Novel agents for muscle-invasive and advanced urothelial cancer

Abstract

Conventional front-line platinum-based combination chemotherapy yields high response rates but suboptimal long-term outcomes for advanced urothelial cancer. Salvage therapy is an unmet need, with disappointing outcomes. The profusion of novel biological agents offers the promise of improved outcomes. Neoadjuvant therapy before cystectomy for muscle-invasive bladder cancer provides an important paradigm and an interesting approach in developing novel agents. Patients who are not candidates for cisplatin require special attention. A multidisciplinary approach and collaboration among laboratory scientists, oncologists, urologists and radiation oncologists is necessary to make therapeutic advances. Recent and ongoing trials of novel chemotherapeutic and biologic agents are reviewed.

Abbreviations

UC

urothelial cancer

BSC

best supportive care

GC

gemcitabine, cisplatin

(DD)-MVAC

(dose-dense) methotrexate, vinblastine, doxorubicin, cisplatin

RR

response rate

SD

stable disease

PFS

progression-free survival

OS

overall survival

pCRM

pathological complete remission

CR

PR, complete, partial response

VEGF(R)

vascular endothelial growth factor (receptor)

ERCC1

excision repair cross complementing 1

nab

nanoparticle albumin-bound

IHC

immunohistochemistry

FISH

fluorescence in situ hybridization

CALGB

Cancer and Leukaemia Group B

EGFR

epidermal growth factor receptor

TKI

tyrosine kinase inhibitor

PDGFR

platelet-derived growth factor receptor

FT(I)ase

farnesyl transferase (inhibitor)

EORTC

European Organization for Research and Treatment of Cancer

ER

oestrogen receptor.

INTRODUCTION

Conventional cisplatin-based front-line chemotherapy regimens for urothelial cancer (UC) include methotrexate, vinblastine, doxorubicin, cisplatin (MVAC), dose-dense (DD) MVAC or gemcitabine and cisplatin (GC) [1–3]. Despite initial high response rates (RRs) of 40–70% in advanced disease, chemotherapy is generally not curative and the overall 5-year survival is suboptimal, at 5–20%. A recently reported randomized trial showed no improved overall survival (OS) with the addition of paclitaxel to GC [4]. While neoadjuvant cisplatin-based combination chemotherapy before radical cystectomy for muscle-invasive UC improves the outcome, there is recurrence in about half the patients [5,6]. Salvage chemotherapy for advanced UC (taxanes, gemcitabine) yields suboptimal response rates of 20% and a median survival of 6–9 months [7–9]. Renal dysfunction (usually defined as a creatinine clearance of <60 mL/min), poor performance status and old age are relatively common, and preclude cisplatin chemotherapy [10]. Carboplatin-based combined regimens are feasible in such patients, but appear to be worse than cisplatin-based regimens [11–13]. Regimens not based on platinum (taxane-gemcitabine) also appear to be reasonable alternatives in patients with renal dysfunction [14–17]. Ongoing randomized trials are specifically evaluating regimens in this population (Table 1). Therefore, the development of novel and tolerable agents for UC is warranted, coupled with the discovery of factors that predict response, such as excision repair cross complementing 1 (ERCC1) [18]. In this review we describe novel agents under development for the therapy of TCC of the urothelium. One caveat when comparing phase II studies in advanced UC is that important poor prognostic factors (visceral metastasis, Karnofsky performance status <80) might be distributed differently among studies. In the analysis of patients treated at the Memorial Sloan Kettering Cancer Center with MVAC, the median survival of patients with 0, one or two risk factors was 33, 13.4 and 9.3 months, respectively [19].

Table 1.  Ongoing randomized trials in advanced urothelial cancer and renal dysfunction

Source	No. of patients	Eligibility	Group 1	Group 2
Cr Cl, creatinine clearance; CHF, congestive heart failure; PS, WHO performance status.
Multinational	450	Cr Cl 20–60 or CHF	Gemcitabine	Vinflunine Gemcitabine
EORTC	381	PS = 2 or	Carboplatin	Carboplatin
		or GFR 30–60	Methotrexate Vinblastine	Gemcitabine

USE OF NEOADJUVANT THERAPY TO DEVELOP NOVEL AGENTS

The usual route for the development of novel agents is their initial evaluation in advanced disease, with the most common endpoints being the objective RR, progression-free (PFS) and OS. The paradigm of neoadjuvant therapy before surgery in localized disease permits a rapid in vivo assessment of pathological response, and might be critical toward the development of novel systemic therapies. Pathological complete remission (pCRM) might be an excellent surrogate for the efficacy of neoadjuvant chemotherapy and long-term outcomes [5,6]. In addition, most patients with muscle-invasive bladder cancer have localized or locally advanced disease that is amenable to neoadjuvant therapy. Neoadjuvant therapy has been shown to be safe and does not increase the risk of postoperative complications [5]. Therefore, the neoadjuvant paradigm might accelerate the development of novel agents. Because of the availability of tissue before and after chemotherapy, it might be possible to determine molecular and biological characteristics that predict chemosensitivity.

