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Antiangiogenic-Based Combination Therapy ImprovesSurvival in Patients with Metastatic Colorectal Cancer: Role of Predictive Biomarkers in Patient SelectionMEsetdimiuamte:dOtnilminee to complete: 45 min To parti cipate in this activity online, go to www.mycme.com Released: November 2015 Expires: November 2016Introduction is characterized by an imbalance between factors promoting angiogenesis andColorectal cancer (CRC) is the third most antiangiogenesis,5 and results in an irregularcommon cancer in the United States with and leaky blood vessel endothelium.6approximately 132,700 new cases and an The microenvironment is acidotic withestimated 49,700 deaths annually.1 From decreased oxygen concentration due to2007 to 2011, the incidence of CRC has decreased ability to supply oxygen viadecreased at a rate of about 3.6% per tumor vessel.7 The vascular endothelialyear, with a similar decrease in deaths at growth factor (VEGF) signaling pathwayabout 2.6%-3% per year.1 However, the has been studied extensively in tumorincidence of CRC in developing countries biology. There are five glycoproteins inis increasing, and though the mortality the VEGF family (VEGF-A, VEGF-B,of CRC has decreased in recent years, VEGF-C, VEGF-D, and placental growththe overall 5-year survival for metastatic factor [PlGF]) and 3 tyrosine kinasecolorectal cancer (mCRC) remains poor receptors (VEGF receptor [VEGFR]-1at around 13%, with approximately 20% [FLT-1], VEGFR-2 [FLK-1/KDR], andof new cases presenting with metastatic VEGFR-3 [FLT-4]).8 The binding ofdisease.1 VEGFR-2 with VEGF-A has demonstrated angiogenesis in its promotion ofSince the approval of fluorouracil for CRC endothelial proliferation, survival, andin 1962 there was no other approved migration.9 VEGF and VEGFRs representcytotoxic chemotherapy until 2000, when two major targets for research. There havecapecitabine, oxaliplatin, and irinotecan been multiple approaches to targetingwere approved. Systemic chemotherapy the VEGF signaling pathway includingwith combination cytotoxic agents has been VEGF-A ligand binding, blockingthe standard of care in mCRC. Today’s VEGFR-2 with monoclonal antibodiesstandard regimens include infusional (MoAbs), and inhibition of tyrosineFOLFOX (fluorouracil, leucovorin, and kinases. Bevacizumab (MoAb targetingoxaliplatin), FOLFIRI (fluorouracil/ VEGF) was one of the first molecularleucovorin/irinotecan), FOLFOXIRI targeted agents to gain FDA approval for(fluorouracil/leucovorin/oxaliplatin/ mCRC (in 2004). Since then, regorafenibirinotecan), and XELOX (capecitabine (an oral multikinase inhibitor of VEGFR),with oxaliplatin).2,3 With the emergenceof new molecularly targeted agents, the This activity is supported by an educationalsurvival of patients with metastatic disease grant from Lilly USA, LLC.has showed improvement.Tumor AngiogenesisAngiogenesis is one of the major targetsfor these molecular agents. Angiogenesisis the formation of new blood vessels andis essential in normal tissue formation aswell as in tumorigenesis.4 Tumorigenesis

Antiangiogenic-Based Combination Therapy Improves Survival in Patients withMetastatic Colorectal Cancer: Role of Predictive Biomarkers in Patient Selectionaflibercept (a fusion protein targeting hypertension (4%-11%), gastrointestinalVEGF), and ramucirumab (MoAb targeting perforation (<1%-1.5%), and proteinuriaVEGFR-2) have also demonstrated efficacy (<1%) with the addition of bevacizumab toin targeting angiogenesis in mCRC. The conventional chemotherapy.12-14clinical benefits of these agents have led With the establishment of bevacizumab’sto questions on their timing, sequencing, efficacy, studies have emerged to answer keyuse as maintenance therapy, and the new questions of maintaining clinical benefit afterdevelopment of agents targeting the progression with bevacizumab-containingangiogenesis pathway in mCRC. regimens. The BRiTE and ARIES trials were two early observational studies that suggestedTargeting Angiogenesis benefit with the continuation of bevacizumabBevacizumab: beyond first progression of disease. In the large observational cohort BRiTE study,Bevacizumab is a humanized MoAb targeting the mOS was significantly improved forVEGF and has demonstrated promising the group receiving bevacizumab beyondpreclinical data with tumor growth inhibition progression compared to the chemotherapyin human tumors