An overview of experimental and investigational multikinase inhibitors for the treatment of metastatic colorectal cancer

Bibliography

• Grothey A, Sargent D. Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single-agent therapy is used first line. J Clin Oncol 2005;23:9441–2
   PubMed Web of Science ®Google Scholar
• Sargent DJ, Kohne CH, Sanoff HK, et al. Pooled safety and efficacy analysis examining the effect of performance status on outcomes in nine first-line treatment trials using individual data from patients with metastatic colorectal cancer. J Clin Oncol 2009;27:1948–55
   PubMed Web of Science ®Google Scholar
• Grothey A, Sugrue MM, Purdie DM, et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin Oncol 2008;26:5326–34
   PubMed Web of Science ®Google Scholar
• Van Cutsem E, Rivera F, Berry S, et al. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol 2009;20:1842–7
   PubMed Web of Science ®Google Scholar
• Gallagher DJ, Kemeny N. Metastatic colorectal cancer: from improved survival to potential cure. Oncology 2010;78:237–48
   PubMed Web of Science ®Google Scholar
• 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;381:303–12
   PubMed Web of Science ®Google Scholar
• Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003;9:669–76
   PubMed Web of Science ®Google Scholar
• Sivakumar B, Harry LE, Paleolog EM. Modulating angiogenesis: more vs less. Jama 2004;292:972–7
   PubMed Web of Science ®Google Scholar
• Ellis LM. Mechanisms of action of bevacizumab as a component of therapy for metastatic colorectal cancer. Semin Oncol 2006;33:S1–7
   PubMed Web of Science ®Google Scholar
• Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 2008;8:579–91
   PubMed Web of Science ®Google Scholar
• 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;18:1004–12
   PubMed Web of Science ®Google Scholar
• 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;14:29–37
   PubMed Web of Science ®Google Scholar
• Lockhart AC, Rothenberg ML, Dupont J, et al. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. Am J Clin Oncol 2010;28:207–14
   PubMed Web of Science ®Google Scholar
• Tabernero J, Van Cutsem E, Lakomy R, et al. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer 2014;50:320–31
   PubMed Web of Science ®Google Scholar
• Pericay C, Folprecht G, Saunders M, et al. Phase 2 randomized, noncomparative, open-label study of aflibercept and modified FOLFOX6 in the first-line treatment of metastatic colorectal cancer (AFFIRM). Annals of Oncology. Oxford univ press; great clarendon st: Oxford OX2 6DP: England: 2012. p. 16–16
   Google Scholar
• Wilhelm SM, Dumas J, Adnane L, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer 2011;129:245–55
   PubMed Web of Science ®Google Scholar
• Kim T, Xu R, Yau T, et al. CONCUR: A ramdomized, placebo-controlled phase 3 study of regorafenib (Reg) monotherapy in asian patients with previously treated metastatic colorectal cancer (mCRC). Ann Oncol 2014;25:iv168–iv69
   Web of Science ®Google Scholar
• 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;381:303–12
   PubMed Web of Science ®Google Scholar
• Mross K, Frost A, Steinbild S, et al. A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin Cancer Res 2012;18:2658–67
   PubMed Web of Science ®Google Scholar
• Strumberg D, Scheulen ME, Schultheis B, et al. Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study. Br J Cancer 2012;106:1722–7
   PubMed Web of Science ®Google Scholar
• George S, Wang Q, Heinrich MC, et al. Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial. J Clin Oncol 2012;30:2401–7
   PubMed Web of Science ®Google Scholar
• Schultheis B, Folprecht G, Kuhlmann J, et al. Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study. Ann Oncol 2013;24:1560–7
   PubMed Web of Science ®Google Scholar
• Argilés G, Saunders MP, Rivera F, et al. Regorafenib plus modified FOLFOX6 as first-line treatment of metastatic colorectal cancer: A phase II trial. Eur J Cancer 2015;51:942–9
   PubMed Web of Science ®Google Scholar
