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Originally published as JCO Early Release 10.1200/JCO.2008.20.8595 on February 17 2009 © 2009 American Society of Clinical Oncology.
From Theoretical Synergy to Clinical Supra-Additive ToxicityUniversité Paris XI, Service des Innovations Thérapeutiques Précoces, Département de Médecine, Institut Gustave Roussy, Villejuif, France
Service de néphrologie, Assistance Publique Hôpitaux de Paris, Hôpital Pitié Salpetrière, Paris, France Inhibition of angiogenesis has emerged as an important therapeutic strategy in a variety of solid tumors. This is particularly true in patients with metastatic renal cell carcinoma (RCC),1 who could potentially benefit from three approved angiogenesis inhibitors that target vascular endothelial growth factor (VEGF) signaling: bevacizumab, sunitinib, and sorafenib.2–5 Combining agents with related targets may enhance antitumor activity through vertical inhibition of a single pathway in which blockade is reinforced at multiple sites.6 This strategy has been used successfully in infectious disease, where the combination of two bacteriostatic agents (trimethoprim and sulfamethoxazole) targeting the folate pathway at two different levels led to a widely available bactericidal antibiotic (cotrimoxazole). The study by Feldman et al7 in this issue of Journal of Clinical Oncology is a phase I trial combining bevacizumab and sunitinib in patients with metastatic RCC. The underlying hypothesis of this trial is that this combination is expected to provide more effective blockade and enhanced antitumor efficacy, even though no preclinical evaluation of either the efficacy or the toxicity of such a combination is available in the literature. This is probably due to the inability of bevacizumab to block mouse VEGF and the scant availability of its murine equivalent. However, multiple theoretical arguments can be put forward to support the bevacizumab/sunitinib combination. Beyond the maximal blockade of the VEGF pathway, one can argue that these agents can potentially act complementarily based on the different mechanisms of action underlying each strategy. In particular, bevacizumab blocks the neuropilin pathway, which is not affected by sunitinib; conversely, sunitinib blocks c-KIT, which is not affected by bevacizumab. Neuropilins, first described as coreceptors implicated in neuronal guidance, are also expressed in endothelial cells where they act as coreceptors of VEGF receptor 2 (VEGFR2) and bind VEGF165.8 As mentioned, no preclinical model was available to predict the safety of this combination before the conduct of this clinical trial. Although the combination of cytotoxic agents usually leads to the addition of common toxicities (such as neutropenia, anemia, and thrombocytopenia), it cannot be assumed that molecular targeted agents (MTAs) will give rise to similar adverse effects, especially if they inhibit different signaling pathways. Two safe MTAs may lead to synergistic toxicity because of different toxicity profiles and the inhibition of different targets, in contrast to the additive hematologic toxicity profiles of most chemotherapies. In this respect, the preclinical evaluation of a combination of MTAs appears to be an important prerequisite to phase I clinical trials.9 This may help anticipate unexpected toxicities specific to each MTA combination. Interestingly enough, an analysis of the literature shows that available preclinical models, before implementation of the current phase I trial by Feldman et al, suggested that downregulation or neutralization of circulating VEGF may play an important role in the induction of proteinuria (and kidney failure), as described in various kidney diseases and in women with pre-eclampsia.10 The phase I trial reported by Feldman et al7 is striking because of the high degree of vascular, renal, and hematologic toxicities reported, along with the timing of the occurrence of such events, most frequently beyond cycle 1. The traditional approach in oncology phase I clinical trials is to determine the maximum-tolerated dose (MTD) with a dose-escalation approach. In classic phase I trials, dose-limiting toxicities are defined during the first cycle of treatment. With cytotoxic drugs, the