Ongoing Clinical Investigations in Metastatic RCC
Other Targeted Agents
• Everolimus—An orally bioavailable derivative of the immunosuppressant macrolide rapamycin that targets mTOR kinase, everolimus (RAD-001, Certican) has shown activity in preclinical models of the cancer. In a phase II study, the clinical efficacy of everolimus in patients with metastatic RCC was evaluated. A total of 25 patients with progressive metastatic RCC were treated with everolimus at a dose of 10 mg daily with continuous dosing. The primary endpoint of the study was time to progression and the secondary endpoint included response rate and toxicity. The median time to progression was 6+ months. A total of 7 patients had partial responses and 11 had stable disease. Treatment-related adverse events included mucositis, skin rash, pneumonitis, hypophosphatemia, hyperglycemia, thrombocytopenia, and anemia. A large phase III trial of RAD-001 vs placebo in treatment-refractory RCC has completed accrual, and results are highly anticipated.
• Pazopanib—Pazopanib is an oral multitarget receptor tyrosine kinase inhibitor with potent effects against VEGFR-1, -2, -3, PDGF receptor (PDGFR)-alpha, -beta, and c-kit. A randomized discontinuation trial of pazopanib at 800 mg daily in treatment-refractory RCC patients was preliminarily reported and demonstrated an objective partial response rate of 40%. Toxicity was generally similar to that observed with other small-molecule VEGFR inhibitors, with the notable lower incidence of hand-foot syndrome. A phase III randomized trial of pazopanib vs placebo in cytokine-refractory patients has completed accrual, and results are anticipated.
• Axitinib—Axitinib (AG-013736) is a substituted imidazole derivative that inhibits the tyrosine kinase portion of all VEGF receptors and PDGFR-beta at low nanomolar concentrations. A phase II trial of axitinib was conducted in cytokine-refractory RCC patients, demonstrating a 44% objective response rate and a median time to progression of 15.7 months. Treatment-related adverse events included diarrhea, hypertension, fatigue, nausea, and hoarseness.
A subsequent trial enrolled sorafenib(Drug information on sorafenib)-refractory RCC patients and demonstrated a partial response in 13 (21%) of 62 evaluable patients, while 55% experienced some degree of tumor regression. One of 14 patients who received both prior sorafenib and prior sunitinib exhibited a partial response. With a median follow-up of 8.1 months, the overall median PFS is 7.4 months. The high objective response rates with this agent and long PFS may be a result of the more potent inhibition of the VEGF receptor. Further study in front-line refractory RCC is planned (Table 2).
• Perifosine—Perifosine is a synthetic, substituted heterocyclic alkylphospholipid that has been shown to inhibit Akt activity; it also has cell-dependent effects upon the MAP kinase pathway. Perifosine has demonstrated activity in patients with metastatic RCC in a randomized phase II trial comparing the weekly vs daily dose of perifosine in patients with solid tumors (2 partial responses among 13 RCC patients). In general, perifosine has most commonly been associated with dose-related nausea, vomiting, diarrhea, and fatigue.
Phase I combination trials of perifosine with sunitinib and sorafenib, in addition to a phase II trial in sorafenib/sunitinib-refractory RCC are ongoing. A phase II/III trial of perifosine (with or without sorafenib) vs sorafenib monotherapy is planned.
• AMG386—Angiopoietin-1 and -2 (Ang1 and Ang2) are naturally occurring ligands for the Tie2 receptor, which is present on endothelial cells and stimulates angiogenesis upon Ang2 engagement. Selective antagonists of Ang2 have inhibited tumor growth in murine xenograft models. AMG386 is a fusion protein containing a synthetic peptide exhibiting high affinity for angiopoietins fused to the constant region of human IgG1.
AMG386 is administered intravenously weekly and is being studied in combination with several VEGF inhibitors in a phase IB trial. Based on the rationale derived from preclinical data of enhanced antitumor effect in combination with VEGF inhibition, a randomized phase II trial of sorafenib monotherapy vs one of two doses of AMG386 is ongoing in previously untreated metastatic RCC patients (Table 2).
