primeLINES CLINICAL OPINION POLL

June 2010 Issue

NEWS FROM THE 2010 ONCOLOGY ANNUAL MEETING IN CHICAGO

The 46th Oncology Annual Meeting in Chicago, held June 4-8, brought more than 30,000 researchers, oncology specialists and other health professionals from all over the world to discuss the most current achievements in oncology. The theme of this year’s meeting was “Advancing Quality Through Innovation,” and it featured several new initiatives and programs during educational and scientific sessions. This newsletter summarizes several of the most compelling presentations, some of which offer potentially practice-changing insights.

Breast Cancer

Update of ABCSG-12 Trial and Antitumor Activity of Zoledronic Acid in Early Breast Cancer

If there was ever any doubt that zoledronic acid (Zometa^®) has potent anticancer effects in patients with breast cancer, there should be no longer. For years, there have been intriguing bits of evidence to suggest that bisphosphonates do more than just stabilize the bone. They can also inhibit tumor growth and metastasis. However, definitive in vivo evidence has been lacking.

Benefit of zoledronic acid is sustained

During this year’s Oncology Annual Meeting in Chicago, Michael Gnant, MD, PhD (Medical University of Vienna, Vienna, Austria), presented follow-up data from ABCSG-12 based on 186 disease-free survival (DFS) events and 73 deaths at a median follow-up of 62 months. The mature results showed that patients in both the anastrozole/goserelin and tamoxifen/goserelin arms continue to benefit from the addition of zoledronic acid regardless of nodal status. Disease-free survival was significantly improved (hazard ratio [HR] = 0.68; P = .009), and a trend toward better overall survival (OS) was observed (HR = 0.67; P = .094). Zoledronic acid was well tolerated and reduced the risk of locoregional and distant recurrences (both, inside and outside the bone). This study has provided clear clinical evidence that the antitumor effects of zoledronic acid, which have been observed in a variety of preclinical models, can translate to a meaningful clinical benefit in the adjuvant setting. Comparing endocrine therapy in the ABCSG-12 trial, no significant difference was observed in DFS between arms of ovarian suppression in combination with either anastrozole or tamoxifen, However, superior OS was demonstrated in the tamoxifen/goserelin arm, which might be an effect of post-relapse therapy.

J Clin Oncol. 2010;28(7s): Abstract 533.

Is BMI important for anastrozole efficacy?

Georg Pfeiler, MD (Medical University of Vienna, Vienna, Austria), presented results of a retrospective analysis from the ABCSG-12 trial that showed decreased DFS and OS in overweight patients treated with anastrozole/goserelin compared with overweight patients treated with tamoxifen/goserelin, but no differences in outcomes for normal-weight patients. The worse outcomes in overweight patients are most likely due to aromatase activity in fat tissue. The discussant, Pamela Goodwin MD, MSc (University of Toronto, Toronto, Canada), noted that these findings are interesting and important, and that the obesity interaction could be a class effect relevant to all aromatase inhibitors (AIs). She highlighted that findings are not currently practice changing, but further research in randomized trials is required to demonstrate similar effects and to evaluate aromatase inhibition and estrogen levels according to BMI in patients receiving AIs.

J Clin Oncol. 2010;28(7s): Abstract 512.

Disseminated tumor cells: A surrogate marker of the anticancer activity of zoledronic acid

In addition to the ABCSG-12 trial, evidence of the anticancer activity of zolendronic acid was demonstrated in study presented by Sally Greenberg, MD (University of California, San Francisco, California, United States). This trial evaluated the effect of zoledronic acid (4 mg once monthly for 24 months) on disseminated tumor cells (DTCs) in the bone marrow of 45 patients with high-risk, early-stage breast cancer receiving adjuvant therapy. An initial bone marrow aspiration was performed after neoadjuvant or adjuvant chemotherapy to assess baseline levels of DTCs (defined as positive if >4 DTC/mL), and repeat aspirations were performed at 12 months and 24 months. Median follow-up was 49 months. DTC ≥30/mL at baseline was predictive of recurrence (P = .0002). More importantly, treatment with zoledronic acid for 2 years significantly reduced DTC from baseline at both 12 months and 24 months (P<.001). In addition, in a significant proportion of patients, conversion to DTC-negative bone marrow was seen at 12 months and 24 month, 32% and 24%, respectively. These findings support the hypothesis that DTCs are a surrogate marker of the anticancer effect of zoledronic acid.

