A growing understanding of the underlying molecular biology of renal cell carcinoma (RCC) has established the vascular endothelial growth factor (VEGF) pathway as a relevant therapeutic target. The pathogenesis of RCC was elucidated by the discovery of the VHL gene from study of von Hippel-Lindau (VHL) syndrome families.1VHL is a tumor suppressor gene in which 1 allele is inactivated through a deletion (also known as loss of heterozygosity) observed in >90% of noninherited (sporadic) clear cell RCC.2 The remaining VHL allele is inactivated either through gene mutation (approximately 50% of clear cell RCC3-5) or through gene silencing by methylation (approximately 5%-10% of cases1, 6). This biallelic gene inactivation promotes a tumor phenotype. VHL encodes the VHL protein, which is a component of an E3 ubiquitin ligase complex that targets a transcription factor called hypoxia-inducible factor (HIF) for ubiquitinization and proteasome-mediated degradation (Fig. 1). If VHL is inactivated, then a defective VHL protein is produced, and HIF is not degraded. The VHL protein also is unable to bind HIF in conditions of hypoxia, as occurs in RCC and other solid tumors. Activated HIF then translocates into the nucleus and leads to the transcription of VEGF and of a variety of genes that play a central role in tumor progression.7
Inactivation of the von Hippel-Lindau tumor suppressor gene in most sporadic renal cell carcinoma (RCC) tumors leads to a fundamental reliance on elements of this pathway, namely, the potent proangiogenic factor, vascular endothelial growth factor (VEGF). Thus, VEGF-targeted therapeutics have undergone extensive clinical testing in RCC. Approaches to bind circulating VEGF protein (eg, bevacizumab) and small molecule inhibitors of the receptor on which the VEGF ligand binds (eg, sunitinib, sorafenib, axitinib, and pazopanib) have been tested. Robust clinical effects have been observed, including high objective response rates, prolonged progression-free survival, and evidence of long overall survival for patients with metastatic RCC patients who are treated with these agents. Future directions include investigation of combination and sequenced therapy, elucidation of mechanisms of response and resistance, and exploration of the effect of these agents in other disease settings. Cancer 2009;115(10 suppl):2306-12. © 2009 American Cancer Society.
Sunitinib (Sutent; Pfizer Inc., New York, NY) is a small molecule inhibitor of the tyrosine kinase portion of the VEGF family of receptors.8 Initial phase 2 trials of sunitinib given at a dose of 50 mg orally every day for 4 weeks on followed by 2 weeks off in patients with metastatic RCC (n = 169 total patients) who failed on prior cytokine-based therapy demonstrated an investigator-assessed objective response rate of 45%, a median response duration of 11.9 months, and a median progression-free survival (PFS) of 8.4 months (Table 1).9, 10 A phase 3 trial in patients with untreated, metastatic RCC (n = 750) of sunitinib versus interferon-alpha demonstrated a significant advantage in an independently assessed objective response rate (31% vs 6%; P < .001) and in PFS (11 months vs 5 months). The hazard ratio for progression was 0.42 (P < .001) for sunitinib-treated patients.11 Baseline clinical features that were predictive of improved PFS at 12 months in sunitinib-treated patients included an Eastern Cooperative Oncology Group performance status of 0, a time from diagnosis to metastases ≥1 year, and a corrected serum calcium level ≤10 mg/dL.11 Overall survival (OS) data also were reported recently.12 Sunitinib-treated patients had a median OS of 26.4 months versus 21.8 months for interferon-treated patients (P = .051). It is noteworthy that several patients who were randomized to receive interferon received sunitinib and other active, targeted therapy on progression, likely under powering this trial to detect a difference in OS. Clearly, the very high median OS numbers compared with historic controls support the finding that targeted therapy has meaningfully extended the lives of patients with metastatic RCC. On the basis of these data, sunitinib has emerged as a front-line standard of care in metastatic RCC. This drug is notable for a superior objective response rate compared with the other agents balanced against toxic effects, including fatigue, hand-foot syndrome, diarrhea, hypertension, and hypothyroidism.13 Cardiac toxicity also has been described with sunitinib as well as sorafenib. These events largely comprise declines in ejection fraction/congestive heart failure as well as cardiac ischemia.14, 15 Descriptions of cardiotoxicity have come largely from retrospective, single-institution reviews. Thus, more thorough, prospective investigation of these potentially relevant toxicities is needed to define appropriate monitoring and intervention and to properly equate the risk/benefit of these agents.
