This month we will be discussing various topics and data from different meetings and resources. I hope you enjoy the following articles and find them useful in your research and practice. Also, please keep an eye out for next month’s issue, full of data from the 2009 American Society of Clinical Oncology^® (ASCO) Annual Meeting in Orlando, Florida!

Glioblastoma Multiforme

Genentech announced on May 5, 2009 the accelerated US Food and Drug Administration (FDA) approval of bevacizumab for people with glioblastoma multiforme who had progressed on prior therapy. The approval is based on an open-label phase II trial named AVF3708g of 167 patients with glioblastoma who had progressed following prior therapy with radiation and temozolomide. Patients were randomly assigned to either bevacizumab alone or with irinotecan in a non-comparative analysis. The FDA analysis suggested a tumor response rate of 25.9% in the 85 patients treated with bevacizumab alone and a 4.2 month median duration of response. Strict response criteria were established as part of the trial using magnetic resonance imaging (MRI) and the World Health Organization (WHO) radiographic criteria as well as stable or decreased steroid usage. These data were supported by another study (NCI 06-C-0064E) where 56 patients with progressive glioblastoma following prior therapy were treated with bevacizumab alone. The response rate was reported as 20%, with a median duration of response of 3.9 months. Safety data from AVF3708g in those patients treated with bevacizumab alone were summarized and included 10% grade 3 or higher infection, 8% hypertension, 4% fatigue, 4% headache, and 1% diarrhea. Two deaths, possibly related to therapy, included a retroperitoneal hemorrhage and a neutropenic infection. Grade 3-5 adverse events were more common in patients who received bevacizumab in combination with irinotecan. The Radiation Therapy Oncology Group (RTOG) and National Cancer Institute (NCI) will be sponsoring a randomized clinical trial for patients with newly diagnosed glioblastoma multiforme and will compare temozolomide and radiation with or without bevacizumab.

News from the American Association for Cancer Research (AACR) Annual Meeting: Prostate Cancer

Dr Jianfeng Xu from Wake Forest University and his colleagues presented regarding the development of a risk model for determining a man’s risk for prostate cancer based on family history and single nucleotide polymorphisms (SNPs). The group studied 14 risk alleles among 2893 men with prostate cancer and 1781 men without prostate cancer who had previous participated in a Swedish case-control study. Investigators then estimated the absolute risk for prostate cancer based on the individual genotype and the family history. They found that the risk of prostate cancer increased as the number of risk alleles increased. Each additional risk allele was associated with an odds ratio of 1.14. The results were confirmed with available data from the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial. As an example, for a man with 7 or fewer risk alleles and a negative family history, he has an 8% absolute risk of developing prostate cancer between the ages of 55 and 74, and this number rises to 17% with a positive family history. Alternatively, a man with 14 risk alleles and a negative family history has a 24% chance of being diagnosed with prostate cancer in the same age range, and this increased to 52% with a family history. Dr Xu did suggest that one of the limits of the model was the inability to predict for the development of indolent versus more aggressive forms of prostate cancer. Dr Xu’s group continues to study different SNPs to help distinguish between these 2 clinical types of prostate cancer. The authors suggested that the current risk model could be used to assist in the decision-making for the use of PSA as a screening method as well as for the use of chemoprevention using finasteride. Future plans include the development of a prospective prostate cancer prevention trial using this risk model of family history and risk alleles to guide chemoprevention with finasteride.

Medullary Thyroid Cancer

Dr Elaine Lam and her colleagues at Ohio State University presented the results of a phase II clinical trial assessing the objective response rate of the small molecule multi-kinase inhibitor sorafenib in patients with advanced, metastatic, hereditary, and sporadic medullary thyroid cancer (MTC). Sorafenib is known to target the pathogenic defects of RET kinase and vascular endothelial growth factor receptors in medullary thyroid cancer. The study also sought to correlate clinical response with serum tumor markers, FDP-PET, and RET genotyping. Five patients with hereditary MTC and 16 with sporadic MTC were presented. Nineteen of 20 patients developed either an objective response or stable disease with only 1 disease progression as the best response. Ten of 16 patients with sporadic MTC and 2 of 4 patients with hereditary MTC developed durable stable disease lasting for a minimum of 6 months. The study remains open to patients with hereditary MTC. Adverse events were typical for sorafenib and included hand-foot syndrome and hypertension.