J Clin Oncol. 2010;28(7s): Abstract 1002.

Eribulin: A Novel Tubulin Inhibitor Breaks New Ground

Eribulin mesylate (E7389) is the first single-agent chemotherapy to demonstrate a statistically significant OS benefit in patients with heavily pretreated metastatic breast cancer (MBC), highlighted Christopher Twelves, MD (University of Leeds, Leeds, United Kingdom), during his presentation. Eribulin is a novel tubulin inhibitor with a unique binding site that distinguishes it from established agents, including taxanes, vinca alkaloids, and epothilones, and has significant antitumor activity in taxane-refractory patients. In the phase III EMBRACE trial, patients with MBC who previously had been treated with both a taxane and an anthracycline were randomized to either eribulin or treatment of physician’s choice (TPC). Patients randomized to the TPC arm received a variety of chemotherapy agents, most commonly vinorelbine, gemcitabine, and capecitabine, which reflect standard clinical practice in this setting. Patients enrolled in this study had received a median of 4 prior regimens, and approximately 75% had received prior capecitabine. In the primary intent to treat analysis, median OS was 13.1 months with eribulin versus 10.7 months with TPC (P = .04). The objective response rate (ORR) was also significantly improved (12% eribulin versus 5% TPC; P = .005).

What really distinguishes eribulin from taxanes and ixabepilone is the fact that it is not associated with hypersensitivity reactions and can be rapidly infused (5 minutes) without the need for premedication. It is also less neurotoxic. These results from EMBRACE trial establish eribulin as a new treatment option for women with heavily-pretreated MBC.

J Clin Oncol. 2010;28(7s): Abstract CRA1004.

Ovarian Cancer

Bevacizumab: First Targeted Therapy for Ovarian Cancer

Until now, targeted therapy has not played a major role in the treatment of ovarian cancer. The standard of care for the past decade has been platinum-based doublet chemotherapy (primarily carboplatin plus paclitaxel). However, there is a strong rationale for angiogenesis inhibitors in this disease, and bevacizumab (Avastin^®) has demonstrated promising phase II activity as monotherapy in recurrent ovarian cancer. The Gynecologic Oncology Group (GOG) 0218 study reported at the plenary session by Robert Burger, MD (Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States), enrolled 1873 patients with newly diagnosed, stage III or IV ovarian cancer who underwent debulking surgery and were then randomized to either chemotherapy alone (carboplatin plus paclitaxel), chemotherapy plus concurrent bevacizumab (15 mg/kg), or chemotherapy plus concurrent and maintenance bevacizumab (15 cycles). Chemotherapy plus concurrent and maintenance bevacizumab significantly reduced the risk of first progression or death by 28% (HR = 0.717; P<.0001) and improved median progression-free survival (PFS) by 3.8 months compared to chemotherapy alone at median follow up 17.4 months. Overall survival was similar across the treatment groups, however, the survival data are not yet mature. Importantly, adverse events were manageable and no unexpected events were observed. Addition of bevacizumab lead to an increased incidence of grade 3/4 hypertension, but, overall, the incidence of grade ≥3 gastrointestinal (GI) perforation, hemorrhage, and fistula was relatively low compared with chemotherapy alone (2.6% to 2.8% versus 1.2%).

Bevacizumab is the first targeted agent to show benefit in patients with advanced epithelial ovarian cancer, and the investigators concluded that carboplatin and paclitaxel combined with concurrent and maintenance bevacizumab should be considered as a first-line treatment option.