|VEGF receptor inhibition|
|Sunitinib||30%-45% (In both cytokine-refractory and treatment- naive patients)||11 Mo vs 5 mo for IFN (P<.000001) in treatment-naive patients; 8.4 mo in cytokine-refractory patients (pooled phase 2 trial data)||OS: 26.4 mo vs 21.8 mo for IFN-treated patients (P = .051); common toxic effects include fatigue, mucositis, hand-foot syndrome, diarrhea, hypertension, and hypothyroidism|
|Sorafenib||2%-10%||5.7 Mo vs 5.6 mo in IFN arm (P = .5) in treatment-naive patients (randomized phase 2 trial); 5.5 mo vs 2.8 mo in placebo arm (P<.000001) in cytokine-refractory patients (phase 3 trial)||OS: 17.8 mo vs 15.2 mo for patients in the placebo group (HR, 0.88; P = .146); common toxic effects include fatigue, mucositis, hand-foot syndrome, diarrhea, and hypertension|
|Axitinib||44% (Cytokine- refractory RCC), 23% (sorafenib- refractory RCC)||15.7 Mo (cytokine-refractory RCC); 7.4 mo (sorafenib-refractory RCC)||Common toxic effects include fatigue, diarrhea, and hypertension; phase 3 in front-line refractory RCC vs sorafenib ongoing (AXIS trial)|
|Pazopanib||35%||11.9 Mo (phase 2 trial; phase 3 trial vs placebo completed and 69% without prior treatment)||Phase 3 trial vs sunitinib in treatment-naive RCC patients ongoing|
|VEGF ligand binding|
|Bevacizumab||10%-13% (Monotherapy: Bukowski 2007,18 Yang 200325), 26%-31% (in combination with IFN)||8.5 Mo in treatment-naive patients as monotherapy; 8.5 mo and 10.2 mo in treatment-naive patients in combination with IFN; 4.8 mo in cytokine-refractory patients||OS data from phase 3 trials pending; common toxic effects include fatigue, anorexia, hypertension, and proteinuria|
Sorafenib (Nexavar; Bayer Pharmaceuticals [West Haven, Conn] and Onyx Pharmaceuticals [Richmond, Calif]) is a small molecule inhibitor of VEGF and related receptors and also inhibits an intracellular signaling enzyme, raf kinase.16 A phase 3 trial of sorafenib randomized 905 patients with treatment-refractory, metastatic RCC to receive either sorafenib 400 mg orally twice daily or placebo. A PFS advantage in the treatment arm of 5.5 months versus 2.8 months was observed (P < .000001) (Table 1).17 The hazard ratio for disease progression in the sorafenib group was 0.44 (P < .01). The median OS was 17.8 months for patients in the sorafenib group and 15.2 months for patients in the placebo group (hazard ratio, 0.88; P = .146). However, there was a suggestion of improved survival with sorafenib after the censoring of placebo patients who crossed over to the sorafenib arm (17.8 months vs 14.3 months; P = .03) with similar concerns of on-study and off-study crossover, as noted above with sunitinib.18 These phase 3 data are somewhat in contrast to the results from a smaller, randomized phase 2 study of sorafenib versus interferon in 189 patients with previously untreated, metastatic RCC. The median PFS in that trial was 5.7 months with sorafenib versus 5.6 months with interferon.19 Currently, the reason for the lack of a significant effect compared with interferon in the front-line setting is not entirely clear but may result from weaker inhibition of the VEGF receptor compared with sunitinib.16 Toxic effects with sorafenib generally are the same type as those with sunitinib but may be somewhat less in severity. Although, in some patients, sorafenib is a preferred initial agent because of the toxicity profile or other considerations, the use of sorafenib has moved toward second-line and later therapy. Studies are needed to identify the phenotype of patients in whom sorafenib is the preferred initial treatment.