• Clinicaltrials.gov. Study to determine the efficacy of regorafenib in metastatic colorectal cancer patients and to discover biomarkers. Available from: https://clinicaltrials.gov/ct2/show/NCT01949194?term=NCT01949194&rank=1 [Last Accessed 15 February 2015]
   Google Scholar
• Carrato A, Swieboda-Sadlej A, Staszewska-Skurczynska M, et al. Fluorouracil, leucovorin, and irinotecan plus either sunitinib or placebo in metastatic colorectal cancer: a randomized, phase III trial. J Clin Oncol 2013;31:1341–7
   PubMed Web of Science ®Google Scholar
• Hoff PM, Hochhaus A, Pestalozzi BC, et al. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol 2012;30:3596–603
   PubMed Web of Science ®Google Scholar
• Hecht JR, Trarbach T, Hainsworth JD, et al. Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol 2011;29:1997–2003
   PubMed Web of Science ®Google Scholar
• Tabernero J, Garcia-Carbonero R, Cassidy J, et al. Sorafenib in combination with oxaliplatin, leucovorin, and fluorouracil (modified FOLFOX6) as first-line treatment of metastatic colorectal cancer: the RESPECT trial. Clin Cancer Res 2013;19:2541–50
   PubMed Web of Science ®Google Scholar
• Clinicaltrials.gov. Leucovorin and fluorouracil with or without SU5416 in treating patients with metastatic colorectal cancer. Available from: https://clinicaltrials.gov/ct2/show/NCT00004252?term=%22semaxanib%22+and+%22colorectal%22&rank=1 [Last Accessed 15 February 2015]
   Google Scholar
• Stopeck A, Sheldon M, Vahedian M, et al. Results of a Phase I dose-escalating study of the antiangiogenic agent, SU5416, in patients with advanced malignancies. Clin Cancer Res 2002;8:2798–805
   PubMed Web of Science ®Google Scholar
• Rosen PJ, Amado R, Hecht JR, et al. Phase I/II Study of SU5416 in combination with 5-FU/Leucovorin in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol (Meeting Abstract) 2000;19:3a5D
   Google Scholar
• Koehne C, Bajetta E, Lin E, et al. Results of an interim analysis of a multinational randomized, double-blind, phase III study in patients (pts) with previously treated metastatic colorectal cancer (mCRC) receiving FOLFOX4 and PTK787/ZK 222584 (PTK/ZK) or placebo (CONFIRM 2). J Clin Oncol (Meeting Abstracts) 2006;24(Suppl 18):3508
   PubMed Web of Science ®Google Scholar
• Lee L, Sharma S, Morgan B, et al. Biomarkers for assessment of pharmacologic activity for a vascular endothelial growth factor (VEGF) receptor inhibitor, PTK787/ZK 222584 (PTK/ZK): translation of biological activity in a mouse melanoma metastasis model to phase I studies in patients with advanced colorectal cancer with liver metastases. Cancer Chemother Pharmacol 2006;57:761–71
   PubMed Web of Science ®Google Scholar
• Los M, Roodhart JM, Voest EE. Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer. Oncologist 2007;12:443–50
   PubMed Web of Science ®Google Scholar
• Schmoll HJ, Cunningham D, Sobrero A, et al. Cediranib with mFOLFOX6 versus bevacizumab with mFOLFOX6 as first-line treatment for patients with advanced colorectal cancer: a double-blind, randomized phase III study (HORIZON III). J Clin Oncol 2012;30:3588–95
   PubMed Web of Science ®Google Scholar
• Hoff PM, Hochhaus A, Pestalozzi BC, et al. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, Phase III study (HORIZON II). J Clin Oncol 2012;30(29):3596–603
   PubMed Web of Science ®Google Scholar
• Van Cutsem E, Bajetta E, Valle J, et al. Randomized, placebo-controlled, phase III study of oxaliplatin, fluorouracil, and leucovorin with or without PTK787/ZK 222584 in patients with previously treated metastatic colorectal adenocarcinoma. J Clin Oncol 2011;29:2004–10
   PubMed Web of Science ®Google Scholar
• Michael M, Zalcberg J, Gibbs P, et al. A phase I trial of imatinib in combination with mFOLFOX6-bevacizumab in patients with advanced colorectal cancer. Cancer Chemother Pharmacol 2013;71:321–30
   PubMed Web of Science ®Google Scholar
• Clinicaltrials.gov. Study to identify biomarkers of clinical response to aflibercept in patients with metastatic colorectal cancer. Available from: https://clinicaltrials.gov/ct2/show/NCT02045030?term=NCT02045030&rank=1 [Last Accessed 15 February 2015]
