Dr Dreicer on the Complexities of Prostate Cancer

Robert Dreicer, MD, deputy director, director, solid tumor oncology, Division of Hematology/Oncology, professor, medicine and urology, the University of Virginia Cancer Center, 

discusses the overall goal of his presentations

, “From PSA Failure to Hormone Sensitive Metastatic Prostate Cancer?” and “CRPC: Start of the Art,” given at 

 Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies, highlighting a case study in prostate cancer.

The goal of the presentations was to provide an overview of the complexities of prostate cancer, Dreicer begins, adding that he highlighted the disease’s heterogeneity and the diversity among the oncologists who manage it. By discussing cases that reflect the broad spectrum of prostate cancer, Dreicer states that he set the stage for more detailed conversations and case-based discussions during the meeting.

In the metastatic castration-resistant prostate cancer setting, Dreicer focused on the factors that make advanced prostate cancer unique compared with other solid tumors, particularly in terms of treatment sequencing. Treating oncologists have limited data guiding appropriate treatment sequences, and treatment approaches can vary significantly depending on whether a patient is managed by a urologist, a medical oncologist, or a genitourinary medical oncologist, he explains. Although this variability may be acceptable in the absence of strong evidence, it’s not ideal for patient care, Dreicer adds.

One case study that Dreicer highlighted in the presentations involved a patient with locally advanced disease, which typically requires multimodality therapy for the best chance of cure. The challenge here lies in integrating next-generation imaging, like prostate–specific membrane antigen [PSMA] PET CT, into treatment decisions, he says. These imaging results may suggest more distant disease, raising questions about whether to pursue curative-intent strategies based on historical imaging approaches or adapt based on the new imaging findings, despite the lack of evidence from current trials that include PSMA PET imaging, according to Dreicer. This represents a real-world challenge in managing prostate cancer today, Dreicer concludes.

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Robert Dreicer, MD, discusses his presentation from the 17th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies.

	The Prostate Cancer Clinical States model was first proposed by Scher and colleagues nearly 10 years ago. As this model has been refined, it provides a framework for thinking about prostate cancer from a clinical management perspective and in the context of conducting investigational studies for new drug development.

	Historically, androgen-deprivation therapy (ADT) has been used as a first-line treatment for advanced prostate cancer, with a goal of achieving testosterone levels in the body nearly equivalent to the levels afforded by surgical castration (

 Based on Medicare data from the Surveillance, Epidemiology, and End Results (SEER) program, the use of ADT among Medicare beneficiaries was used in 44.8% of all prostate cancer cases diagnosed between 2000 and 2002; in 15% of patients, ADT was used as an adjuvant with radiation, and in 14% of patients, it was given as primary therapy.

	ADT initially induces remission or stabilization in most patients with locally advanced or metastatic prostate cancer, but within 18 to 24 months, nearly all will experience disease progression.

 Prior to the advent of prostate-specific antigen (PSA) testing, patients with known metastatic disease who developed disease-related symptoms (eg, pain, progressive fatigue, weight loss) were believed to be experiencing progression, which was verified using bone scanning and/or computed tomography (CT) imaging. Patients progressing on hormonal therapy were typically identified as androgen independent or hormone refractory. Median survival from the onset of progression for androgen-independent patients with metastatic disease was 10 to 12 months.

	In today’s PSA era, the identification of “progression” is typically a rising PSA in the setting of castrate levels of testosterone (<50 ng/dL). Recent evidence from hypothesis-generating studies has resulted in proposals to reduce the target castrate level of testosterone to ≤20 ng/dL, which has been associated with improved progression-free survival.

 However, a subset of patients treated with luteinizing hormone releasing hormone (LHRH) agonists, a therapy commonly used since the early 1970s, failed to achieve a target level of 50 ng/dL,

 and, of course, even patients who achieve this nadir eventually progress.

	Management of patients with disease progression following ADT has typically involved an empiric effort to maintain patients at castrate levels of testosterone, though evidence to support this practice has been limited. Second-line hormonal therapies with antiandrogens or other agents such as ketoconazole, aminoglutethimide, and estrogenic compounds have been used. Although only relative minorities of patients respond and the response tends to be quite brief, patients occasionally will manifest a response that can be very durable.