Axitinib (AG-013736; Pfizer Inc.) is a substituted imidazole derivative that inhibits the tyrosine kinase portion of all VEGF receptors and platelet-derived growth factor receptor (PDGFR)-β at notably low nanomolar concentrations. Oral, twice daily axitinib dosing results in significant tumor growth inhibition in several human xenograft and murine models through an antiangiogenic mechanism. A phase 2 trial of axitinib at a dose of 5 mg orally twice daily (continuous dosing) was conducted in 52 patients with RCC, all of whom had failed on prior cytokine therapy.20 In an intention-to-treat analysis, 2 complete responses and 21 partial responses were noted for an objective response rate of 44.2%, and most patients displayed some tumor shrinkage. The median response duration was 23 months, and the median time to progression was 15.7 months. The median time to progression, the objective response rate, and the response duration in that study compare favorably with available data for other drugs, although such comparisons are limited given the investigator-assessed response and separate conduct of the trials. A hypothesis can be generated that the high picomolar potency of axitinib against VEGF receptors 1, 2, and 3 accounts for the high level of antitumor activity. Treatment-related adverse events included diarrhea, hypertension, proteinuria, fatigue, nausea, and hoarseness. Treatment-related hypertension occurred in 30 patients and resolved with antihypertensive treatment in all but 8 patients, including 7 patients who had a history of hypertension at baseline. The notable toxic effects of hypertension and proteinuria likely reflect potent inhibition of the VEGF receptor.
Patients with sorafenib-refractory RCC were enrolled in a subsequent multicenter, open-label, phase 2 study.21 Axitinib was administered at 5 mg orally twice daily, with dose escalation up to 10 mg twice daily allowed if tolerable. Patients in that study were treatment refractory and had received a median of 2 prior therapies (range, 1-8 prior therapies); all patients had received prior sorafenib, and 14 patients also had received prior sunitinib. A partial response was observed in 13 of 62 evaluable patients (23%), whereas 55% experienced some degree of tumor regression. One of 14 patients who received both prior sorafenib and sunitinib exhibited a partial response. With a median follow-up of 8.1 months, the overall median PFS was 7.4 months. A phase 3 trial of axitinib versus sorafenib currently is underway in patients with metastatic RCC who failed front-line therapy.
Pazopanib (GlaxoSmithKline, Research Triangle Park, NC) is an oral multitarget receptor tyrosine kinase inhibitor of VEGF receptors 1, 2, and 3; PDGFR; and c-kit that has a significant inhibitory effect on endothelial cell proliferation and inhibition of VEGF-induced VEGF receptor-2 phosphorylation in mouse lungs and cornea in a dose-dependent manner.22 A randomized, discontinuation design, phase 2 study recently was conducted in patients who had received either no systemic therapy or 1 prior systemic therapy.23 Two hundred twenty-five patients with metastatic RCC were treated (69% previously untreated patients and 84% patients with good or intermediate risk). The independently reviewed objective response rate was 34.7%, and the median PFS was 11.9 months. The PFS in the randomized comparison (n = 55) was 11.9 months for pazopanib versus 6.2 months for placebo (P = .0128). Toxic effects included those typical of this class of VEGF receptor inhibitors, including fatigue, diarrhea, and hypertension, with a notably low incidence (12% any grade) of hand-foot syndrome. A phase 3 trial versus placebo in patients with RCC who either received no prior therapy or failed on prior therapy with cytokines or bevacizumab has completed accrual, and those results are expected in 2009. In addition, a phase 3 trial versus sunitinib in patients with treatment-naive RCC is underway.
Bevacizumab (Avastin; Genentech, South San Francisco, Calif) is a monoclonal antibody that binds and neutralizes circulating VEGF protein.24 The activity of this agent in RCC was identified initially in small randomized trials.18, 25 More recently, multicenter international studies have established bevacizumab-based therapy as robust in the front-line setting.26, 27 A phase 3 trial randomized 649 untreated patients with metastatic RCC to receive treatment either with interferon (Roferon; Roche, Basel, Switzerland) plus placebo infusion or interferon plus bevacizumab infusion at a dose of 10 mg/kg every 2 weeks.26 A significant advantage was observed for bevacizumab plus interferon (objective response rate, 31% vs 13%; P < .0001; PFS, 10.2 months vs 5.4 months; P < .0001) (Table 1). The hazard ratio for progression in the bevacizumab plus interferon arm was 0.63 (P = .0001). A second multicenter phase 3 trial, which was conducted in the United States and Canada through the Cancer and Leukemia Group B, was nearly identical in design with the exception that it lacked a placebo infusion and did not require prior nephrectomy.27 In that trial, the median PFS was 8.5 months in patients who received bevacizumab plus interferon versus 5.2 months for patients who received interferon monotherapy (P < .0001). The hazard ratio for progression in patients who received bevacizumab plus interferon after adjusting for stratification factors was 0.71 (P < .0001). In addition, among patients with measurable disease, the objective response rate was higher in patients who received with bevacizumab plus interferon (25.5%) than for patients who received interferon monotherapy (13.1%; P < .0001). The contribution of interferon to the antitumor effect of this regimen currently is unclear, although preliminary results indicate a longer PFS and a higher response rate than expected with bevacizumab monotherapy.25 In addition, a subset analysis revealed a similar benefit with the combination in patients who had an interferon dose reduction because of toxic effects.28 Given the lack of dose response for interferon, it is possible that lower interferon doses in this combination can reduce toxic effects and preserve efficacy. Such a hypothesis requires prospective testing. Combination interferon and bevacizumab therapy is more toxic than either agent as monotherapy, notably for fatigue, anorexia, hypertension, and proteinuria. Thus, the use of interferon with bevacizumab requires evaluation of the risk-benefit ratio for each patient. On the basis of these findings, regulatory approval of bevacizumab plus interferon in patients with advanced RCC has occurred in Europe and is expected in the United States. Given the presence of high-level evidence consisting of 2 positive phase 3 trials of this combination, it is likely that bevacizumab plus interferon will join sunitinib as a front-line standard of care.
