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`Author Manuscript
`Hematol Oncol Clin North Am. Author manuscript; available in PMC 2013 June 01.
`Published in final edited form as:
`Hematol Oncol Clin North Am. 2012 June ; 26(3): 447–481. doi:10.1016/j.hoc.2012.02.013.
`
`Therapeutic antibodies against cancer
`
`Mark J. Adler and Dimiter S. Dimitrov
`Protein Interactions Group, Center for Cancer Research Nanobiology Program, National Cancer
`Institute, National Institutes of Health, Frederick, Maryland 21702
`
`Abstract
`Antibody-based therapeutics against cancer are highly successful in clinic and currently enjoy
`unprecedented recognition of their potential; 13 monoclonal antibodies (mAbs) have been
`approved for clinical use in the European Union and in the United States (one, mylotarg, was
`withdrawn from market in 2010). Three of the mAbs (bevacizumab, rituximab, trastuzumab) are
`in the top six selling protein therapeutics with sales in 2010 of more than $5 bln each. Hundreds of
`mAbs including bispecific mAbs and multispecific fusion proteins, mAbs conjugated with small
`molecule drugs and mAbs with optimized pharmacokinetics are in clinical trials. However,
`challenges remain and it appears that deeper understanding of mechanisms is needed to overcome
`major problems including resistance to therapy, access to targets, complexity of biological systems
`and individual variations.
`
`Keywords
`therapeutics; antibodies; cancer; immunogenicity; safety; efficacy
`
`1. Introduction
`Antibody therapy has its roots thousands of years ago; early forms of vaccination against
`infectious diseases were developed in China as early as 200 BC. However, the history of
`true antibody therapy began much more recently with the discovery that serum from animals
`immunized with toxins, for example, diphtheria toxin or viruses, is an effective therapeutic
`against the disease caused by the same agent in humans. This discovery resulted in the
`development of the serum therapy which saved thousands of lives; von Behring who in the
`1880s developed an antitoxin that did not kill the bacteria, but neutralized the toxin that the
`bacteria release into the body was awarded the first Nobel Prize in Medicine in 1901 for his
`role in the discovery and development of a serum therapy for diphtheria. Interestingly,
`although historically successes of antibody (serum) therapy were initially mostly in the
`treatment of patients with infectious diseases currently there is only on monoclonal antibody
`(mAb) approved for treatment of any infectious disease (synagis) and it is for prevention of
`the infection not for therapy of already established infection. Initial attempts to treat cancer
`patients with serum therapy were not successful. It was not until several decades ago when a
`
`© 2012 Elsevier Inc. All rights reserved
`Address for correspondence Mark J. Adler, MD UC San Diego Cancer Center 1200 Garden View Encinitas, California 92024
`oncologic@gmail.com. Dimiter S. Dimitrov, PhD, ScD Protein Interactions Group Center for Cancer Research Nanobiology Program
`National Cancer Institute, National Institutes of Health Bldg 469, Rm 150B Frederick, Maryland 21702 Tel: (301) 846-1352 Fax:
`(301) 846-5598 dimiter.dimitrov@nih.gov.
`Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our
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`number of revolutionary scientific discoveries were made that allowed the development of
`recombinant therapeutic resulting in the approval of the first anti-cancer therapeutic
`antibody – mAb rituximab in 1997 (Table 1). Since than 13 mAbs have been approved for
`clinical use against cancer in the European Union and the United States and 12 are on the
`market in August 2011; one of them, Gemtuzumab ozogamicin (Mylotarg), was withdrawn
`(Table 1); in contrast we still have to wait for the first approved mAb-based therapeutic
`against an infectious disease (synagis is for prevention). In 2010 sales of the top four
`recombinant therapeutic antibodies (bevacizumab, rituximab, trastuzumab, cetuximab)
`exceeded US$ 20 bln (Table 2).).
`
`Dating back to mummies and up to the recent successes with ipilimumab it has become
`axiomatic that the human immune system has an inherent capacity for anti-tumor activity.
