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The Evolution of Biomarkers to Guide the Treatment of Metastatic Colorectal Cancer
Lisa E. Davis, PharmD, FCCP, BCPS, BCOP
Participating Faculty

The Evolution of Biomarkers to Guide the Treatment of Metastatic Colorectal Cancer

Lisa E. Davis, PharmD, FCCP, BCPS, BCOP
Pembrolizumab and nivolumab were FDA approved in 2017 for the treatment of adult and pediatric patients with dMMR and MSI-H mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.33,34 Approval for each was by the accelerated pathway and continued approval is predicated on future trial results. The CheckMate 142 trial is evaluating nivolumab in 74 patients with MSI-H mCRC who received either single-agent nivolumab or nivolumab plus ipilimumab. Early results indicate that 31.3% of patients receiving nivolumab responded. Responses to nivolumab were seen in patients regardless of tumor PD-L1 expression, KRAS/BRAF mutation status, or clinical history (ie, Lynch syndrome).17,40 Nivolumab demonstrated durable responses as well as disease control in patients with dMMR/MSI-H mCRC and the treatment was well tolerated with no new safety issues.17,41 The trial is ongoing.17,41 For pembrolizumab, several small trial results were pooled, for a total of 149 patients with MSI-H cancers, of which 90 were CRC.40,42 Among the 90 patients with CRC, the objective response rate (ORR) was 36% (95 CI, 26%-46%) and lasted from  1.6 to 22.7 months.40,42

Atezolizumab targets PD-L1 and has been approved for previously treated non-small cell lung cancer and locally advanced or metastatic urothelial carcinoma.43 Atezolizumab is currently in several clinical trials for colorectal cancer in combination with targeted or chemotherapy regimens. Researchers of phase 3 clinical trials are investigating atezolizumab as a third-line treatment for mCRC as monotherapy or in combination with cobimetinib.44 Tremelimumab is in phase 1 (NCT03005002, NCT02754856, NCT03202758) and phase 2 (NCT03007407, NCT03122509, NCT03202758, NCT02870920, NCT02888743) clinical trials in combination with durvalumab for mCRC. Durvalumab targets PD-L1 and tremelimumab targets CTLA-4.44,45 Results presented at the 2018 Gastrointestinal Cancers Symposium demonstrated that in the phase 2 CheckMate 142 trial, the combination of nivolumab plus ipilimumab in patients with dMMR or MSI-H mCRC provided durable clinical benefits. The ORR was 55% at 12.4 months and the rate of disease control that persisted longer than 12 weeks was 80%.46

Pharmacists must be aware that the checkpoint inhibitors are associated with unique immune-related adverse effects and toxicities. Healthcare professionals who treat these patients must be able to adequately address the individual toxicities and provide patient management and care considerations. Additionally, immunotherapy takes longer to elicit responses as compared with chemotherapy. Therefore, patients may have stable disease or disease progression after initial treatment and before they observe clinical improvement.47 Table 6 lists the common immune-related toxicities and outlines an appropriate management approach.47

Additional Emerging Targeted and Immunotherapy Therapies

Other emerging targeted therapies include BRAF inhibitors (dabrafenib, vemurafenib, encorafenib), anti-fibroblast growth factor receptor (FGFR) agents (ponatinib, BGJ398), anti-RET agents (ponatinib, cabozantinib, vandetanib, apatinib, ponatinib, RXDX-105, sunitinib, sorafenib), anti-HER2 agents (sapitinib, neratinib, HER2 vaccine, trastuzumab, pertuzumab, lapatinib, tucatinib), and anti-hepatocyte growth factor receptor (HGFR) and the ligand c-MET (crizotinib, tivantinib, cabozantinib, INC280, AMG102, AV299).35,48 Most are being explored as single agents, but some are in trials as a component of combination therapies. Table 7 from Fellner 2017 outlines some of the promising drugs in development for mCRC.44

Both molecularly targeted agents such as encorafenib (LGX-818) + binimetinib (MEK-162), masitinib (AB-1010), napabucasin (BBI-608) as well as immunotherapies, such as atezolizumab and pembrolizumab, are being investigated as first-, second-, or third-line treatments (see Table 2).44 BRAF and MEK protein kinases are key in the MAPK signaling pathway. Encorafenib is an oral small-molecule selective BRAF inhibitor that is being investigated in combination with binimetinib, an oral small-molecule inhibitor of MEK1/2 for the second-line treatment of patients with BRAF-mutant mCRC. It is coadministered with cetuximab.44 Masitinib is an oral phenylaminothiazole-type tyrosine kinase inhibitor (TKI). It targets both the wild-type and mutated forms of c-Kit (stem cell factor receptor), platelet-derived growth factor receptor (PDGFR) alpha/beta, Lyn tyrosine kinase, and fibroblast growth factor receptor 3 (FGFR3).44,49 Napabucasin is an oral cancer agent that inhibits cancer stemness pathways that allow cancer stem cells to self-renew and differentiate into heterogenous cancer cells. It targets signal transducer and activator of transcription 3 (STAT3).44