Impaired Response to EGFR-Targeted Therapies

Dr Nicolantonio from the University of Turin Medical School and colleagues presented data from their studies regarding the evaluation of gene mutations in BRAF, PIK3CA, and KRAS as well as loss of PTEN expression, and the correlation with response to epidermal growth factor receptor (EGFR)–targeted therapies such as cetuximab and panitumumab. She suggested that KRAS mutations account for only about 40% to 50% of the nonresponsive cases of metastatic colorectal cancer. The question to be asked was whether there were other biomarkers that could explain resistance in patients with metastatic cancer. In order to further evaluation this hypothesis, these gene alterations were evaluated in 132 patients with metastatic colorectal cancer who were actively being treated with a regimen containing 1 of these 2 drugs. KRAS, BRAF, and PIK3CA mutations were present in 35, 11, and 17 cases respectively, and loss of PTEN was found in 41 cases. Twenty-six of the 132 patients exhibited clinical benefit from their treatment with either cetuximab or panitumumab. Twenty-three of 26 were “wild-type” for the 4 genes, and 3 showed mutations in KRAS (2) or loss of PTEN expression (1). Of the 106 patients with no clinical benefit, 74 had tumors with 1 or more gene alterations, and 32 were “wild-type” for all 4 genes. In multivariate analysis, mutations of KRAS and loss of PTEN were the only independent predictors of lack of objective response. Cox multivariate analyses for survival demonstrated that mutations of BRAF and loss of PTEN are independently associated with a decreased overall survival, with a trend towards significance for KRAS mutations. The presence of mutations in at least 1 gene among KRAS, BRAF, or PIK3CA was significantly associated with lack of response to EGFR targeted monoclonal antibodies, and negatively impacted on both progression-free and overall survival. The authors suggested that prospective studies were needed to address the role of BRAF, PIK3CA, and PTEN in helping to select and stratify patients with metastatic colorectal cancer who are treated with anti-EGFR therapies.

News from the American Urological Association (AUA) Annual Meeting: Immunotherapy for Prostate Cancer

Dr David Penson and colleagues presented data from the phase III Immunotherapy for Prostate AdenoCarcinoma Treatment (IMPACT) study. The study randomized 512 patients with asymptomatic or minimally symptomatic metastatic, castrate-resistant prostate cancer. The men were randomly assigned in a 2:1 fashion to either sipuleucel-T or placebo. Sipuleucel-T is a vaccine that is individually manufactured from a patient’s own circulating immune cells. The patient has extraction of their antigen presenting cells (APCs), and these cells are admixed with the protein prostatic acid phosphatase which is fused with granulocyte macrophage colony-stimulating factor (GM-CSF). The mixture is then given back to a patient intravenously several days later, and 3 cycles are given over the course of 1 month. Dr Penson presented the survival data from the trial. The median survival was 25.8 months for patients receiving the vaccine, and 21.7 months for those receiving placebo. The 3-year survival was 31.7% versus 23%, respectively. The most common toxicities reported were chills, fever, headache, and flu-like symptoms.

Other ongoing trials with sipuleucel-T include a phase III randomized trial in men with early stage, androgen-dependent prostate cancer (Trial P-11).

Schellbammer PF, Higano C, Berger ER, et al. A randomized, double-blind, placebo-controlled, multi-center, phase III trial of sipuleucel-T in men with metastatic, androgen independent prostatic adenocarcinoma (AIPC) American Urologic Association 10th Annual Scientific Meeting; April 28, 2009. Late braking abstract 9.

Chemoprevention for Prostate Cancer

The results from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial were presented by Dr Gerald Andriole and colleagues. The REDUCE trial is a phase III multinational, randomized, placebo-controlled trial of 8200 men aged 50 to 75 years with an elevated prostate-specific antigen (PSA [2.5 ng/mL - 10.0 ng/mL]) and a negative prostate biopsy at baseline. Patients were randomized to the dihydrotestosterone 5-alpha reductase inhibitor dutasteride 0.5 mg daily, or placebo. Prostate-specific antigen levels were measured biennially for 4 years, and prostate biopsies were conducted at 2 and 4 years. At 2 years, prostate cancer was found in 17.2% of men on placebo, and 13.4% of men on dutasteride. At year 4, prostate cancer was diagnosed in another 11.8% and 9.1% respectively. There was no difference between the 2 groups with regards to the percentage of patients developing a high Gleason score prostate cancer. Dutasteride is a dual 5 alpha-reductase inhibitor and inhibits both type I and type II isoenzymes of 5 alpha-reductase. Finasteride, which has been shown to significantly reduce the incidence of prostate cancer by 30% for men in the Prostate Cancer Prevention Trial, inhibits just type II 5-alpha reductase. These new data continue to support the concept of chemoprevention in men at a higher risk of the development of prostate cancer.

OncoFacts™ Editor:

Christy Russell, MD

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