`This was bolstered in the 1900s by the finding of spontaneous remissions recorded—often in
`sparse anectodal findings-- in nearly ever stage and form of cancer, by the more common
`observation of spontaneous regressions of melanoma and renal carcinoma, the success of
`non-specific immune-stimulants such as BCG or Coley's toxin and the increasingly targeted
`use of antibodies against antigens more specific to certain cell types [1]. Indeed, the
`antibody specificity was perhaps the first and still the most powerful story supporting the
`ubiquitous catch-call of personalized medicine.
`
`With all of the elegance of the specificity story and more than 35 years since Kohler and
`Milstein's recipe for generating monoclonal antibodies [2], the clinical promise has been
`largely disappointing. With rare exceptions, these molecular missiles have not annihilated
`their target tumors and have fallen far short of the marvel of the antibiotic revolution. The
`rarity of cures should not dampen the substantial, if incremental, progress that has been
`made. Even in the age of single nucleotide etiologies there is a strong case that cancer, by
`the time of its clinical visibility, consists of many broken parts; hence the growing argument
`that targeted therapies may parallel the breakthrough to cure with chemotherapy in the
`1970's with the move to, not one, but a cocktail of simultaneous, combined agents. As in the
`case of combination chemotherapy, antibody therapy may come to utilize different effector
`pathways in this assault.
`
`Therapeutic mAbs and other therapeutic proteins have been reviewed previously (see recent
`reviews [3–15] and articles cited there). Therefore, here, we review the monoclonal
`antibodies used directly in treatment, shed some light on presumed primary mechanism of
`action, and survey use—from initial indication to the wider adoption based principally on
`clinical trials and trends. This line-up, with its wide spectrum of targets and mechanisms
`may give some hope yet that the long trek may yet reach the originally envisioned summit.
`If not, these agents are undoubtedly part of the solution. We focus mainly on those native,
`unconjugated antibodies that directly impact solid tumors. Bevacizumab, though its anti-
`vascular action is indirect, has gained such wide application for solid tumors (and been
`subject of much controversy) that it seemed important to include. Finally, while immune-
`conjugates have been well reviewed elsewhere [16–18] and not the present focus
`brentuximab vedontin, as the first new indication for Hodgkin's in 30 years warranted
`special inclusion. Its success represents a partial rescue of a paradigm after the first
`approved antibody-drug conjugate, gemtuzumab was withdrawn in 2010 due to lack of
`efficacy and increased deaths [19]. In the context of the present review it may also point to
`some limiting aspects in unconjugated tumor-directed antibodies, which as has been stated,
`have not delivered their quarter-century promise.
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`2. mAbs approved for clinical use
`Currently, (as of August 2011) 13 mAbs are approved for clinical use in the European Union
`(EU) or United States (US) (Table 1). One of the approved mAbs, gemtuzumab ozogamicin
`(Mylotarg) was withdrawn from the market because of lack of clinical benefit and safety
`reasons after a clinical trial in which a greater number of deaths occurred in the group of
`patients with acute myeloid leukemia (AML) who received Mylotarg compared with those
`receiving chemotherapy alone. Mylotarg as well as removab which is not approved in the
`USA yet, and the two radiotherapeutic mAbs, Bexxar and Zevalin, will not be reviewed
`here.
`
`2.1 Rituximab
`The first candidate out of the starting box remains in many ways the poster child for both
`specificity and efficacy. Rituxamab (MabThera, Rituxan), initially developed in San Diego
`in the late 1980's, and father to that regions biotech explosion, was based upon the finding of
`CD20 antigen on normal and malignant lymphocytes; it is not appreciably expressed at
`either pole of lymphocyte ontogeny--stem cells and plasma cells--nor on other non-
`lymphoid cellular compartments. In contrast to many emerging cancer targets clearly
`connected with signal transduction circuitry there is no clear consensus on the function of
`CD20. Nonetheless, the chosen antigen-antibody duo in CD20/rituximab rendered a striking
`clinical success and ushered in a continuing wave of similarly conceived agents albeit with
`variant tactical goals and mechanisms of effect. It is interesting to note that only after many
`years afterward were clinical agents developed to target perhaps the ultimate tissue-specific
`bull's eye: the individual epitope of each B lymphocyte population—separating the
`malignant fiend from over a million brethren lymphocytes by one signature antigen
`expressed on one malignant subspecies.
