Targeted Therapies for Colorectal Cancer in the Adjuvant Setting: Are You Already Doing This Without the Data?

Table of Contents:Earn Continuing Medical Education CreditA Word From the EditorIntroductionBackgroundTargeted Agents in the Adjuvant SettingRationale for the Use of Anti-VEGF Antibody in the Adjuvant SettingRationale for the Use of Anti-EGFR Antibodies in the Adjuvant SettingTargeted Agents Successfully Used in Other Adjuvant SettingsTo Use or Not To Use Antibodies in the Adjuvant Treatment of Resected Colorectal Cancer Key PointsReferencesCONTINUING MEDICAL EDUCATION Activity Release Date: October 1, 2008 Activity Expiration Date: October 1, 2009 About the Activity This activity is based on a brief article developed as part of the E-Update Series and posted on the Web. It was developed from an identified educational need for information about practical management issues in the practice of medical, surgical, and radiation oncology. This activity has been developed and approved under the direction of CME LLC. After completing this series of activities, the clinician should be able to: (1) Demonstrate knowledge of the phase III studies that have established a role for biologic agents in the metastatic setting, and be able to incorporate a game plan, tailored to the individual, using biologic agents and chemotherapy in this setting (2) Demonstrate knowledge of adjuvant studies of biologic agents, the biologic agents already approved in the metastatic setting, the possible use of biomarkers, and next generation targets and agents (3) Apply a solid treatment strategy when dealing with toxicity issues resulting from biologic therapy (4) Appraise the use of dual targeted therapy (EGFR and VEGF) Target Audience This activity targets physicians in the fields of oncology and hematology. Accreditation This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of CME LLC and The Oncology Group. CME LLC is accredited by the ACCME to provide continuing medical education for physicians. Continuing Education CreditAMA PRA Category 1 Credit™ . CME LLC designates this educational activity for a maximum of 2 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Compliance Statement This activity is an independent educational activity under the direction of CME LLC. The activity was planned and implemented in accordance with the Essential Areas and policies of the ACCME, the Ethical Opinions/Guidelines of the AMA, the FDA, the OIG, and the PhRMA Code on Interactions with Healthcare Professionals, thus assuring the highest degree of independence, fair balance, scientific rigor, and objectivity. However, CME LLC, the Grantor, and CMPMedica shall in no way be liable for the currency of information or for any errors, omissions, or inaccuracies in the activity. Discussions concerning drugs, dosages, and procedures may reflect the clinical experience of the author(s) or may be derived from the professional literature or other sources and may suggest uses that are investigational in nature and not approved labeling or indications. Activity participants are encouraged to refer to primary references or full prescribing information resources. The opinions and recommendations presented herein are those of the author(s) and do not necessarily reflect the views of the provider or producer. Financial Disclosures Dr. Marshall has acted as a speaker for, received research support from, and acted as a consultant for Roche, Sanofi, Pfizer, Genentech, Bristol-Myers Squibb, and Amgen. Dr. Helft has served on the speakers bureau for Sanofi-Aventis and Genentech; and has acted as a consultant for Sanofi-Aventis. Copyright Copyrights owned by CME LLC. Copyright © 2008. All rights reserved. Contact Information We would like to hear your comments regarding this or other activities provided by CME LLC. In addition, suggestions for future activities are welcome. Contact us at: Director of Continuing Education CME LLC Harborside Financial Center Plaza 3, Suite #806 Jersey City, NJ 07311 Phone: 888-618-5781