However, it is possible that activity in early disease might not translate to efficacy in advanced disease. Biological agents tend to be cytostatic and might not induce a pCRM. Conversely, significant necrosis with no pCRM might also signify clinically relevant biological activity. A precise pathological stage is not available before surgery, and neoadjuvant therapy might represent over-treatment in some patients with low-volume disease. Some resistant tumours might progress due to delay of surgery.

The choice of novel agents should be based on the knowledge of potential molecular targets that is emerging from studies examining the biology of UC. The optimum primary endpoint in phase II trials of neoadjuvant therapy has not been established. With novel agents used alone, feasibility and target modulation with a validated assay from the laboratory might be used as the primary endpoints. Supportive evidence for biological activity includes markers of increased apoptosis, and decreased proliferation and angiogenesis. However, such pathological surrogates are not necessarily reliable measures of biological activity, and the threshold of biological activity predictive of improved outcomes is unclear.

If biological activity can be shown in initial small pilot trials (e.g. 15–25 patients with an appropriate statistical design to detect a biological effect), additional larger phase II studies of novel agents alone or combined, potentially using randomized phase II designs, might be planned with more stringent efficacy endpoints (pCRM). Additional goals might be discovering markers predictive of efficacy, including overall gene expression assays. As conventional GC and MVAC induce pCRMs in 30–40% of patients, it might be reasonable to establish this as the threshold of interest, while a pCRM of >40–50% might be of greater interest for the further development of a novel regimen [5,20]. DD-MVAC is being evaluated as neoadjuvant therapy at the Dana Farber Cancer Institute (Table 2). With GC being a more tolerable regimen, it is probably the preferable platform to combine with novel agents. Imaging endpoints also need to be explored. A prolonged time to progression might be used an endpoint, although this might negate the prime advantage of the early determination of activity. A regimen’s efficacy in advanced disease also requires consideration in the ‘go/no-go’ decision process of embarking on a randomized trial that entails a large sample size and prolonged follow-up.

Table 2.  Ongoing and planned trials of novel agents and regimens for UC

Drug/regimen	Institution	Eligibility	Trial phase/design
CaG, carboplatin, gemcitabine; Cr, creatinine; AG, doxorubicin, gemcitabine; renal dys, renal dysfunction.
Vinflunine	Multicentre	Second-line	Phase II Vinflunine + BSC vs BSC
E7389	USC	Front-line, salvage	Phase II
Irinotecan	SWOG	Salvage	Phase II
Nab-paclitaxel	Canadian	Second-line	Phase II
Ifosfamide-Cisplatin-Nab paclitaxel	MSKCC	Neoadjuvant	Phase I/II
CaG-Nab-paclitaxel	U Minnesota	Neoadjuvant	Phase I/II
Cisplatin-Pemetrexed	Spanish	Front-line	Phase I/II
Oxaliplatin-Docetaxel	Stanford	Front-line, Cr < 1.8 mg/dL	Phase II
AG-Paclitaxel	MDACC	Front-line, renal dys	Phase II
AG-Bortezomib	MDACC	Front-line	Phase I/II
GC-Bevacizumab	HOG	Front-line	Phase II
GC ± Bevacizumab	CALGB	Front-line	Phase III
GC-Bevacizumab	MUSC	Neoadjuvant	Phase II
CaG-Bevacizumab	MSKCC	Front-line, renal dys	Phase II
DD-MVAC	DFCI	Neoadjuvant	Phase II
DD-MVAC-Bevacizumab	MDACC	Neoadjuvant	Phase II
VEGF-Trap	NCI	Salvage, frontline	Phase II
Docetaxel ± ZD6474	DFCI	Salvage	Randomized phase II
Lapatinib	US Oncology	Salvage	Randomized discontinuation
GC ± Gefitinib	European	Front-line	Randomized phase II
Erlotinib	UNC	Neoadjuvant	Phase II with correlative studies
Docetaxel ± Gefitinib	MDACC	Second-line consolidation	Randomized phase II
Cetuximab ± Paclitaxel	Fox Chase	Second-line	Randomized phase II
GC ± Cetuximab	U Michigan	Front-line	Randomized phase II
Trastuzumab-Paclitaxel-RT	RTOG	Front-line	Phase II bladder conserving
Sorafenib	ECOG	Salvage	Phase II
GC-Sorafenib	MSKCC	Front-line	Phase II
CaG-Sorafenib	Yale	Front-line	Phase II
Sunitinib	MSKCC	Second-line	Phase II
Sunitinib	U Michigan	Second-line consolidation	Randomized phase II
Sunitinib	Cleveland Clin	Neoadjuvant	Phase II with correlative studies
Gemcitabine-Sunitinib	DFCI	Front-line, renal dys	Phase II
GC-Sunitinib	Baylor-HOG	Neoadjuvant	Phase II
Pazopanib	NCI	Salvage, Front-line	Phase II
Dasatinib	Baylor-HOG	Neoadjuvant	Phase II with correlative studies
Ipilimumab	MDACC	Neoadjuvant	Phase I with correlative studies
Tamoxifen	Baylor	Salvage	Phase II