`
`In 1997 rituximab was approved by the US FDA for treatment of relapsed indolent B-cell
`non-Hodgkin's lymphoma. The antibody is a mouse-human chimera utilizing murine
`variable regions to effect anti-CD20 specificity and human IgG1k constant region to
`facilitate effector function including complement mediated lysis and antibody directed
`cellular cytotoxicity [20, 21]. Additional mechanisms include caspase activation [22] a
`“vaccinal effect” based upon increased idiotype-specific T cell response to follicular
`lymphoma [23], and upregulation of proapoptotic proteins such as Bax [24, 25].
`
`Its well-known, early recognized and sometimes fatal chief toxicity has been acute infusion
`reactions. Rare fatalities, occurring mainly during first infusion, have been considered
`secondary to a cytokine reaction; generally associated with flu-like symptoms they may
`progress to life threatening hypotension, bronchospasm and hypoxia, but can usually be
`controlled by stopping or adjusting of rates of infusion and proper premedication [26].
`Blackbox events include tumor lysis syndrome, severe mucocutaneous reactions and
`progressive multifocal leukoencephalopathy (PML) resulting in death [27, 28].
`
`Rituxumab has demonstrated clinical activity across the spectrum of lymphoproliferative
`disorders but the greatest impact has been in non-Hodgkin's lymphoma, where combinations
`and optimizations, have sought to raise response rates and ultimately cure. Since its 1997
`start with relapsed indolent non-Hodgkin's lymphoma (NHL), rituximab has obtained the
`following additional indications for lymphoma per package insert: relapsed and refractory,
`follicular or low-grade, CD20-positive, B-cell NHL as single agent; previously untreated
`CD20-positive, follicular, B-cell NHL in combination with first line chemotherapy; as single
`agent maintenance therapy for patients achieving a partial or complete response to rituximab
`in combination with chemotherapy; for non-progressing (including stable), CD20 positive,
`low-grade, B-cell NHL, as a single agent after first-line combination of cyclophosphamide,
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`vincristine, and prednisone (CVP) chemotherapy; previously untreated CD20 positive,
`diffuse large B-cell NHL in combination with anthracycline-based chemotherapy, for
`example, in the workhorse, R-CHOP [29]. It also has an oft-used indication for treatment of
`previously treated or untreated patients with CD20 chronic lymphocytic leukemia (CLL) in
`combination with fludarabine and cyclophosphamide (FC) [30].
`
`It has found off-label use in the clinic in all or nearly all malignant (and many non-
`malignant) settings where B-cells are presumed to participate in pathogenesis and been the
`subject of many scholarly reviews. Common use spans from aggressive to low grade
`lymphoproliferative disorders including: combination with chemotherapy for induction in
`second line therapy for relapsed lymphoma anticipating autologous transplant [31];
`combination with chlorambucil for indolent and with bendamustine in treatment of relapsed
`or refractory CLL [32]; induction for Burkitt's, use for gastric and non-gastric mucosa-
`associated lymphoid tissue (MALT tumors [33, 34], Mantle cell tumor [35], primary
`cutaneous B-cell [36], splenic marginal zone NHL [37] Waldenström's macroglobulinemia/
`lymphoplasmacytic lymphoma [38]. Its uses have been tailored to mutational status of
`del(17p) and del(11q) with refractory CLL (National Comprehensive Cancer Network
`(NCCN) guidelines - http://www.nccn.org/index.asp) and combined in “cocktail” with other
`antibodies such as alemtuzumab for refractory lymphoid malignancies.
`
`The evolution of treatment for CLL mirrors, in many ways, that of NHL as it leads from
`purines to chemo-immunotherapy and most recently to novel antiCD20 antibodies.
`Conventional treatment of CLL evolved from alkylators to purine analogues when it was
`demonstrated that fludarabine (F) yielded greater efficacy with better complete response
`(CR), progression-free and overall survival (PFS and OS) rates than chlorambucil as primary
`therapy [39]. Subsequently, the combination of fludarabine with cyclophosphamide (FC)
`showed better CR and PFS than F [40]. Based upon the activity of rituximab (R) alone as a
`front line agent, it was added to FC and compared to FC alone; in a phase III randomized
`trial the combination FCR demonstrated better OR, CR, and PFS, establishing both the
`regimen and the concept of chemo-immunotherapy in this setting as the upfront standard of
`care [41].