   Google Scholar
• Diaz R, Aparicio J, Girones R, et al. Analysis of prognostic factors and applicability of Kohne’s prognostic groups in patients with metastatic colorectal cancer treated with first-line irinotecan or oxaliplatin-based chemotherapy. Clin Colorectal Cancer 2005;5:197–202
   PubMedGoogle Scholar
• Watine J, Friedberg B. Laboratory variables and stratification of metastatic colorectal cancer patients: recommendations for therapeutic trials and for clinical practice guidelines. Clin Chim Acta 2004;345:1–15
   PubMed Web of Science ®Google Scholar
• Major P, Trarbach T, Lenz H, et al. A meta-analysis of two randomized, double-blind, placebo-controlled, phase III studies in patients (pts) with metastatic colorectal cancer (mCRC) receiving FOLFOX4 and PTK/ZK to determine clinical benefit on progression-free survival (PFS) in high LDH pts. ASCO Annual Meeting Proceedings; 2006. p. 3529
   Google Scholar
• Chun YS, Vauthey JN, Boonsirikamchai P, et al. Association of computed tomography morphologic criteria with pathologic response and survival in patients treated with bevacizumab for colorectal liver metastases. Jama 2009;302:2338–44
   PubMed Web of Science ®Google Scholar
• Stroobants S, Goeminne J, Seegers M, et al. 18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). Eur J Cancer 2003;39:2012–20
   PubMed Web of Science ®Google Scholar
• Morgan B, Thomas AL, Drevs J, et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J Clin Oncol 2003;21:3955–64
   PubMed Web of Science ®Google Scholar
• Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009;15:7412–20
   PubMed Web of Science ®Google Scholar
• Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol 2007;25:1753–9
   PubMed Web of Science ®Google Scholar
• Hu-Lowe DD, Zou HY, Grazzini ML, et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res 2008;14:7272–83
   PubMed Web of Science ®Google Scholar
• Infante JR, Reid TR, Cohn AL, et al. Axitinib and/or bevacizumab with modified FOLFOX-6 as first-line therapy for metastatic colorectal cancer: a randomized phase 2 study. Cancer 2013;119:2555–63
   PubMed Web of Science ®Google Scholar
• Bendell JC, Tournigand C, Swieboda-Sadlej A, et al. Axitinib or bevacizumab plus FOLFIRI or modified FOLFOX-6 after failure of first-line therapy for metastatic colorectal cancer: a randomized phase II study. Clin Colorectal Cancer 2013;12:239–47
   PubMed Web of Science ®Google Scholar
• Porebska I, Harlozinska A, Bojarowski T. Expression of the tyrosine kinase activity growth factor receptors (EGFR, ERB B2, ERB B3) in colorectal adenocarcinomas and adenomas. Tumour Biol 2000;21:105–15
   PubMed Web of Science ®Google Scholar
• Tong WM, Ellinger A, Sheinin Y, Cross HS. Epidermal growth factor receptor expression in primary cultured human colorectal carcinoma cells. Br J Cancer 1998;77:1792–8
   PubMed Web of Science ®Google Scholar
• Blick SK, Scott LJ. Cetuximab: a review of its use in squamous cell carcinoma of the head and neck and metastatic colorectal cancer. Drugs 2007;67:2585–607
   PubMed Web of Science ®Google Scholar
• Keating GM. Panitumumab: a review of its use in metastatic colorectal cancer. Drugs 2010;70:1059–78
   PubMed Web of Science ®Google Scholar
• 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;15:569–79
   PubMed Web of Science ®Google Scholar
• Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007;357:2040–8
   PubMed Web of Science ®Google Scholar
• Forbes SA, Beare D, Gunasekaran P, et al. COSMIC: exploring the world’s knowledge of somatic mutations in human cancer. Nucleic Acids Res 2015;43:D805–11
   PubMed Web of Science ®Google Scholar
• Peeters M, Price TJ, Cervantes A, et al. Final results from a randomized phase 3 study of FOLFIRI {+/-} panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol 2014;25:107–16
   PubMed 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;369:1023–34
   PubMed Web of Science ®Google Scholar