implanted into nude mice, alone after progression group (HR=0.48;with changes in vascular structure and noted P<0.001).15 Similarly, the ARIESdecreased vessel diameter, density, and observational cohort study demonstratedpermeability.10 In a phase II evaluation of improved OS with bevacizumab usagebevacizumab with fluorouracil/leucovorin beyond progression.16 The major criticismsversus fluorouracil/leucovorin in patients of these studies were their non-randomizedwith mCRC, the bevacizumab group and non-controlled design. The TML (MLdemonstrated promising results with high 18147) trial is the first randomized study toresponse, longer median time to disease address the role of continuing bevacizumabprogression, and longer median survival.11Based on the clinical benefit of this phaseII study, several phase III studies were after progression on first-line chemotherapyperformed and demonstrated improved containing bevacizumab.17 The phaseoverall survival (OS) with bevacizumab III study randomized 820 patients within combination with fluoropyrimidine- mCRC, who have progressed on first-linecontaining regimens.11,12 The pivotal phase bevacizumab-containing regimen to second-III trial on the addition of bevacizumab to line fluoropyrimidine-containing regimenbolus fluorouracil/leucovorin/irinotecan with or without bevacizumab at a 2.5 mg/kg(IFL) in chemotherapy-naive mCRC patients per week equivalent (5 mg/kg every 2 weeksdemonstrated an impressive survival benefit or 7.5 mg/kg every 3 weeks). The studywith median overall survival (mOS) from demonstrated a significant improvement in15.6 months to 20.3 months when compared the mOS, of 11.2 months in the bevacizumabto patients receiving IFL alone (P<0.001).12 group versus 9.8 months in the chemotherapy-At the same time, the ECOG (Eastern alone group (HR=0.81; P=0.0062), andCooperative Oncology Group) E3200 study median progression-free survival (mPFS),analyzed bevacizumab in combination of 5.7 months in the bevacizumab groupwith FOLFOX in the second-line setting in versus 4.1 months in the chemotherapy-alonepatients previously exposed to irinotecan but group (HR=0.68; P<0.0001; Figure 1). Therenot bevacizumab, which showed an increase was no significant increase in incidence ofin mOS from 10.8 months to 12.9 months bevacizumab-related grade 3-5 toxicities when compared with FOLFOX alone.13 with the continuation of bevacizumab2 Toxicities of grade ≥ 3 included hemorrhage beyond progression of disease.17 This trial(2%-3.4%), thromboembolism (3.4%-10%), provided evidence of the benefit and safety

Antiangiogenic-Based Combination Therapy Improves Survival in Patients withMetastatic Colorectal Cancer: Role of Predictive Biomarkers in Patient Selectionof using bevacizumab in combination with bevacizumab alone arm (HR=0.79;conventional chemotherapy beyond first- P=0.036). The most common gradeline exposure to bevacizumab-containing 3-4 toxicities observed were skinregimens in patients with mCRC. rash (21% in bevacizumab/erlotinib, none in bevacizumab alone), diarrheaBevacizumab in combination with erlotinib, (10% in the combination arm, <1%an epidermal growth factor receptor (EGFR) in bevacizumab alone), and asthenia.tyrosine kinase inhibitor, was studied in the This study suggests a potential roleGERCOR DREAM study, a phase III study for the combination of bevacizumabevaluating the role of maintenance therapy with erlotinib as maintenance therapyof the combination after first-line therapy in after first-line chemotherapy, but thepatients with mCRC.18 The study randomized application of this to current clinical224 patients to receive bevacizumab alone practice may be limited.(7.5 mg/kg every 3 weeks) and 222 patientsto receive bevacizumab with erlotinib Aflibercept:(bevacizumab at 7.5 mg/kg every 3 weeks,erlotinib at 150 mg/day) after completion of Aflibercept is a recombinant VEGFfirst-line therapy and without progression. The that binds to the domains of humanmedian follow-up was 51.0 months VEGFR 1/2 and the Fc portion offor the bevacizumab-alone arm and human IgG1 fusion protein, designed48.3 months in the bevacizumab/ to sequester VEGF and prevent it fromerlotinib arm. The mPFS was 5.4 binding to VEGFR.19 In the phasemonths in the bevacizumab/erlotinib III VELOUR trial, aflibercept wasarm as compared to 4.9 months studied in combination with FOLFIRI inwith bevacizumab alone (HR=0.81; mCRC patients who were previously