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Recognizing Patient Subtypes in Late-line Colorectal Cancer for Selection of Targeted Therapy
Hyunjee Song, 2018 PharmD Candidate, and Michael R. Page, PharmD, RPh
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Recognizing Patient Subtypes in Late-line Colorectal Cancer for Selection of Targeted Therapy

Hyunjee Song, 2018 PharmD Candidate, and Michael R. Page, PharmD, RPh
Targeted Therapy Agents: Anti-VEGF antibodies
Bevacizumab, a humanized monoclonal anti-VEGF antibody, has been associated with fewer dermal side effects than anti-EGFR antibodies and may thus be better tolerated by some patients.8 However, the results of several studies suggest that use of bevacizumab plus fluorouracil/leucovorin with or without irinotecan has shown clinical improvement in both OS and PFS in patients with colorectal liver metastases (CLM).3

In treatment of mCRC, bevacizumab was first approved in 2004 for use in combination with fluorouracil and leucovorin as first-line therapy in mCRC.9 This approval was based on study results showing that in patients with mCRC who failed first-line therapy with irinotecan-based regimens, the combination of bevacizumab and FOLFOX4 improved PFS and OS compared with FOLFOX4 monotherapy.10 Evidence for the addition of bevacizumab is stronger for patients receiving it with irinotecan-based regimens than with oxaliplatin-based regimens.9 As a result, although the evidence shows some benefit of bevacizumab plus FOLFOX4, use of this VEGF inhibitor in combination with oxaliplatin-based therapy is not currently considered first-line treatment for patients with CLM.3
 
Targeted Therapy Agents: Newer agents

Newer targeted therapy agents approved for use in mCRC include regorafenib (Stivarga), ramucirumab (Cyramza), and ziv-aflibercept (Zaltrap).
Regorafenib is a broad inhibitor of protein kinases, including kinases involved in tumor angiogenesis regulation, oncogenesis, and tumor microenvironment. Compared with best supportive care alone, regorafenib improves OS in patients with mCRC who previously received all available standard therapies. Regorafenib also has shown benefit in OS and PFS in patients with both colon cancer and rectal cancer; however, on both OS and PFS, the benefits of regorafenib appeared to be greater in patients with colon cancer versus patients with rectal cancer. Additionally, study results of patients from eastern Europe failed to demonstrate any difference between regorafenib and supportive care on PFS, which may have clinical relevance in treatment.11

Ramucirumab is a fully humanized monoclonal antibody that elicits antitumor activity by inhibiting VEGF, thereby inhibiting cell signaling and proliferation.12 In the RAISE study, which evaluated treatment with ramucirumab versus placebo in patients with mCRC receiving second-line FOLFIRI after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine, adding ramucirumab to FOLFIRI improved both OS and PFS relative to placebo.13

Ziv-aflibercept is a recombinant fusion protein that exerts anti-VEGF activity by binding to VEGF, thus preventing VEGF ligands from binding to endogenous receptors. In one study, the addition of ziv-aflibercept to FOLFIRI provided OS and PFS benefits in patients with mCRC who had received oxaliplatin-containing therapy. Ziv-aflibercept is the first agent to show an OS benefit in this patient population.14
 
Understanding Targeted Therapies Beyond Class Effects
Targeted therapies are part of a movement toward personalized medicine and more effective cancer treatment. The results of several phase 3 studies have shown PFS and OS benefits with the use of targeted treatments, either with chemotherapy alone or in patients who received prior therapies.15 However, to avoid overtreating patients, it is important to consider available regimens, patient-specific factors, and any background therapies. To treat patients in an evidence-based manner, it is important to consider treatment options based on the specific population for which a treatment has been studied rather than extrapolating data for one agent within a therapeutic class to all agents within that class.