Dear Colleague: Do you like to be an innovator, to be the first, or among the first, to try a new device or add a new chemotherapy drug because it seems like the right thing to do? Certainly I was. I have given my share of adjuvant IFL and used to recommend bone marrow transplant to breast cancer patients. My experience has made me aware that many of us have added biologics to the adjuvant setting and yet currently there is no data to support doing. So why do we do it? Are we hoping for more and willing to take the risk? In this fourth and final edition of our E-Update series on “Targeted Therapy in Colorectal Cancer,” Paul R. Helft, MD, of Indiana University School of Medicine, reviews the adjuvant data with regards to biologics so that we might all rethink our current practices in the context of the latest data. When you click on the links below, you will find Dr. Helft’s useful and balanced discussion entitled, "Targeted Therapies for Colorectal Cancer in the Adjuvant Setting: Are You Already Doing This Without the Data?" I encourage you to take time from your busy schedule to review this contribution from Dr. Helft. It will be time well spent. New patients present with new challenges, and the knowledge we gain today will help us to better serve our patients in the future. After reading this E-Update, you will have an opportunity to earn 2 Continuing Medical Education credits online at no cost. This and the previous three online educational activities in our “Targeted Therapy in Colorectal Cancer” E-Update series are designed to provide you, the practicing community oncologist, with the most up-to-date clinical strategies for treating your patients with metastatic colorectal cancer. Colorectal cancer is the second leading cause of cancer-related mortality; this year alone it will account for the deaths of approximately 50,000 persons in the United States. Further, more than 800,000 new cases of colorectal cancer will be identified worldwide. Though the 5-year survival rate for patients diagnosed with later stage metastatic disease remains dismal, advances have been observed in recent years with the development of novel cytotoxic and biologic agents. I hope you have found this series worthwhile overall, and we look forward to continuing it next year. Best regards, John L. Marshall, MD Chief, Division of Hematology and Oncology Lombardi Comprehensive Cancer Center Georgetown University Washington, DC Introduction Despite advances in endoscopic and other screening techniques, less than half of US adults at risk for colorectal cancer undergo adequate screening. As a consequence, approximately half of all new cases of colorectal cancer are diagnosed in later stages. In 2007, the American Cancer Society estimated that 153,760 new cases of colorectal cancer were diagnosed, and 52,180 adults in the United States died from this disease.[1] For decades, fluorouracil remained the only beneficial drug for the treatment of colorectal cancer, but the past decade has seen major additions to the clinical armamentarium, including new cytotoxic agents and three monoclonal antibodies. These new medicines have demonstrated proven benefits for patients with metastatic colorectal cancer; however, no targeted agent has yet been proven to provide meaningful benefits in the setting of surgical adjuvant therapy. Anecdotally, clinicians have begun to use antibodies in addition to chemotherapy, probably for high-risk patients with resected colorectal cancer. This E-Update examines the question of whether such a practice makes sense. Background Approximately 20% of diagnosed cases of colorectal cancer have overt evidence of metastatic spread at diagnosis. Patients whose macroscopic disease has been resected surgically remain at risk for recurrence, a result of viable tumor cells that have metastasized prior to surgery but are undetectable using current techniques. The goal of administering adjuvant chemotherapy after a presumed curative operation is to eradicate these so-called micrometastases before they are able to grow into viable tumors. The history of adjuvant chemotherapy for colon cancer dates back at least three decades, with fluorouracil (5-FU) being the primary cytotoxic agent used since it was patented in 1957. Early trials of 5-FU used in the surgical adjuvant setting for resected colon cancer were underpowered and, as a consequence, demonstrating the superiority of 5-FU-based regimens over observation was difficult. In 1988, Buyse et al performed a meta-analysis of all randomized, controlled trials of adjuvant therapy for colorectal cancer. The results of trials assessing the roles of radiotherapy and/or chemotherapy were combined and demonstrated, at best, only a marginal survival benefit in trials utilizing 5-FU-based regimens.[2] The pivotal study, published by Charles Moertel in 1990,[3] demonstrated improved overall survival (OS) and disease-free survival (DFS) for 12 months of treatment with bolus 5-FU and levamisole (Ergamisol), and led to the first National Cancer Institute (NCI) consensus recommendation for stage III colon cancer.