ANDROGEN RECEPTOR: PROSTATE CANCER’S HOLY GRAIL

	Prostate cancer cells depend on androgens to survive and proliferate, which is the rationale behind androgen-ablative therapy.

 The most potent androgens are testosterone and dihydrotestosterone (DHT). In the initial development of prostate cancer and in progression of the disease, testosterone and DHT bind to and activate the androgen receptor (AR). DHT has a binding affinity for AR that is nearly 10 times that of testosterone. AR, a phosphoprotein, functions as a transcription factor to mediate the effects of these steroids on the cell cycle.

	Intraprostatic levels of testosterone and DHT (in situ and metastatic) remain elevated, despite achieving serum castrate levels with ADT.

 In addition, PSA—encoded by an androgen-responsive gene&mdash;is detectable in nearly all cases of Castration-Resistant Prostate Cancer (CRPC). It is clear that the AR-signaling pathway remains persistently activated despite androgen blockade.

	In patients with CRPC, resumed progression is likely due to AR mutations, AR gene amplification, AR overexpression, modulation of AR via signaling pathways, alteration of coactivators, or a combination of molecular mechanisms.

 Some patients appear to have a hypersensitive AR phenotype that renders prostate cancer cells exquisitely sensitive to extremely low levels of testosterone and DHT.

	The development of newer and more effective methods of blocking AR synthesis may have therapeutic promise for patients with CRPC. Abiraterone acetate and MDV3100, two novel AR antagonists, are currently being evaluated in phase III studies. In preclinical and clinical studies, these drugs have shown promising activity against metastatic CRPC.

	Abiraterone acetate is an important compound in late-stage development for CRPC and has been under investigation for more than 2 decades. It is an oral bioavailable prodrug of abiraterone, which selectively and irreversibly inhibits the activity of 17-hydroxylase/17,20-lyase (CYP17), an enzyme principally responsible for androgen and estrogen biosynthesis.

 CYP17 inhibition results in significantly lower levels of circulating dehydroepiandrosterone (DHEA) and androstenedione, a metabolite of DHEA that is synthesized into the more potent androgens testosterone and DHT.

	Abiraterone is 10 to 30 times more potent than the nonspecific antiandrogen ketoconazole at inhibiting CYP17.

 Abiraterone acetate results in decreased levels of adrenal androgens downstream of CYP17. These levels do not increase at progression, demonstrating the irreversibility of abiraterone’s androgen blockade.

 Conversely, ketoconazole is associated with an increase in steroid levels downstream of CYP17 at progression.

	Continuous CYP17 inhibition leads to elevated levels of adrenocorticotropic hormone, which in turn increases the levels of corticosterone and deoxycorticosterone upstream of CYP17. While this helps to prevent adrenocortical insufficiency, some patients develop mineralocorticoid excess syndrome, evidenced by symptoms of fluid retention, hypertension, and hypokalemia (

). These toxicities are easily and effectively managed using mineralocorticoid antagonists or low-dose glucocorticoids.

Phase II Trial in Chemotherapy-Naïve Patients

	In the first half of 2010, updated data from 2 phase II trials of abiraterone acetate were published.

 Combined with data from a phase II trial published in 2009,

 they continue to support the activity of abiraterone acetate in metastatic CRPC (

) and provide rationale for phase III studies, which have completed accrual and are maturing.

	In a phase I/II study, Attard and colleagues found the drug highly active in men with chemotherapy-naïve CRPC. A preliminary analysis of phase II data published in the 

 in 2009 showed that a 1000 mg dose of abiraterone daily for 12 weeks reduced PSA levels by ≥50% compared with baseline in 28 of 42 patients (67%). Of these patients, 8 had a PSA decline of ≥90% from baseline.

	The men in this study had progressed after a median of 3 lines of hormonal treatment prior to enrollment, including LHRH analogs and antiandrogens. At baseline, CT scanning showed measurable tumors in 57% of patients, and a bone scan showed bone metastases in 76% of patients.