NOVEL CHEMOTHERAPY FOR UROTHELIAL CARCINOMA

Vinflunine ditartrate (Javlors, Pierre Fabre Me’dicament, Boulogne-Billancourt, France) is a novel antitubulin agent obtained from a Vinca alkaloid. Fifty-one patients with recurrent advanced UC were treated with vinflunine; nine responded, for an overall RR of 18%, and 67% achieved disease control (response + stability) [21]. Responses were predominantly in patients who had previously responded to chemotherapy. However, five of 25 (20%) patients with visceral involvement had a response and there were also responses in patients with primary chemoresistant disease. The median PFS was 3 months and the median OS was 6.6 months. There was febrile neutropenia in five patients (10%), of whom two died. Constipation was frequent but manageable and not cumulative, and was grade 3–4 in only 8% of patients; there was grade 3 nausea and vomiting in 6%, but no severe neuropathy. Salvage therapy with vinflunine plus best supportive care (BSC) is being compared with BSC in a multinational randomized trial (Table 2). Another ongoing randomized trial is comparing the combination of front-line vinflunine and gemcitabine against gemcitabine alone in patients ineligible for cisplatin (Table 1).

Pemetrexed (Alimta; Eli Lilly, Indianapolis, IN, USA) is a novel, multi-targeted antifolate agent. Early studies showed that concomitant supplementation of vitamin B12 and folate attenuated toxicity without compromising efficacy. Paz-Ares et al.[22] investigated front-line single agent pemetrexed (with no folic acid and vitamin B12 supplementation) in patients with advanced UC. Pemetrexed yielded an objective RR of 30% and stable disease (SD) was achieved in 35% of patients. Toxicities included grade 4 neutropenia (35%), grade 3/4 anaemia (17%), and grade 3/4 thrombocytopenia (9%); 22% of patients developed febrile neutropenia and two patients died. Forty-seven patients were enrolled in another phase II trial, with metastatic disease that had progressed at any time after initial therapy for metastatic disease or within 12 months of perioperative chemotherapy [23]. There were three (6%) complete responses (CRs) and 10 (21%) partial responses (PRs), for an overall RR of 28%, while 10 patients (21%) had SD. The median time to progressive disease was 2.9 months and the median OS was 9.6 months. Grade 3 or 4 haematological events were thrombocytopenia (8.5%, 0%), neutropenia (4%, 4%) and anaemia (2%, 2%). A second phase II trial of second-line pemetrexed from the Memorial Sloan Kettering Cancer Center, there was an objective response in one of 12 evaluable patients, for an overall RR of 8% (90% upper limit 29%) [24]. This level of activity did not meet the criteria for expansion, based on the predefined optimum two-stage Simon design, and the trial was concluded after only 13 patients were enrolled.

Combined front-line treatment with pemetrexed-gemcitabine was evaluated in 62 patients with advanced UC, 59% of whom had visceral metastases [25]. The RR was 26.5% and the median OS was 10.1 months. Grade 3/4 toxicities included anaemia (13%), thrombocytopenia (10%), neutropenia (37%), febrile neutropenia (18%) and neutropenic sepsis (3%). These results were not much better than those achieved with gemcitabine alone as a single agent. Currently, a phase II trial is evaluating combined cisplatin and pemetrexed as front-line therapy for advanced UC (Table 2).