[4] Intergroup (INT) 0089 assessed the relative contributions of leucovorin and levamisole, as well as shorter vs longer durations of therapy, in this group of patients.[5] The final report of this study found no statistical differences among any of the treatment arms after adjustment for multiple comparisons, demonstrating that 6 to 8 months of adjuvant therapy provided equal benefit as longer durations, and that low dose leucovorin was equivalent to high dose leucovorin. This study defined the North American standard of care for many years, until the results of the Multi-center International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial were reported. [6] The results of this study led to the US Food and Drug Administration (FDA) approval in 2004 of oxaliplatin (Eloxatin) in addition to bolus and infusional 5-FU and leucovorin (FOLFOX) for the adjuvant therapy of stage III colon cancer. The approval was based on demonstration of the statistical superiority of FOLFOX to infusional plus bolus 5-FU/leucovorin (LV5FU2 regimen) in 3-year and 4-year DFS in the subgroup of patients with stage III colon cancer.[7] The FOLFOX regimen thus became the standard adjuvant treatment for stage III colon cancer patients and has remained so since 2004. For a summary of these trials, see Table 1. Table 1. Early Trials of Adjuvant Chemotherapy for Colon Cancer

DFS = disease-free survival; 5-FU = fluorouracil; FOLFOX = fluorouracil, leucovorin, oxaliplatin; MOSAIC = Multi-center International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer; OS = overall survival Targeted Agents in the Adjuvant Setting Options for treating colorectal cancer patients with advanced disease have expanded in recent years with the FDA’s approval of three monoclonal antibodies. The humanized antivascular endothelial growth factor monoclonal antibody bevacizumab (Avastin), and the chimeric antiepidermal growth factor receptor antibody cetuximab (Erbitux) were approved in February 2004. The humanized antiepidermal growth factor receptor antibody panitumumab (Vectibix) was approved in September 2006. These antibodies, used in patients with metastatic colorectal cancer in both first-line and later settings, and alone and in combination, have all been subjects of active investigation. Following success in treating patients with metastatic colorectal cancer, several trials were designed and began accrual since early 2004 (Table 2). One large North American study of FOLFOX with or without bevacizumab for the adjuvant treatment of patients with resected stage II and III colon cancer was launched in February 2004 and has now completed accrual. Known as C-08, this trial of more than 2,700 patients is intended to compare 3-year DFS among patients treated with and without bevacizumab. Interim safety data from C-08 were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in 2008. The interim safety analysis showed no new or unexpected safety events in the bevacizumab-containing arm of the trial. The incidence of noncancer-related deaths was similar between the treatment arms and consistent with prior phase III adjuvant colon cancer trials. No significant increases in gastrointestinal (GI) perforation, hemorrhage, arterial or venous thrombotic events, or deaths were observed in the bevacizumab arm.[8] A second study of bevacizumab in the adjuvant setting is a randomized, phase III, multinational study consisting of 3,450 patients with high risk stage II or III colon cancer at 350 centers in 36 countries. This study, known as AVANT, seeks to compare DFS among three treatment regimens: FOLFOX with or without bevacizumab, and XELOX, the combination of oxaliplatin and oral capecitabine (Xeloda), with bevacizumab. Initial data from this study are expected in late 2008. Finally, the Eastern Cooperative Oncology Group study E5202 seeks to compare 3-year DFS in 3,438 high risk stage II patients randomly assigned to FOLFOX or FOLFOX plus bevacizumab. As with bevacizumab, the rationale for anti-EGFR therapy and the success of cetuximab in advanced colorectal cancer have led to research into the use of cetuximab in the adjuvant setting. At this time, there is one phase III study ongoing in North America. The North Central Cancer Treatment Group (NCCTG) launchedN0147 in February 2004. This trial began as a randomized phase III trial comparing three different chemotherapy regimens with or without cetuximab in patients with completely resected stage III colon cancer. However, after regimens containing oxaliplatin were demonstrated to be more effective than regimens containing irinotecan (CPT-11, Camptosar), the trial was modified, and all irinotecan-containing arms were closed as of June 2005.