566
Views
4
CrossRef citations to date
0
Altmetric
Review

Update on optimal treatment for metastatic colorectal cancer from the AGITG expert meeting: ESMO congress 2019

, , , , , , , , , , & show all
Pages 251-270 | Received 19 Dec 2019, Accepted 16 Mar 2020, Published online: 06 Apr 2020

References

  • Koopman M, Seymour MT, Punt CJ. The CAIRO and FOCUS studies: which lesson is to be learned? Oncologist. 2009;14(2):192–193.
  • Seymour MT, Maughan TS, Ledermann JA, et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007;370(9582):143–152.
  • Koopman M, Antonini NF, Douma J, et al. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007;370(9582):135–142.
  • Ducreux M, Malka D, Mendiboure J, et al. Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000–05): an open-label, randomised, phase 3 trial. Lancet Oncol. 2011;12(11):1032–1044.
  • Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22(2):229–237.
  • Colucci G, Gebbia V, Paoletti G, et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell’Italia Meridionale. J Clin Oncol. 2005;23(22):4866–4875.
  • Komatsu Y, Takashima A, Denda T, et al. 474OTreatment outcome according to tumor RAS mutation status in TRICOLORE trial: A randomized phase 3 trial of S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment for metastatic colorectal cancer. Ann Oncol. 2017;28(suppl_5). DOI:10.1093/annonc/mdx393.001
  • Baba H, Yamada Y, Takahari D, et al. S-1 and oxaliplatin (SOX) plus bevacizumab versus mFOLFOX6 plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer: updated overall survival analyses of the open-label, non-inferiority, randomised phase III: SOFT study. ESMO Open. 2017;2(1):e000135–e000135.
  • Peeters M, Price T. Biologic therapies in the metastatic colorectal cancer treatment continuum–applying current evidence to clinical practice. Cancer Treat Rev. 2012;38(5):397–406.
  • Falcone A, Ricci S, Brunetti I, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007;25(13):1670–1676.
  • Loupakis F, Cremolini C, Masi G, et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014;371(17):1609–1618.
  • 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.
  • Cremolini C, Antoniotti C, Lonardi S, et al. Updated results of TRIBE2, a phase III, randomized strategy study by GONO in the first- and second-line treatment of unresectable mCRC. J Clin Oncol. 2019;37(15_suppl):3508.
  • Souglakos J, Androulakis N, Syrigos K, et al. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006;94(6):798–805.
  • Modest DP, Martens UM, Riera-Knorrenschild J, et al. FOLFOXIRI plus panitumumab as first-line treatment of RAS wild-type metastatic colorectal cancer: the randomized, open-label, phase II VOLFI study (AIO KRK0109). J Clin Oncol JCO.19.01340. 2019;37:3401–3411.
  • Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–2342.
  • Saltz LB, Clarke S, Díaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26(12):2013–2019.
  • Tebbutt NC, Wilson K, Gebski VJ, et al. Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian gastrointestinal trials group randomized phase III MAX Study. J Clin Oncol. 2010;28(19):3191–3198.
  • Cunningham D, Lang I, Marcuello E, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol. 2013;14(11):1077–1085.
  • Botrel TEA, Clark LGO, Paladini L, et al. Efficacy and safety of bevacizumab plus chemotherapy compared to chemotherapy alone in previously untreated advanced or metastatic colorectal cancer: a systematic review and meta-analysis. BMC Cancer. 2016;16:677.
  • Hurwitz HI, Tebbutt NC, Kabbinavar F, et al. Efficacy and safety of bevacizumab in metastatic colorectal cancer: pooled analysis from seven randomized controlled trials. Oncologist. 2013;18(9):1004–1012.
  • Passardi A, Nanni O, Tassinari D, et al. Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. Ann Oncol. 2015;26(6):1201–1207.
  • Díaz-Rubio E, Gómez-España A, Massutí B, et al. First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: the phase III MACRO TTD study. Oncologist. 2012;17(1):15–25.
