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© 2001 American Society for Clinical Oncology
Clinical Trials of Antiangiogenic Drugs: Opportunities, Problems, and Assessment of Initial ResultsByFrom the Department of Medical Biophysics, University of Toronto, Toronto, Canada. Address reprint requests to Robert S. Kerbel, PhD, Molecular and Cellular Biology Research, Sunnybrook and Women’s College Health Sciences Centre, Department of Medical Biophysics, University of Toronto, S-218 2075 Bayview Ave, Toronto, Ontario M4N 3M5, Canada; email: robert.kerbel{at}swchsc.on.ca
THE HYPOTHESIS THAT tumors can be treated chronically with antiangiogenic drugs to induce a state of prolonged dormancy was first envisioned by Judah Folkman in 1971.1 It was not readily accepted for the next 15 to 20 years, but a series of major discoveries, many of them from Folkman’s laboratory, changed this picture dramatically, as summarized recently.2 A baker’s dozen of some the most important of these discoveries are listed in Table 1. Such discoveries have resulted in a large number of drugs developed intentionally, or positioned as angiogenesis inhibitors, being evaluated in current phase I, II, or III clinical trials. This information can be retrieved from the Web site of the Angiogenesis Foundation (http://www.angio.org). A summary ofsuch ongoing phase I, II, and III clinical trials, as of April 2001, is shown in Table 2 (phase I), Table 3 (phase II), and Table 4 (phase III).
Tables 2, 3, and 4 illustrate the great diversity of drugs and corresponding molecular targets potentially available for antiangiogenic therapy. With respect to how they function, angiogenesis inhibitors can be subdivided into several categories, such as (1) growth factor inhibitors, (2) endothelial cell signal transduction inhibitors, (3) inhibitors of endothelial cell proliferation, (4) inhibitors of matrix metalloproteinases, (5) inhibitors of endothelial cell survival, and (6) inhibitors of endothelial bone marrow precursor cells, among others. As far as molecular target diversity is concerned, it is interesting to compare the known targets of almost all of the common cytotoxic chemotherapeutic agents with angiogenesis inhibitors, as summarized in Fig 1. This diversity poses certain challenges, but it also presents significant opportunities, especially with respect to combination therapy. Moreover, the list of potential molecular targets will almost certainly grow significantly over the next few years with the use of various genomic or proteomic techniques applied to the activated endothelial cells of newly formed tumor blood vessels versus established mature vasculature.3 Such studies have already revealed evidence that the two types of vessel are qualitatively distinct, at least from a gene expression point of view3; the molecular changes, especially the highly upregulated (eg, 10-fold or more) tumor endothelial markers, offer not only potential new targets for therapy, but also possibilities for diagnostic imaging, and, it is hoped, exploitation as soluble (secreted) surrogate molecular markers of tumor angiogenesis. The last possibility is particularly important because most antiangiogenic drugs are cytostatic, at least when they are used as monotherapies, and the absence of tumor shrinkage (objective responses) makes evaluation of the potential efficacy of such drugs in phase I and phase II a more difficult problem. This is similar to the problems associated with the initial testing of oncogene-targeting signal transduction inhibitors, such as epidermal growth factor (EGF) receptor or erbB-2/neu blocking drugs, eg, C225, ZD1839 (Iressa; AstraZeneca, United Kingdom), and trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA), which are also cytostatic in nature.4-10