	Median follow-up for the 42 phase II patients was 505 days. CT scanning was conducted every 12 weeks and bone scans were obtained every 24 weeks. In addition, counts were taken of circulating tumor cells (CTCs) using CellSearch technology on the first day of every 28-day cycle. On the last day of each cycle, levels of PSA, lactate dehydrogenase, and alkaline phosphatase were assessed. For the 24 patients with measurable tumors at baseline, 9 experienced tumor shrinkage according to RECIST criteria, for an objective response rate of 37.5%.

 Of the 17 patients with baseline CTC counts ≥5 per 7.5 mL, 10 (59%) saw a decline to <5 CTCs per 7.5 mL.

	The median time to PSA progression (TTPP) for patients who received only abiraterone was 225 days (95% confidence interval [CI], 122-383 d).

 There was a positive correlation between TTPP and PSA decline, with a TTPP of 393 days for patients whose PSA dropped ≥90% (95% CI, 252-533 d).

	The study design allowed for concomitant administration of 0.5 mg per day of dexamethasone with abiraterone acetate at progression, and 39 patients received this combination. Some patients had prior exposure to  dexamethasone, and one-third of these patients had a secondary PSA decline ≥50% when dexamethasone was added to abiraterone acetate, prompting investigation into combining abiraterone acetate with a corticosteroid.

	In a multicenter phase II trial, Danila and associates administered abiraterone acetate and prednisone to 58 men with metastatic CRPC who had all failed docetaxel-based chemotherapy. Nearly half (47%) had prior ketoconazole. PSA levels declined ≥50% in 22 patients (36%), and in the 22 patients with RECIST-evaluable lesions, 4 (18%) had partial response, 13 (59%) experienced stable disease >3 months, and 5 (23%) progressed. Overall median TTPP was 169 days (95% CI, 82-200 d), and 16 (28%) patients saw improvements in ECOG PS.

	In this study, patients pretreated with ketoconazole had worse outcomes than patients who were ketoconazolenaïve. They were less likely to achieve the primary endpoint of a PSA decline ≥50% and had shorter TTPP. However, 30% of patients previously treated with ketoconazole did experience a decline of ≥50% in PSA levels, indicating no cross-resistance between these therapies. Data from ongoing prospective studies investigating abiraterone in ketoconazole treated patients with CRPC are needed to validate this hypothesis.

	The addition of prednisone contributed to reduced rates of mineralocorticoid-associated toxicities of hypertension (5%), hypokalemia (<5%), and fluid retention (<10%) and obviated any need for a mineralocorticoid antagonist. One case of grade 3 fatigue was the only adverse event >grade 2.

	In a similar phase II study of 47 men with CRPC pretreated with docetaxel, once-daily abiraterone acetate alone led to a PSA decline ≥50% in 24 (51%) patients.

 Another 7 (15%) experienced a PSA decline ≥90%. Median TTPP in this trial was also 169 days (95% CI, 113-281 d). CTC counts declined in 11 of the 27 patients (41%) with baseline counts ≥5 per 7.5 mL. In this study, 55% of patients experienced hypokalemia, 17% developed hypertension, and 15% had fluid retention. This trial has been advanced to a phase III study comparing abiraterone acetate with placebo. The trial rapidly completed accrual, and data may be available as early as the end of 2010.

	Based on these studies, abiraterone acetate demonstrates objective antitumor activity in a preponderance of patients, measured biochemically with PSA testing and as antitumor activity in soft-tissue disease. It is active in men with CPRC who have been treated previously with a range of therapies, from LHRH analogs, to docetaxel-based chemotherapy and ketoconazole. Abiraterone appears more potent than currently used antiandrogens and lacks the highly toxic adverse effects associated with ketoconazole.

	A novel second-generation antiandrogen that has had demonstrated success in preclinical and clinical studies is MDV3100, an orally available, small-molecule AR antagonist. MDV3100 was specifically engineered to bind to AR with greater affinity than the approved antiandrogen bicalutamide.