MTD (ie, the upper limit of the therapeutic range) is usually associated with the maximum clinical benefit. However, evidence suggests that the MTD of antiangiogenic agents is not necessarily the most effective dose.11 Moreover, identifying both acute and long-term toxicities associated with MTA is important for the management of patients who will be chronically exposed to these agents. Late toxicities appearing beyond cycle 1 do not define the dose-limiting toxicity and MTD but may lead to clinically unacceptable toxic profiles. The most frequently reported grade 3/4 adverse events in this trial included hypertension (60%), proteinuria (36%), and thrombocytopenia (24%).7 Furthermore, five patients had laboratory and clinical features consistent with microangiopathic hemolytic anemia (MAHA). We will comment on the frequency and pathophysiology of hypertension, proteinuria, MAHA, and thrombotic microangiopathy (TMA), as currently reported with antiangiogenic agents. Hypertension is one of the most frequently observed adverse effects of systemic inhibition of VEGF signaling. In the trial reported by Feldman et al, most of the patients experienced hypertension (92%) and 60% exhibited grade 3/4 hypertension. A meta-analysis of randomized controlled trials with patients receiving bevacizumab indicated a relative risk of 3.0 for hypertension with bevacizumab at a low dose (2.5 to 7.5 mg/kg) and 7.5 at a high dose (10 to 15 mg/kg).12 The overall incidence of bevacizumab-related hypertension was as high as 32%, with 11% to 16% of patients experiencing grade 3 hypertension requiring intensive antihypertensive therapy; 1% had a life-threatening grade 4 hypertensive crisis. The incidence of hypertension in patients on sunitinib was 24% (8% had grade 3) in a phase III trial.2 The pathogeneses of VEGF signal inhibition–induced hypertension could be summarized as follows: VEGF signal antagonism leads to inhibition of nitric synthase, which in turn lowers levels of nitric oxide, leading to elevated blood pressure through vasoconstriction and decreased sodium ion renal excretion. Conversely, angiogenesis inhibitor–induced hypertension may also be secondary to vascular rarefaction, leading to increased peripheral vascular resistance.13 Finally, renal thrombotic microangiopathy per se may induce elevated blood pressure.14 Proteinuria is also a class effect of VEGF antagonists, but its mechanism is not as well understood as that of hypertension. In their meta-analysis, Zhu et al12 indicated a relative risk for proteinuria of 1.4 and 1.6 with low-dose (2.5 to 7.5 mg/kg) and high-dose (10 to 15 mg/kg) bevacizumab, respectively. Proteinuria (ranging from clinically silent to nephrotic syndrome) is reversible by stopping the VEGF antagonist and by controlling blood pressure, suggesting a possible hemodynamic effect. Increased hypertension may also contribute to proteinuria observed in patients receiving inhibitors of VEGF signaling. Podocytes normally express VEGF at high levels. VEGF could be considered as a double-edged sword in the sense that too little or too much VEGF expression induces proteinuria. Anti-VEGF antibodies and soluble FMS-like tyrosine kinase 1 cause rapid glomerular endothelial cell detachment and hypertrophy, in association with downregulation of nephrin, a key epithelial protein in the glomerular filtration apparatus.10,15 Eremina et al16 showed that podocyte-specific heterozygosity for VEGF resulted in nephrotic-range proteinuria, endotheliosis, and hyaline deposits that resemble the pathologic lesions seen in renal biopsy specimens from patients with pre-eclampsia. Moreover, blockade of VEGF accelerates proteinuria via a decrease in nephrin expression in rat crescentic glomerulonephritis. Conversely, podocyte-specific overexpression of the VEGF164 isoform led to end-stage renal failure caused by collapsing glomerulopathy, the pathologic lesion seen in HIV-associated nephropathy.17 Thrombocytopenia and MAHA also occurred frequently in this trial. TMA is a microvascular disorder characterized by platelet thrombi in the renal or systemic vascular beds. Hemolytic uremic syndrome (or MAHA) and thrombotic thrombocytopenic purpura are the clinical entities comprising TMA, with predominantly renal