  • Simkens LH, van Tinteren H, May A, et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch colorectal cancer group. Lancet. 2015;385(9980):1843–1852.
  • Aparicio T, Bennouna J, Malicot KL, et al. Final results of PRODIGE 9, a randomized phase III comparing no treatment to bevacizumab maintenance during chemotherapy-free intervals in metastatic colorectal cancer. J Clin Oncol. 2016;34(15_suppl):3531.
  • Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360(6):563–572.
  • Tournigand C, Chibaudel B, Samson B, et al. Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): A randomised, open-label, phase 3 trial. Lancet Oncol. 2015;16(15):1493–1505.
  • Puthillath A, Patel A, Fakih MG. Targeted therapies in the management of colorectal carcinoma: role of bevacizumab. Onco Targets Ther. 2009;2:1.
  • Hegewisch-Becker S, Graeven U, Lerchenmuller CA, et al. Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol. 2015;16(13):1355–1369.
  • Zhou M, Yu P, Qu J, et al. Efficacy of bevacizumab in the first-line treatment of patients with RAS mutations metastatic colorectal cancer: a systematic review and network meta-analysis. Cell Physiol Biochem. 2016;40(1–2):361–369.
  • Modest DP, Stintzing S, von Weikersthal LF, et al. Impact of subsequent therapies on outcome of the FIRE-3/AIO KRK0306 trial: first-line therapy with FOLFIRI plus cetuximab or bevacizumab in patients with KRAS wild-type tumors in metastatic colorectal cancer. J Clin Oncol. 2015;33(32):3718–3726.
  • Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the eastern cooperative oncology group study E3200. J Clin Oncol. 2007;25(12):1539–1544.
  • Stintzing S, Modest DP, Rossius L, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol. 2016;17(10):1426–1434.
  • Maughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011;377(9783):2103–2114.
  • Tveit KM, Guren T, Glimelius B, et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol. 2012;30(15):1755–1762.
  • Douillard J-Y, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010;28(31):4697–4705.
  • Douillard J-Y, Oliner KS, Siena S, et al. Panitumumab–FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369(11):1023–1034.
  • Sorich M, Wiese M, Rowland A, et al. Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol. 2014;26(1):13–21.
  • Pietrantonio F, Cremolini C, Petrelli F, et al. First-line anti-EGFR monoclonal antibodies in panRAS wild-type metastatic colorectal cancer: A systematic review and meta-analysis. Crit Rev Oncol Hematol. 2015;96(1):156–166.
  • Aranda E, Garcia-Alfonso P, Benavides M, et al. First-line mFOLFOX plus cetuximab followed by mFOLFOX plus cetuximab or single-agent cetuximab as maintenance therapy in patients with metastatic colorectal cancer: phase II randomised MACRO2 TTD study. Eur J Cancer. 2018;101:263–272.
  • Pietrantonio F, Morano F, Corallo S, et al. Maintenance vs panitumumab plus fluorouracil-leucovorin in patients with RAS wild-type metastatic colorectal cancer: a phase 2 randomized clinical trial. JAMA Oncol. 2019;5(9):1268–1275.
  • Benedix F, Kube R, Meyer F, et al. Comparison of 17,641 patients with right-and left-sided colon cancer: differences in epidemiology, perioperative course, histology, and survival. Dis Colon Rectum. 2010;53(1):57–64.
  • Boeckx N, Koukakis R, Op de Beeck K, et al. Primary tumor sidedness has an impact on prognosis and treatment outcome in metastatic colorectal cancer: results from two randomized first-line panitumumab studies. Ann Oncol. 2017;28(8):1862–1868.
  • Boeckx N, Koukakis R, Op de Beeck K, et al. Effect of primary tumor location on second- or later-line treatment outcomes in patients with RAS wild-type metastatic colorectal cancer and all treatment lines in patients with RAS mutations in four randomized panitumumab studies. Clin Colorectal Cancer. 2018;17(3):170–178e173.
