HER inhibitor dacomitinib plus the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutation-positive colorectal, non-small-cell lung and pancreatic cancer. Br J Cancer. 2020;122(8):1166‐74.
   PubMed Web of Science ®Google Scholar
• McCormick F. Sticking it to KRAS: covalent Inhibitors Enter the Clinic. Cancer Cell. 2020;37(1):3‐4.
   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):578‐89.
   PubMed Web of Science ®Google Scholar
• Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumor immunity. Nature. 2019;575(7781):217‐23.
   PubMed Web of Science ®Google Scholar
• Govindan R, Fakih MG, Price TJ, et al. 446PD Phase I study of AMG 510, a novel molecule targeting KRAS G12C mutant solid tumors. Ann Oncol. 2019;30(suppl_5):v159–v193.
   PubMedGoogle 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.
   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.
   PubMed Web of Science ®Google Scholar
• Jänne PA. AACR-NCI-EORTC International Conference on Molecular Targets, Boston, USA. October 28 (2019).
   Google Scholar
• Corcoran RB. New therapeutic strategies for BRAF mutant colorectal cancers. J Gastrointest Oncol. 2015;6(6):650‐9.
   PubMed Web of Science ®Google Scholar
• Korphaisarn K, Kopetz S. BRAF-directed therapy in metastatic colorectal cancer. Cancer J. 2016;22(3):175‐8.
   PubMed Web of Science ®Google Scholar
• Yang H, Higgins B, Kolinsky K, et al. Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer. Cancer Res. 2012;72(3):779‐89.
   Web of Science ®Google Scholar
• Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015;373(8):726‐36.
   PubMed 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):4032‐8.
   Web of Science ®Google Scholar
• Laquerre S, Arnone M, Moss K, et al. A selective Raf kinase inhibitor induces cell death and tumor regression of human cancer cell lines encoding B‐RafV600E mutation. Mol Cancer Ther. 2009;8(12_suppl):B88.
   Web of Science ®Google Scholar
• Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumors: a phase 1 dose-escalation trial. Lancet. 2012;379(9829):1893–1901.
   PubMed Web of Science ®Google Scholar
• Stuart DD, Li N, Poon DJ, et al. Preclinical profile of LGX818: A potent and selective RAF kinase inhibitor. Cancer Res. 2012;72(8):Abstract 3790.
   Google Scholar
• Gomez-Roca CA, Delord J, Robert C, et al. Encorafenib (Lgx818), an oral braf inhibitor, in patients (Pts) with braf V600E metastatic colorectal cancer (Mcrc): results of dose expansion in an open-label, phase 1 study. Ann Oncol. 2014;25(suppl 4):iv167–iv209.
   Google Scholar
• Corcoran RB, Dias-Santagata D, Bergethon K, et al. BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci Signal. 2010;3(149):ra84.
   PubMed Web of Science ®Google Scholar
• Corcoran RB, Atreya CE, Falchook GS, et al. Combined BRAF and MEK inhibition with Dabrafenib and Trametinib in BRAF V600-mutant colorectal cancer. J Clin Oncol. 2015;33(34):4023‐31.
   Web of Science ®Google Scholar
• Kefford R, Sullivan RJ, Miller WH, et al. Phase Ib/II, open-label, dose-escalation study of LGX818, an oral selective BRAF inhibitor, in combination with MEK162, an oral MEK1/2 inhibitor, in patients with BRAF V600-dependent advanced solid tumors: preliminary results. J Transl Med. 2014;12(S1):P5.
   PubMedGoogle Scholar
• Prahallad A, Sun C, Huang S, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012;483(7387):100‐3.
   PubMed Web of Science ®Google Scholar
• Corcoran RB, Ebi H, Turke AB, 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):227–235.
   PubMed Web of Science ®Google Scholar
• Yaeger R, Cercek A, O’Reilly EM, et al. Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients. Clin Cancer Res. 2015;21(6):1313–1320.
   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.
   PubMed Web of Science ®Google Scholar
• van Geel RMJM, Tabernero J, Elez E, et al. A phase Ib dose-escalation study of encorafenib and cetuximab with or without alpelisib in metastatic BRAF-mutant colorectal cancer. Cancer Discov. 2017;7(6):610–619.
   PubMed Web of Science ®Google Scholar
• Prewett MC, Hooper AT, Bassi R, et al. Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin Cancer Res. 2002;8(5):994–1003.
   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):1352‐65.
   Web of Science ®Google Scholar
• Kopetz S, McDonough SL, Lenz HJ, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406). J Clin Oncol. 2017;35(4_suppl):520.
   Web of Science ®Google Scholar
• Coffee EM, Faber AC, Roper J, et al. Concomitant BRAF and PI3K/mTOR blockade is required for effective treatment of BRAF(V600E) colorectal cancer. Clin Cancer Res. 2013;19(10):2688–2698.
   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):1460‐9.
   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):1632‐43.
   PubMed Web of Science ®Google Scholar
• Kopetz S, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab with or without binimetinib for BRAF V600E metastatic colorectal cancer: updated survival results from a randomized, three-arm, phase III study versus choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). J Clin Oncol. 2020;38(15_suppl):4001.
   Google Scholar
• Grothey A, Tabernero J, Taieb J, et al. LBA-5 ANCHOR CRC: a single-arm, phase 2 study of encorafenib, binimetinib plus cetuximab in previously untreated BRAF V600E-mutant metastatic colorectal cancer. Ann Oncol. 2020;31(suppl_3):S242–S243.
   Google Scholar
• Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–413.
   PubMed Web of Science ®Google Scholar
• Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;8(9):1182–1191.
   Google Scholar
• Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36(8):773‐9.
   PubMed Web of Science ®Google Scholar
• Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509‐20.
   PubMed Web of Science ®Google Scholar
• Le DT, Kim TW, Van Cutsem E, et al. Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164. J Clin Oncol. 2020;38(1):11‐9.
   Web of Science ®Google Scholar
• Andre T, Shiu -K-K, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: the phase 3 KEYNOTE-177 Study. J Clin Oncol. 2020;38(18_suppl):LBA4.
   Web of Science ®Google Scholar