J Clin Oncol. 2010;28(7s): Abstract LBA1.

Prostate Cancer

Denosumab Beats Zoledronic Acid in CRPC

In this head-to-head, randomized, phase III trial, denosumab (Prolia^®), a human monoclonal antibody against the receptor activator of nuclear factor kappaB ligand (RANKL), significantly delayed time to first skeletal-related event (SRE) by 3.6 months compared to zoledronic acid in patients with castration-resistant prostate cancer (CRPC) that had metastasized to bone. Karim Fizazi, MD, PhD (Institut Gustave-Roussy, Villejuif, France), presented the results during the genitourinary (prostate) cancer oral abstract session. To date, zoledronic acid is the only agent approved to prevent or delay SREs in patients with bone metastases from CRPC. In a multiple event analysis, denosumab also significantly delayed time to first or subsequent SRE (HR = 0.82; P = .008). The discussant, Robert Coleman, MD (University of Sheffield, Sheffield, United Kingdom), pointed out that this study is consistent with 2 other identically designed trials showing that denosumab significantly delays time to first SRE compared to zoledronic acid in patients with bone metastases/lesions from breast cancer or multiple myeloma and from other solid tumors. However, the question does remain whether the delay to SRE correlates with any improvement in quality of life in patients with CRPC.

J Clin Oncol. 2010;28(7s): Abstract LBA4507.

Cabazitaxel Improves Survival in CRPC

Since 2004, docetaxel has been the standard first-line chemotherapy for CRPC based on evidence that it improved survival compared to mitoxantrone plus prednisone (MP). Now the novel taxane, cabazitaxel, has demonstrated a statistically significant OS benefit in patients with CRPC who progressed during or after docetaxel chemotherapy. One of the key features of cabazitaxel is a low affinity for the multidrug resistance transporter P-glycoprotein, and studies have shown activity in patients with taxane-resistant MBC. In this large, multinational, phase III trial (TROPIC) presented by Johann De Bono, MD, PhD (Royal Marsden Hospital, London, United Kingdom), 755 men were randomized to either mitoxantrone (12 mg/m²) plus prednisone (10 mg/day) or cabazitaxel (25 mg/m²) plus prednisone. Median OS was 15.1 months in the cabazitaxel/prednisone arm and 12.7 months in the MP arm (HR = 0.72; P<.0001). Progression-free survival, response rates, and time to progression (TTP) (by RECIST and PSA) also significantly favored cabazitaxel/prednisone. There was an increased risk of ≥ grade 3 febrile neutropenia and diarrhea with cabazitaxel compared with MP (7.5% vs 1.3% and 6.2% vs 0.3%, respectively). Although the majority of death in the study was due to progressive disease (71% MP vs 59% cabazitaxel), there was an increased death rate of 4.9% due to adverse events in the cabazitaxel arm observed outside of North America. In their conclusion, the investigators recommended the proactive management of side effects, in particular neutropenia and diarrhea. The discussant, Ian Tannock, MD, PhD (Princess Margaret Hospital, Toronto, Canada), concluded that, based on these results, cabazitaxel will likely become the new standard of care as second-line therapy for CRPC; although during his discussion he also voiced concern regarding the toxicity issue and questioned the used dose of cabazitaxel in heavily pretreated, elderly, patients with CRPC.

J Clin Oncol. 2010;28(7s): Abstract 4508.

Lung Cancer

BATTLE: Zeroing in on the Target

The recently reported phase II BATTLE [Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination] has demonstrated that it is feasible (using fresh tissue biopsies) to identify biomarker groups according to their signaling pathways (EGFR, KRAS, BRAF, Cyclin D1) and then to tailor therapy with erlotinib, sorafenib, vandetanib, or erlotinib plus bexarotene for patients with non-small cell lung cancer (NSCLC) accordingly. The data showed that each of the 4 treatments targeted a specific molecular signature better than the other three. The primary 8-week disease control predicted OS was more than 11 months in patients who had disease control, versus 7.5 months in those who did not.