  • Holch JW, Ricard I, Stintzing S, et al. The relevance of primary tumour location in patients with metastatic colorectal cancer: A meta-analysis of first-line clinical trials. Eur J Cancer. 2017;70(SupplementC):87–98.
  • Arnold D, Lueza B, Douillard JY, et al. Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials. Ann Oncol. 2017;28(8):1713–1729.
  • National Comprehensive Cancer Network. Colon cancer v3. 2019 [ cited October 14]. https://www.nccn.org/professionals/physician_gls/PDF/colon.pdf
  • National Health and Medical Research Council. Clinical guidelines for prevention, early detection and management of colorectal cancer. Australia: National Health and Medical Research Council; 2017.
  • Yoshino T, Arnold D, Taniguchi H, et al. Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO–ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS. Ann Oncol. 2017;29(1):44–70.
  • Petrelli F, Borgonovo K, Barni S. The predictive role of skin rash with cetuximab and panitumumab in colorectal cancer patients: a systematic review and meta-analysis of published trials. Target Oncol. 2013;8(3):173–181.
  • Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2008;27(5):672–680.
  • Khattak MA, Martin H, Davidson A, et al. Role of first-line anti-epidermal growth factor receptor therapy compared with anti-vascular endothelial growth factor therapy in advanced colorectal cancer: a meta-analysis of randomized clinical trials. Clin Colorectal Cancer. 2015;14(2):81–90.
  • O’Neil BH, Venook AP. Trying to understand differing results of FIRE-3 and 80405: does the first treatment matter more than others? J Clin Oncol. 2015;33(32):3686–3688.
  • Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16(5):499–508.
  • Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30(28):3499–3506.
  • Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14(1):29–37.
  • Ciardiello F, Normanno N, Martinelli E, et al. Cetuximab continuation after first progression in metastatic colorectal cancer (CAPRI-GOIM): a randomized phase II trial of FOLFOX plus cetuximab versus FOLFOX. Ann Oncol. 2016;27(6):1055–1061.
  • Bennouna J, Hiret S, Bertaut A, et al. Continuation of bevacizumab vs cetuximab plus chemotherapy after first progression in KRAS wild-type metastatic colorectal cancer: the UNICANCER PRODIGE18 randomized clinical trial. JAMA Oncol. 2019;5(1):83–90.
  • Hecht JR, Cohn A, Dakhil S, et al. SPIRITT: a randomized, multicenter, phase II study of panitumumab with FOLFIRI and bevacizumab with FOLFIRI as second-line treatment in patients with unresectable wild type KRAS metastatic colorectal cancer. Clin Colorectal Cancer. 2015;14(2):72–80.
  • Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337–345.
  • 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.
  • Price TJ, Peeters M, Kim TW, et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014;15(6):569–579.
  • Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303–312.
  • Li J, Qin S, Xu R, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16(6):619–629.
  • Bekaii-Saab TS, Ou F-S, Ahn DH, et al. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019;20(8):1070–1082.
  • Argiles G, Margalef NM, Valladares-Ayerbes M, et al. O-026Results of REARRANGE trial: A randomized phase 2 study comparing different dosing approaches for regorafenib (REG) during the first cycle of treatment in patients (pts) with metastatic colorectal cancer (mCRC). Ann Oncol. 2019;30(mdz154.025). DOI:10.1093/annonc/mdz154.025
  • Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909–1919.
  • Ohtsu A, Yoshino T, Falcone A, et al. Onset of neutropenia as an indicator of treatment response in the phase 3 RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo in patients with metastatic colorectal cancer. J Clin Oncol. 2017;35(4_suppl):775.
  • Santini D, Vincenzi B, Addeo R, et al. Cetuximab rechallenge in metastatic colorectal cancer patients: how to come away from acquired resistance? Ann Oncol. 2012;23(9):2313–2318.
  • Karoulia Z, Gavathiotis E, Poulikakos PI. New perspectives for targeting RAF kinase in human cancer. Nat Rev Cancer. 2017;17:676–691.
  • 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.