[9] The modified trial compares FOLFOX with or without cetuximab. The study is expected to enroll 2,648 patients and is designed to assess 3-year DFS as the primary endpoint. The Pan-European group is also examining the benefits to 3-year DFS of the addition of adjuvant cetuximab to FOLFOX in the Pan-European Trials in Adjuvant Colon Cancer (PETACC)-8. Planned recruitment through November 2008 aims to accrue 1,900 patients. Although initial toxicity data from NSABP C-08 have been reported, no efficacy data from any of these adjuvant trials examining the impact of antibody therapy added to chemotherapy have been reported, and thus proof that these targeted agents add to the benefits achieved with 5-FU and oxaliplatin in the adjuvant setting remains to be established. Table 2.Ongoing Trials of Targeted Agents for Treating Metastatic Colorectal Cancer in the Adjuvant Setting

DFS = disease-free survival; ECOG = Eastern Cooperative Oncology Group; FOLFOX = fluorouracil, leucovorin, oxaliplatin; NCCTG = North Central Cancer Treatment Group; PETACC = Pan-European Trials in Adjuvant Colon Cancer; XELOX = oxaliplatin, oral capecitabine Rationale for the Use of Anti-VEGF Antibody in the Adjuvant Setting The idea that tumor-derived factors could promote necessary new blood vessel growth was postulated more than half a century ago.[10] Algire and colleagues then suggested that tumor growth might be uniquely dependent on the development of a neovasculature.[11] Folkman subsequently hypothesized in the early 1970s that inhibition of the process of angiogenesis could play a role in treating human cancers.[12] Extensive research has led to the identification and isolation of several regulators of angiogenesis, some of which represent therapeutic targets. It is widely agreed that vascular endothelial growth factor (VEGF) signaling is a crucial rate-limiting step in physiological angiogenesis, and seems to be important to tumor angiogenesis as well. VEGF expression has been demonstrated to be upregulated in a large number of human tumor types,[13, 14] and oncogenic mutations or amplification of RAS have been associated with VEGF upregulation.[15] Each of these important discoveries validated VEGF as an important target for tumor angiogenesis, and led to the pursuit of clinically relevant agents, such as monoclonal antibodies targeting VEGF, as well as small molecules that inhibit VEGF-receptor signaling, antisense oligonucleotides, and antibodies against FLK1. The first proof that angiogenesis inhibition could lead to important clinical benefits was seen in a phase III clinical trial of untreated metastatic colorectal cancer patients. This trial, known as AVF2107, demonstrated a superior overall median survival in patients treated with 5-FU/leucovorin, irinotecan, and bevacizumab over those treated with 5-FU and irinotecan alone.[16] Since then, bevacizumab has been shown to increase the median survival of patients with metastatic non-small-cell lung cancer when combined with chemotherapy, and to increase progression-free survival in patients with untreated metastatic breast cancer. More recently, bevacizumab combined with irinotecan has shown a promising response rate and 6-month overall survival in patients with glioblastoma multiforme.[17] Despite these major therapeutic advances and the proof of principle that has come with the use of antiangiogenic antibody therapy, no trial has yet demonstrated a clinically meaningful benefit for any relevant endpoint in the setting of adjuvant therapy for completely resected solid tumors. Moreover, whether micrometastases that have spread prior to surgical removal of a cancer are dependent upon a neovasculature-and thus may be subject to the effects of VEGF inhibition-or whether they may be able to derive necessary nutrients from their microenvironment in the absence of recruited neovessels, making their survival independent of angiogenic signals, remains an unanswered question. Rationale for the Use of Anti-EGFR Antibodies in the Adjuvant Setting Transforming growth factor (TGF) alpha has been identified as a key modulator in the process of cell proliferation in both normal and malignant epithelial cells. TGF alpha binds to its specific cell membrane receptor, the epidermal growth factor receptor (EGFR), with subsequent activation of the EGFR tyrosine kinase enzymatic activity that triggers the intracellular signaling pathway.