Roy Herbst, MD (University of Texas, M. D. Anderson Cancer Center, Houston, Texas, United States), presented the results of a subset analysis of the BATTLE study examining the 8-week disease control rate (DCR) for patients treated with sorafenib based on their biomarker status. It was found that sorafenib was more effective than erlotinib against tumors with a KRAS mutation (DCR: 61% vs 32%, P = .06) and that sorafenib had significantly lower activity in patients with EGFR mutations versus no mutation (DCR: 23% vs 64%; P = .012) or EGFR gene amplification compared with normal copy number (27% vs 62%; P = .048). These findings suggest that sorafenib may be most effective against tumors with wildtype, non-amplified EGFR and with KRAS mutations. These are precisely the patients who are unlikely to benefit from EGFR inhibitors, which are most effective against tumors with EGFR mutations and wildtype KRAS.

J Clin Oncol. 2010;28(7s): Abstract 7609.

ALK: The Newest Target in NSCLC

One of the outstanding abstracts selected for presentation in the plenary session was a phase II study of crizotinib (PF-1066), an oral, selective small molecule inhibitor of ALK and c-MET/HGF receptor tyrosine kinases demonstrating high activity when applied to patients with advanced NSCLC harboring the EML4-ALK fusion gene (detected by FISH). It was first reported in 2007 that approximately 5% of NSCLC (primarily adenocarcinomas) express the oncogenic EML4-ALK (Anaplastic Lymphoma Kinase) fusion protein. Yung-Jue Bang, MD, PhD (Seoul National University Hospital, Seoul, Korea) presented results of 82 ALK-positive patients with advanced NSCLC included in an ongoing phase II trial with crizotinib (250 mg BID). Almost all patients had a histology of adenocarcinoma, were never-smokers or former-smokers, and received a median of 3 (range, 0-7) prior therapies. The median duration of treatment was 5.7 months. Amazingly, the ORR was 57% and DCR at 8 weeks was 87%. Moreover, 72% of patients were progression free at 6 months and median PFS has not be reached. Overall, crizotinib was well tolerated. The most frequently reported adverse events were mild nausea/vomiting and diarrhea that resolved fairly quickly, and about 40% of patients reported visual disturbances (changes in light/dark accommodation). Based on these very promising results, a phase III trial has been initiated. The discussant, Martin Edelman, MD (University of Maryland, Baltimore, Maryland, United States), commented that the results are impressive and questioned whether a phase III comparative trial is necessary considering this excellent response, durable PFS, good tolerability, and known poor response of ALK-positive patients to chemotherapy.

J Clin Oncol. 2010;28(7s): Abstract 3.

Melanoma

Ipilimumab: New Treatment for Metastatic Melanoma

Improving survival in advanced metastatic melanoma has been an elusive goal for decades. Because melanoma is notoriously resistant to chemotherapy, the focus of research has been on immunotherapy. In the plenary session, Steve O’Day, MD (The Angeles Clinic and Research Institute, Santa Monica, California, United States), presented the results of a 3-arm, double-blind, randomized, phase III trial with OS as the primary endpoint. This study randomized 676 patients with stage III/IV melanoma 1:1:3 to the HLA-A2–restricted melanoma vaccine gp100 alone, the monoclonal antibody against cytotoxic T-lymphocyte antigen 4 (CTLA4) ipilimumab (3 mg/kg every 3 weeks) alone, or the combination of ipilimumab plus gp100 for 4 cycles. Eligible patients were selected for HLA-A2 expression. Both arms containing ipilimumab demonstrated a significant improvement in OS compared to gp100 alone (median 10 months vs 6 months). The 12-month OS rate was 46% with ipilimumab and 44% with ipilimumab plus gp100 compared to 25% in the gp100 alone arm. Median PFS, best overall response rate (BORR) and DCR were also significantly improved. Interestingly, ipilimumab monotherapy performed better than the combination. Most important adverse events were immune related and included rash, colitis, diarrhea, and hepatitis. Most were manageable and reversible; however, for grade 3/4 adverse events, treatment with high-dose steroids was required. The authors concluded that patients with metastatic melanoma whose disease progressed during treatment with one or more prior therapies may benefit from treatment with ipilimumab. Results from this study have been published online ahead of print in the New England Journal of Medicine (N Engl J Med. 2010 June 14. [Epub ahead of print]).