  • Saridaki Z, Papadatos-Pastos D, Tzardi M, et al. BRAF mutations, microsatellite instability status and cyclin D1 expression predict metastatic colorectal patients’ outcome. Br J Cancer. 2010;102(12):1762–1768.
  • Samowitz WS, Sweeney C, Herrick J, et al. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res. 2005;65(14):6063–6069.
  • Rajagopalan H, Bardelli A, Lengauer C, et al. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature. 2002;418(6901):934.
  • Chen D, Huang J-F, Liu K, 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.
  • Venderbosch S, Nagtegaal ID, Maughan TS, et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN and FOCUS studies. Clin Cancer Res clincanres. 0332.2014. 2014;20:5322–5330.
  • Sepulveda AR, Hamilton SR, Allegra CJ, et al. Molecular biomarkers for the evaluation of colorectal cancerguideline from the american society for clinical pathology, college of american pathologists, association for molecular pathology, and American society of clinical oncology. Am J Clin Pathol. 2017;147(3):221–260.
  • Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009;361(1):98–99.
  • Seligmann JF, Fisher D, Smith CG, et al. Investigating the poor outcomes of BRAF-mutant advanced colorectal cancer: analysis from 2530 patients in randomised clinical trials. Ann Oncol. 2016;28(3):562–568.
  • Schirripa M, Bergamo F, Cremolini C, et al. BRAF and RAS mutations as prognostic factors in metastatic colorectal cancer patients undergoing liver resection. Br J Cancer. 2015;112(12):1921–1928.
  • Schirripa M, Biason P, Lonardi S, et al. Class 1, 2, and 3 BRAF-mutated metastatic colorectal cancer: a detailed clinical, pathologic, and molecular characterization. Clin Cancer Res. 2019;25(13):3954–3961.
  • Yao Z, Yaeger R, Rodrik-Outmezguine VS, et al. Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. Nature. 2017;548(7666):234–238.
  • Price TJ, Hardingham JE, Lee CK, 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):2675–2682.
  • Rowland A, Karapetis C, Kichenadasse G, 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.
  • 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.
  • 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.
  • Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–2342.
  • Ince WL, Jubb AM, Holden SN, et al. Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J Natl Cancer Inst. 2005;97(13):981–989.
  • Goey KKH, Elias SG, van Tinteren H, et al. Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study. Ann Oncol. 2017;28(9):2128–2134.
  • Yoshino T, Portnoy DC, Obermannová R, et al. Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE—a global phase III study. Ann Oncol. 2018;30(1):124–131.
  • Wirapati P, Pomella V, Vandenbosch B, et al. Velour trial biomarkers update: impact of RAS, BRAF, and sidedness on aflibercept activity. J Clin Oncol. 2017;35(15_suppl):3538.
  • 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.
  • 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.
  • Corcoran RB, Ebi H, Turke AB, et al. EGFR-mediated reactivation of MAPK signaling contributes to insensitivity of BRAF-mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012;2(3):227–235.
  • 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):4023–4031.
  • Desai J, Markman B, Ananda S, et al. A phase I/II trial of combined BRAF and EGFR inhibition in patients (pts) with BRAF V600E mutated (BRAFm) metastatic colorectal (mCRC): the EViCT (erlotinib and vemurafenib in combination trial) study. J Clin Oncol. 2017;35(15_suppl):3557.
  • Geel RV, Elez E, Bendell JC, et al. Phase I study of the selective BRAFV600 inhibitor encorafenib (LGX818) combined with cetuximab and with or without the α-specific PI3K inhibitor BYL719 in patients with advanced BRAF-mutant colorectal cancer. J Clin Oncol; 2014;32(5_suppl):3514.
  • Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E–mutated colorectal cancer. N Engl J Med. 2019;381:1632–1643.
  • 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):428–443.
  • 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.
  • 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.
  • Dudley JC, Lin M-T, Le DT, et al. Microsatellite instability as a biomarker for PD-1 blockade. Clin Cancer Res. 2016;22(4):813–820.
  • Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–2520.
  • Llosa NJ, Cruise M, Tam A, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015;5(1):43–51.