manifestations in the former, and neurologic signs dominating the latter. TMA can be induced by chemotherapeutic agents (such as mitomycin and gemcitabine). However, VEGF inhibitors are the cancer drugs that, by recent reports, most frequently induce TMA. Eleven TMA cases have been reported in the literature to be related to anti-VEGF agents, including bevacizumab.18–21 Eight patients had laboratory findings consistent with MAHA. However, TMA could not be confirmed because kidney biopsies were not performed in all patients. The pathophysiologic mechanism behind this drug toxicity remains unclear. In our experience, none of the patients with VEGF inhibition–related TMA explored had detectable auto-antibodies against a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13. Some authors propose directly induced endothelial damage with simultaneous activation of the clotting cascade.22 Recently, Eremina et al14 used an interesting murine model to study VEGF inhibitor–related TMA, thus providing a significant step forward toward understanding the pathophysiology of this renal syndrome. TMA was found to result from direct deletion of VEGF from podocytes in mice and from exposure to an agent that inhibits VEGF in humans. VEGF production by podocytes seems to be required for normal functioning and maintenance of the adjacent glomerular endothelium. Pharmacologic or genetic disruption of VEGF function results in this characteristic pattern of renal damage. TMA in patients treated with an anti-VEGF agent therefore seems to result from lowered glomerular VEGF production—a direct on-target effect of the drug.14 Overall, the wide spectrum of toxicity reported in this phase I trial combining two inhibitors of the VEGF pathway simply highlights the fact that targeting angiogenesis is not a tumor-specific approach. It is difficult to draw definitive conclusions regarding the clinical activity reported in the article by Feldman et al,7 due to the limited number of patients treated in this phase I trial. Table 1 summarizes the main efficacy and toxicity features reported in selected trials testing bevacizumab, sunitinib, and sorafenib in RCC, either as single agents or in combination.2–5,7,23,24 Although no formal comparison can be performed, combining sunitinib and bevacizumab yielded the highest reported partial response rate (54%), along with a significant proportion of stable disease (36%). Furthermore, in the trial by Feldman et al, two patients are long-term responders with no evidence of disease for more than 9 months, despite early termination of therapy. This could suggest that this combination schedule could be used for a short period of time.
In conclusion, although maximal inhibition of the VEGF pathway seems to be a promising approach, the current report by Feldman et al demonstrates that potential synergistic inhibition of the VEGF pathway also induces an unexpected degree of toxicity, with a heightened incidence and greater intensity of cardiac, nephrologic, and hematologic adverse effects. Optimizing the management of adverse effects and better selection of patients for treatment with this combination may help refine the dose and schedule of sunitinib plus bevacizumab in patients with cancer. As suggested by Feldman et al, previous nephrectomy performed in 88% of RCC patients included in this trial may have contributed to the high rate of adverse events, because glomerular hyperperfusion and hyperfiltration from chronic renal insufficiency are predisposing risk factors to bevacizumab-induced TMA.25 In that regard, it is important to highlight that a trial of the same anticancer combination administered in a different population (all solid tumors) is currently ongoing without high rates of adverse events (Cooney et al).24 This suggests that the bevacizumab/sunitinib combination may still hold promise but should be carefully developed. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Jean-Charles Soria, Pfizer, Hoffman La-Roche Research Funding: None Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Jean-Charles Soria, Christophe Massard, Hassane Izzedine Collection and assembly of data: Jean-Charles Soria, Christophe Massard, Hassane Izzedine Data analysis and interpretation: Jean-Charles Soria, Christophe Massard, Hassane Izzedine Manuscript writing: Jean-Charles Soria, Christophe Massard, Hassane Izzedine Final approval of manuscript: Jean-Charles Soria, Christophe Massard, Hassane Izzedine Acknowledgment We would like to thank Kapil Dhingra (former global head of Oncology Clinical Development, Hoffmann-La Roche) and Matthew Cooney (University Hospitals, Ireland Cancer Center) for helpful discussions, as well as Lorna Saint Ange for editing. REFERENCES
