Bevacizumab is a monoclonal antibody that binds and neutralizes circulating VEGF protein. The activity of this agent in RCC was initially identified by small randomized trials.[26,27] More recently, two multicenter international studies have established bevacizumab(Drug information on bevacizumab)-based therapy as robust in the front-line setting.[28,29]
The AVOREN trial randomized 649 untreated patients with metastatic RCC to treatment with IFN alfa-2a (Roferon-A) plus placebo infusion or to IFN alfa-2a with bevacizumab at 10 mg/kg IV every 2 weeks. This trial demonstrated a significant difference in favor of the bevacizumab-containing arm for objective response rate (31% vs 13%, P < .0001) and PFS (10.2 vs 5.4 months, P < .0001).
The second trial, conducted through the Cancer and Leukemia Group B (CALGB), was nearly identical in design, with the exception of using IFN alfa-2b (Intron A) instead of IFN alfa-2a, lacking a placebo infusion, and not requiring prior nephrectomy. This trial also demonstrated a significant difference in favor of the bevacizumab-containing arm for objective response rate (25% vs 13%, P < .0001) and PFS (8.5 vs 5.2 months, P < .0001). The contribution of IFN-alpha to the antitumor effect of this regimen, especially when balanced against increased toxicity, is unclear, although preliminary results indicate a longer PFS and higher response rate than expected with bevacizumab monotherapy.
Based on these findings, regulatory approval of bevacizumab-based therapy in advanced RCC has been granted in Europe and is expected in the United States, and it is likely that bevacizumab-based therapy will join sunitinib as a front-line standard of care. Although the response rate is lower than that seen with sunitinib, bevacizumab is very well tolerated day-to-day and is familiar to community oncologists given its common use in colorectal and lung cancers.
Temsirolimus is an inhibitor of mTOR, a molecule implicated in multiple tumor-promoting intracellular signaling pathways. Regulation of mTOR pathway activation is mediated through a series of complex signaling interactions linking growth factor receptor signaling and other cell stimuli, phosphatidylinositol 3-kinase (PI3K) activation, and activation of the Akt/PKB pathway.
mTOR phosphorylates and activates p70 S6 kinase (p70S6K), leading to enhanced translation of certain ribosomal proteins and elongation factors. This process leads to—among other effects—the production of HIF-1 alpha, which regulates the transcription of genes that stimulate cell growth and angiogenesis, including VEGF. The second major mTOR effect is on the 4E binding protein-1 (4E-BP1) and eukaryotic initiation factor-4 subunit E (eIF-4E) complex, promoting dissociation of this complex and allowing eIF-4E to stimulate an increase in the translation of mRNAs that encode cell-cycle regulators such as c-myc, cyclin D1, and ornithine decarboxylase.
Retrospective analysis of a prior phase II trial in treatment-refractory metastatic RCC suggested that antitumor activity was more pronounced in a poor-risk subset. A randomized phase III trial was subsequently conducted in patients with metastatic RCC and three or more adverse risk features as defined by the following: Karnofsky performance status < 80%, lactate dehydrogenase > 1.5 × laboratory upper limit of normal, hemoglobin < laboratory lower limit of normal, serum calcium corrected for albumin > 10 mg/dL, time from first diagnosis of RCC to start of therapy < 1 year, plus a sixth factor, ie, three or more metastatic sites identified as prognostic in a separate analysis.[31,32] A total of 626 patients were randomized to temsirolimus at 25 mg IV weekly vs IFN-alpha at 18 MU three times per week vs temsirolimus at 15 mg IV weekly plus IFN-alpha at 6 MU three times per week.
Patients treated with temsirolimus had a statistically longer overall survival than IFN-alpha monotherapy patients (10.9 vs 7.3 months, P = .0069; Table 1). The investigators also found a progression-free survival benefit from temsirolimus monotherapy vs IFN-alpha (median = 3.8 vs 1.9 months, P < .0001). There was no survival advantage to the combination-therapy arm over IFN-alpha monotherapy, perhaps due to the lower dose of temsirolimus, which may have been inadequate for mTOR inhibition.
