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Systemic Therapy in BRAF V600E-Mutant Metastatic Colorectal Cancer: Recent Advances and Future Strategies

  • Systemic Therapies in Colorectal Cancer (SM Kazmi, Section Editor)
  • Published:
Current Colorectal Cancer Reports

Abstract

Purpose of Review

This review seeks to detail the clinical and pathologic features specific to BRAFV600E colorectal cancer. Application of novel preclinical findings translated into the clinic for the development of new therapeutic options for patients with BRAFV600E metastatic colorectal cancer will be detailed.

Recent Findings

While BRAF inhibitors as monotherapy do not have the same clinical activity for colorectal cancer relative to other solid tumors harboring an oncogenic BRAFV600E mutation, combination approaches targeting BRAF + MEK + EGFR hold promise for patients with BRAFV600E colorectal cancer.

Summary

Simultaneous targeting of multiple drivers along the MAPK pathway improves clinical outcomes for patients with BRAFV600E colorectal cancer. Targeted therapies and immunotherapy hold great promise in the years to come for patients with this subtype of colorectal cancer.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30.

    Article  PubMed  Google Scholar 

  2. Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757–65.

    Article  CAS  PubMed  Google Scholar 

  3. • 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 First report of microsatellite instability as a predictive biomarker for benefit to immune checkpoint blockade therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54.

    Article  CAS  PubMed  Google Scholar 

  6. Wan PT, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116(6):855–67.

    Article  CAS  PubMed  Google Scholar 

  7. Tran B, Kopetz S, Tie J, Gibbs P, Jiang ZQ, Lieu CH, 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):4623–32.

    Article  CAS  PubMed  Google Scholar 

  8. Tie J, Gibbs P, Lipton L, Christie M, Jorissen RN, Burgess AW, et al. Optimizing targeted therapeutic development: analysis of a colorectal cancer patient population with the BRAF(V600E) mutation. Int J Cancer. 2011;128(9):2075–84.

    Article  CAS  PubMed  Google Scholar 

  9. 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).

  10. Li WQ, Kawakami K, Ruszkiewicz A, Bennett G, Moore J, Iacopetta B. BRAF mutations are associated with distinctive clinical, pathological and molecular features of colorectal cancer independently of microsatellite instability status. Mol Cancer. 2006;5:2.

    Article  CAS  PubMed  Google Scholar 

  11. Ogino S, Nosho K, Kirkner GJ, Kawasaki T, Meyerhardt JA, Loda M, et al. CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut. 2009;58(1):90–6.

    Article  PubMed  Google Scholar 

  12. Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature. 2002;418(6901):934.

    Article  CAS  PubMed  Google Scholar 

  13. Kane MF, Loda M, Gaida GM, et al. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 1997;57(5):808–11.

    CAS  PubMed  Google Scholar 

  14. Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP. CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A. 1999;96(15):8681–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kambara T, Simms LA, Whitehall VL, et al. BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut. 2004;53(8):1137–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. O’Brien MJ, Yang S, Clebanoff JL, et al. Hyperplastic (serrated) polyps of the colorectum: relationship of CpG island methylator phenotype and K-ras mutation to location and histologic subtype. Am J Surg Pathol. 2004;28(4):423–34.

    Article  PubMed  Google Scholar 

  17. Yang S, Farraye FA, Mack C, Posnik O, O’Brien MJ. BRAF and KRAS mutations in hyperplastic polyps and serrated adenomas of the colorectum: relationship to histology and CpG island methylation status. Am J Surg Pathol. 2004;28(11):1452–9.

    Article  PubMed  Google Scholar 

  18. Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006;38(7):787–93.

    Article  CAS  PubMed  Google Scholar 

  19. O’Brien MJ, Yang S, Mack C, et al. Comparison of microsatellite instability, CpG island methylation phenotype, BRAF and KRAS status in serrated polyps and traditional adenomas indicates separate pathways to distinct colorectal carcinoma end points. Am J Surg Pathol. 2006;30(12):1491–501.

    Article  PubMed  Google Scholar 

  20. Shen L, Toyota M, Kondo Y, Lin E, Zhang L, Guo Y, et al. Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proc Natl Acad Sci U S A. 2007;104(47):18654–9.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Campisi J. Suppressing cancer: the importance of being senescent. Science. 2005;309(5736):886–7.

    Article  CAS  PubMed  Google Scholar 

  22. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997;88(5):593–602.