[18,19] The EGFR is part of a subfamily of four closely related receptors: EGFR (or ErbB-1), HER2/neu (ErbB-2), HER3 (ErbB-3), and HER4 (ErbB-4).[20,21] EGFR signaling appears to play a significant role in processes critical to cancer progression, including cell proliferation, angiogenesis, metastatic spread, and the inhibition of apoptosis.[22] In addition, overexpression of EGFR has implications for therapeutics, having also been associated with resistance to hormonal therapy, cytotoxic agents, and radiotherapy.[23,24,25] Thus, EGFR is clearly a rational target for cancer therapeutics. Monoclonal antibodies primarily directed at the extracellular domain of the EGFR and small molecule inhibitors of the EGFR tyrosine kinase have represented the two most promising therapeutic approaches. Although no small molecule tyrosine kinase inhibitors have yet to demonstrate meaningful clinical benefit in colorectal cancer patients, the FDA approved the chimeric monoclonal anti-EGFR antibody, cetuximab, in February 2004, and the humanized monoclonal anti-EGFR antibody, panitumumab, in September 2006, both for the treatment of refractory disease. Both antibodies have demonstrated superior DFS and overall survival in patients with refractory colorectal cancer, compared to best supportive care.[26, 27] For both mechanistic reasons and reasons of rational therapeutics, using anti-EGFR antibodies as a component of adjuvant therapy makes good scientific and clinical sense; however, definitive evidence regarding their actual benefit is lacking. The Intergroup trial N0147, which includes cetuximab in a randomized study design, has had trouble accruing patients. This is partially because of competition with NSABP C-08, which was accruing an overlapping group of patients simultaneously, and partially because trial design changes, necessitated by emerging evidence regarding the differential benefits of oxaliplatin vs irinotecan, led to delays. Targeted Agents Successfully Used in Other Adjuvant Settings There is evidence in other adjuvant settings that in some cases, targeted agents can lead to dramatic benefits. The most notable of these is in patients with HER2/neu-positive breast cancer. The humanized monoclonal antibody trastuzumab (Herceptin) was approved by the FDA in September 1998 for the treatment of metastatic breast cancer patients whose tumors overexpress the HER2 (human epidermal growth factor receptor 2) protein. On January 18, 2008, the FDA approved trastuzumab as a single agent for the adjuvant treatment of HER2–overexpressing, node-negative (estrogen receptor-negative/progesterone receptor-negative or with one high-risk feature) or node-positive breast cancer for use after the completion of multimodality, anthracycline-based therapy. This approval was based on the Herceptin Adjuvant (HERA) trial, as well as results of the NSABP B31 trial and the NCCTG N9831 trial. In this select group of HER-2 overexpressing breast cancer patients in these trials, the addition of trastuzumab to their adjuvant therapy led to an approximate 50% percent improvement in disease-free survival. Another striking example of a successful use of a targeted agent in the surgical adjuvant setting is the use of imatinib (Gleevec) following complete resection of gastrointestinal stromal tumors (GIST). Imatinib mesylate is an oral, small molecule protein-tyrosine kinase inhibitor that inhibits the Bcr-Abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in chronic myeloid leukemia (CML). More than 90% percent of GIST tumors have mutations in one of two genes, called KIT and PDGFRα. Imatinib targets both of these mutated genes. The American College of Surgeons Oncology Group (ACOSOG) trial Z9001 examined the benefits of adjuvant imatinib vs observation in a randomized, phase III, double blind, placebo controlled trial of 708 patients with completely resected GIST greater than 3 cm and expressing KIT. Accrual to the trial was halted based on a recommendation of the ACOSOG External Data Monitoring Committee based on the results of a planned interim analysis of 644 evaluable patients. Patients assigned to the imatinib arm had a 1-year recurrence-free survival (RFS) of 97%, while those assigned to the placebo arm had a 1-year RFS of 83%, with a hazard ratio of 0.325 (95% confidence interval [CI]: 0.198-0.534), and a nominal unadjusted log-rank P value of .0000014.