In this regard, as summarized in Fig 2, there are some drugs, generally referred to as vascular-targeting agents, that can cause acute, cytotoxic-like effects by rapid destruction of existing tumor blood vessels.11,12 These drugs may be viewed as having the advantage that it may be possible to use objective (ie, partial or complete) tumor responses as a means of readily assessing their potential efficacy in phase I and II clinical trials. Although inability to induce rapid tumor regressions or objective responses is viewed as a disadvantage by most oncologists, it should be pointed out that the value of detecting such responses in phase I or II clinical trials is frequently of little or no value in predicting whether a drug or therapy will ultimately have truly meaningful effects in prolonging survival or bringing about cures.13,14 Indeed, as pointed out by Takahashi and Nishioka,13 it is probably the duration of the stable disease phase (after cytotoxic therapy), especially if this lasts more than 90 days, and not tumor shrinkage, that is more critical to whether or not chemotherapy (and presumably other drugs) will ultimately prolong the survival of cancer patients.13 From this perspective, the cytostatic nature of most antiangiogenic drugs could be viewed as an advantage, rather than the opposite. This is an important aspect of such drugs and should be kept in mind, especially when assessing the results of phase I toxicity clinical trials in which drugs such as angiostatin and endostatin have been used as monotherapies to treat advanced metastatic (incurable) cancers. Thus far, these two drugs have been found to have some biologic activities relevant to inhibiting angiogenesis and are devoid of host toxicity15,16—encouraging findings, obviously, for a phase I clinical trial—but the absence of significant frequencies of compelling tumor regressions is being viewed in some quarters (especially, perhaps, by the lay media) as disappointing. This is premature and is no doubt related in part to the inflated expectations of such drugs, fueled in part by intense media interest.17-19 However, as described elsewhere,20,21 these and similar (cytostatic) drugs, such as signal transduction inhibitors, are likely to have their greatest effect primarily, or only, in the context of combination therapy, when they are combined either with conventional standard-of-care chemotherapy (or radiation) regimens9,20,21 or with each other.22,23
THE ISSUE OF ACQUIRED DRUG RESISTANCE TO ANTIANGIOGENIC DRUGS On theoretical grounds, one of the advantages that antiangiogenic drugs may have over all other forms of anticancer therapy—both new and old—is an ability to avoid acquired drug resistance because of the nature of their cellular target: the genetically stable endothelial cell of a newly formed tumor blood vessel, rather than rapidly mutating, genetically unstable cancer cells per se.24,25 Although there is some preclinical and clinical evidence to support this possibility,26,27 there is also accumulating preclinical evidence that a number of antiangiogenic drugs or strategies can lose their activity over time and that this can be caused by several possible mechanisms, as summarized recently by Kerbel et al.23 Such mechanisms include (1) the great redundancy of tumor cell–secreted proangiogenic growth factors28-30 when only one such factor is the target of an antiangiogenic therapy; (2) the antiapoptotic/prosurvival function for activated endothelial cells of high local concentrations of various proangiogenic growth factors, such as vascular endothelial cell growth factor (VEGF)—which may antagonize the proapoptotic function of various antiangiogenic agents31-33; (3) the effect of transient epigenetic changes induced in activated endothelial cells, which may promote endothelial cell survival properties; and (4) the heterogeneous vascular dependence of tumor cells, ie, the fact that some tumor cells in a tumor mass seem to require close proximity to tumor blood vessels for their survival, whereas others do not.34 These considerations highlight two important points. First, antiangiogenic drugs can be categorized as direct acting versus those that are indirect acting.35 The latter refers to drugs such as anti-VEGF antibodies that interfere with some tumor cell function, eg, VEGF production, to block angiogenesis. The redundancy of tumor cell