treatedP=0.059). The mOS during the with oxaliplatin-containing regimens.20 Thefinal analysis were 24.9 months study randomized patients to receive eitherin the bevacizumab/erlotinib aflibercept (4 mg/kg; N=612) or placeboarm versus 22.1 months in the (N=614) in combination with FOLFIRI. The addition of aflibercept to FOLFIRI was noted to have a significant improvement of mOS at 13.5 months versus 12.1 months for the placebo group (HR=0.817; P=0.0032). The mPFS in the aflibercept arm was also significantly improved at 6.9 months versus 4.67 months for the placebo arm (HR=0.758; P<0.0001). Prespecified subgroup analysis demonstrated consistent effects on OS and PFS including among patients previously treated with bevacizumab (Table 1). Due to 3

Antiangiogenic-Based Combination Therapy Improves Survival in Patients withMetastatic Colorectal Cancer: Role of Predictive Biomarkers in Patient Selectionthe study not being powered to evaluate the for the use of regorafenib in patients withtreatment difference with regard to the benefit mCRC who have been previously treatedof aflibercept in the prior bevacizumab- with fluoropyrimidine-, oxaliplatin-, andtreated subgroup, it is difficult to draw a irinotecan-based chemotherapy, an anti-conclusion on its efficacy. Grade 3/4 adverse VEGF therapy, and (if KRAS wild-type) aneffects were noted to be slightly higher (2%) anti-EGFR therapy.25in the aflibercept arm with regard to diarrhea, Ramucirumab:asthenia, fatigue, stomatitis, infections, Ramucirumab is a fully human IgG1 MoAbhypertension, neutropenia, and proteinuria.21 that binds to the extracellular domain ofThese data led to the FDA approval of VEGFR-2 to inhibit proliferation and migrationaflibercept with FOLFIRI in August 2012 of endothelial cells. In a phase I study tofor patients with mCRC and progression evaluate safety, maximum-tolerated doseor resistance following an oxaliplatin- (MTD), pharmacokinetics, and anticancercontaining regimen. activity of ramucirumab, 37 patients withRegorafenib: advanced solid malignancies were givenRegorafenib is a novel oral multikinase ramucirumab and demonstrated an overallinhibitor of angiogenic, stromal, oncogenic, response rate (ORR) of 30% for at leastand intracellular signaling receptor kinases, 6 months. Dose-limiting toxicities wereincluding VEGFR-1/2/3, PDGFR-β, fibroblast hypertension and deep vein thrombosis.26growth factor receptor 1 (FGFR-1), TIE2, The efficacy of ramucirumab in mCRC wasc-KIT, RET, and BRAF.22,23 The approval of evaluated in the phase III RAISE trial.27 In thisregorafenib in the United States for mCRC double-blind randomized trial, 1072 patientswas based on results from the CORRECT who had disease progression during or aftertrial, an international, randomized, placebo- first-line therapy were randomized to receivecontrolled phase III trial evaluating ramucirumab (8 mg/kg every two weeks) orregorafenib in patients with mCRC who have placebo in combination with FOLFIRI untilprogressed through all standard regimens.24 disease progression or unacceptable toxicity.The study randomized 760 patients who had The mOS was improved with ramucirumabrefractory mCRC—including to anti-VEGF at 13.3 months versus 11.7 months forand anti-EGFR therapies—to receiveregorafenib (160 mg daily for 3 weeksand 1 week off; N=505) or placebo(N=255) with best supportive care.The study met its primary endpoint ofOS at a pre-planned interim analysisand demonstrated an improved mOSof 6.4 months with regorafenib versus5.0 months for placebo (HR=0.773;P=0.0052). Regorafenib also had animproved mPFS of 1.9 months versus1.7 months in the placebo group(HR=0.493; P<0.000001; Figure 2).The most common grade ≥ 3 adverseevents were hand-foot reaction(17%), fatigue (10%), diarrhea (7%), hypertension (7%), and skin rash (6%).4 Based on this study, the U.S. FDAgranted approval in September 2012