`
`2.2 Ofatumumab
`Unfortunately, the activity of rituximab as a single agent is only modest [42] and duration of
`response in relapsed disease is generally measured in months [43]. This was part of the
`impetus to develop newer anti-CD20 targeted antibodies with a goal to improve such
`characteristics as binding affinity, specificity and effector function, and efficacy [44].
`Ofatumumab (ofa), a fully human monoclonal IgG1 binds to a unique epitope [45], induces
`considerably higher complement dependent cytotoxicity (CDC) than rituximab [46] and
`shows activity in rituxan-refractory B cell lymphoma [47].
`
`On the basis of these potential biological advantages and modest early phase clinical activity
`[48] ofa was tested against CLL which was either refractory to fludarabine and alemtuzumab
`or refractory to fludarabine with disease considered too bulky for efficacy with
`alemtuzumab [49]. The drug was well tolerated, though complicated by infections in 25% of
`the patients, but the impressive clinical results including median OS of 13.7 or 15.4 months,
`within two high risk groups, respectively, contributed to the approval of ofa for disease
`refractory to fludara and for those who have failed alemtuzumab [50, 51].
`
`Given the potential advantages of ofa versus rituximab and FCR established as standard of
`care in front line, substituting ofa for rituxan in the so-call O-FC regimen was tested in a
`multinational, randomized phase II trial in treatment naïve patients [52]. Of the two tested
`doses, the higher dose arm yielded a CR rate of 50%. It remains unclear how to position this
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`with respect to such other findings as the initial randomized phase III trial that established
`FCR as standard of care. The precedent of combining permutations of purine analogues,
`alkylators and antibodies including newer regimens like Ofa/bendamustine continues to
`inform ongoing studies [53].
`
`2.3 Ipilimumab
`The novel treatment agents for melanoma, vemurafenib (b-raf inhibitor) and ipilimumab (an
`antibody against cytotoxic T lympocyte antigen 4 (CTLA-4)), represent perhaps the most
`significant advance in oncology in several years. How they will fit in tactical treatment
`strategies, and with respect to conventional dacarbazine, IL-2, and a new gp100 based
`vaccine is a welcome and exciting challenge after decades without appreciable progress
`[54]. Blockade of the CTLA-4 has been the subject of long and intensive investigation [55,
`56].
`
`Among the most active immune inhibitory pathways is the CD28/CTLA-4:B7-1/B7-2
`receptor/ligand grouping which modulate peripheral tolerance to tumors and outgrowth of
`immune-evasive clones. Inhibition is both toward the overexpressed self targets via
`upregulation of inhibitory ligands on lymphocytes. Thus blockade of CTLA-4 has potential
`for both mono-therapy and in synergy with other therapies that enhance presentation of
`tumor epitopes to the immune system [56]. Genetic ablation of CTLA-4 leads to a massive
`and lethal lympho-proliferative disorder [57]. Antibody blockade of CTLA-4 induces potent
`anti-tumor activity through enhancing effector cells and concomitantly inhibiting T
`regulatory activity [58].
`
`Given that this inhibition is not tumor-specific it is not surprising that other tumors including
`ovarian cancer, prostate cancer, and renal cell cancer have demonstrated durable remissions
`[59].
`
`In a recent phase III trial, patients with melanoma refractory to chemotherapy or IL-2 who
`received ipilimumab had improved overall survival compared to those receiving the gp100
`peptide vaccine, and on this basis received FDA approval in 2011 [60].
`
`Ipilimumab holds an FDA indication for the treatment of unresectable or metastatic
`melanoma,with NCCN guidelines that largely elucidate specific contexts consistent with this
`approval including use as single agent for unresectable stage III in-transit metastases, local/
`satellite and/or in-transit unresectable recurrence, incompletely resected nodal recurrence,
`limited recurrence or metastatic disease, and disseminated recurrence or metastatic disease
`in patients with good performance status.