J Clin Oncol. 2010;28(7s): Abstract 4.

Re-induction of ipilimumab is effective

Patients in the study described above who had an objective response or stable disease for at least 3 months following initial therapy were eligible (at disease progression) for re-induction with the same regimen. As reported by Stephan Hodi, MD (Dana-Farber Cancer Institute, Boston, Massachusetts, United States), re-induction with ipilimumab monotherapy (n = 9) or ipilimumab + gp100 (n = 29) resulted in a 67% and 52% DCR, respectively; no response was observed in vaccine-alone arm. This suggests that these patients remain responsive to immunotherapy, which could have important implications for the long-term management of metastatic melanoma.

J Clin Oncol. 2010;28(7s): Abstract 8509.

Ipilimumab is active for brain metastases

In the study reported by Donald Lawrence, MD (Massachusetts General Hospital, Boston, Massachusetts, United States), ipilimumab treatment yielded the response rate of 15.7% in the patients with brain metastases without corticosteroids therapy, and only 1.8% for those who received steroids. Importantly, the median duration of response for responding patients was 15.3 months.

J Clin Oncol. 2010;28(7s): Abstract 8523.

Chronic Myelogenous Leukemia

Second-Generation TKIs Superior Therapy for Newly Diagnosed Chronic-Phase CML

A decade ago, the use of the BCR-ABL inhibitor imatinib mesylate (Gleevec^®/Glivec^®) transformed Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML) from a deadly disease to a manageable chronic disease, thus establishing imatinib as a standard first-line treatment for CML. Two second-generation tyrosine kinase inhibitors (TKIs)--nilotinib (Tasigna^®) and dasatinib (Sprycel^®)--have been approved for second-line therapy for patients who are intolerant or have became resistant to imatinib. Both second generation TKIs were shown to be more potent and selective BCR-ABK inhibitors than imatinib. Two large international, randomized, phase III trials compared efficacy and safety of each of the new TKI with imatinib in newly diagnosed CML and updated results of these studies were presented at this year’s Oncology Annual Meeting in Chicago.

Sustained superiority of nilotinib over imatinib

Richard Larson, MD (University of Chicago, Chicago, Illinois, United States), presented updated results from the ENESTnd trial, which compared the efficacy and safety of nilotinib with imatinib in patients with newly diagnosed Ph+, chronic-phase CML. In this trial, patients were randomized to either nilotinib (300 mg or 400 mg BID) or imatinib (400 mg/day). The primary endpoint was major molecular response rate (MMR) at 12 months, and the secondary endpoint was complete cytogenetic response rate (CCyR) at 12 months. Results from the primary analysis (median follow-up of 13.8 months) were presented at the Hematology Annual Meeting in New Orleans in December 2009 and demonstrated a significantly superior MMR (44% and 43% vs 22%, P<.001) and CCyR (80% and 78% vs 65%) for both doses of nilotinib versus imatinib. The current analysis (median follow-up of 18.5 months) demonstrated that both the MMR and CCyR were significantly higher at 18 months and 24 months for patients treated with nilotinib (both doses), and nilotinib also significantly delayed progression to accelerated phase or blast crisis compared to imatinib. Both nilotinib and imatinib were generally well tolerated and rates of grade 3/4 myelosuppression were similar across treatment arms. In addition, no patients demonstrated clinically relevant QT prolongation or decrease from baseline in mean left ventricular ejection fraction in either arm. These longer follow-up data clearly demonstrate the sustained superiority of nilotinib over imatinib in patients with newly diagnosed Ph+, chronic-phase CML. Dr Larson concluded that longer follow-up supports nilotinib as a new standard of care in patients with newly diagnosed, chronic-phase CML. Results from this study have been published online ahead of print in the New England Journal of Medicine (N Engl J Med. 2010;362(24):2251-2259).