The epothilones are novel non-taxane tubulin polymerization agents, and aza-epothilone B (BMS-247550; ixabepilone) is a semi-synthetic analogue of the natural product epothilone B. Ixabepilone was evaluated for the second-line therapy of advanced UC in a phase II trial in 45 patients, of whom 40% had received a previous taxane [26]. Five patients had a PR among the 42 eligible patients, for a RR of 12%, and the median OS was 8 months. Toxicities were moderate, with neutropenia, fatigue, and sensory neuropathy being the most common. Further development is being considered.

Oxaliplatin is a non-nephrotoxic third-generation platinum analogue. Winquist et al.[27] evaluated oxaliplatin 130 mg/m² every 3 weeks in 18 evaluable patients with previously treated advanced UC, in a phase II trial. Patients were stratified as ‘cisplatin-sensitive’ or ‘cisplatin-resistant’ on the basis of previous cisplatin treatment. There was one PR in 10 cisplatin-sensitive patients, and no responses in eight who were cisplatin-resistant. The combination of oxaliplatin and gemcitabine was evaluated in a front-line phase II trial of 30 patients, and a serum creatinine up to 1.5× the upper limit of normal was allowed [28]. There were three CRs and 11 PRs, for an overall RR of 47%; the median survival was 15 months, and toxicities were manageable. Of interest, the combination of oxaliplatin and docetaxel is being evaluated in an ongoing front-line therapy trial, and patients with a serum creatinine level of <1.8 mg/dL are eligible (Table 2).

Nanoparticle albumin-bound (nab) paclitaxel (Abraxane, Abraxis) is a novel solvent-free, albumin-bound formulation of paclitaxel. It was designed to avoid solvent-related toxicities and to deliver paclitaxel to tumours via molecular pathways involving an endothelial cell-surface albumin receptor and an albumin-binding protein expressed by tumour cells and secreted into the tumour interstitium (‘secreted protein acid rich in cysteine’) [29]. Nab-paclitaxel is being evaluated for the salvage therapy of progressive UC, and as a component of combined regimens in the neoadjuvant setting (Table 2).

OTHER NOVEL CHEMOTHERAPEUTIC AGENTS AND COMBINATIONS

E7389 (Eisai) is a synthetic derivative of the marine sponge product halichondrin-B that inhibits tubulin polymerization and has activity in refractory breast and non-small cell lung cancer [30]. A phase II trial is evaluating front-line E7389 in patients with advanced UC with and without renal insufficiency (Table 2). Other ongoing trials are evaluating novel agents and combinations (Table 2).

MONOCLONAL ANTIBODIES

TRASTUZUMAB

Her-2/neu expression in UCs is variable and might be associated with a more aggressive clinical course [31]. Patients with advanced TCC or squamous cell carcinoma that expressed Her 2/neu (by immunohistochemistry, IHC, serology or fluorescence in situ hybridization, FISH) in primary or metastatic site were treated with trastuzumab combined with paclitaxel, carboplatin and gemcitabine [32]. Fifty-seven (52%) of 109 registered patients were Her-2/neu-positive using several different methods. Her-2/neu-positive patients had more metastatic sites and a higher rate of visceral metastasis than did Her-2/neu-negative patients. Forty-four of 57 Her-2/neu-positive patients were treated with the regimen. Overall, 33% of patients had previously received peri-operative chemotherapy, and 55% had visceral metastases. The most common grade 3/4 toxicity was myelosuppression, with two deaths from toxicity. Grade 3 sensory neuropathy occurred in 14% of patients, and 23% had grade 1–3 cardiac toxicity. Thirty-one (70%) of 44 patients responded (five CRs and 26 PRs), and 25 (57%) of 44 were confirmed responses. The median time to progression and survival were 9.3 and 14.1 months, respectively. Given the aggressive course of disease in this high-risk population, these outcomes are considered promising, and appear to warrant a randomized trial to definitively assess the value of adding trastuzumab to combined chemotherapy. Trastuzumab is also being evaluated in combination with paclitaxel and radiotherapy for bladder conservation (Table 2).