`
`Based upon its mechanism of unleashing the immune recognition and effector system there
`was rationale to test the interactive effects with tumor specific antigen. Specifically, the
`melanoma antigen, gp100, overexpressed on this tumor and among the antigens presented in
`the appropriate genetic major histocompatibility complex (MHC) context (HLA*A201)
`represented a prime vaccine candidate. In a phase III randomized trial increased response
`rates were seen when vaccine was added to IL-2 compared to IL-2 alone (16% versus 6%,
`P=0.03); progression free survival was also significantly improved with a trend toward
`improved overall survival [61]. Questions arose, nonetheless, whether gp100 vaccine was an
`appropriate control in the aforementioned phase III trial for ipilimumab. Another phase III
`randomized clinical trial treating previously untreated patients with metastatic melanoma
`compared ipilimumab (every 3 weeks for four doses followed by `maintenance' every three
`months) with and without dacarbazine as the standard control; improved OS was seen
`including a difference at 3 years of nearly 21% vs. 12% [62].
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`The cluster of well-identified side effects induced by CTLA-4 inhibition have been referred
`to as “immune-related adverse events” (IRAEs). These unique adverse effects are likely a
`direct effect of impairing immune tolerance. They include colitis/diarrhea, dermatitis,
`hepatitis, uveitis, nephritis, inflammatory myopathy and endocrinopathies. While these
`reactions have gained a blackbox designation for occasional severe and even fatal instances
`they are generally manageable and reversible with treatment guidelines which include
`systemic corticosteroids [63]. These toxicities may be prolonged, suggestive of sustained
`release from immune tolerance, and perhaps a different response profile including long
`periodsof stable disease, and correlation of toxicity with efficacy. In one report with high-
`risk melanoma ipilimumab-treated patients who experienced high grade IRAEs had a
`significantly higher rate of tumor regression than those without IRAEs (36% versus 5% of
`patients) [64].
`
`Based upon a mechanism of action clearly different from IL-2, which increases
`responsiveness to immune targets, and is non-overlapping with chemotherapy, earlier phase
`trials and future efforts will focus upon combinations of vaccines, chemo, and other
`immune-modulators [59]. Furthermore, given the prolonged time course of side effects and
`the resulting requirement for prolonged steroids, timing of its use with respect to IL-2 and
`vaccines will be the subject of much attention [65].
`
`2.4 Trastuzumab
`HER2 is overexpressed in 20–30 % of invasive breast cancers and associated with a worse
`prognosis [66]. Trastuzumab is a humanized monoclonal antibody targeting the human
`epidermal growth factor receptor 2 (HER2) which was approved by the FDA in 1998 as the
`first monoclonal for a solid tumor indicated for patients with invasive breast cancer that
`overexpresses HER2. It is now a standard part of treatment for HER2 positive tumors in
`both metastatic and adjuvant settings. Since, across the range of studies, tumors that
`overexpress HER2 receptor respond better, considerable effort has been expended to
`accurately assess receptor status [67–69].
`
`HER2 is part of a family of transmembrane tyrosine kinase receptors which normally
`regulate cell growth and survival, differentiation and migration [70]. It consists of an
`extracellular binding domain, a transmembrane segment and an intracellular tyrosine kinase
`domain. The receptor is activated by homo- or hetero- dimerization generally, but not
`always activated through ligand binding; it can dimerize and thus activate, independent of
`ligand [71] through either overexpression or mutation [72]. Thus activated by
`overexpression, signal-transduction cascades act to promote a host of pro-growth activities
`including proliferation, survival, and invasion. Such signal transduction is mediated through
`the RAS-MAKP pathway, inhibiting cell death through the m-TOR pathway [73].
`Additionally, it inhibits P13K pathway, reducing PTEN phosphorylation and AKT
`dephosphorylation and thus increasing cell death [74] [75].
`
`The human IgG1 is capable of inducing antibody dependent cell-mediated cytotoxicity
`(ADCC) in vitro [76] and of recruitment of effector cells in animal studies [77]. An immune
`mechanism is suggested by the increased lymphoid infiltration into tumor after preoperative
`administration of trastuzumab [78]. There is also evidence that it causes regression of
`vasculature by modulating angiogenic factors [79].