 MDV3100 also reduces the efficiency of nuclear translocation of AR, prevents DNA binding to androgen response elements, and impairs recruitment of coactivators.

	In 2009, Tran and associates reported that MDV3100 inhibited tumor growth and induced apoptosis in the AR-amplified VCaP cell line in vitro. This cell line proved resistant to bicalutamide.

 Additional in vitro experiments compared bicalutamide and MDV3100 in a CRPC cell line engineered to overexpress wild-type AR (LNCaP/AR). Bicalutamide demonstrated agonist effects; MDV3100 did not.

 Finally, in castrated mice with LNCaP/AR xenograft tumors, treatment with MDV3100 resulted in apoptosis and tumor regression, whereas bicalutamide only slowed tumor growth.

	It is theorized that the agonist activity of bicalutamide in tumors with AR amplification is why some patients experience antiandrogen withdrawal syndrome, evidenced by a swift decline in PSA levels after discontinuing therapy.

 AR amplification is evident in as many as 20% to 30% of hormone-refractory prostate tumors but is rarely seen in hormone-sensitive tumors.

 MDV3100 is purely antagonistic, which might partially explain why it was more effective than bicalutamide in murine models with AR amplification.

	Based on the highly positive results from preclinical studies, the Prostate Cancer Clinical Trials Consortium selected MDV3100 for a phase I/II human trial. A US multicenter trial was initiated in 2007, with preliminary data presented at various oncology and urology conferences.

	Scher and associates enrolled 140 patients (median age, 68 y) with progressive, metastatic CRPC at 5 centers in the United States.

 This was a dose-escalation trial, with the first cohort of 3 patients initiated on a 30 mg dose of MDV3100. After establishing the safety of this dose, 24 more patients were enrolled, half of who had received previous chemotherapy. Starting doses for these and subsequent patients accrued ranged from 60 mg to 600 mg daily, but doses for all patients were later dropped to ≤240 mg, which was established as the maximum tolerated dose.

	Median duration of therapy with MDV3100 was 21 weeks. Each month, patients were assessed for toxicities and blood samples were analyzed for platelet count, serum chemistry, and levels of PSA and creatinine. CTC count was obtained at baseline and reassessed at weeks 4 and 12. Patients who had metastatic disease at enrollment underwent imaging studies every 3 months versus every 6 months for those without metastases. Every patient also received several electrocardiograms throughout the course of the study. Twenty-two patients enrolled in a concurrent trial at Memorial Sloan-Kettering Cancer Center that assessed therapy response using 16β-18F-fluoro-5α-dihydrotestosterone (FDHT) and 2-18F-fluoro-deoxy-D-glucose (FDG) PET-CT scanning.

	Antitumor effects were evident at all dose levels. More than half (54%) the patients had received prior chemotherapy, but no significant difference was observed between this cohort and the chemotherapy-naïve cohort in the proportion of patients achieving a >50% decrease in PSA level from baseline (51% vs 62%, respectively; 

 = .23). A significant difference was noted between these two groups at 12 weeks when looking at PSA declines only for those patients who remained on MDV3100 a minimum of 12 weeks (

). In the prior-chemotherapy arm, 36% of patients experienced a decline in PSA levels >50% from baseline compared with 57% of chemotherapy-naïve patients (

	The extent of PSA decline was dose dependent, but only up to 150 mg daily. No additional clinical benefit was seen with doses above 150 mg to 240 mg daily, even though patients at daily dose levels of 360 mg and 480 mg had substantially higher plasma concentrations of MDV3100.

	In patients with soft tissue lesions, 22% had partial response and 29% experienced stable disease (SD). In patients with bone metastases, 56% had SD. Of the 51 patients who had unfavorable CTC counts at baseline (≥5 cells per 7.5 mL of blood), counts dropped to <5 cells per 7.5 mL for 26 (49%). A lower proportion of patients in the prior-chemotherapy group than in the chemotherapy-naïve group who had baseline unfavorable CTC counts  experienced conversion to favorable counts after treatment (37% vs 75%, respectively; 

 = .02). Almost all patients (91%) who started with a favorable CTC count retained this status throughout the study.