  • Taieb J, Shi Q, Pederson L, et al. Prognosis of microsatellite instability and/or mismatch repair deficiency stage III colon cancer patients after disease recurrence following adjuvant treatment: results of an ACCENT pooled analysis of seven studies. Ann Oncol. 2019;30(9):1466–1471.
  • 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.
  • 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, JCO.19.02107. 2020;38(1):11–19.
  • Diaz LA, Le DT, Yoshino T, et al. KEYNOTE-177: randomized phase III study of pembrolizumab versus investigator-choice chemotherapy for mismatch repair-deficient or microsatellite instability-high metastatic colorectal carcinoma. J Clin Oncol. 2017;35(4_suppl):TPS815–TPS815.
  • 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;18(9):1182–1191.
  • 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):773–779.
  • Hochster HS, Bendell JC, Cleary JM, et al. Efficacy and safety of atezolizumab (atezo) and bevacizumab (bev) in a phase Ib study of microsatellite instability (MSI)-high metastatic colorectal cancer (mCRC). J Clin Oncol; 2017;35(4_suppl):673–673.
  • Sinicrope FA, Ou F-S, Shi Q, et al. Randomized trial of FOLFOX alone or combined with atezolizumab as adjuvant therapy for patients with stage III colon cancer and deficient DNA mismatch repair or microsatellite instability (ATOMIC, Alliance A021502). J Clin Oncol. 2017;35(15_suppl):TPS3630–TPS3630.
  • Lau D, Kalaitzaki E, Church DN, et al. Rationale and design of the POLEM trial: avelumab plus fluoropyrimidine-based chemotherapy as adjuvant treatment for stage III mismatch repair deficient or POLE exonuclease domain mutant colon cancer: a phase III randomised study. ESMO Open. 2020;5:1.
  • Liu B, Nicolaides NC, Markowitz S, et al. Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nat Genet. 1995;9:48.
  • Sharma P, Hu-Lieskovan S, Wargo JA, et al. Adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168(4):707–723.
  • Bendell JC, Kim TW, Goh BC, et al. Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC). J Clin Oncol. 2016;34(15_suppl):3502.
  • 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):849–861.
  • Wallin J, Pishvaian MJ, Hernandez G, et al. Clinical activity and immune correlates from a phase Ib study evaluating atezolizumab (anti-PDL1) in combination with FOLFOX and bevacizumab (anti-VEGF) in metastatic colorectal carcinoma. AACR; Cancer Res. 2016;76(14_suppl):Abstract nr 2651.
  • Grothey A, Tabernero J, Arnold D, et al. LBA19Fluoropyrimidine (FP) + bevacizumab (BEV) + atezolizumab vs FP/BEV in BRAFwt metastatic colorectal cancer (mCRC): findings from Cohort 2 of MODUL – a multicentre, randomized trial of biomarker-driven maintenance treatment following first-line induction therapy. Ann Oncol. 2018;29(suppl_8). DOI:10.1093/annonc/mdx807
  • Shahda S, Noonan AM, Bekaii-Saab TS, et al. A phase II study of pembrolizumab in combination with mFOLFOX6 for patients with advanced colorectal cancer. J Clin Oncol. 2017;35(15_suppl):3541.
  • Tabernero J, Melero I, Ros W, et al. Phase Ia and Ib studies of the novel carcinoembryonic antigen (CEA) T-cell bispecific (CEA CD3 TCB) antibody as a single agent and in combination with atezolizumab: preliminary efficacy and safety in patients with metastatic colorectal cancer (mCRC). J Clin Oncol. 2017;35(15_suppl):3002.
  • Yonesaka K, Zejnullahu K, Okamoto I, et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med. 2011;3(99):99ra86.
  • Martin V, Landi L, Molinari F, et al. HER2 gene copy number status may influence clinical efficacy to anti-EGFR monoclonal antibodies in metastatic colorectal cancer patients. Br J Cancer. 2013;108(3):668–675.