    Article  CAS  PubMed  Google Scholar 

  23. Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell. 2008;132(3):363–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009;361(1):98–9.

    Article  CAS  PubMed  Google Scholar 

  25. Van Cutsem E, Kohne CH, Lang I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29(15):2011–9.

    Article  CAS  PubMed  Google Scholar 

  26. Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–7.

    Article  CAS  Google Scholar 

  27. Roth AD, Tejpar S, Delorenzi M, Yan P, Fiocca R, Klingbiel D, 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.

    Article  CAS  PubMed  Google Scholar 

  28. Kalady MF, Dejulius KL, Sanchez JA, et al. BRAF mutations in colorectal cancer are associated with distinct clinical characteristics and worse prognosis. Dis Colon Rectum. 2012;55(2):128–33.

    Article  PubMed  Google Scholar 

  29. Price TJ, Hardingham JE, Lee CK, Weickhardt A, Townsend AR, Wrin JW, et al. Impact of KRAS and BRAF gene mutation status on outcomes from the phase III AGITG MAX trial of capecitabine alone or in combination with bevacizumab and Mitomycin in advanced colorectal Cancer. J Clin Oncol. 2011;29(19):2675–82.

    Article  CAS  PubMed  Google Scholar 

  30. Safaee Ardekani G, Jafarnejad SM, Tan L, Saeedi A, Li G. The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. PLoS One. 2012;7(10):e47054.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chen D, Huang JF, Liu K, Zhang LQ, Yang Z, Chuai ZR, et al. BRAFV600E mutation and its association with clinicopathological features of colorectal cancer: a systematic review and meta-analysis. PLoS One. 2014;9(3):e90607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Samowitz WS, Sweeney C, Herrick J, Albertsen H, Levin TR, Murtaugh MA, et al. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res. 2005;65(14):6063–9.

    Article  CAS  PubMed  Google Scholar 

  33. Saridaki Z, Papadatos-Pastos D, Tzardi M, Mavroudis D, Bairaktari E, Arvanity H, et al. BRAF mutations, microsatellite instability status and cyclin D1 expression predict metastatic colorectal patients’ outcome. Br J Cancer. 2010;102(12):1762–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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  CAS  PubMed  Google Scholar 

  35. 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.

    Article  CAS  PubMed  Google Scholar 

  36. • 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 BRAF V600E mutation is not predictive for benefit to anti-EGFR therapies in patients with metastatic colorectal cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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):5705–12.

    Article  CAS  PubMed  Google Scholar 

  38. Laurent-Puig P, Cayre A, Manceau G, Buc E, Bachet JB, Lecomte T, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009;27(35):5924–30.

    Article  CAS  PubMed  Google Scholar 

  39. Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, 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):715–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Seymour MT, Brown SR, Middleton G, Maughan T, Richman S, Gwyther S, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pietrantonio F, Petrelli F, Coinu A, di Bartolomeo M, Borgonovo K, Maggi C, 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):587–94.

    Article  CAS  PubMed  Google Scholar 

  42. Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014;371(17):1609–18.

    Article  CAS  PubMed  Google Scholar 

  43. Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, 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):1306–15.

    Article  CAS  PubMed  Google Scholar 

  44. Morris V, Overman MJ, Jiang ZQ, Garrett C, Agarwal S, Eng C, 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):164–71.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010;467(7315):596–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358–65.

    Article  CAS  PubMed  Google Scholar 

  50. Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015;373(8):726–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Dietrich S, Glimm H, Andrulis M, von Kalle C, Ho AD, Zenz T. BRAF inhibition in refractory hairy-cell leukemia. N Engl J Med. 2012;366(21):2038–40.

    Article  PubMed  Google Scholar 

  52. Rosove MH, Peddi PF, Glaspy JA. BRAF V600E inhibition in anaplastic thyroid cancer. N Engl J Med. 2013;368(7):684–5.

    Article  CAS  PubMed  Google Scholar 

  53. Brose MS, Cabanillas ME, Cohen EE, et al. Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17(9):1272–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Paraiso KH, Fedorenko IV, Cantini LP, et al. Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy. Br J Cancer. 2010;102(12):1724–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867–76.

    Article  CAS  PubMed  Google Scholar 

  56. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30–9.