Because VEGF-targeting agents have established themselves as active monotherapies in metastatic RCC, several questions have emerged. Sequencing of monotherapies has become the empiric standard, with retrospective and emerging prospective data supporting this treatment paradigm. Whether a specific sequence is preferred requires additional testing. In addition, combinations of these agents to maximize VEGF pathway inhibition and potentially augment the antitumor effect have begun initial assessment for safety and efficacy. Large trials of high-risk, resected, localized RCC have begun to delineate the value of this approach in the adjuvant setting. Further, additional work is needed to identify the clinical and molecular phenotype of response and resistance to this approach in an effort to more appropriately individualize therapy.
Multiple approaches to block the action of VEGF have emerged as therapeutically viable strategies in metastatic RCC. VEGF-targeted agents have revolutionized the management of this disease and are now the standard of care. Additional clinical and translational research is needed now to optimize the use of these agents. The relative risks and benefits to each approach for an individual patient require further study.
The questions and discussion below follow from the oral presentation given at the Third Cambridge Conference on Innovations and Challenges in Renal Cancer and do not correspond directly to the written article, which is a more general review.
Discussion after Brian I. Rini's presentation.
Michael Atkins: With regard to the thyroid problems that happened with sunitinib, it seems to happen in patients who continue taking the drug for a long period. Do you think this effect is anything more than just a toxic effect on the thyroid? Is there any evidence that it might be immune mediated?
Dr. Rini: I am not aware of any evidence that it is immune mediated.
Dr. Atkins: So patients on the drug longer are more likely to develop thyroid dysfunction?
Dr. Rini: I think so.
Robert Figlin: Is it a chemical or clinical effect?
Dr. Rini: First it is biochemical, then clinical.
Marston Linehan: Does this reverse?
Dr. Rini: It reverses with discontinuation of the drug.
Bernard Escudier: I have patients in complete remission with sunitinib. I have stopped the drug, and they remain in complete remission. I know that most of you would probably continue with the drug, but while they were in complete remission they had no reason to continue. The longest duration is 6 months.
Dr. Rini: I think there will be a tail of the curve. To say there are no complete remissions or no durability is not known yet.
Ronald Bukowski: There is a tail with interferon, too.
Dr. Atkins: It is fair to say that those data are based on patients treated in 1988. A lot more has been done since then in terms of selecting patients who get therapy. In 2000, the response rates to high-dose IL-2 were in the 20% to 25% range, and 10% of people had durable complete remissions. It is possible that there may be ways to select even further using various markers.
Dr. Rini: More people have not embraced this because it is such a highly selective procedure applied to a highly selective population, but IL-2 still has some role.
Dr. Atkins: What do you think explains the difference in activity between sorafenib and sunitinib? Do you think it has to do with how effectively they block VEGF receptor signaling, or are there other targets of these agents that may be critical in explaining their different response rates?
Dr. Rini: It could be both. My bias is that it is potency and selectivity against the VEGF receptor.
Dr. Atkins: It seems like the data with sunitinib, which has less off-target effect, probably support that.
Conflict of Interest Disclosures
The program was made possible by educational grants provided by Genentech, Novartis Pharmaceuticals, Pfizer, Inc., and Wyeth Pharmaceuticals. Program management and CME sponsorship were provided by InforMEDical Communications, Inc., Carlisle, Massachusetts.
Brian I. Rini has served as a consultant and received research funding from Bayer, Genetech, Pfizer, and Wyeth.