J Clin Oncol. 2010:28(7s): Abstract 6501.

Dasatinib better than imatinib

A similar trial (DASISION), reported by Hagop Kantarjian, MD (M. D. Anderson Cancer Center, Houston, Texas, United States), randomized 519 newly-diagnosed patients with Ph+, chronic-phase CML to treatment with dasatinib (100 mg/day) or imatinib (400 mg/day). This study showed that dasatinib was significantly superior to imatinib based on CCyR (77% vs 66%; P = .007) and MMR (46% vs 28%, P<.0001) at 12 months. This compares favorably to the 12-month MMR observed in the ENESTnd trial. These findings led the authors to conclude that dasatinib may improve long-term outcomes among patients with newly diagnosed chronic-phase CML. Results from this study have also been published online ahead of print in the New England Journal of Medicine (N Engl J Med. 2010;362(24:2260-2270).

J Clin Oncol. 2010;28(7s): Abstract LBA6500.

Michael Mauro, MD (Oregon Health and Science University, Portland, Oregon, United States), who discussed both of the trials, concluded his discussion that "2010 may redefine the best therapy for chronic phase CML."

Non-Hodgkin Lymphoma

Rituximab Once Again Raises the Bar

Rituximab (Rituxan^®) is commonly combined with first-line chemotherapy for follicular lymphoma, and retreatment with rituximab is typically reserved until first relapse. However, the PRIMA study conducted by Goupe d' Etude des Lymphomes de l' Adulte (GELA) has demonstrated that addition of 2 years of rituximab maintenance therapy significantly delays progression with little added toxicity. Gilles Salles, MD, PhD (Hospices Civils de Lyon and Université de Lyon, Lyon, France), presented the results of this practice-changing study during the lymphoma oral abstract session. Patients responding to standard first-line immunochemotherapy, consisting of either 8 cycles of R-CVP, or 6 cycles of R-CHOP or R-FCM, (1,018 eligible patients) were randomized to either observation or rituximab maintenance (375 mg/m² every 8 weeks for 2 years). At a median follow-up of 25 months from randomization (31 months from study entry), rituximab maintenance was associated with a significant improvement in PFS (HR = 0.50; P<.0001). Two-year PFS was 82% in the rituximab arm versus 66% with observation. During the discussion, Richard Fisher, MD (University of Rochester, Rochester, New York, United States), concluded that based on all the currently available evidence, rituximab should be offered as maintenance therapy to all appropriate patients rather than waiting until relapse. Studies are ongoing to determine whether rituximab maintenance is superior to re-induction with rituximab at first relapse.

J Clin Oncol. 2010;(7s)28: Abstract 8004.

Multiple Myeloma

Lenalidomide Maintenance Following ASCT Delays Disease Progression

Interim results of 2 large phase III, placebo-controlled trials have shown that maintenance therapy with lenalidomide (Revlimid^®) significantly delays disease progression following autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM).

Philip McCharty, MD (Roswell Park Cancer Center, Buffalo, New York, United States), presented results from the Intergroup trial CALGB 100104, which evaluated the efficacy and safety of lenalidomide following high-dose chemotherapy and single ASCT in patients aged <70 years with stage I-III MM. Patients with stable disease or better were randomized to lenalidomide (10 mg/day increasing to 15 mg/day over 3 months) or placebo until relapse. The trial was stopped at the second interim analysis after a highly significant improvement in TTP was observed in favor of lenalidomide. Results of the second interim analysis demonstrated a median TTP of 25.5 months in the placebo group, and median TTP has not been reached in the lenalidomide group (HR = 0.42; P<.0001). The number of deaths was not significantly different.

J Clin Oncol. 2010;28(7s): Abstract 8017.