Genomics-Driven Therapeutic Approaches

As next-generation sequencing of refractory tumors to inform therapeutic decision making outside of clinical trials continues, prescribers may identify actionable molecular alterations to support on- or off-label use of potentially beneficial targeted treatments. Common actionable targets include mutations in KRAS, CDKN2A/B, PIK3CA, FGFR, PTEN/AKT, and HER2, among others.50 Although the overall value of this approach remains unproven, reports and anecdotal experiences of patients benefiting from genomic-driven targeted therapy are encouraging, and off-label use of anticancer agents in this setting will likely continue to increase.51-55


Patients with unresectable mCRC remain incurable, with unsatisfactory survival rates, indicating a critical need to improve therapeutic outcomes. Recent advances in targeted therapy and immunotherapy represent meaningful progress in treatment strategies for advanced and mCRC; clinicians need to be familiar with genetic biomarkers that identify patients who are appropriate candidates for specific therapies. Progress in classifying CRC based on clinical and molecular features has led to a molecular subtype algorithm that may inform treatment decisions but is currently not recommended for clinical practice. Most recently, the angiogenesis inhibitor ramucirumab; trifluridine-tipiracil, a novel oral cytotoxic inhibitor of cell growth and proliferation; and PD-1 inhibitors nivolumab and pembrolizumab have demonstrated improved survival in selected settings and are now approved for patients with mCRC. The wide array of molecular alterations in mCRC has provided multiple therapeutic targets against which numerous emerging targeted therapies are currently in development.