proangiogenic growth factors would presumably ensure the eventual selection of mutants or variants that can induce angiogenesis in the absence of the blocked proangiogenic growth factor targeted by the drug. Thus, this type of antiangiogenic drug would run up against the problem of the massive and diverse tumor cell genetic instabilities36,37 and, as a consequence, acquired drug resistance in a manner essentially identical to any anticancer drug that directly targets some tumor cell–associated molecular alteration or property,23 whether it is a conventional cytotoxic drug38 or one of the newly developed signal transduction inhibitor drugs, including anti-EGF receptor antibodies39 and STI571 (Gleevec; Novartis, East Hanover, NJ).40,41 In contrast, drugs such as endostatin or chemotherapeutic drugs exploited as antiendothelial cell–targeting agents seem to act directly on endothelial cells and hence bypass the need for blocking tumor cell functions to manifest their antitumor (antiangiogenic) activity. Such drugs may be less vulnerable, or even invulnerable, to inactivation by acquired drug resistance.23 This may explain the observation that long-term, cyclic endostatin treatment in one preclinical study did not induce drug resistance.26 Long-term treatment with indirect angiogenesis inhibitors, such as interferon alfa-2a, which blocks production of basic fibroblast growth factor (bFGF),42 will not result in acquired drug resistance when there is no redundancy of proangiogenic growth factors in the targeted tumor cell population being treated. This seems to be the case when nonmalignant neoplasms, such as childhood hemangiomas or giant cell tumors of the mandible, are treated with such a drug in a chronic (eg, 1-year) low-dose, daily fashion, because angiogenesis in such tumors seems to be driven primarily by a single proangiogenic growth factor, bFGF; ie, there is no redundancy.27,43 Nevertheless, as discussed previously, there are mechanisms that could also result in eventual resistance to direct-acting angiogenesis inhibitors when malignant tumors are treated. This leads to the second important point: the potential advantages to be gained by the use of combination antiangiogenic therapy approaches.23 These are increased overall efficacy, such that even marked tumor regressions can sometimes be induced, albeit usually slowly and gradually, when two different cytostatic antiangiogenic agents are used22,44-46 and significant delay or avoidance of acquired drug resistance.22,44 An example of these potential benefits is shown in Fig 3, in which a continuous low-dose metronomic/antiangiogenic chemotherapy scheduling/dosing regimen22 (with vinblastine) was used with a monoclonal anti–VEGF receptor-2-blocking antibody (called DC101) in a preclinical human neuroblastoma xenograft tumor model.22,47 Neither the low-dose continuous chemotherapy regimen, which was designed to optimize the antiangiogenic side effect of chemotherapy,44 nor the DC101 antibody induced tumor regressions (as expected), and moreover, the cytostatic responses were eventually terminated; ie, a form of eventual escape, was observed when the drugs were used as monotherapies.22 In sharp contrast, the combination of the two drugs resulted in complete and sustained responses—no relapse was noted, despite the prolonged nature of therapy, ie, almost 7 months, an unusually prolonged course of therapy for a mouse study.22 A number of other examples of similar preclinical findings have been reported.44-46 In addition, a single small-molecule drug, called SU-6668, which blocks not only the VEGF receptor-2 (KDR) kinase, but also the platelet-derived growth factor receptor tyrosine kinase and the bFGF receptor tyrosine kinase, can cause acute regressions of large established human tumor xenografts,48 whereas such potent antitumor effects are seldom observed with use of drugs which preferentially target only the VEGF receptor, such as SU5416 or PTK787/2K222584.49,50 Treatment with SU-6668 could be viewed as a kind of combination therapy, even though only a single drug was used.