• Siena S, Sartore-Bianchi A, Trusolino L, et al. Trastuzumab and lapatinib in HER2-amplified metastatic colorectal cancer patients (mCRC): The HERACLES trial. J Clin Oncol (Meeting Abstracts) 2015;33(Suppl):abstract 3508
   Google Scholar
• Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507–16
   PubMed Web of Science ®Google Scholar
• Townsley CA, Major P, Siu LL, et al. Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer. Br J Cancer 2006;94:1136–43
   PubMed Web of Science ®Google Scholar
• Meyerhardt JA, Zhu AX, Enzinger PC, et al. Phase II study of capecitabine, oxaliplatin, and erlotinib in previously treated patients with metastastic colorectal cancer. J Clin Oncol 2006;24:1892–7
   PubMed Web of Science ®Google Scholar
• Kuo T, Cho CD, Halsey J, et al. Phase II study of gefitinib, fluorouracil, leucovorin, and oxaliplatin therapy in previously treated patients with metastatic colorectal cancer. J Clin Oncol 2005;23:5613–19
   PubMed Web of Science ®Google Scholar
• Fisher GA, Kuo T, Ramsey M, et al. A phase II study of gefitinib, 5-fluorouracil, leucovorin, and oxaliplatin in previously untreated patients with metastatic colorectal cancer. Clin Cancer Res 2008;14:7074–9
   PubMed Web of Science ®Google Scholar
• Pai R, Soreghan B, Szabo IL, et al. Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat Med 2002;8:289–93
   PubMed Web of Science ®Google Scholar
• Saif MW. Colorectal cancer in review: the role of the EGFR pathway. Expert Opin Investig Drugs 2010;19:357–69
   PubMed Web of Science ®Google Scholar
• Arteaga CL. ErbB-targeted therapeutic approaches in human cancer. Exp Cell Res 2003;284:122–30
   PubMed Web of Science ®Google Scholar
• Montagut C, Settleman J. Targeting the RAF-MEK-ERK pathway in cancer therapy. Cancer Lett 2009;283:125–34
   PubMed Web of Science ®Google Scholar
• Saif MW, Chu E. Biology of colorectal cancer. Cancer J 2010;16:196–201
   PubMed Web of Science ®Google Scholar
• Wang D, Boerner SA, Winkler JD, LoRusso PM. Clinical experience of MEK inhibitors in cancer therapy. Biochim Biophys Acta 2007;1773:1248–55
   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;29:1021–8
   PubMed Web of Science ®Google Scholar
• COSMIC: catalogue of somatic mutations in cancer. Available from: http://cancer.sanger.ac.uk/cosmic/browse/tissue#sn=large_intestine&ss=all&hn=all&sh=all&in=t&src=tissue&all_data=n [Last Accessed 15 February 2015]
   Google Scholar
• Carnero A. The PKB/AKT pathway in cancer. Curr Pharm Des 2010;16:34–44
   PubMed Web of Science ®Google Scholar
• Bendell JC, Nemunaitis J, Vukelja SJ, et al. Randomized placebo-controlled phase II trial of perifosine plus capecitabine as second- or third-line therapy in patients with metastatic colorectal cancer. J Clin Oncol 2011;29:4394–400
   PubMed Web of Science ®Google Scholar
• Bendell JC, Ervin TJ, Senzer NN, et al. Results of the X-PECT study: A phase III randomized double-blind, placebo-controlled study of perifosine plus capecitabine (P-CAP) versus placebo plus capecitabine (CAP) in patients (pts) with refractory metastatic colorectal cancer (mCRC). J Clin Oncol 2012;30:abstract LBA 3501
   Google Scholar
• Aligayer H, Boyd DD, Heiss MM, et al. Activation of Src kinase in primary colorectal carcinoma: an indicator of poor clinical prognosis. Cancer 2002;94:344–51
   PubMed Web of Science ®Google Scholar
• Ellis LM, Staley CA, Liu W, et al. Down-regulation of vascular endothelial growth factor in a human colon carcinoma cell line transfected with an antisense expression vector specific for c-src. J Biol Chem 1998;273:1052–7
   PubMed Web of Science ®Google Scholar
• Daud AI, Krishnamurthi SS, Saleh MN, et al. Phase I study of bosutinib, a src/abl tyrosine kinase inhibitor, administered to patients with advanced solid tumors. Clin Cancer Res 2012;18:1092–100
   PubMed Web of Science ®Google Scholar
• Sharma MR, Wroblewski K, Polite BN, et al. Dasatinib in previously treated metastatic colorectal cancer: a phase II trial of the University of Chicago Phase II Consortium. Invest New Drugs 2012;30:1211–15