Author affiliation: Professor, Department of Pharmacy Practice & Science, College of Pharmacy, University of Arizona, Tucson, AZ.
Funding source: Taiho Oncology, Inc.
Author disclosure: Dr Davis has no relevant financial relationships with commercial interests to disclose.
Authorship information: Concept and design, drafting of the manuscript, and critical revision of the manuscript for important intellectual content.
Address correspondence to:
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30.
doi: 10.3322/caac.21442.
2. Surveillance Research Program (SEER). Cancer stat facts: colorectal cancer. website. Accessed January 10, 2018.
3. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27(8):1386-1422. doi: 10.1093/annonc/mdw235.
4. Siegel RL, Miller KD, Jemal A. Colorectal cancer mortality rates in adults aged 20 to 54 years in the United States, 1970-2014. JAMA. 2017;318(6):572-574. doi: 10.1001/jama.2017.7630.
5. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30.
doi: 10.3322/caac.21387.
6. National Comprehensive Cancer Network. NCCN guidelines version 2.2018 March 14, 2018. Colon cancer. NCCN website. Accessed March 19, 2018.
7. Graham DM, Coyle VM, Kennedy RD, Wilson RH. Molecular subtypes and personalized therapy in metastatic colorectal cancer. Curr Colorectal Cancer Rep. 2016;12:141-150. doi:10.1007/s11888-016-0312-y.
8. Sepulveda AR, Hamilton SR, Allegra CJ, et al. Molecular biomarkers for the evaluation of colorectal cancer: guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology. J Clin Oncol. 2017;35(13):1453-1486. doi: 10.1200/JCO.2016.71.9807.
9. Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350-1356. doi: 10.1038/nm.3967.
10. Vakiani E, Janakiraman M, Shen R, et al. Comparative genomic analysis of primary versus metastatic colorectal carcinomas. J Clin Oncol. 2012;30(24):2956-2962. doi: 10.1200/JCO.2011.38.2994.
11. Molinari F, Frattini M. Functions and regulation of the PTEN gene in colorectal cancer. Front Oncol. 2013;3:326. doi: 10.3389/fonc.2013.00326.
12. Rodriguez-Salas N, Dominguez G, Barderas R, et al. Clinical relevance of colorectal cancer molecular subtypes. Crit Rev Oncol Hematol. 2017;109:9-19. doi: 10.1016/j.critrevonc.2016.11.007.
13. Linnekamp JF, van Hooff SR, Prasetyanti PR, et al. Consensus molecular subtypes of colorectal cancer are recapitulated in in vitro and in vivo models. Cell Death Differ. 2018;25:616-633. doi: 10.1038/s41418-017-0011-5. website. Updated March 19, 2018. Accessed March 19, 2018.
14. Michael-Robinson JM, Biemer-Hüttmann AE, Purdie DM, et al. Tumour infiltrating lymphocytes and apoptosis are independent features in colorectal cancer stratified according to microsatellite instability status. Gut. 2001;48(3):360-366.
15. Becht E, de Reynies A, Giraldo NA, et al. Immune and stromal classification of colorectal cancer is associated with molecular subtypes and relevant for precision immunotherapy. Clin Cancer Res. 2016;22(16):4057-4066. doi: 10.1158/1078-0432.CCR-15-2879.
16. 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. doi: 10.1056/NEJMoa1500596.
17. Ryan E, Sheahan K, Creavin B, Mohan HM, Winter DC. The current value of determining the mismatch repair status of colorectal cancer: a rationale for routine testing. Crit Rev Oncol Hematol. 2017;116:38-57. doi: 10.1016/j.critrevonc.2017.05.006.
18. Song N, Pogue-Geile KL, Gavin PG, et al. Clinical outcome from oxaliplatin treatment in stage II/III colon cancer according to intrinsic subtypes: secondary analysis of NSABP C-07/NRG oncology randomized clinical trial. JAMA Oncol. 2016;2(9):1162-1169. doi: 10.1001/jamaoncol.2016.2314.
19. 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. doi: 10.1016/S1470-2045(17)30422-9.
20. Yang AD, Fan F, Camp ER, et al. Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res. 2006;12(14 Pt 1):4147-4153. doi: 10.1158/1078-0432.CCR-06-0038.
21. Calon A, Lonardo E, Berenguer-Llergo A, et al. Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat Genet. 2015;47(4):320-329. doi: 10.1038/ng.3225.
22. Teufel M, Schwenke S, Seidel H, et al. Molecular subtypes and outcomes in regorafenib-treated patients with metastatic colorectal cancer (mCRC) enrolled in the CORRECT trial. J Clin Oncol. 2015;33(suppl 15):3558.
23. Chen J, Elfiky A, Han M, Chen C, Saif MW. The role of Src in colon cancer and its therapeutic implications. Clin Colorectal Cancer. 2014;13(1):5-13. doi: 10.1016/j.clcc.2013.10.003.
24. De Sousa EM, Wang X, Jansen M, et al. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat Med. 2013;19(5):614-618. doi: 10.1038/nm.3174.
25. National Comprehensive Cancer Network. NCCN guidelines version 1.2018. Rectal cancer. NCCN website. Accessed March 14, 2018.
26. McRee AJ, Goldberg RM. Optimal management of metastatic colorectal cancer: current status. Drugs. 2011;71(7):869-884. doi: 10.2165/11591770-000000000-00000.
27. Bhushan S, McLeod H, Walko CM. Role of pharmacogenetics as predictive biomarkers of response and/or toxicity in the treatment of colorectal cancer. Clin Colorectal Cancer. 2009;8(1):15-21. doi: 10.3816/CCC.2009.n.003.