The availability and emergence of multiple active monotherapies in RCC has resulted in the clinical use of sequenced therapy. Prior retrospective reviews suggested sequential clinical activity. Despite the lack of prospective data, sequential treatment with VEGF pathway–targeted therapies has become the de facto standard approach in RCC. Thus, prospective investigation of the safety and efficacy of a given targeted agent in the setting of prior exposure to another targeted agent is needed to accurately define the tolerability and clinical benefit of this practice algorithm, as well as studies investigating the mechanisms of progression and resistance to this group of agents.
A study of sunitinib in patients with RECIST-defined disease progression during or within 3 months of bevacizumab(Drug information on bevacizumab)-based treatment (N = 61) reported a partial response in 23% of patients, and 75% of patients overall demonstrated some degree of tumor burden reduction. The median PFS was 30 weeks.
Preliminary data have been reported from a phase II trial examining sorafenib in metastatic RCC patients refractory to either sunitinib or bevacizumab. No objective responses were seen, although nine patients (33%)—six who had received prior sunitinib and three, prior bevacizumab—had ≥ 5% decrease in tumor burden ranging from –7% to –20%. The investigators found no association between tumor shrinkage and response to prior therapy. The median PFS was 3.7 months, with no difference based on prior therapy. Overall, toxicity included hand-foot syndrome, rash, hypertension, diarrhea, and fatigue. There was no difference in toxicity based on prior therapy nor correlation of sorafenib toxicity with toxicity from prior bevacizumab/sunitinib.
The only other prospective trial to date is axitinib in sorafenib-refractory RCC noted above. These preliminary data support the concept that an antitumor effect of VEGF-targeted therapy in RCC can be preserved despite prior exposure to VEGF-targeted therapy.
Several prospective trials will provide further insight into treatment sequencing (Table 2). A large phase III trial will randomize sunitinib-refractory RCC patients to either temsirolimus or sorafenib. Such a trial will begin to investigate whether changing drug mechanisms/targets after the failure of VEGF receptor–targeted therapy is of benefit. Additionally, a phase III trial will randomize front-line refractory RCC patients to axitinib or sorafenib to determine whether more potent VEGFR inhibition by axitinib translates into improved clinical benefit in this setting.
Finally, a multicenter trial will investigate multiple two-drug sequences. Untreated metastatic RCC patients (N = 240) will be randomized to initial sunitinib, bevacizumab, or temsirolimus, with randomization to one of the two drugs not received initially upon first treatment failure. This approach produces six different two-drug sequences and may provide insight into which sequence(s) produce the longest overall duration of disease control. It may also clarify the impact of a given prior treatment on response to subsequent treatment. In the future, it is hoped that this empiric testing of sequences can be supplemented by knowledge of mechanisms of response and resistance from preclinical studies to guide treatment decisions.
Oncology drug development has been marked by the testing of combination regimens involving active single agents. Historically, no particularly active single agents have been available for RCC, and no combinations of modestly active agents ever demonstrated a benefit over monotherapy. As combinations of targeted agents undergo investigation, it will be critical for these combinations to demonstrate clinical benefit above and beyond those of sequential monotherapy with the same agents, in order to justify the added toxicity and risk. Thus, prospective data in this regard are critical, and some data have recently emerged.
Several groups have recently reported on the combination of sorafenib and IFN-alpha. A phase II study examined 40 patients with metastatic RCC receiving a standard dose and schedule of IFN-alpha in addition to sorafenib at 400 mg twice daily. This study reported a 33% response rate and a median PFS of 10 months. At the same time, a Southwest Oncology Group (SWOG) trial was reported, with a 19% response rate and 7-month PFS. These trials generate interesting hypotheses about the potential for combinations of cytokine immunomodulatory therapy with antiangiogenic agents. At this point, however, such combinations cannot be recommended for routine use outside of a clinical trial setting. Additional preclinical data have described potentially favorable immunomodulation with sunitinib therapy. Such data may provide a rationale for combination strategies with immunotherapy to optimize antitumor effect. A greater understanding of the pleiotropic effects of targeted agents is needed to rationally build combinations.