	Slightly more than three-quarters of patients who showed CTC conversion had a PSA decline ≥50%. In the phase II study of abiraterone in patients post-docetaxel, Reid and colleagues found no significant correlation between maximal changes in CTC counts and PSA levels in the overall population, but they did report a significant correlation between these endpoints in patients with ERG gene-arranged tumors.

 Scher and associates did not stratify outcomes according to ERG gene arrangements, but they concluded that there was a general—if inconsistent&mdash;association between PSA declines or lack of progression and favorable CTC counts.

 Some studies have linked favorable CTC counts at baseline and with therapy to improved survival in metastatic prostate cancer.

	Median time to radiological progression was 47 weeks overall, but it was not reached for the subset of patients who were chemotherapy-naïve. For patients previously treated with chemotherapy, median TTPP was 29 weeks. Based on Prostate Cancer Clinical Trials Working Group 2 criteria of a confirmed PSA rise ≥25% from nadir, median TTPP progression was 32 weeks overall, 41 weeks for patients who had not had prior chemotherapy, and 29 weeks for patients who had received prior chemotherapy.

	Like abiraterone acetate, MDV3100 appears to be a much more potent antiandrogen than those in current clinical use. In this select population, MDV3100 was associated with relatively high rates of biochemical response, objective activity, stable disease on bone imaging, and relatively protracted periods before evidence of biochemical and radiographic progression.

	Fatigue appeared to be the most frequent grade 3-4 adverse event, experienced by 11% of patients. The onset of fatigue seemed to coincide with the time it took MDV3100 plasma concentration to reach a steady state, which was approximately 4 weeks. The fatigue typically resolved 2 to 4 weeks after doses were reduced.

	All other grade 3-4 adverse events affected <5% of the study population, and with the exception of anemia, occurred more frequently in patients taking doses of MDV3100 >240 mg. Treatment discontinuation was also more likely at doses >240 mg. Two seizures were reported in patients taking ≥360 mg of MDV3100, but these were not confirmed as treatment related. There were no treatment-related cardiovascular effects reported.

	The low rate of serious adverse events is a major improvement over some of the treatments used today for metastatic CRPC and, coupled with the demonstrable activity of MDV3100, justify investigation in phase III trials. At least one phase III trial has already been initiated, comparing MDV3100 with placebo in men with CRPC that has progressed after therapy with docetaxel.

	Androgen deprivation therapy has been the mainstay of the management of advanced prostate cancer for nearly 7 decades. Despite significant changes in patient presentation as a consequence of a ubiquitous screening paradigm, those patients not cured with local therapy have seen limited progress in management over the past several decades. Significant new insights into the biology of the AR have been translated into clinical developments with agents such as abiraterone acetate and MDV3100, both of which are currently in late-stage clinical development with ongoing human trials. Recent FDA approvals of sipuleucel-T (Provenge) and cabazitaxel (Jevtana) provide additional management options for patients with advanced prostate cancer.

	The approval of new therapies is always associated with a subsequent learning curve. Adding agents such as MDV3100 and abiraterone acetate to our therapeutic armatorium will create opportunities and challenges. Determining how to optimally integrate these therapies into our management paradigm will require additional clinical trials. In addition, the added costs of multiple new therapies will need to be taken into consideration, given our evolving healthcare environment. Although the potential to evolve the management of CRPC into a chronic disease paradigm has not quite arrived, perhaps it is not as quixotic as it appeared to be just a short time ago.

Articles

The Prostate Cancer Clinical States model was first proposed by Scher and colleagues nearly 10 years ago.

Novel Agents in the Management of Castration-Resistant Metastatic Prostate Cancer

The past 2 to 3 decades saw a palpable therapeutic nihilism associated with the management of patients with advanced renal cell carcinoma (RCC), interrupted briefly by the initial excitement regarding high-dose interleukin-2.