  • Raghav KPS, Overman MJ, Yu R, et al. HER2 amplification as a negative predictive biomarker for anti-epidermal growth factor receptor antibody therapy in metastatic colorectal cancer. J Clin Oncol. 2016;34(15_suppl):3517.
  • Sartore-Bianchi A, Trusolino L, Martino C, et al., Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol. 17(6): 738–746.2016.
  • Salem ME, Weinberg BA, Xiu J, et al. Comparative molecular analyses of left-sided colon, right-sided colon, and rectal cancers. Oncotarget. 2017;8(49):86356–86368.
  • Kavuri SM, Jain N, Galimi F, et al. HER2 activating mutations are targets for colorectal cancer treatment. Cancer Discov. 2015;5(8):832–841.
  • Hyman DM, Piha-Paul SA, Won H, et al. HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature. 2018;554(7691):189–194.
  • Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 2015;5(1):25–34.
  • Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15(12):731–747.
  • Stransky N, Cerami E, Schalm S, et al. The landscape of kinase fusions in cancer. Nat Commun. 2014;5:4846.
  • Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open. 2016;1(2):e000023.
  • Chao MV. Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci. 2003;4(4):299–309.
  • Sartore-Bianchi A, Amatu A, Bonazzina E, et al. Pooled analysis of clinical outcome of patients with chemorefractory metastatic colorectal cancer treated within phase I/II clinical studies based on individual biomarkers of susceptibility: a single-institution experience. Target Oncol. 2017;12(4):525–533.
  • Pietrantonio F, Di Nicolantonio F, Schrock AB, et al. ALK, ROS1, and NTRK rearrangements in metastatic colorectal cancer. J Natl Cancer Inst. 2017;109:12.
  • Lasota J, Chlopek M, Lamoureux J, et al. Colonic adenocarcinomas harboring ntrk fusion genes: a clinicopathologic and molecular genetic study of 16 cases and review of the literature. Am J Surg Pathol. 2020;44(2):162–173.
  • Lassen UN, Albert CM, Kummar S, et al. 409OLarotrectinib efficacy and safety in TRK fusion cancer: an expanded clinical dataset showing consistency in an age and tumor agnostic approach. Ann Oncol. 2018;29(suppl_8). DOI:10.1093/annonc/mdy279.397
  • Hyman DM, van Tilburg CM, Albert CM, et al. 445PDDurability of response with larotrectinib in adult and pediatric patients with TRK fusion cancer. Ann Oncol. 2019;30(Supplement_5). DOI:10.1093/annonc/mdz244.007
  • Drilon A, Laetsch TW, Kummar S, et al. Efficacy of Larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731–739.
  • Drilon A, Siena S, Ou SI, et al. Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017;7(4):400–409.
  • Rolfo C, Dziadziuszko R, Doebele RC, et al. 476PUpdated efficacy and safety of entrectinib in patients with NTRK fusion-positive tumors: integrated analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Ann Oncol. 2019;30(Supplement_5).
  • Hyman D, Kummar S, Farago A, et al. Abstract CT127: phase I and expanded access experience of LOXO-195 (BAY 2731954), a selective next-generation TRK inhibitor (TRKi). Cancer Res. 2019;79(13 Supplement):CT127.
  • Drilon A, Cho BC, Kim D-W, et al. 444PDSafety and preliminary clinical activity of repotrectinib in patients with advanced ROS1/TRK fusion-positive solid tumors (TRIDENT-1 study). Ann Oncol. 2019;30(Supplement_5). DOI:10.1093/annonc/mdz244.006
  • Lindsay CR, Jamal-Hanjani M, Forster M, et al. KRAS: reasons for optimism in lung cancer. Eur J Cancer. 2018;99:20–27.
  • Janes MR, Zhang J, Li LS, et al. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell. 2018;172(3):578–589 e517.
  • Lindsay CR, Blackhall FH. Direct Ras G12C inhibitors: crossing the rubicon. Br J Cancer. 2019;121(3):197–198.
  • Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575:217–223.