Combinations of VEGF-targeting agents have also undergone initial testing. The combination of sorafenib and bevacizumab showed preliminary evidence of antitumor activity, but the full doses of each agents were not reached due to dose-limiting toxicity related primarily to hand-foot syndrome, functional stomatitis, anorexia, and fatigue. Sunitinib and bevacizumab have also been combined in two separate phase I trials: one limited to RCC patients and the other enrolling all solid tumors.[48,49] Although a maximum tolerated dose (as defined by dose-limiting toxicities occurring during the first cycle) was not reached in either study, relevant toxicity has occurred with prolonged treatment. Thus, the optimal dose and schedule to optimize efficacy while minimizing toxicity is not yet well-defined.
Targeting multiple pathways simultaneously may be the optimal combination approach. One such strategy has combined VEGF pathway inhibition with bevacizumab and mTOR pathway inhibition with temsirolimus. A small phase I study (N = 12) reported safety for the active monotherapy doses for each drug and preliminary efficacy in the form of tumor burden shrinkage for most patients. This approach is now undergoing phase II testing in treatment-refractory patients and will be compared to bevacizumab plus interferon in a phase III trial (Table 2).
Temsirolimus and sorafenib have also been combined in a phase I trial, but full doses were not reached due to toxicity. On a cautionary note about indiscriminate combination of drugs off trial, the combination of sunitinib and temsirolimus was not tolerable, even at the lowest doses of each drug (Temsirolimus, package insert).
An ongoing trial will simultaneously test multiple combinations against bevacizumab monotherapy. The Bevacizumab/Sorafenib/Temsirolimus (BeST) trial, sponsored by the ECOG, will randomize 240 untreated RCC patients to bevacizumab monotherapy or combination therapy with either bevacizumab/sorafenib, bevacizumab/temsirolimus or temsirolimus/sorafenib. This trial will benchmark the PFS of combination therapy against a monotherapy to identify a signal of activity for further testing of one or more combinations.
• Clinical Trial Considerations—The emergence of active agents in RCC has far outpaced the ability to rapidly and definitively test all possible permutations of combinations, sequences, and other approaches to maximizing their benefit. Thus, in light of the relatively limited number of RCC patients eligible for clinical trials, several strategies have emerged.
The optimal strategy for clinical investigation is not clear. Progression-free survival may be the most practical endpoint, given the probable contamination by subsequent active agents limiting the ability to demonstrate improved overall survival in any one trial. The pending survival analyses in the sunitinib and bevacizumab trials will provide additional data on this issue. Several randomized phase II trials are in progress to estimate the benefit of combinations over monotherapy. While suffering from a lack of power to detect small but meaningful differences, these trials can be useful in selecting the best potential combination, which must then be verified in a larger randomized setting. Given the number of important questions to be addressed, continued support of clinical and translational investigation by cooperative groups, the National Cancer Institute, and Industry is needed.
Metastatic RCC is a model solid tumor, in which the elucidation of underlying biology has identified relevant targets. Drugs targeting these pathways have produced robust clinical effects, far surpassing the minimal antitumor activity of historical agents. Further testing of combinations, sequences, and novel agents has the potential to build upon these important advances. Also critical, we will need a deeper understanding of the biology of response and resistance to targeted therapy in order to optimize the use of these agents.
Excitement over targeted therapy is balanced by the lack of complete responses, need for chronic therapy, and toxicity of these agents. If the benefit of these drugs could be considered the excitement of a baseball triple, the home run of a cure may be as hard to achieve as stealing home.
Financial Disclosure: Dr. Bukowski is on the advisory board and is a consultant for Pfizer, Bayer, Genentech, Novartis, and Wyeth. He is also a speaker for Pfizer, Bayer, Genentech, and Wyeth. Dr. Rini has done consulting and has received research funding from Wyeth, Pfizer, Genentech, and Bayer.