 Over the past several years, phase I/II clinical trials of tyrosine kinase inhibitors (TKIs), vascular endothelial growth factor (VEGF) inhibitors, and mammalian target of rapamycin (mTOR) inhibitors in advanced RCC (primarily of clear cell histology) demonstrated intriguing, paradigm-shifting activity. This led to a series of phase III trials that culminated with the FDA’s approval of 6 new drugs in a 5-year span for the management of advanced RCC.

As we reach the midway point of the first decade of targeted therapeutics in RCC, some high-level observations can be made. Despite unequivocal progress, none of the currently available agents cure patients with metastatic RCC and few complete responses are seen with any of them. Although clinical studies with the mTOR inhibitor temsirolimus (Torisel) provided evidence of an improvement in overall survival (OS) in patients with poor risk (per Memorial Sloan-Kettering criteria) disease, demonstrating improvement in survival with other agents has been problematic. This is likely because studies for most of these drugs allowed crossover by large numbers of patients.

 From a patient management perspective, these agents are generally associated with significant toxicity, negatively affecting the quality of life for many patients. Although published data on sequential therapy are limited, it has become a de facto standard of care. Using these agents in combination is more than a little challenging, pending results from additional studies.

 PROPOSED MECHANISMS OF RESISTANCE IN SEQUENTIAL THERAPY

It was the significant progress in our understanding of the molecular pathogenesis of RCC during the past decade that led to the development of therapies targeting the VEGF and mTOR pathways.

 Results from a series of phase III studies provide compelling evidence that sunitinib (Sutent), pazopanib (Votrient), temsirolimus, and the combination of bevacizumab (Avastin) and interferon-alpha are clinically active in patients with metastatic RCC as initial therapies or following initial cytokine therapy. The objective response rate (ORR) ranged from 7% to 31% with these agents, and progression-free survival (PFS) ranged from 4 to 11 months.

In chronic myeloid leukemia, another malignant disease commonly treated with targeted agents (eg, imatinib [Gleevec] and nilotinib [Tasigna]), the mechanism of drug resistance is presumed to be mutation of a gene that encodes a key tyrosine kinase receptor targeted by the drug. In contrast, investigators exploring resistance mechanisms in RCC note that because the main target for VEGF receptor (VEGFR) inhibitors resides on the surface of endothelial cells,

 a mutation conferring treatment resistance would most likely have to occur in the tumor endothelium, but it is highly improbable that such a mutation would occur simultaneously in the endothelium of each individual tumor metastasis.

 Other proposed mechanisms for acquired resistance include reemergence of VEGF-driven vasculature, upregulation of alternative proteins in the setting of persistent VEGF or mTOR blockade, and novel mechanisms that are not antiangiogenic in nature.

Following FDA approval of sunitinib, many clinicians managing RCC patients with disease progression on sorafenib (Nexavar) empirically used sunitinib as a salvage option. Retrospective series soon appeared in the literature documenting responses to both agents when used in sequence and reporting clinical activity in patients with disease progression following other VEGFtargeting agents, such as bevacizumab.

More recently, prospectively designed phase II trials have addressed the issue of cross-resistance when using VEGFtargeted therapeutics in sequence. Rini and associates conducted a prospective multicenter phase II trial of sunitinib in 61 patients with metastatic clear cell RCC that had evidence of progression following a bevacizumab-based therapy regimen. Patients received 50 mg of sunitinib daily in 6-week cycles, comprising 4 weeks on therapy followed by 2 weeks off therapy. The researchers observed an ORR of 23% with a median PFS of 30 weeks and a median OS of 47 weeks. Observed treatment-related toxicity was typical of sunitinib in other settings.

The investigational drug axitinib is an oral, potent, selective inhibitor of VEGFRs 1, 2, and 3 that demonstrated substantial activity in a phase II trial of patients with cytokine-refractory metastatic RCC.

 In this multicenter trial, Rini and associates administered 5 mg of axitinib twice daily to patients with metastatic RCC (all histologic subtypes) whose disease progressed following therapy with sorafenib. The prior number of therapies a patient had received was not a limiting factor in enrollment. All 62 patients enrolled had received prior sorafenib and 74.2% had received ≥2 prior systemic treatments. The ORR, which was the study’s primary endpoint, was 23%. The median duration of response was 17.5 months and median OS was 7.4 months.

