Issues have been raised about the sequencing of effective agents to optimize outcome. Following treatment with sunitinib, both everolimus and sorafenib(Drug information on sorafenib) have been associated with improvement in PFS in patients with metastatic RCC. Even as third-line or later therapy, these drugs continue to show excellent tolerability, allowing for continuation of therapy. These observations have led most investigators to recommend the sequencing of therapies unless and until there is high-level evidence to support the safety and efficacy of a combinatorial approach. Despite the growing need for guidance on the optimal sequencing of available therapies, the limited number of cases together with the growing number of treatments makes it unlikely that definitive trials will be performed comparing variations in sequencing. Thus, treating oncologists are left with guidance from the available phase III studies (summarized in Figure).
Some investigators have proposed that, in contrast to sequential administration, combinations may yield synergy and hence more potent clinical activity. Combinations of STIs have been proposed that pair agents having either horizontal relationships (eg, VEGFR + epidermal growth factor receptor [EGFR]) or vertical relationships (eg, VEGF + VEGFR). The initial attempts at combination therapy, including combinations of bevacizumab(Drug information on bevacizumab) with sorafenib and sunitinib, resulted in unacceptable toxicity. Since that time, investigators have opted to determine whether synergy in RCC exists with other, more horizontal combinations. Phase II studies have shown promising results for bevacizumab in combination with mTOR inhibitors.
mTOR inhibitors+ VEGF inhibitors
A phase I trial of tivozanib and temsirolimus in VEGF inhibitor–refractory RCC was performed. The investigators were able to achieve full doses of both agents without dose-limiting toxicities (DLTs). Clinical activity included a 28% PR rate and 64% with SD. Of note, in the phase III study of temsirolimus vs interferon vs a combination of the two, the objective response rate for temsirolimus alone was 8.6%.
Not all combinations have run as smoothly. In a phase I/II trial of sorafenib/everolimus, therapy required dosing at 50% of monotherapy doses because of toxicities, and concurrent therapy was not recommended over sequential therapy due to the lack of improved benefit.
The TORAVA study randomized patients 2:1:1 to receive first-line temsirolimus/bevacizumab, sunitinib, or bevacizumab/IFN-alfa. This phase II study demonstrated significant toxicity of the temsirolimus/bevacizumab combination, which caused 51% of patients in this treatment arm to discontinue treatment before progression was noted. This finding caused the TORAVA investigators to conclude that this combination was not suitable for first-line treatment. A subsequent report from the TORAVA investigators suggested that the smaller randomized phase II setting may not be appropriate for comparisons of regimens such as these. In smaller studies, imbalances in the study arms that may not normalize through randomization make the final results uninterpretable.
A phase II study of everolimus with bevacizumab showed activity in the first and second lines, with ORRs of 30% and 23%, respectively. A phase III study of this combination is underway. In another trial, ~700 patients with TKI-refractory RCC will be treated with this combination. The anticipated completion date is March 2013. In addition, a randomized phase II trial is comparing bevacizumab/everolimus with bevacizumab/IFN-alfa as first-line therapy in mRCC.
Eastern Cooperative Oncology Group (ECOG) trial 2804 is a phase II study comparing different combinations of bevacizumab, temsirolimus, and sorafenib vs bevacizumab alone. Approximately 360 patients have been randomized into four arms: bevacizumab; bevacizumab/temsirolimus; bevacizumab/sorafenib; or temsirolimus/sorafenib. Results from this accrued study are anxiously anticipated.
VEGFR inhibitor + EGFR inhibitor: cediranib + gefitinib(Drug information on gefitinib) (Iressa)
Overexpression of EGFR has long been recognized in RCC. Epidermal growth factor (EGF) is capable of stimulating proliferation of RCC both in vitro and in vivo. It also appears to be linked to tumorigenesis in von Hippel–Lindau (VHL)-mutant xenografts. Clinical trials of EGFR inhibitors such as erlotinib (Tarceva) have not shown impressive clinical activity, although in a prospective study of papillary RCC, an ORR of 11% was reported. A phase II study of gefitinib was also initiated but has shown no responses. In the phase III setting, lapatinib (Tykerb) was shown to improve median OS in patients with cytokine-refractory disease compared with hormonal therapy (a historic control in RCC studies), with a shift from 37.9 to 46.0 weeks (HR, 0.69; P = .02).
Some consideration has been given to whether EGFR inhibition alone is sufficient to impact tumor biology, given the modest effects of therapy. Combinations of EGFR inhibitors with VEGFR inhibitors have been attempted. In a phase I/II trial of sunitinib with gefitinib, investigators found the addition of gefitinib to be tolerable if the sunitinib dose was reduced to 37.5 mg. Of patients who received the maximum tolerated dose (MTD) of gefitinib (in combination with 37.5 mg of sunitinib), 37% experienced a PR while 34% had SD, for a clinical benefit rate of 71%. With this combination, the DLT was diarrhea. An alternative approach using cediranib instead of sunitinib (ie, cediranib + gefitinib) has also been tested. This regimen was also well tolerated, with diarrhea, anorexia, and fatigue being the most common adverse events. Of the 18 patients with RCC in this study, 6 achieved a PR.