BEVACIZUMAB

Vascular endothelial growth factor (VEGF) receptors are expressed on UC and preclinical evidence supports the antitumour efficacy of targeting this pathway in combination with chemotherapy [33]. Bevacizumab is administered i.v. and is commonly used in combination with chemotherapy in colorectal cancer, and increasingly in other solid tumours. Separate phase II trials are evaluating neoadjuvant GC or DD-MVAC plus bevacizumab followed by radical cystectomy in patients with muscle-invasive and resectable TCC of the bladder (Table 2). Another phase II trial by the the Hoosier Oncology Group is evaluating front-line GC plus bevacizumab for metastatic TCC, while the Cancer and Leukaemia Group B (CALGB) is planning a front-line randomized phase III trial of GC vs GC-bevacizumab (Table 2).

CETUXIMAB

Human TCCs overexpress epidermal growth factor receptor (EGFR), that confers a poor prognosis [34]. Cetuximab is an i.v. administered EGFR monoclonal antibody commonly used in colorectal cancer, and in head and neck cancers. Pre-clinically, cetuximab alone and combined with paclitaxel inhibited tumour growth and metastasis by inhibiting neovascularization and inducing apoptosis [35]. A trial is planned to evaluate the combination of cetuximab with front-line GC, as well as with salvage paclitaxel.

SMALL-MOLECULE BIOLOGICAL AGENTS

EGFR AND HER2 RECEPTOR TYROSINE KINASE INHIBITORS (TKIS)

The CALGB reported a phase II trial of front-line GC and gefitinib (an orally bioavailable EGFR TKI) in advanced UC, with a RR of 51% and a median survival of 14.4 months [36]. An ongoing randomized study is evaluating GC with or without gefitinib. Erlotinib, another oral EGFR TKI, used commonly in the treatment of non-small cell lung cancer, is being studied in the neoadjuvant setting before cystectomy, with primarily correlative and pharmacodynamic end-points (Table 2). Patients receive erlotinib once daily for 4 weeks, followed by radical cystectomy and adjuvant erlotinib. Tumour tissue is evaluated to assess effects on targeted signalling pathways. Microarray analysis is used to define predictive factors and to determine the effects of therapy on gene expression. Lapatinib is an oral TKI which targets EGFR and HER2, and that has been successful in combination with capecitabine chemotherapy in breast cancer. In a preliminary report of a phase II trial of 59 patients with EGFR and/or HER2 expression (1–3+ by IHC), lapatinib was active as salvage therapy for advanced UC, with PRs in 3% and clinical benefit (response + stability ≥ 16 weeks) in 12% of patients [37]. The median time to progression was 8.6 weeks and there was a trend towards clinical benefit in those with EGFR or HER2 2+/3+ by IHC. A randomized discontinuation trial being conducted by the US Oncology Research Network is evaluating salvage therapy with lapatinib in HER2-expressing (by FISH) UC.

VEGFR TKIS

Sorafenib was the first orally bioavailable multitargeted receptor TKI to be approved for use as second-line therapy in advanced renal cancer. It was designed as a c- and b-raf kinase inhibitor, as the ras/raf signalling pathway mediates tumour cell proliferation and angiogenesis. Sorafenib also inhibits several receptor TKs, among them VEGFR-2, platelet-derived growth factor receptor (PDGFR)-β, Flt-3 and c-KIT. Sorafenib is being studied for the second-line therapy of advanced UC, while the combination of sorafenib with carboplatin/cisplatin and gemcitabine is being evaluated for front-line therapy (Table 2).

Sunitinib, another oral small-molecule multitargeted receptor TKI, is also approved for the therapy of RCC. It targets VEGFR-2, PDGFR-β, KIT and Flt3 receptors. A preclinical study recently showed significant activity for sunitinib both as a single agent and combined with cisplatin [38]. Preliminarily, activity was shown in a phase II trial of sunitinib for the salvage therapy of UC (Table 2) [39]. Another trial is evaluating sunitinib vs placebo in patients who have stable disease or responding to front-line chemotherapy (Table 2). A neoadjuvant phase II trial of sunitinib combined with GC is planned by a Baylor College of Medicine-led and Hoosier Oncology Group-supported consortium with pCRM as the primary endpoint. The Cleveland Clinic is evaluating neoadjuvant sunitinib alone with primarily correlative studies. Axitinib, a somewhat similar multitargeted receptor TKI, caused regression of subcutaneous human UC xenografts and inhibited angiogenesis and VEGFR-2 and PDGFR-α phosphorylation [40]. A randomized phase II trial led by the Dana Farber Cancer Institute is evaluating salvage docetaxel alone or with ZD6474, a dual EGFR and VEGFR-TKI (Table 2).