`
`As a single agent in metastatic breast cancer, and receptor status using earlier
`immunohistochemistry (IHC) expression criteria, trastuzumab produced response rates of 11
`to 26% [80]. From the earliest studies, though time has sharpened the assessment, it has
`been clear that the best results occur in tumors that overexpress Her2. The breakthrough trial
`for trastuzumab in metatstatic disease came in a randomized phase III trial when it was used
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`in combination with chemotherapy for Her-2 positive patients [81]. As first line therapy for
`metastatic disease patients were given either chemo alone or in combination. Patients were
`given an anthracycline and cyclophosphamide or, paclitaxel (if they had previous
`anthracycline in adjuvant settting). Results showed not only improvement in response rate
`(RR) and progression free interval but in overall survival. Trastuzumab was subsequently
`showed to have efficacy and safety with a variety of other chemotherapeutics including
`docetaxel [82], vinorelbine [83], and doxil [84] in nonrandomized trials.
`
`As for the adjuvant setting, large randomized trials established significant benefits from the
`addition of trastuzumab to both anthracycline and non-anthracycline early breast cancer
`[85]. Four major adjuvant trials including >13,000 women with HER2-positive early breast
`cancer utilized different adjuvant regimens with trastuzumab; in these studies overall,
`trastuzumab reduced the 3-year risk of recurrence by about half in this population [86]. On
`this basis, trastuzumab has become part of standard adjuvant therapy. Both the international
`Consensus Group and NCCN recommend its use for women with HER2 positive, node
`positive tumors as well as for node negative disease when the primary is >1cm.
`
`Trastuzumab, combined with chemotherapy has also shown improvement in pathological
`responses and event free survival when used in the neoadjuvant setting prior to surgery [87].
`In a randomized phase III trial patients with advanced gastroesophageal and gastric
`adenocarcinoma tumors which overexpressed HER2 showed significant increase in overall
`survival when trastuzumab was added to their chemotherapy [88]. Trastuzumab now has an
`FDA indication for use in combination with cisplatinum and fluorouracil (5FU) or
`capecitabine for first line treatment of gastric and gastroesophageal tumor which
`overexpress HER 2.
`
`The most significant toxicity associated with trastuzumab is cardiomyopathy ranging from
`subclinical decreases in left ventricular ejection fraction (LVEF) to cardiac failure
`manifesting as congestive heart failure (CHF). The risk is greatest when administered
`concurrently with anthracyclines [81]. Use following anthracyclines was associated
`commonly with asymptomatic cardiac dysfunction but most severe decreases recovered with
`time [89]. Close monitoring of clinical status and cardiac function, sequential rather than
`concomitant use, and development of non-anthracycline regimens [90] [91] have all been
`objectives.
`
`2.5 Bevacizumab
`The discussion of bevacizumab (bev) here will be asymmetric in bulk and breadth compared
`to the other antibodies owing to its conceptual and actual application in many tumor types,
`it's unique mechanism and toxicity profile. Bevacizumab is a humanized IgG1 mAb that
`binds to and neutralizes the ligand vascular endothelial growth factor (VEGF) rather than
`binding the cell surface receptor. In fact many tissues and most malignancies produce VEGF
`whose native function, whether acting from a distance or in an autocrine loop, operates
`through binding and activation of the VEGF receptor [91]. The latter includes an
`extracellular binding domain and a cytoplasmic kinase domain. Following VEGF binding,
`the otherwise inactive monomer receptor undergoes dimerization, autophosphorylation of
`the tyrosisne kinase domain and downstream activation of many of the usual signal
`transduction suspects including MAPK and protein kinase C pathways which mediate
`proliferative events - in this setting, endothelial proliferation and angiogenesis [92]; such
`neoangiogensis is required by tumors once they grow greater than 2 mm [93].