[28] Although there remain questions about whether adjuvant imatinib actually lowers the risks of recurrence or merely delays recurrence, these results in a large, prospective, randomized trial are impressive, and speak to the potential of agents targeted at important biomarkers to augment the curative potential of adjuvant therapy. To Use or Not To Use Antibodies in the Adjuvant Treatment of Resected Colorectal Cancer On the surface, use of one of the three FDA-approved targeted antibodies routinely employed, along with standard adjuvant chemotherapy, in the treatment of metastatic colorectal cancer seems to defy basic principles of evidence-based medicine. Evidence-based medicine holds that medical decisions should follow from the best available evidence in patients who are reasonably similar to those patients from whom the relevant evidence was acquired. Two errors can follow from this principle: 1.) failing altogether to implement a treatment established as effective at a high level of evidence; or 2.) examining the best available evidence and implementing it incorrectly (eg, wrong treatment or poor patient selection). In many cases, where very high level evidence is lacking for a particular medical decision, one uses the best available evidence to guide decision-making. Using inadequate evidence in this way is, in fact, entirely consistent with the principles of evidence-based medicine. In the case of using antibody therapy in addition to chemotherapy in the adjuvant therapy of resected colorectal cancer patients, there simply is no direct evidence on which to base a decision. If one decides to make such a decision, it can only be on the basis of extrapolations based on data from other settings (eg, benefits observed in metastatic colorectal cancer) or imputation of a beneficial effect based on other considerations (eg, mechanism of action). Another type of error, an error of omission, may follow from a dogmatic view of evidence-based medicine. Such a view would hold that, although there is a complete lack of direct evidence on which to base a decision to provide antibody therapy in addition to adjuvant chemotherapy to patients with resected colorectal cancer, not to provide a therapy which has a reasonable chance of providing additional benefit merely because we lack definitive proof ignores the potential benefits of the new therapy. In other words, since there is a reasonable chance that the addition of antibody therapy to chemotherapy will yield additional benefits to colorectal adjuvant therapy, to omit it is to lose this potential opportunity. My own view is that when clinical trials are available that include the unproven agent being considered, patients should be enrolled in the clinical trials. These trials are, after all, meant to answer the question at hand in a way that using the drugs on individual patients in an uncontrolled way can never do. Enrolling patients honors the principle of equipoise, or uncertainty regarding the superiority of either the control or experimental arm of a randomized trial. In the absence of an available clinical trial of the unproven agent under consideration, I favor a conservative risk-benefit analysis for each patient as an individual. In this analysis, quantifiable risks are given more weight than hypothetical benefits. Such analyses usually lead me to conclude that the real and proven risks of these antibodies outweigh the theoretical and unproven benefits that they may or may not provide in the adjuvant setting. So I am, along with the rest of you, anxiously waiting for proof one way or another. Key Points Since 2004, three new antibody therapies have been added to the clinical armamentarium for metastatic colorectal cancer patients. Good scientific and clinical rationales exist for testing the benefits of targeted antibody therapies in the surgical adjuvant setting for patients with resected colorectal cancer. Fully accrued and ongoing clinical trials are evaluating the benefits of targeted antibodies used as part of adjuvant therapy for patients with resected colorectal cancer. At this time, given the complete lack of definitive evidence that adding antibodies to chemotherapy adds to the therapeutic benefits of adjuvant chemotherapy, a risk-benefit analysis leads to the conclusion that using antibodies in the adjuvant setting should remain part of clinical trials.
 

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28.  DeMatteo R, Owzar K, Maki R, et al: Adjuvant imatinib mesylate increases recurrence free survival in patients with completely resected localized primary GI stromal tumor: North American Intergroup Phase III trial ACOSOG Z9001 (abstract 10079). J Clin Oncol 25:18s, 2007.