28. Tol J, Punt CJ. Monoclonal antibodies in the treatment of metastatic colorectal cancer: a review. Clin Ther. 2010;32(3):437-453. doi: 10.1016/j.clinthera.2010.03.012.
29. Lin Z, Zhang Q, Luo W. Angiogenesis inhibitors as therapeutic agents in cancer: challenges and future directions. Eur J Pharmacol. 2016;793:76-81. doi: 10.1016/j.ejphar.2016.10.039.
30. Skårderud MR, Polk A, Vistisen KK, Larsen FO, Nielsen DL. Efficacy and safety of regorafenib in the treatment of metastatic colorectal cancer: a systematic review. Cancer Treat Rev. 2018;62:61-73. doi: 10.1016/j.ctrv.2017.10.011.
31. Cyramza [prescribing information]. Indianapolis, IN: Eli Lilly and Company; 2017. Accessed March 20, 2018.
32. Lonsurf [prescribing information]. Princeton, NJ: Taiho Oncology, Inc; 2017. Accessed March 20, 2018.
33. US Food and Drug Administration. FDA approves first cancer treatment for any solid tumor with a specific genetic feature. Accessed January 10, 2018.
34. US Food and Drug Administration. FDA grants nivolumab accelerated approval for MSI-H or dMMR colorectal cancer. FDA website. Accessed January 10, 2018.
35. Tabernero J, Yoshino T, Cohn AL, et al; RAISE Study Investigators. 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. doi: 10.1016/S1470-2045(15)70127-0.
36. Obermannova R, Van Cutsem E, Yoshino T, et al. Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression. Ann Oncol. 2016;27(11):2082-2090. doi: 10.1093/annonc/mdw402.
37. Mayer RJ, Van Cutsem E, Falcone A, et al; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909-1919. doi: 10.1056/NEJMoa1414325.
38. de Guillebon E, Roussille P, Frouin E, Tougeron D. Anti program death-1/anti program death-ligand 1 in digestive cancers. World J Gastrointest Oncol. 2015;7(8):95-101. doi: 10.4251/wjgo.v7.i8.95.
39. 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. doi: 10.1158/2159-8290.CD-14-0863.
40. Passardi A, Canale M, Valgiusti M, Ulivi P. Immune checkpoints as a target for colorectal cancer treatment. Int J Mol Sci. 2017;18(6):1324. doi: 10.3390/ijms18061324.
41. Overman MJ, Lonardi S, Leone F, et al. Nivolumab in patients with DNA mismatch repair deficient/microsatellite instability high metastatic colorectal cancer: update from CheckMate 142. J Clin Oncol. 2017;35(suppl 4): Abstract 519.
42. Lemery S, Keegan P, Pazdur R. First FDA approval agnostic of cancer site—when a biomarker defines the indication. N Engl J Med. 2017;377(15):1409-1412. doi: 10.1056/NEJMp1709968.
43. Tecentriq [prescribing information]. South San Francisco, CA: Genentech, Inc; 2017. Accessed March 20, 2018.
44. Fellner C. Promising drugs in clinical development to treat advanced colorectal cancer. P T. 2017;42(4):262-265.
45. Rizvi N, Chaft J, Balmanoukian A, et al. Tumor response from durvalumab (MEDI4736) + tremelimumab treatment in patients with advanced non-small cell lung cancer (NSCLC) is observed regardless of PD-L1 status. J Immunother Cancer. 2015;3(suppl 2):P193. doi: 10.1186/2051-1426-3-S2-P193.
46. Nivolumab, ipilimumab combo improves colorectal cancer outcomes. Specialty Pharmacy Times®. Published January 29, 2018. Accessed January 30, 2018.
47. Dine J, Gordon R, Shames Y, Kasler MK, Barton-Burke M. Immune checkpoint inhibitors: an innovation in immunotherapy for the treatment and management of patients with cancer. Asia Pac J Oncol Nurs. 2017;4(2):127-135. doi: 10.4103/apjon.apjon_4_17.
48. Ahn DH, Ciombor KK, Mikhail S, Bekaii-Saab T. Genomic diversity of colorectal cancer: changing landscape and emerging targets. World J Gastroenterol. 2016;22(25):5668-5677. doi: 10.3748/wjg.v22.i25.5668.
49. Dubreuil P, Letard S, Ciufolini M, et al. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PloS One. 2009;4(9):e7258. doi: 10.1371/journal.pone.0007258.
50. Sohal DP, Rini BI, Khorana AA, et al. Prospective clinical study of precision oncology in solid tumors. J Nat Cancer Inst. 2015;108(3). doi: 10.1093/jnci/djv332.
51. Parikh A, Atreya C, Korn WM, Venook AP. Prolonged response to HER2-directed therapy in a patient with HER2-amplified, rapidly progressive metastatic colorectal cancer. J Natl Compr Canc Netw. 2017;15(1):3-8.
52. Rodrigues HV, Ke D, Lim J, et al. Phase I combination of pazopanib and everolimus in PIK3CA mutation positive/PTEN loss patients with advanced solid tumors refractory to standard therapy. Invest New Drugs. 2015;33(3):700-709. doi: 10.1007/s10637-015-0238-2.
53. 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.
doi: 10.1200/JCO.2015.63.2471.
54. Martchenko K, Schmidtmann I, Thomaidis T, et al. Last line therapy with sorafenib in colorectal cancer: a retrospective analysis. World J Gastroenterol. 2016;22(23):5400-5405. doi: 10.3748/wjg.v22.i23.5400.
55. Ghiringhelli F, Richard C, Chevrier S, Végran F, Boidot R. Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein. World J Gastroenterol. 2016;22(48):10680-10686. doi: 10.3748/wjg.v22.i48.10680.
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