Antiangiogenic-Based Combination Therapy Improves Survival in Patients withMetastatic Colorectal Cancer: Role of Predictive Biomarkers in Patient Selectionpatients receiving placebo (HR=0.844; in mOS and mPFS. The toxicity profilesP=0.0219), and mPFS was also improved of these agents are relatively similar andwith ramucirumab at 5.7 months versus 4.5 manageable. These trials do bring up keymonths (HR=0.793; P<0.005; Figure 3). questions regarding the limited benefits in this therapy class. One approach may be utilizing certain patient selection criteria to determine which patients are likely to have the maximal benefit from therapy. One example of this is the emergence of KRAS testing in patients with CRC and the use of anti-EGFR therapy. Identification of biomarkers to predict sensitivity or resistance to VEGF signaling pathway inhibitors may potentially increase the clinical benefits of these agents. Currently there have been no specific approved biomarkers to help in selecting patients who would benefit from antiangiogenic- based regimen.Adverse events of grade ≥ 3 were noted as Several studies have attempted to 5neutropenia (38% for ramucirumab group address the identification of potentialvs. 23% for placebo), febrile neutropenia biomarkers. Pectasides and colleagues(3% vs. 2%), hypertension (11% vs. 3%), measured plasma concentrationsdiarrhea (11% vs. 10%), and fatigue (12% of nitric oxide (NO), osteopontinvs. 8%). The study populations were similar (OPN), transforming growth factor beta 1to typical clinical practice populations in (TGF-β1) and VEGF-A in patients receivingcontinuing antiangiogenic agents after irinotecan, capecitabine, and bevacizumabprogression on first-line antiangiogenesis (XELIRI-bevacizumab) or FOLFIRI withtherapy. The results from this study lead to bevacizumab and noted in a multivariateapproval by the U.S. FDA in April 2015 analysis that plasma OPN concentrationfor use in combination with FOLFIRI in had prognostic significance for OS andmCRC patients whose disease progressed on PFS.29 VEGF polymorphism has also beenfirst-line fluoropyrimidine-, oxaliplatin-, and evaluated in patients with mCRC receivingbevacizumab-containing regimen.28 irinotecan-based therapy with bevacizumab and suggested a potential predictive role ofPredictive Markers VEGF genotypes for response rate and OS.30 In animal models, VEGF(165)b, a VEGF-ALarge studies have demonstrated clinical splice form, has been noted to confer resistancebenefit, though limited, for antiangiogenic to bevacizumab.31 Low VEGF(165)b toagents in combination with standard cytotoxic VEGF(total) ratio was noted to be a potentialchemotherapy in mCRC. Interestingly, these predictive marker for bevacizumab benefitmolecular targeted agents—bevacizumab, in mCRC.32 Low pre-therapeutic serumaflibercept, regorafenib, and ramucirumab— angiopoietin-2 (Ang-2), an inhibitory ligandall have similar increments of improvement of the endothelial Tie-2 receptor, has been suggested to predict a better response rate, longer mPFS, and reduction in hazard of death in patients receiving bevacizumab-containing

Antiangiogenic-Based Combination Therapy Improves Survival in Patients with Metastatic Colorectal Cancer: Role of Predictive Biomarkers in Patient Selection therapy.33 Taking a step further, Liu and agents, and sequencing of these agents in colleagues evaluated 41 protein biomarkers order to maximize benefit. Development in 38 patients with mCRC receiving XELOX and identification of potential predictive with bevacizumab.34 They demonstrated biomarkers for VEGF signaling pathway baseline levels of vWF and Ang-2 correlated inhibitors may assist in maximizing the with PFS, and VCAM-1, vWF, TSP-2, IL-8, clinical benefits of these agents in addition MMP-2, and Ang-2 levels correlated with to improving cost-benefit ratios in the usage OS. The study identified baseline signatures of antiangiogenic agents. The potential (Ang-2, IGFBP-3, IL-6, and VCAM-1), combination of these antiangiogenic agents enabling stratification of patients into low- with immune checkpoint inhibitors and other risk and high-risk groups (mOS, 33.9 months molecular targeted agents is an exciting vs. 18.1 months, respectively; P = 0.016). area of research. We are moving in the right The team also identified biomarker signature direction with the increase in new agents for to evaluate treatment-related changes and mCRC, but there is room for improvement, stratify patients into low-risk and high-risk especially given today’s focus on precision groups (mPFS, 15.5 months vs. 7.7; P = medicine. 0.004; Figure 4). These translational studies References 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65(1):5-29. 2. Fakih MG. Metastatic colorectal cancer: Current state and future directions. J Clin Oncol 2015; 33(16):1809-1824. 