Unlike chemotherapy, which acts broadly and indiscriminately, targeted therapies have the potential for less toxicity to healthy cells. To better manage cancer, which is characterized by heterogeneous tumors, targeted therapies may represent the most promising set of treatments. This is because cancers are prone to mutations, which may give rise to subclones that have an ever-changing set of molecular characteristics, even within a single patient. Effective targeted therapies should be used in the context of an understanding and comprehension of the generic and molecular characteristics of the tumor as well as of the important differences between treatments in the specific populations studied.16

1. Castellino A. Left vs. right: anatomic location matters for clinical outcomes in advanced colorectal cancer. American Society of Clinical Oncology website. am.asco.org/left-vs-right-anatomic-location-matters-clinical-outcomes-advanced-colorectal-cancer. Published June 7, 2016. Accessed July 14, 2017.
2. Wang F, Bai L, Liu TS, et al. Right- and left-sided colorectal cancers respond differently to cetuximab. Chin J Cancer. 2015;34(24):1-10. doi: 10.1186/s40880-015-0022-x.
3. Feng QY, Wei Y, Chen JW, et al. Anti-EGFR and anti-VEGF agents: important targeted therapies of colorectal liver metastases. World J Gastroenterol. 2014;20(15):4263-4275. doi: 10.3748/wjg.v20.i15.4263.
4. Krawczyk PA, Kowalski DM. Genetic and immune factors underlying the efficacy of cetuximab and panitumumab in the treatment of patients with metastatic colorectal cancer. Contemp Oncol (Pozn). 2014;18(1):7-16. doi: 10.5114/wo.2013.38566.
5. Hutchinson RA, Adams RA, McArt DG, Salto-Tellez M, Jasani B, Hamilton PW. Epidermal growth factor receptor immunohistochemistry: new opportunities in metastatic colorectal cancer. J Transl Med. 2015;13:217. doi: 10.1186/s12967-015-0531-z.
6. 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. doi: 10.1016/ S1470-2045(14)70118-4.
7. Mittman N, Au HJ, Tu D, et al; Working Group on Economic Analysis of National Cancer Institute of Canada Trials Group; Australasian Gastrointestinal Interest Group. Prospective cost-effectiveness analysis of cetuximab in metastatic colorectal cancer: evaluation of National Cancer Institute of Canada Clinical Trials Group CO.17 trial. J Natl Cancer Inst. 2009;101(17):1182-1192. doi: 10.1093/jnci/djp232.
8.  Hagan S, Orr MC, Doyle B. Targeted therapies in colorectal cancer-an integrative view by PPPM. EPMA J. 2013;4(1):3. doi: 10.1186/1878-5085-4-3.
9. Koukourakis GV, Sotiropoulou-Lontou A. Targeted therapy with bevacizumab (Avastin) for metastatic colorectal cancer. Clin Trasnl Oncol. 2011;13(10):710-714. doi: 10.1007/s12094-011-0720-z.
10. Yildiz R, Buyukberber S, Uner A, et al. Bevacizumab plus irinotecan-based therapy in metastatic colorectal cancer patients previously treated with oxaliplatin-based regimens. Cancer Invest. 2010;28(1):33-37. doi: 10.3109/07357900802562996.
11. Grothey A, Van Cutsem E, Sobrero A, et al; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312. doi: 10.1016/S0140-6736(12)61900-X.
12. ElHalawani H, Abdel-Rahman O. Critical evaluation of ramucirumab in the treatment of advanced gastric and gastroesophageal cancers. Ther Clin Risk Manag. 2015;11:1123-1132. doi: 10.2147/TCRM.S71045.
13. 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 [erratum in Lancet Oncol. 2015;16(6):e262. doi: 10.1016/S1470-2045(15)70273-1c]. Lancet Oncol. 2015;16(5):499-508.
14. 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. doi: 10.1200/JCO.2012.42.8201.
15. Camidge DR. Targeted therapy vs chemotherapy: which has had more impact on survival in lung cancer? does targeted therapy make patients live longer? Hard to prove, but impossible to ignore. Clin Adv Hemat Oncol. 2014;12(11):763-766.
16. Joo WD, Visintin I, Mor G. Targeted cancer therapy—are the days of systemic chemotherapy numbered? Maturitas. 2013;76(4):308-314. doi: 10.1016/j.maturitas.2013.09.008.
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