 Although these studies have limitations, including their design and small size, they provide compelling clinical evidence that cross-resistance is not inevitable when patients who fail on one VEGF-targeting drug switch to another.

Motzer and colleagues recently reported the results of an international phase III trial testing the role of mTOR inhibition following disease progression on agents that target VEGF.

 Patients who received prior therapy with bevacizumab, interleukin-2, or interferon-alfa were also permitted to participate. Researchers randomly assigned patients at a 2:1 ratio to 10 mg of the mTOR inhibitor everolimus (Afinitor; n = 272) or placebo (n = 138) daily. The primary endpoint was median PFS, which was documented using Response Evaluation Criteria in Solid Tumors and assessed via a blinded, independent central review. At the time of disease progression, treatment was unblinded and patients receiving placebo were offered open-label everolimus. Objective antitumor activity was observed, with 60% of patients treated with everolimus experiencing tumor shrinkage compared with 10% given placebo. Based on independent review, median PFS in the everolimus arm was 4 months versus 1.9 months in the placebo group, representing significant improvement (hazard ratio [HR], 0.30; 95% confidence interval [CI], 0.22-0.40; 

 <.001). When stratifying patients according to prior VEGF TKI therapy, the PFS advantage for everolimus persisted across all groups (

The current clinical paradigm for the management of advanced RCC is rapidly evolving. Following the FDA approval of sorafenib and sunitinib, and given the scarcity of effective therapies, patients treated with 1 of these agents were typically treated with the alternative agent following progression. Clinical evidence indicating a lack of cross-resistance between these TKIs validated this empiric approach. Subsequent studies provided additional data on sequencing approaches, such as evidence from a phase III study supporting the utility of everolimus following therapy with a VEGF TKI.

Investigators exploring the role of combination therapy have applied the concepts of vertical blockade and horizontal blockade.

 A vertical blockade uses at least 2 agents to target 1 pathway at ≥2 levels; a horizontal blockade uses ≥2 agents to target separate pathways with different functions in parallel.

The initial attempt to test the concept of horizontal blockade was a phase II trial of bevacizumab in combination with the epidermal growth factor receptor inhibitor erlotinib (Tarceva). Patients were treated with 10 mg/kg of bevacizumab every 2 weeks and an oral, 150-mg dose of erlotinib daily. Of 58 evaluable patients, 12 (21%) had objective partial remissions. At a median follow-up of 15 months, median PFS was 11 months; 43% of patients were progression-free at 12 months and 26% were progression-free at 18 months.

 The subsequent addition of the platelet-derived growth factor receptor inhibitor imatinib to the combination was not tolerable.

Bukowski and colleagues attempted to define the role of combination therapy further by conducting a randomized, placebo-controlled phase II trial.

 Eligible patients had metastatic RCC, predominantly of clear cell histology, and they were randomized to receive 10 mg/kg of bevacizumab every 2 weeks combined with 150 mg daily of erlotinib or placebo. For patients treated with bevacizumab plus erlotinib, the ORR was 13% and median PFS was 8.5 months compared with an ORR of 14% and median PFS of 9.9 months for patients treated with bevacizumab alone. The study provided additional data supporting the single-agent activity of bevacizumab.

Recent reports describe attempts to achieve vertical blockade by blocking the VEGF-VEGFR axis and/or hypoxiainducible factor. Feldman and associates conducted a phase I trial evaluating bevacizumab plus sunitinib in patients with metastatic RCC.

 Patients who received ≤2 prior therapy regimens, excluding bevacizumab or sunitinib, were eligible. Bevacizumab was administered at a fixed dose of 10 mg/kg every 2 weeks, combined with an escalating dose of sunitinib.

The study determined that the maximum tolerated dose (MTD) for the regimen consisted of 50 mg of sunitinib and 10 mg/kg of bevacizumab. The authors noted, however, that chronic therapy with the MTD dose frequently resulted in grades 3/4 levels of hypertension and hematologic and vascular toxicities, with approximately half the patients stopping therapy secondary to adverse events.