1. Motzer RJ, Bukowski RM: Targeted therapy for metastatic renal cell carcinoma. J Clin Oncol 24:5601–5608, 2006. 2. Motzer RJ, Hutson TE, Tomczak P, et al: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124, 2007. 3. Escudier B, Eisen T, Stadler WM, et al: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134, 2007. 4. Escudier B, Pluzanska A, Koralewski P, et al: Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: A randomised, double-blind phase III trial. Lancet 370:2103–2111, 2007.[CrossRef][Medline] 5. Rini BI, Halabi S, Rosenberg JE, et al: Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 26:5422–5428, 2008. 6. Ellis LM, Hicklin DJ: VEGF-targeted therapy: Mechanisms of anti-tumour activity. Nat Rev Cancer 8:579–591, 2008.[CrossRef][Medline] 7. Feldman DR, Baum MS, Ginsberg MS, et al: Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 27:1432–1439, 2009. 8. Ellis LM: The role of neuropilins in cancer. Mol Cancer Ther 5:1099–1107, 2006. 9. Verheul HM, Pinedo HM: Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer 7:475–485, 2007.[CrossRef][Medline] 10. Sugimoto H, Hamano Y, Charytan D, et al: Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J Biol Chem 278:12605–12608, 2003. 11. Shaked Y, Bocci G, Munoz R, et al: Cellular and molecular surrogate markers to monitor targeted and non-targeted antiangiogenic drug activity and determine optimal biologic dose. Curr Cancer Drug Targets 5:551–559, 2005.[CrossRef][Medline] 12. Zhu X, Wu S, Dahut WL, et al: Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: Systematic review and meta-analysis. Am J Kidney Dis 49:186–193, 2007.[CrossRef][Medline] 13. Izzedine H, Rixe O, Billemont B, et al: Angiogenesis inhibitor therapies: Focus on kidney toxicity and hypertension. Am J Kidney Dis 50:203–218, 2007.[CrossRef][Medline] 14. Eremina V, Jefferson JA, Kowalewska J, et al: VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 358:1129–1136, 2008. 15. Garovic VD, Wagner SJ, Petrovic LM, et al: Glomerular expression of nephrin and synaptopodin, but not podocin, is decreased in kidney sections from women with preeclampsia. Nephrol Dial Transplant 22:1136–1143, 2007. 16. Eremina V, Sood M, Haigh J, et al: Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 111:707–716, 2003.[CrossRef][Medline] 17. Korgaonkar SN, Feng X, Ross MD, et al: HIV-1 upregulates VEGF in podocytes. J Am Soc Nephrol 19:877–883, 2008. 18. Roncone D, Satoskar A, Nadasdy T, et al: Proteinuria in a patient receiving anti-VEGF therapy for metastatic renal cell carcinoma. Nat Clin Pract Nephrol 3:287–293, 2007.[CrossRef][Medline] 19. Frangié C, Lefaucheur C, Medioni J, et al: Renal thrombotic microangiopathy caused by anti-VEGF-antibody treatment for metastatic renal-cell carcinoma. Lancet Oncol 8:177–178, 2007.[CrossRef][Medline] 20. Kapiteijn E, Brand A, Kroep J, et al: Sunitinib induced hypertension, thrombotic microangiopathy and reversible posterior leukencephalopathy syndrome. Ann Oncol 18:1745–1747, 2007. 21. Izzedine H, Brocheriou I, Deray G, et al: Thrombotic microangiopathy and anti-VEGF agents. Nephrol Dial Transplant 22:1481–1482, 2007. 22. Groff JA, Kozak M, Boehmer JP, et al: Endotheliopathy: A continuum of hemolytic uremic syndrome due to mitomycin therapy. Am J Kidney Dis 29:280–284, 1997.[CrossRef][Medline] 23. Azad NS, Posadas EM, Kwitkowski VE, et al: Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J Clin Oncol 26:3709–3714, 2008. 24. Cooney MM, Garcia JA, Elson P, et al: Sunitinib and bevacizumab in advanced solid tumors: A phase I trial. J Clin Oncol 26:160s; 2008 (suppl) abstr 3530. 25. Katavetin P, Katavetin P: VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 359:205–206, 2008.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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