HOW ARE WE TO VIEW THE CLINICAL TRIAL RESULTS OF THE FIRST GENERATION OF ANTIANGIOGENIC DRUGS? The first antiangiogenic drug to undergo clinical testing, TNP-470, was first assessed in 1992, less than 10 years ago.51 Since then there have been a relatively small number of completed trials of this and other antiangiogenic drugs, the reports of which have only just begun to appear in the peer-reviewed literature in meaningful numbers over the last 1 to 2 years and the majority of which have not involved combination therapy.52-59 There are also the well-known difficulties in assessing the antitumor activity of such cytostatic drugs in patients; these difficulties have been discussed in detail by others4,5,60 and previously in this article. These include the following: (1) The optimal biologic dose of such drugs is usually less than the maximum-tolerated dose and is therefore much more difficult to define; consequently, in many trials there is a high probability that the optimal doses have not been used or are not being used. (2) Similarly, issues of drug scheduling are important, but the optimal schedules for many antiangiogenic drugs in humans are unknown and therefore have probably not been used. As an example, on the basis of pharmacokinetic studies in patients and studies involving continuous administration of drugs in preclinical models, drugs such as TNP-47061,62 and angiostatin63 should have superior antitumor effects when administered continuously compared with administration once a day or once every few days. These findings are only now just being translated to the clinic. (3) There are not yet any accepted reliable surrogate markers or assays to measure antiangiogenic activity in vivo in cancer patients, and this makes the decision of whether to proceed from phase I or II clinical trials to the pivotal phase III randomized trials difficult. (4) The optimal way to combine an antiangiogenic drug with chemotherapy, radiation, or antihormonal therapies is far from clear. (5) Finally, antiangiogenic drugs are more likely to work best in adjuvant settings rather than end-stage, bulky metastatic disease, but it is in such latter disease circumstances that these drugs are still being tested. With all these handicaps and problems, the overall clinical results thus far of this new treatment paradigm could be viewed as surprisingly encouraging. Although phase III trials of a number of protease inhibitors have not yet lived up to expectations,64 there are other more encouraging examples, such as the exciting results with thalidomide in chemoresistant multiple myeloma patients65—although it must be acknowledged that it is not at all clear whether the benefits seen are caused by an antiangiogenic effect.66 The same uncertainty cannot be said of humanized monoclonal anti-VEGF antibodies, eg, bevacizumab (Avastin; Genentech), for which phase II clinical trial efficacy results in patients with, eg, end-stage lung cancer, look quite promising in terms of prolongation of survival.67 Indeed, in a recently reported clinical trial in advanced nonsquamous lung cancer, the results obtained were deemed by the authors to be reminiscent of those seen previously in advanced breast cancer treated with trastuzumab plus chemotherapy and suggest that bevacizumab may prolong survival in nonsquamous non–small-cell lung cancer patients without engendering unacceptable toxicity.67 It may be useful to examine the results of the recent and small number of antiangiogenic drug–based clinical trials in the comparative light of clinical trials testing chemotherapy drugs. How much progress can we truthfully say has been made with this traditional treatment paradigm in the common adult solid tumors despite literally many thousands of clinical trials over approximately 50 years? Skeptics might also point out, by way of comparison, the truly encouraging results of clinical trials on signal transduction inhibitors such as trastuzumab in breast cancer9 or the C225 monoclonal antibody (cetuximab), such as when it is used with irinotecan in irinotecan-resistant, metastatic colon cancer.68 Or they may point out the dramatic results of STI571, the bcr-abl/c-kit antagonist in the indolent phase of chronic myelogenous leukemia (CML)69 or in gastrointestinal stromal tumors.70-72 With respect to the former results, it should be pointed out that drugs that molecularly target the EGF or erbB-2 receptor tyrosine kinases may work, in part, by blocking tumor angiogenesis.39,73,74 As for the STI571 results, exciting as they are, thus far they relate to relatively rare tumors or to earlier stage disease, such as indolent, chronic-phase CML,69,75 as opposed to acute blast phase CML.76 By comparison, antiangiogenic drugs have been assessed in much more challenging or common malignancies, equivalent to or even more difficult than the blast phase or crisis CML stage. In conclusion, there is much to be excited about, but it is equally clear that we are in the early days of the clinical testing of antiangiogenic drugs. We have a great deal to learn, both from our failures as well as from our successes. What is needed now is a combination of more good, basic science, rigorous clinical trial testing, patience, and, perhaps above all, enlightened thinking, along with realistic expectations of what can be achieved with this new treatment paradigm over the next 5 years.
Supported by grant no. MT-5815 from the Canadian Institute for Health Research and grant no. CA-41223 from the National Institutes of Health. R.S.K. is a recipient of a Canada Research Chair Tier I award. I thank Cassandra Cheng for her excellent secretarial contribution.
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INTRODUCTION
REFERENCES