Given an unlikely toxic synergy, STIs have been tested in combination with immunotherapy approaches. The ROSORC trial randomly assigned treatment-naive patients to sorafenib with or without IL-2. Despite patients experiencing toxicity from IL-2 that required dose reduction, no benefit was detected for the addition as measured by PFS. Similarly, a combination of sorafenib with the tumor necrosis factor (TNF)-alpha antagonist infliximab(Drug information on infliximab) (Remicade) resulted only in increased toxicity without improvement in response. Combinations of sorafenib with low-dose IFN also did not significantly impact outcome. Another group tested recombinant interleukin-21 (rIL-21) with sunitinib, given preclinical data that rIL-21 sustained antitumor responses in engineered models of sunitinib resistance. This combination resulted in excessive hematologic toxicity that prevented completion of the phase I study. A similar finding occurred with tremelimumab (CP-675206; an antibody against CTLA-4). Rapid-onset acute renal failure was seen unexpectedly, preventing completion of the dose escalation.
Tolerable combinations include bevacizumab with IFN and temsirolimus with IFN. However, the combination of temsirolimus with IFN, while tolerable, did not yield an improvement in OS in phase III evaluation.
Perioperative systemic therapy has been shown in several clinical settings to impact clinical outcomes. Current practice guidelines do not include recommendations for adjuvant or neoadjuvant therapy. The earliest clinical studies defining the use of known active agents in this setting have not yet matured. Advances in this field have been largely limited by the lack of highly effective treatments with acceptable toxicity in the perioperative setting.
A formal exploration of the safety and feasibility of neoadjuvant VEGFR inhibition was reported for patients undergoing nephrectomy for RCC. All patients had clear-cell carcinoma and were eligible regardless of nodal status or metastases, provided they were deemed appropriate for nephrectomy. Using an alternative dosing scheme of 37.5 mg daily for 12 weeks, the investigators found no surgical complications in the sunitinib arm, with 85% of patients experiencing reduction in tumor size. A similar experience was reported using sunitinib before nephron-sparing surgery for RCC. Another study with short-course sorafenib showed partial responses without significant negative impact on the surgical procedure. A fourth study using bevacizumab with or without erlotinib was conducted; wound dehiscence that was attributed to bevacizumab was noted.
The use of STIs in the adjuvant setting has been and continues to be explored. Earlier studies in the adjuvant setting suffered from either a lack of effective treatments or excessive toxicity from cytokines. With the introduction of active targeted agents, a number of trials have emerged that have involved sorafenib (ASSURE), sunitinib (ASSURE, S-TRAC), pazopanib (PROTECT), and everolimus (EVEREST). Other trials are also in development with newer compounds. A positive impact on clinical outcomes holds potential for a significant advance in the clinical care of patients with advanced RCC, for whom the current standard of care calls for observation.
Cytoreductive Nephrectomy for Metastatic Disease
The traditional teaching in RCC has been that cytoreductive nephrectomy improves outcomes from systemic therapy. This teaching has been based on phase III data showing an improvement in response to IFN following nephrectomy in the metastatic setting.[75,76]
The generalizability of this statement to noncytokine therapies has been called into question. At this time, there are only limited data to guide practitioners. In a retrospective analysis of 314 patients beginning VEGFR-targeted therapy, cytoreductive nephrectomy did correlate with improved OS (19.8 vs 9.5 mo; HR, 0.44; P < .01). However, the same study showed that patients who underwent nephrectomy were younger, had better performance status, and tended to have fewer sites of disease.
The emergence of data in the perioperative setting demonstrating biological activity and safety calls for further investigation to determine the optimal timing or role of nephrectomy in the treatment of advanced disease.
As clinical data with cytokines, STIs, and immunomodulators become available, the therapeutic options for patients with RCC will only continue to grow. The multiplicity of options offers new hope for patients, but at the same time has led to a decrease in clinical trial participation, which is urgently needed to enable this field to advance. With so many promising agents, the inability to complete appropriately powered clinical studies threatens to stymie the rate of advancement in RCC clinical research. It has become more important now for treating physicians to be aware of areas of development so that patients appropriate for study can be identified.
Now more than ever, the potential for utilization of these therapies in concert with surgery and/or radiation therapy underscores the need for multidisciplinary teams centered on patients with RCC. In short, there are a number of promising treatments that appear to be active where currently available therapies are not. These include a series of TKIs against not only VEGFR and mTOR, but also FGFR and AKT. Additionally, the field of immunomodulation continues to evolve beyond cytokine therapy. This diversity of growth promises to continue to create opportunities for significant advancement toward a cure for this disease. At the current time, the sequential use of STIs that target the VEGF/VEGFR and mTOR pathways has the highest level of evidence for clinical practice. Integration of IL-2 into this paradigm requires an understanding of the risk/benefit ratio and the importance of patient selection. In the future, options for patients will ultimately derive from the performance of carefully designed clinical trials and the integration of comparative effectiveness research into the changing paradigm for this disease. As clinical investigators, we must contend with the limited pool of patients that exists. The small size of the patient pool stands in stark contrast to the large number of potential studies that could be performed to determine the comparative efficacy of emerging treatments. Thus, we must emphasize the need for collaborative networks to be organized to allow for efficient multicenter studies with clear clinical endpoints and aggressive biospecimen banking that will allow for translational research and advancement in this area. Given the complexity of such studies, partnerships between the pharmaceutical industry, academic institutions, and government regulators must be formed to lead these efforts. Ultimately, without aggressive and informative biospecimen interrogation, rationales for variations in the sequence or combination of therapies cannot be strongly hypothesis-driven. Emerging studies in the area of RCC demonstrate that scientific partnerships such as these that allow for translational research are possible, but care must be taken in deciding how to advance the next generation of agents into the clinical arena and determining in which settings they should be tested.
In summary, the field of RCC therapy is seeing a number of advances in current treatment paradigms. These include the introduction not only of newer and more potent drugs, but also of new molecular targets, new therapeutic strategies, and novel uses of existing treatments, all of which must be combined with aggressive research. For this field to continue to move forward, continued academic efforts must be supported.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.