These data led to US Food and Drug Administration approval of temsirolimus for advanced RCC on May 31, 2007, and validated mTOR as a relevant therapeutic target in RCC, at least in the subset of patients with multiple adverse-risk features. This agent is being used frequently in patients who have failed prior therapy, including prior VEGF-targeted therapy, for whom no safety or efficacy data is yet available. The utility of this agent in patients who do not meet the poor-risk criteria of the phase III trial awaits further study.
Management Strategies for Metastatic RCC Patients
Given the availability of multiple treatment options, each with a slightly different profile of risk and benefit, there are currently several options for initial therapy. The choice of treatment requires appreciation of the risks and benefits of the agents discussed as well as knowledge of the limitations of the current data. The goal for every metastatic RCC patient upon presentation is to maximize overall therapeutic benefit, delaying for as long possible a life-threatening burden of disease while maximizing quality of life and patient convenience. This translates into selecting the treatment with the optimal risk-benefit ratio for a given patient, while realizing that limited criteria exist to predict response to a given agent and that multiple sequential treatments are ultimately likely to be pursued for most patients.
When Should Systemic Therapy Be Started?
Although several active agents are now available for metastatic RCC, their inability to produce durable complete responses necessitates chronic therapy in the majority of patients. Therefore, benefits must be weighed against the overall burden of treatment, including toxicity, time commitment, and cost. A subset of metastatic RCC patients has low-volume, slow-growing disease. For these patients, the overall goal of controlling tumor burden and maximizing quality of life may be achieved more successfully by not initiating immediate systemic therapy.
Evidence suggests that treatment benefit is preserved even if therapy is delayed. For example, Ratain et al reported on 28 patients who were randomized to placebo on the sorafenib(Drug information on sorafenib) randomized discontinuation trial, where sorafenib was readministered upon disease progression. These patients continued on sorafenib until further progression for a median of 24 weeks, identical to the PFS for patients initially randomized to continue sorafenib. These data suggest that some asymptomatic patients can have treatment delayed without compromising the ability to achieve subsequent clinical benefit to therapy.
This critical question of whether a given agent offers identical clinical benefit after a period of observation will require prospective study. This treatment delay could also provide a window for exploring investigational therapy with low toxicity.
Which Agent First?
All the targeted therapies noted above have demonstrated benefit in a phase III setting vs either interferon monotherapy or placebo. None of these agents have been directly compared to one another, and thus definitive answers to this question are not readily available. As noted above, patients are likely to be treated with multiple agents in the course of their disease, and therefore a careful assessment of risk and benefit for each patient is warranted in choosing the most appropriate therapy.
Sunitinib is distinguished by the highest objective response rate. For most patients, control of overall disease burden over the long term is more important than objective response. Nevertheless, a subset of RCC patients have bulky, symptomatic disease, and these patients may require a greater degree of tumor burden reduction in the short term. In this context, sunitinib is the most appropriate choice.
Temsirolimus is the only agent to date to demonstrate an overall survival benefit, albeit restricted to a poor-risk subset of patients. The utility of this agent in an unselected, better-risk population awaits further study.
Bevacizumab-based therapy is noteworthy for a favorable toxicity profile. However, this agent requires infusion therapy and subcutaneous injections if interferon is added.
Sorafenib has not yet demonstrated effects in the front-line setting that are as robust as those of the other agents. Still, its oral availability and favorable toxicity profile may make it a reasonable initial choice in a subset of patients.
As noted below, investigation into sequential therapy may help identify which agent is preferred initially, as exposure of RCC tumors to certain agents may affect tumor biology and response to subsequent therapy. We are also missing tools with which to predict benefit in individual patients from individual drugs. While characteristics such as normal hemoglobin may predict for better response to a single agent (eg, to sunitinib), such general clinical features may not distinguish among the multiple available agents. Translational investigation to identify the molecular phenotype of response and resistance to each of the agents is needed.