A second phase III trial reported by Michel Attal, MD (Purpan Hospital, Toulouse, France), included over 600 patients aged <65 years with non-progressive multiple myeloma 6 months after ASCT following high-dose induction chemotherapy. Patients received lenalidomide consolidation therapy (25 mg/day for 21 days per month) for 2 months, after which they were stratified based on response to ASCT, beta-2 microgobulin, and chromosome 13 deletions before being randomized to either maintenance lenalidomide (10 to 15 mg/day) or placebo until relapse. At a median follow-up of 24 months, an interim analysis demonstrated that consolidation lenalidomide therapy improved response in 20% of patients, and maintenance lenalidomide significantly improved 3-year PFS by 54% (HR = 0.46; P<10-7). This benefit of maintenance lenalidomide was seen in all stratified subgroups of patients. No difference was observed in OS (88% vs 80%). Treatment with maintenance lenalidomide was well tolerated without an increased incidence of deep venous thrombosis or peripheral neuropathy.

J Clin Oncol. 2010;28(7s): Abstract 8018.

Evidence of Antitumor Efficacy of Zoledronic Acid in Multiple Myeloma

Bisphosphonates are standard of care for patients with bone lesions from MM based on evidence that they significantly reduce bone pain and skeletal complications such as pathologic fractures. In an effort to further define the potential anticancer effect of zoledronic acid, the Medical Research Council Myeloma IX Study investigated the effects of zoledronic acid (4 mg IV q 21-28 days) versus oral clodronate (1600 mg/day) in combination with standard antimyeloma therapy in 1970 patients with newly diagnosed MM. At a median follow-up of approximately 4 years, zoledronic acid not only reduced the percentage of patients with an SRE compared to clodronate (27% vs 35%; P = .0004), but also significantly improved both PFS and OS. Median PFS was improved by 2 months (19.5 months vs 17.5 months; P = .0179), and median OS was improved by 5.5 months (50.0 vs 44.5 months; P = .0118). Importantly, the OS benefit associated with zoledronic acid was maintained after adjustment in a Cox model for the potential effects of SREs on survival. This study provides further clinical evidence of the anticancer activity of zoledronic acid. The authors reported that both bisphosphonates were generally well-tolerated. Decreased renal function was similar in both treatment groups. Osteonecrosis of the jaw occurred in 3.5% of patients treated with zoledronic acid and 0.3% of patients treated with oral clodronate.

J Clin Oncol. 2010;28(7s): Abstract 8021.

Renal Cell Carcinoma

Prognostic Genomic Markers for Renal Cell Carcinoma

The prognosis of localized, clear cell renal cell carcinoma (ccRCC) is currently based on clinical and pathologic features that provide only general estimate of recurrence risk. However, a gene expression profile specific to individual tumors could improve risk determination for localized ccRCC similar to the 21-gene recurrence score assay in breast cancer. Brian Rini, MD (Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio, United States), provided preliminary data of the largest prospectively defined observational genomic study of stage I-III ccRCC involving clinical/pathology data and evaluable tissue blocks of 931 patients. From 732 candidate genes, 448 genes were significant for relapse-free interval without adjustment for baseline covariates and false discovery rate. A multivariate model identified 29 genes that remained significantly and strongly associated with recurrence-free interval (RFI) after adjustment for clinical/pathologic covariates (microscopic necrosis, Fuhrman grade, stage, tumor size and lymph node involvement), 72 genes were selected for further preliminary analysis. Among the 72 genes, increased expression of angiogenesis-related genes and cell-mediated cytotoxic response genes was associated with lower risk of recurrence. Tumors with a high risk of recurrence were characterized by high expression of interleukin (IL)-6 and IL-8 genes, high expression of cell cycle genes and invasion genes. The authors concluded that these results can be used to create a multigene algorithm that may accurately predict risk of recurrence of an individual patient and predict treatment benefit in patients with localized ccRCC.

J Clin Oncol. 2010;28(7s): Abstract 4501.