FARNESYL TRANSFERASE (FTASE) INHIBITORS

Protein farnesylation by FTase is required for signal transduction by Ras, which is frequently overexpressed in UC, and provides a rationale to evaluate FTase inhibitors (FTI) [41]. Lonafarnib was studied in 19 patients as salvage therapy and yielded no responses in 10 evaluable patients [42]. In a multicentre European Organization for Research and Treatment of Cancer (EORTC) study, salvage combined therapy with SCH66336 and gemcitabine in patients with advanced UC was evaluated [43]. In 31 evaluable patients there was a RR of 32.3% (95% CI 17–51%). In another phase II trial, R115777 was examined in 34 patients who had received up to one previous systemic chemotherapy regimen [44]. Two patients (6%) with no previous chemotherapy had PRs and 13 (38%) had SD. Overall, despite a sound rationale, FTIs have been considered to have marginal activity and their future development is unclear.

OTHER NOVEL AGENTS AND THE QUEST FOR PREDICTIVE FACTORS

Based on oestrogen receptor (ER)-β expression in UCs, that increases with increasing stage and grade, and the inhibitory effect of selective ER modulators in pre-clinical models, salvage therapy with oral tamoxifen is being evaluated in a multi-institutional phase II trial of advanced UC at the Baylor College of Medicine, in collaboration with colleagues in Los Angeles and Rome (Table 2) [45,46]. Bortezomib, a proteasome inhibitor, was recently reported to be ineffective as a single agent [47]. However, based on synergism with chemotherapeutic agents, the evaluation of a combination of bortezomib with chemotherapeutic regimens is ongoing (Table 2). Key mediators in signalling pathways, including FGFR3, PTEN and AKT, are being developed, premised on pre-clinical data. Other novel avenues of research, including gene therapy and immunomodulation (ipilimumab to down-regulate CTLA-4 expressing T-regulatory lymphocytes), are being evaluated in pre-clinical or early clinical studies (Table 2) [48].

To guide optimum patient selection, the discovery of predictive factors should proceed in concert with the development of novel agents. mRNA levels of ERCC1 were evaluated in 57 evaluable patients with advanced bladder cancer and treated with either GC or the triplet containing paclitaxel and GC [18]. Other markers evaluated included RRM1, caveolin-1 and BRCA1 expression. The correlation between relative gene expression levels and response to cisplatin-based therapy was evaluated. An increased gene expression of ERCC1 was inversely associated with survival in patients with advanced UC treated with platinum-based chemotherapy, similar to that reported in patients with lung cancer [49].

CONCLUSIONS

Few patients achieve long-term survival with the currently used regimens for advanced UC. Systemic chemotherapy for muscle-invasive and advanced UC is poised for further advances, with the profusion of novel biological agents. A comprehensive and thoughtful approach based on a thorough understanding of biology is necessary to wisely use patient and financial resources. The use of the neoadjuvant paradigm entails collaborating with urologists and laboratory scientists to accelerate drug development and to discover factors predictive of efficacy. A special focus on patients who have recurrence after previous chemotherapy or are not candidates for cisplatin is necessary, as they currently have particularly poor outcomes. In addition, factors predictive of response to specific agents need to be defined to facilitate personalized therapy.

CONFLICTS OF INTEREST

Guru Sonpavde; Speakers’ bureau for Sanofi-Aventis, Pfizer and Novartis; Research support from Pfizer, Eli Lilly, BMS, Astrazeneca and Cytogen. Robert Ross; Research support from Sanofi-Aventis, Novartis, Genentech, Astra-Zeneca, and Advisory board for Novartis. Thomas Powles; support from GSK. Christopher J. Sweeney; none. Noah Hahn; none; Thomas E. Hutson; research support from Bayer/Onyx, Pfizer, GlaxoSmithKline; Advisory board/consultant for Bayer/Onyx, Pfizer, Dendreon, Sanofi-Aventis; Speakers’ bureau for Bayer/Onyx, Pfizer, Amgen, Sanofi-Aventis, and Genentech. Matthew D. Galsky; speakers’ bureau for Pfizer. Seth P. Lerner; research support form Pfizer, Eli Lilly, Cytogen; Cora N. Sternberg has received research support from Eli Lilly, Sanofi-Aventis, Pharmion, GPC Biotech and Bayer/Onyx.