`
`Many of this antibody's common toxicities are related to its impact on microvasculature
`including hypertension, proteinuria, rare bowel perforation, impaired wound healing and
`bleeding [94]. Other than the rare bowel perforation these can generally be managed and
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`without necessitating cessation of therapy. While there will naturally be some specificity of
`side effects and adverse reactions dependent upon the drugs with which bevacizumab is
`paired, with some notable exceptions, toxicities are generally neither drug combination nor
`tumor specific.
`
`More severe and fatal consequences of bevacizumab have been the subject of a number of
`meta-analyses and reports of large institution experience. In perhaps the largest of these,
`fatal adverse events (FAEs) were considered in a meta-analysis of over 10,000 patients with
`various solid tumor types, comparing regimens with and without the addition of
`bevacizumab. The overall incidences of fatal adverse events were 2.5% and among these the
`highest percentages were nearly a quarter attributable to hemorrhage, about half of that
`related to neutropenia, and a smaller amount to perforation. There was increased relative risk
`attributable to combining bevacizumab with taxanes or platinum but not with other agents,
`nor were there significant tumor-specific increases. In another large meta-analysis
`bevacizumab was associated with high-grade congestive heart failure in breast cancer with
`an overall incidence of 1.6% [95]. Yet a third large meta-analysis identified a 12% risk of
`thromboembolic events [96]. Of note, a pooled analysis of phase II and phase III trials did
`not show an increase in venous thromboembolic events--important to recognize with a
`baseline of tumor--associated venous thromboembolic events (VTEs) of around 10% with or
`without this agent [97]. Massive hemoptysis has been linked to large central lesions at risk
`for cavitation [98], and avoided in these circumstances, and more generally in squamous
`cancer where this risk is increased. Bowel perforation occurred with an incidence under 2%
`in a large institution with a treated population of over 1400 patients; it was generally
`managed without the need for surgical intervention [99].
`
`Bevacizumab demonstrated nil [100] to small [101] response rates as mono-therapy and,
`with such exceptions as maintenance regimens and single agent use with recurrent
`glioblastoma, its predominant clinical role lies in combination with chemotherapy. In 2004,
`based upon improvement of response rates progression-free survival, and overall survival,
`bevacizumab, when combined with chemotherapy in metastatic colorectal cancer [102],
`became the first anti-angiogenic agent approved for clinical use. Since then it has gained
`indications for metastatic breast, metastatic renal cancer, metastatic (as well as advanced or
`recurrent) non-small cell lung cancer, and glioblastoma. Increasing use of bevacizumab is
`also being seen with hepatocellular and ovarian cancer.
`
`2.5.1 Colorectal cancer—At this time bevacizumab has an indication in metastatic
`colorectal cancer in both first and second line settings. The initial approval followed its use
`with bolus irinotecan, fluorouracil, and leucovorin (IFL) where addition of bevacizumab
`significantly improved response rate and median survival (20 versus 16 months) compared
`to chemo only [102]. While bolus IFL has fallen out of general use due to its toxicity profile,
`studies have supported the value of bevacizumab in combination with more widely used
`treatments including FOLFIRI (FOL – leucovorin plus F – fluorouracil (5-FU) and IRI –
`irinotecan (Camptosar)) [103, 104], and three oxaliplatin-containing regimens [105]. In
`addition, when bevacizumab was added to 5FU/leucovorin in the absence of irinotecan or
`oxaliplatin, response rates were approximately doubled and median survival improved
`compared to chemo alone [106, 107].
`
`Efforts to apply bevacizumab in the adjuvant setting for colorectal cancer moved from initial
`enthusiasm to disappointment. As noted above, bevacizumab had shown favorable impact in
`metastatic disease in a number of settings including in combination with IFL (irinotecan,
`5FU and leucovorin) for metastatic colorectal cancer. Borrowing the prevailing paradigm for
`chemotherapy--which attempts to apply results in metastatic disease to adjuvant use on the
`presumption of potential elimination of micro-metastases - bevacizumab was studied in the
`
`Hematol Oncol Clin North Am. Author manuscript; available in PMC 2013 June 01.
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`NIH-PA Author Manuscript
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`NIH-PA Author Manuscript
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`NIH-PA Author Manuscript
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`Adler and Dimitrov
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`adjuvant setting for colorectal cancer. Two recently publish