  • Govindan R, Fakih M, Price T, et al. OA02.02 phase 1 study of safety, tolerability, PK and efficacy of AMG 510, a novel KRAS G12C inhibitor, evaluated in NSCLC. J Thorac Oncol. 2019;14(10):S208.
  • Govindan R, Fakih MG, Price TJ, et al. 446PDPhase I study of AMG 510, a novel molecule targeting KRAS G12C mutant solid tumours. Ann Oncol. 2019;30(Supplement_5):v163-v164.
  • Lise M, Pian PPD, Nitti D, et al. Colorectal metastases to the liver: present results and future strategies. J Surg Oncol. 1991;48(S2):69–73.
  • Bismuth H, Adam R, Navarro F, et al. Re-resection for colorectal liver metastasis. Surg Oncol Clin N Am. 1996;5(2):353–364.
  • Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008;371(9617):1007–1016.
  • Primrose J, Falk S, Finch-Jones M, et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial. Lancet Oncol. 2014;15(6):601–611.
  • Folprecht G, Grothey A, Alberts S, et al. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol. 2005;16(8):1311–1319.
  • Ye L-C, Liu T-S, Ren L, et al. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013;31(16):1931–1938.
  • Gruenberger T, Bridgewater J, Chau I, et al. Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial. Ann Oncol. 2014;26(4):702–708.
  • Ruers T, Punt CJA, Coevorden F, et al. Radiofrequency ablation (RFA) combined with chemotherapy for unresectable colorectal liver metastases (CRC LM): long-term survival results of a randomized phase II study of the EORTC-NCRI CCSG-ALM Intergroup 40004 (CLOCC). J Clin Oncol. 2015;33(15_suppl):3501.
  • van Hazel GA, Heinemann V, Sharma NK, et al. SIRFLOX: randomized phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. J Clin Oncol. 2016;34(15):1723–1731.
  • Wasan HS, Gibbs P, Sharma NK, et al. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017;18(9):1159–1171.
  • Saxena A, Bester L, Shan L, et al. A systematic review on the safety and efficacy of yttrium-90 radioembolization for unresectable, chemorefractory colorectal cancer liver metastases. J Cancer Res Clin Oncol. 2014;140(4):537–547.
  • Agolli L, Bracci S, Nicosia L, et al. Lung metastases treated with stereotactic ablative radiation therapy in oligometastatic colorectal cancer patients: outcomes and prognostic factors after long-term follow-up. Clin Colorectal Cancer. 2017;16(1):58–64.
  • Katz AW, Carey-Sampson M, Muhs AG, et al. Hypofractionated stereotactic body radiation therapy (SBRT) for limited hepatic metastases. Int J Radiat Oncol Biol Phys. 2007;67(3):793–798.
  • Chang DT, Swaminath A, Kozak M, et al. Stereotactic body radiotherapy for colorectal liver metastases: a pooled analysis. Cancer. 2011;117(17):4060–4069.
  • Elias D, Gilly F, Boutitie F, et al. Peritoneal colorectal carcinomatosis treated with surgery and perioperative intraperitoneal chemotherapy: retrospective analysis of 523 patients from a multicentric French study. J Clin Oncol. 2010;28(1):63–68.
  • Simkens GA, van Oudheusden TR, Braam HJ, et al. Treatment-related mortality after cytoreductive surgery and hipec in patients with colorectal peritoneal carcinomatosis is underestimated by conventional parameters. Ann Surg Oncol. 2016;23(1):99–105.
  • Yan TD, Zappa L, Edwards G, et al. Perioperative outcomes of cytoreductive surgery and perioperative intraperitoneal chemotherapy for non-appendiceal peritoneal carcinomatosis from a prospective database. J Surg Oncol. 2007;96(2):102–112.
  • Quenet F, Elias D, Roca L, et al. A UNICANCER phase III trial of hyperthermic intra-peritoneal chemotherapy (HIPEC) for colorectal peritoneal carcinomatosis (PC): PRODIGE 7. J Clin Oncol. 2018;36(18_suppl):LBA3503–LBA3503.
