From Theoretical Synergy to Clinical Supra-Additive Toxicity
Authors: Jean-Charles Soria, Christophe Massard, Hassane Izzedine
Journal: Journal of Clinical Oncology (2009)

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), who could potentially benefit from three approved angiogenesis inhibitors that target vascular endothelial growth factor (VEGF) signaling: bevacizumab, sunitinib, and sorafenib. Combining agents with related targets may enhance antitumor activity through vertical inhibition of a single pathway in which blockade is reinforced at multiple sites. 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 al 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. 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. 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. The phase I trial reported by Feldman et al 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. 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%). 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). 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 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 9 MARCH 2