Although activity was seen, with 1 complete and 12 partial responses, the authors said that they did not recommend pursuing this regimen at the MTD because of the significant therapy-related toxicity.

 While this trial documented the constellation of thrombocytopenia, hemolytic anemia, hypertension, proteinuria, and renal insufficiency with microangiopathy in 5 patients, a similar phase I trial that enrolled patients with RCC and other solid tumors did not observe this constellation of events in any participants.

A phase II study recently reported positive data on the efficacy of everolimus in combination with bevacizumab following VEGFtargeted TKI therapy. Investigators gave this doublet to 59 patients, 29 of whom had been previously treated with sunitinib or sorafenib.

 The median PFS in this patient population was 10 months, suggesting that these agents might act synergistically in patients with TKI—refractory disease.

Fischer and colleagues conducted a phase I study of temsirolimus in combination with sunitinib in patients with advanced RCC.

 Patients were eligible if they had received ≤2 prior systemic regimens for metastatic disease. Investigators administered 15 mg of temsirolimus once weekly by intravenous infusion, and 25 mg of sunitinib was administered orally once daily for 4 weeks; this was followed by a 2-week rest period. In the first cohort of 3 patients, 2 patients experienced dose-limiting toxicities. The study was terminated because of the substantial toxicity observed with even the low starting doses of both agents.

Sosman and colleagues conducted a phase I trial investigating the combination of sorafenib and bevacizumab in patients with advanced RCC who had not received prior VEGF TKI therapy.

 Initial doses consisted of 200 mg of sorafenib twice daily with a 5 mg/kg dose of bevacizumab once every 2 weeks in 28-day cycles, with dose modification based on observed toxicities. Therapy was relatively well tolerated, with only 4 of 48 patients discontinuing because of toxicity. The investigators established the MTD at 200 mg daily of sorafenib plus 15 mg/kg of bevacizumab once every 2 weeks. Of the 46 evaluable patients, 21 (46%) achieved a partial response. The median time to progression was 11 months, and 10 patients (21%) were progression-free at 18 months.

Several ongoing prospective trials are testing the role of combination therapy. The Eastern Cooperative Oncology Group is conducting the randomized phase II BEST (Bevacizumab, Sorafenib, and Temsirolimus) trial, which randomizes patients to bevacizumab monotherapy, bevacizumab combined with temsirolimus or sorafenib, or a doublet of sorafenib and temsirolimus.

Ongoing industry randomized trials include a phase III study comparing the combination of bevacizumab and interferon-alpha versus the combination of bevacizumab and temsirolimus, and a randomized phase II trial comparing the combination of everolimus and bevacizumab with interferon-alpha and bevacizumab (

Following a protracted period in which interleukin-2 was the only FDA-approved drug available for the management of advanced RCC, the last several years have seen the approval of sorafenib, sunitinib, temsirolimus, everolimus, bevacizumab (in combination with interferon), and, most recently, pazopanib. The trials that led to the regulatory approval of these agents support their role as initial therapy, but they offer little guidance regarding the optimal means of selecting therapy for patients with clear cell RCC and essentially no guidance for RCC patients with non-clear cell histologies.

Current evidence supports the role of temsirolimus as initial therapy for patients with advanced RCC who are classified as “poor risk,” based on a trial design that used a modified version of the Memorial Sloan-Kettering Cancer Center definition for poor risk. Clinical trial evidence also supports the use of everolimus in patients with disease progression following therapy with sorafenib, sunitinib, or both.

Following disease progression on a front-line agent, data guiding subsequent therapy selection are limited. None of the available data support 1 sequence of agents over another. Currently, therapy decisions are frequently informed by a patient’s disease status, issues regarding therapy logistics (ie, oral vs parenteral therapy), and an agent’s potential toxicity.

The role of combination therapy in advanced RCC remains the subject of ongoing investigation. Experience to date suggests that many combinations present challenges, secondary to significant toxicity. Prospective, randomized trials are needed to determine whether sequential therapy or combination therapy is the optimal approach.

Robert Dreicer, MD, MS

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