  • Seymour MT, Thompson LC, Wasan HS, et al. Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial. Lancet. 2011;377(9779):1749–1759.
  • Extermann M, Boler I, Reich RR, et al. Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score. Cancer. 2012;118(13):3377–3386.
  • Bellera CA, Rainfray M, Mathoulin-Pelissier S, et al. Screening older cancer patients: first evaluation of the G-8 geriatric screening tool. Ann Oncol. 2012;23(8):2166–2172.
  • Chong CY, Wong HL, Jalali A et al. Evolution of RAS mutation analysis in Australasian patients with metastatic colorectal cancer. 21st Australasian Gastrointestinal Trials Group Annual Scientific Meeting; 2019 Aug 21–23; Adelaide, Australia.
  • Wong HL, Christie M, Gately L, et al. Mismatch repair deficiency assessment by immunohistochemistry: for Lynch syndrome screening and beyond. Future Oncol. 2018;14(26):2725–2739.
  • Serebriiskii IG, Connelly C, Frampton G, et al. Comprehensive characterization of RAS mutations in colon and rectal cancers in old and young patients. Nat Commun. 2019;10(1):3722.
  • Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6(224):224ra224.
  • Willis J, Lefterova MI, Artyomenko A, et al. Validation of microsatellite instability detection using a comprehensive plasma-based genotyping panel. Clin Cancer Res. 2019;25(23):7035–7045.
  • Diaz Jr LA Jr, Williams RT, Wu J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012;486(7404):537–540.
  • 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.
  • Garlan F, Laurent-Puig P, Sefrioui D, et al. Early evaluation of circulating tumor DNA as marker of therapeutic efficacy in metastatic colorectal cancer patients (PLACOL study). Clin Cancer Res off J Am Assoc Cancer Res. 2017;23(18):5416–5425.
  • Spindler KL, Pallisgaard N, Vogelius I, et al. Quantitative cell-free DNA, KRAS, and BRAF mutations in plasma from patients with metastatic colorectal cancer during treatment with cetuximab and irinotecan. Clin Cancer Res off J Am Assoc Cancer Res. 2012;18(4):1177–1185.
  • Tie J, Kinde I, Wang Y, et al. Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann Oncol. 2015;26(8):1715–1722.
  • Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012;486(7404):532–536.
  • Cremolini C, Rossini D, Dell’Aquila E, et al. Rechallenge for patients with RAS and BRAF wild-type metastatic colorectal cancer with acquired resistance to first-line cetuximab and irinotecan: a phase 2 single-arm clinical trial. JAMA Oncol. 2019;5(3):343–350.
  • Tie J, Wang Y, Tomasetti C, et al. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med. 2016;8(346):346ra392–346ra392.
  • Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350–1356.
  • Stintzing S, Wirapati P, Lenz H-J, et al. Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial. American Society of Clinical Oncology; 2017.
  • Mooi JK, Wirapati P, Asher R, et al. The prognostic impact of consensus molecular subtypes (CMS) and its predictive effects for bevacizumab benefit in metastatic colorectal cancer: molecular analysis of the AGITG MAX clinical trial. Ann Oncol. 2018;29(11):2240–2246.
  • Lenz HJ, Ou FS, Venook AP, et al. Impact of consensus molecular subtype on survival in patients with metastatic colorectal cancer: results from CALGB/SWOG 80405 (alliance). J Clin Oncol. 2019;37(22):1876–1885.
  • Aderka D, Stintzing S, Heinemann V. Explaining the unexplainable: discrepancies in results from the CALGB/SWOG 80405 and FIRE-3 studies. Lancet Oncol. 2019;20(5):e274–e283.
  • Garrett WS. The gut microbiota and colon cancer. Science. 2019;364(6446):1133–1135.
  • Brennan CA, Garrett WS. Fusobacterium nucleatum - symbiont, opportunist and oncobacterium. Nat Rev Microbiol. 2019;17(3):156–166.
  • Arthur JC, Perez-Chanona E, Muhlbauer M, et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science. 2012;338(6103):120–123.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.