In this study, patients with HIV-KS on a stable HAART regimen received bevacizumab 15 mg/kg every 3 weeks after an initial loading dose. Best ORR was 31% (95% CI, 11% to 58.7%), meeting predefined criteria for consideration in future combination studies. Median PFS was 8.3 months. Compared with bevacizumab monotherapy studies in metastatic renal cell cancer or recurrent ovarian cancer, in which ORRs of 10% to 21% were seen,44–46
responses observed in HIV-KS are quite good. Moreover, these responses were seen in patients with poor prognosis KS,41
and four of five responding patients had received prior cytotoxic chemotherapy (). In contrast to most cytotoxic agents active in KS, bevacizumab does not seem to impair immune reconstitution, an important feature for therapeutic interventions for HIV-KS.
Patients who responded had controlled HIV and increases in CD4 counts while on bevacizumab (). Baseline CD4 lymphocytopenia may have been in part a result of prior chemotherapy in most patients, and cessation of hematotoxic chemotherapy seems to permit the increases in CD4 counts observed in responding patients. A limitation to any phase II study in HIV-KS is that possible immune reconstitution must be taken into consideration, and HAART alone can induce responses in KS (approximately 20% in controlled trials9,13
). Meta-analysis suggests that most patients with HIV-KS who respond to HAART alone have T0
KS (limited disease); only five documented cases were identified in which patients with T1
KS (widespread disease) responded to HAART alone.10
In the current study, all responders had T1
KS, and most had prior cytotoxic chemotherapy, making it unlikely that responses were a result of HAART alone. Moreover, most KS responses to HAART occur soon after the initiation of HAART, although paradoxical worsening of HIV-KS after starting HAART is also described.47,48
To limit these potential biases, we required patients to have either KS not regressing while on HAART for 4 months or progressing on HAART for 1 month. Given the potential role of VEGF dysregulation in the pathophysiology of KS-associated pleural effusions49
and edema, rapid resolution of pleural effusions in one patient and common subjective improvement in tumor-associated edema were noteworthy observations. Nonetheless, definitive assessment of anti-KS efficacy of bevacizumab beyond that of HAART alone requires a randomized controlled trial.
With the exception of decrease from baseline in IL-8, assessment of serum VEGF-A and cytokines did not show substantial changes or association with responses. Bevacizumab binds to VEGF-A, and measurement of bound VEGF-A may affect assay results.50
Although difference between responders and nonresponders was not statistically significant, the decrease in IL-8 is interesting, because KSHV encodes a latently expressed gene, K13
, that transcriptionally upregulates IL-851
and may have a role in mediating angiogenesis in KS.52
Additional studies will be needed to evaluate IL-8 as a biomarker and to sort out its possible biologic role in KS response to bevacizumab.
Bevacizumab was generally well tolerated over a relatively long time. Adverse events () were comparable with those seen in other studies.53
Two noteworthy toxicities at least possibly attributable to long-term bevacizumab were proteinuria (> 1 g/d) in one patient and a decreased cardiac EF in another; in both cases, toxicities improved with bevacizumab discontinuation. In addition, five patients required initiation of antihypertensive agents. Three patients developed soft tissue infections; KS patients are susceptible to soft tissue infections, and it was unclear whether bevacizumab had a role in their pathogenesis. Overall, the toxicity profile observed in this HIV-positive population receiving HAART supports bevacizumab use in future studies in HIV-associated cancers, as well as its use in HIV-positive patients with cancers for which bevacizumab is US Food and Drug Administration approved. This is particularly important given the increasing burden of non–AIDS-defining malignancies such as lung cancer and colon cancer in HIV-infected individuals in the United States.5
KS response rates are affected by extent of disease, degree of immunosuppression, and control of HIV, and response rates can be difficult to compare among clinical trials. The observed ORR here is less than that reported with liposomal anthracyclines13–16
but is comparable to that seen using agents that inhibit angiogenesis through different mechanisms, such as TNP-47054
or the matrix metalloproteinase inhibitor COL-3.55,56
Given the important role of VEGF-A in KS pathogenesis, one must ask why bevacizumab was not more active. One likely reason is that redundant angiogenic and proliferative stimuli activate spindle cell proliferation. In addition to VEGF-A receptors 1 and 2, KS spindle cells express VEGF-A receptor 3 and the receptor for platelet-derived growth factor (PDGF) and proliferate in response to ligands for these receptors (VEGF-C and PDGF).57–60
Furthermore, a number of KSHV genes, such as latency-associated nuclear antigen (LANA
, and kaposin-A
, can inhibit apoptosis or directly contribute to KS spindle cell proliferation.61
Thus, optimal targeted therapy for KS may require targeting two or more of these pathways simultaneously.54–56
Although only a subset of patients responded in this trial, results should be considered in light of the fact that most patients had features making them unlikely to respond to any therapy. Overall, this study suggests that bevacizumab has utility in KS. In particular, bevacizumab may be of value in combination with other drugs or after initial reduction of the tumor burden with cytotoxic chemotherapy, or in patients who are approaching the maximal safe cumulative dose of anthracyclines. A second study of bevacizumab combined with liposomal doxorubicin, followed by bevacizumab maintenance (ClinicalTrials.gov identifier: NCT00923936), is under way, and a randomized trial of bevacizumab is worth considering. With increasing insight into KSHV biology and range of clinical presentations of KS38
and other KSHV-associated malignancies, rational therapeutic approaches such as bevacizumab offer hope for both cytotoxic-sparing treatment options and personalized approaches to difficult-to-manage specific tumor-associated symptoms like chronic edema and effusions.