   PubMed Web of Science ®Google Scholar
• Jain RK. Antiangiogenic therapy for cancer: current and emerging concepts. Oncology (Williston Park) 2005;19:7–16
   PubMedGoogle Scholar
• Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 2014;371:1877–88
   PubMed Web of Science ®Google Scholar
• Johnson DB, Flaherty KT, Weber JS, et al. Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. J Clin Oncol 2014;32:3697–704
   PubMed Web of Science ®Google Scholar
• Prahallad A, Sun C, Huang S, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 2012;483:100–3
   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;2:227–35
   PubMed Web of Science ®Google Scholar
• Siu LL, Shapiro JD, Jonker DJ, et al. Phase III randomized, placebo-controlled study of cetuximab plus brivanib alaninate versus cetuximab plus placebo in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal carcinoma: the NCIC Clinical Trials Group and AGITG CO.20 Trial. J Clin Oncol 2013;31:2477–84
   PubMed Web of Science ®Google Scholar
• Cai ZW, Zhang Y, Borzilleri RM, et al. Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4] triazin-6-yloxy)propan-2-yl)2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215). J Med Chem 2008;51:1976–80
   PubMed Web of Science ®Google Scholar
• Huynh H, Ngo VC, Fargnoli J, et al. Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma. Clin Cancer Res 2008;14:6146–53
   PubMed Web of Science ®Google Scholar
• Kopetz S, Hoff PM, Morris JS, et al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 2010;28:453–9
   PubMed Web of Science ®Google Scholar
• Weickhardt AJ, Price TJ, Chong G, et al. Dual targeting of the epidermal growth factor receptor using the combination of cetuximab and erlotinib: preclinical evaluation and results of the phase II DUX study in chemotherapy-refractory, advanced colorectal cancer. J Clin Oncol 2012;30:1505–12
   PubMed Web of Science ®Google Scholar
• Clinicaltrials.gov. Erlotinib hydrochloride and cetuximab in treating patients with advanced gastrointestinal cancer, head and neck cancer, non-small cell lung cancer, or colorectal cancer. Available from: https://clinicaltrials.gov/ct2/show/NCT00397384?term=NCT00397384&rank=1 [Last Accessed 15 February 2015]
   Google Scholar
• Clinicaltrials.gov. Dual targeting of EGFR with cetuximab and afatinib to treat refractory wtKRAS metastatic colorectal cancer. Available from: https://clinicaltrials.gov/ct2/show/NCT01919879?term=NCT01919879&rank=1 [ Last Accessed 15 February 2015]
   Google Scholar
• Pietras K, Hanahan D. A multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol 2005;23:939–52
   PubMed Web of Science ®Google Scholar
• Kelley RK, Hwang J, Magbanua MJ, et al. A phase 1 trial of imatinib, bevacizumab, and metronomic cyclophosphamide in advanced colorectal cancer. Br J Cancer 2013;109:1725–34
   PubMed Web of Science ®Google Scholar
• Johnsson A, Hagman H, Frodin JE, et al. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol 2013;24:2335–41
   PubMed Web of Science ®Google Scholar
• Tournigand C, Samson B, Scheithauer W, et al. Bevacizumab (Bev) with or without erlotinib as maintenance therapy, following induction first-line chemotherapy plus Bev, in patients (pts) with metastatic colorectal cancer (mCRC): Efficacy and safety results of the International GERCOR DREAM phase III trial. ASCO Annual Meeting Proceedings; 2012. p. LBA3500
   Google Scholar
• Clinicaltrials.gov. Avastin and chemotherapy followed by a KRAS stratified randomization to maintenance treatment for first line treatment of metastatic colorectal cancer. (ACT2). Available from: https://www.clinicaltrials.gov/ct2/show/NCT01229813?term=01229813&rank=1 [Accessed 15 February 2015]
   Google Scholar
• Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509–20
   PubMed Web of Science ®Google Scholar
• Kwilas AR, Donahue RN, Tsang KY, Hodge JW. Immune consequences of tyrosine kinase inhibitors that synergize with cancer immunotherapy. Cancer Cell Microenviron 2015;2
   Google Scholar