3. PDQ Adult treatment editorial board. Colon cancer treatment (PDQ®): Health are promising and require further exploration professional version. In PDQ to help identify appropriate patient selection Cancer Information Summaries; National for antiangiogenic-based combinations, and Cancer Institute: Bethesda, MD, 2002. may increase scrutiny of cost-to-benefit 4. Folkman J. Tumor angiogenesis: ratios in the choice of antiangiogenic- Therapeutic implications. N Engl J Med based combinations for appropriate patient 1971; 285(21):1182-1186. subpopulations. 5. Jain RK. Normalization of tumor vasculature: An emerging concept in Conclusion antiangiogenic therapy. Science 2005; There have been numerous agents that have 307(5706):58-62. gained FDA approval for mCRC in recent 6. Hashizume H, Baluk P, Morikawa S, et al. years. The VEGF signaling pathway has been Openings between defective endothelial a significant target and contributed to recent cells explain tumor vessel leakiness. Am improvements in the treatment of patients J Pathol 2000; 156(4):1363-1380. with mCRC. The clinical benefits of these 7. Fukumura D, Duda DG, Munn LL, et agents elicit important clinical questions al. Tumor microvasculature and6 that have yet to be answered, including the microenvironment: Novel insights potential tumor resistance to antiangiogenic through intravital imaging in pre- agents, crossover tolerability of these clinical models. Microcirculation 2010;

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Antiangiogenic-Based Combination Therapy Improves Survival in Patients withMetastatic Colorectal Cancer: Role of Predictive Biomarkers in Patient Selection23. Mross K, Frost A, Steinbild S, et al. 30. Koutras AK, Antonacopoulou AG,A phase I dose-escalation study of Eleftheraki AG, et al. Vascularregorafenib (BAY 73-4506), an inhibitor endothelial growth factor polymorphismsof oncogenic, angiogenic, and stromal and clinical outcome in colorectalkinases, in patients with advanced cancer patients treated with irinotecan-solid tumors. Clin Cancer Res 2012; based chemotherapy and bevacizumab.18(9):2658-2667. Pharmacogenomics J 2012; 12(6):468-24. Grothey A, Cutsem EV, Sobrero A, 475.et al. Regorafenib monotherapy for 31. Varey AH, Rennel ES, Qiu Y, et al.previously treated metastatic colorectal VEGF 165 B, an antiangiogeniccancer (CORRECT): An international, VEGF-A isoform, binds and inhibitsmulticentre, randomised, placebo- bevacizumab treatment in experimentalcontrolled, phase 3 trial. The Lancet colorectal carcinoma: Balance of pro-2013; 381(9863):303-312. and antiangiogenic VEGF-A isoforms25. U.S. FDA. Regorafenib. Available at: http:// has implications for therapy. Br J Cancerwww.fda.gov/Drugs/InformationOnDrugs/ 2008; 98(8):1366-1379.A p p r o v e d D r u g s / u c m 3 2 1 3 7 8 . h t m . 32. Bates DO, Catalano PJ, Symonds KE,Accessed October 16, 2015. et al. Association between VEGF splice26. Spratlin JL, Cohen RB, Eadens M, et al. isoforms and progression-free survivalPhase I pharmacologic and biologic study in metastatic colorectal cancer patientsof ramucirumab (IMC-1121B), a fully treated with bevacizumab. Clin Cancerhuman immunoglobulin G1 monoclonal Res 2012; 18(22):6384-6391.antibody targeting the vascular endothelial 33. Goede V, Coutelle O, Neuneier J, et al.growth factor receptor-2. J Clin Oncol Identification of serum angiopoietin-22010; 28(5):780-787. as a biomarker for clinical outcome of27. Tabernero J, Yoshino T, Cohn AL, et colorectal cancer patients treated withal. Ramucirumab versus placebo in bevacizumab-containing therapy. Br Jcombination with second-line FOLFIRI Cancer 2010; 103(9):1407-1414.in patients with metastatic colorectal 34. Liu Y, Starr MD, Bulusu A, et al.carcinoma that progressed during or Correlation of angiogenic biomarkerafter first-line therapy with bevacizumab, signatures with clinical outcomes inoxaliplatin, and a fluoropyrimidine metastatic colorectal cancer patients(RAISE): A randomised, double-blind, receiving capecitabine, oxaliplatin,multicentre, phase 3 study. Lancet Oncol and bevacizumab. Cancer Med 2013;2015; 16(5):499-508. 2(2):234-242.28. National Cancer Institute. FDAApproval for Ramucirumab. Availableat: http://www.cancer.gov/about-cancer/treatment/drugs/fda-ramucirumab.Accessed October 16, 2015.29. Pectasides D, Papaxoinis G, KalogerasKT, et al. XELIRI-bevacizumab versusFOLFIRI-bevacizumab as first-linetreatment in patients with metastaticcolorectal cancer: A Hellenic cooperative oncology group phase III trial with8 collateral biomarker analysis. BMCCancer 2012; 12:271.