    Article  CAS  PubMed  Google Scholar 

  57. Dummer R, Ascierto PA, Gogas HJ, 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  CAS  PubMed  Google Scholar 

  58. Planchard D, Smit EF, Groen HJM, Mazieres J, Besse B, Helland Å, et al. Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017;18(10):1307–16.

    Article  CAS  PubMed  Google Scholar 

  59. Subbiah V, Kreitman RJ, Wainberg ZA, Cho JY, Schellens JHM, Soria JC, et al. Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600-mutant anaplastic thyroid Cancer. J Clin Oncol. 2018;36(1):7–13.

    Article  CAS  PubMed  Google Scholar 

  60. • 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 Unlike other advanced malignancies, BRAF inhibitor as a monotherapy is not an effective treatment approach for patients with BRAF V600E metastatic colorectal cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012;379(9829):1893–901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. JD CAG-R, Robert C, Hidalgo M, von Moos R, Arance A, Elez E, et al. Encorafenib (LGX818), an oral BRAF inhibitor, in patients (pts) with BRAF V600E metastatic colorectal cancer (mCRC): results of dose expansion. Ann Oncol. 2014;25(suppl 4):iv167-iv209.

    Google Scholar 

  63. Corcoran RB, Atreya CE, Falchook GS, Kwak EL, Ryan DP, Bendell JC, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. •• 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 In preclinical models of BRAF V600E colorectal cancer, blockade of BRAF V600E generates reflexive activation of EGFR and downstream MAPK signaling.

    Article  CAS  PubMed  Google Scholar 

  65. 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  CAS  PubMed  PubMed Central  Google Scholar 

  66. Mao M, Tian F, Mariadason JM, Tsao CC, Lemos R, Dayyani F, et al. Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents. Clin Cancer Res. 2013;19(3):657–67.

    Article  CAS  PubMed  Google Scholar 

  67. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. •• Kopetz S, McDonough SL, Morris VK, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). J Clin Oncol. 2017;35(4_suppl):520–520 The addition of cetuximab to the BRAF inhibitor vemurafenib improves survival outcomes in patients with BRAF V600E metastatic colorectal cancer.

    Article  Google Scholar 

  69. Network. NCC. NCCN Guidelines Colon Cancer, version 4.2018. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed 23 Oct 2018.

  70. Yaeger R, Cercek A, O’Reilly EM, Reidy DL, Kemeny N, Wolinsky T, et al. Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients. Clin Cancer Res. 2015;21(6):1313–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Corcoran RB, Andre T, Atreya CE, et al. Combined BRAF, EGFR, and MEK inhibition in patients with BRAF(V600E)-mutant colorectal cancer. Cancer Discov. 2018;8(4):428–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. van Geel R, 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):610–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. • Ahronian LG, Sennott EM, Van Allen EM, et al. Clinical acquired resistance to RAF inhibitor combinations in BRAF-mutant colorectal cancer through MAPK pathway alterations. Cancer Discov. 2015;5(4):358–67 Resistance to targeted therapies against BRAF and EGFR in patients with BRAF V600E metastatic colorectal cancer may be driven by acquired activating mutations in genes relevant to propagating MAPK signaling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hazar-Rethinam M, Kleyman M, Han GC, Liu D, Ahronian LG, Shahzade HA, et al. Convergent therapeutic strategies to overcome the heterogeneity of acquired resistance in BRAF(V600E) colorectal cancer. Cancer Discov. 2018;8(4):417–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. •• Van Cutsem E, Cuyle P, Huijberts S, et al. O-027BEACON CRC study safety lead-in: assessment of the BRAF inhibitor encorafenib + MEK inhibitor binimetinib + anti–epidermal growth factor receptor antibody cetuximab for BRAFV600E metastatic colorectal cancer. Ann Oncol. 2018;29(suppl_5):mdy149.026-mdy149.026 Targeted therapies against BRAF, MEK, and EGFR are safe and active for patients with BRAF V600E metastatic colorectal cancer.

    Google Scholar 

  76. Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, 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;18(9):1182–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. •• 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 Patients with BRAF V600E metastatic colorectal cancer and microsatellite instability demonstrate sustained clinical response to immune checkpoint blockade therapy.

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Gastrointestinal Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, 77030, USA

    Van K. Morris

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Morris, V.K. Systemic Therapy in BRAF V600E-Mutant Metastatic Colorectal Cancer: Recent Advances and Future Strategies. Curr Colorectal Cancer Rep 15, 53–60 (2019). https://doi.org/10.1007/s11888-019-00429-z

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