FUNCTIONAL GENOMICS IDENTIFY PROBABLE TARGETS IN RENAL CANCER

NEW YORK (Reuters Health) - Functional genomics has identified 31 potential therapeutic targets that contribute to clear cell renal cell carcinoma (ccRCC) proliferation, researchers report.

The clear cell subtype accounts for about 80% of all RCC cases, and up to 30% of patients present with metastatic disease. As many as 30% of patients who undergo partial or total nephrectomy also develop metastatic disease within 5 years of the original diagnosis.

Dr. John A. Copland from Mayo Clinic Comprehensive Cancer Center in Jacksonville, Florida and colleagues used a high-throughput gene microarray screen to identify genetic transcripts that are overexpressed at all stages of ccRCC (compared with matched normal kidney tissue).

With this approach, they identified 31 genes that are required for ccRCC cell propagation, including one gene (CDH13) that plays a role in tumor angiogenesis and four novel factors (KISS1R, KSR1, CAMK1, and SSPN) that play a pro-migratory role in ccRCC, according to the June 12 Oncotarget online report.

"In addition to the potential of these genes and gene products to help us design new drugs, they could also serve as biomarkers for accurate diagnosis," lead author Christina von Roemeling said in a related news release. "It really is a treasure trove for future research on kidney cancer."

In the same news release, Dr. Copland said, "We are releasing these discoveries to the scientific community so that a large effort can be mounted to find out more about these genes and how they can be effectively targeted. We owe patients speedy research that focuses on new treatments to save lives."

Dr. Copland did not respond to a request for comments.

SOURCE: http://bit.ly/1tWh0Zq

Oncotarget 2014.

SUNITINIB FIRST BETTER THAN EVEROLIMUS FIRST FOR RENAL CANCER

Everolimus (Afinitor, Novartis) is not as effective as sunitinib (Sutent, Pfizer) in the first-line setting for patients with metastatic renal cell carcinoma, and it has a different toxicity profile, according to a phase 2 randomized direct comparator trial.

The study, known as RECORD-3, was published online July 21 in the Journal of Clinical Oncology.

"The hope was that everolimus would be better tolerated and as good as sunitinib in first-line treatment," said lead investigator Robert Motzer, MD, attending physician in the genitourinary oncology service at the Memorial Sloan Kettering Cancer Center and professor of medicine at Weill Medical College at Cornell University in New York City.

However, "in first-line therapy, the efficacy of sunitinib appeared to be better than everolimus. It is clear that sunitinib remains the standard first-line therapy," he explained.

"The current paradigm of sunitinib followed by everolimus at progression should be maintained. The experimental sequence of everolimus first followed by sunitinib second did not appear to be as effective," Dr. Motzer reported.

RECORD-3 was sponsored by Novartis, the maker of everolimus. It is the first head-to-head comparison of the mTOR inhibitor everolimus and the VEGF tyrosine kinase inhibitor (TKI) sunitinib, both of which are orally administered. RECORD-3 is the first study of its kind to look at sequence therapy in renal cell carcinoma, the investigators note.

The standard first-line treatment for metastatic renal cancer is VEGF TKI therapy, such as sunitinib. If a patient progresses, the next step is to switch to everolimus.

Previous studies suggested that everolimus had a "very favorable" safety profile and "good activity" in patients who had progressed on first-line therapy with sunitinib, Dr. Motzer explained. After this is established, the next step in drug development is often a head-to-head comparison with the reference standard.

The RECORD-3 study set out to determine how the efficacy and safety of everolimus compares with sunitinib in the first-line setting, and how the standard sequence of sunitinib followed by everolimus compares with everolimus followed by sunitinib. Quality-of-life issues were also assessed.

At the beginning of the trial, "our opinion was that everolimus was better tolerated by most patients than sunitinib," Dr. Motzer explained.

Crossover Trial Design

The open-label crossover study was conducted at 83 sites in 19 countries from October 2009 to June 2011. Participants were randomized to first-line everolimus (n = 238) or sunitinib (n = 238) until disease progression or discontinuation. At disease progression, patients could crossover to second-line treatment with the other drug.

Median progression-free survival was shorter with first-line everolimus than with first-line sunitinib (7.9 vs 10.7 months; hazard ratio [HR], 1.4). Likewise, median progression-free survival was shorter with everolimus followed by sunitinib than with sunitinib followed by everolimus (21.1 vs 25.8 months; HR, 1.3).

Median overall survival was also shorter with everolimus followed by sunitinib than with sunitinib followed by everolimus (22.4 vs 32.0 months; HR, 1.2).

Different Safety Profiles

Although the safety profiles of the 2 drugs are different, the investigators could not conclude that everolimus is better tolerated than sunitinib, Dr. Motzer reported. Some adverse effects, like hypertension and fatigue, occurred more frequently with sunitinib. Others, like stomatitis, were more common with everolimus. In fact, there was no clear distinction between the drugs regarding quality of life.

"For the common type of kidney cancer, clear cell carcinoma, this study showed that sunitinib is the preferred first-line treatment over everolimus," Dr. Motzer concluded.

The study was funded by Novartis, the manufacturer of everolimus. Dr. Motzer reports financial relationships with Novartis, Pfizer, Genentech, Aveo, and GlaxoSmithKline. Several of the study coauthors report financial relationships with various pharmaceutical companies, and some are employed by Novartis, as detailed in the publication.

J Clin Oncol. Published online July 21, 2014. Abstract

IMMUNOTHERAPY FOR CERVICAL DYSPLASIA

(Reuters) - Inovio Pharmaceuticals Inc announced positive results from its randomized, double-blind, placebo-controlled phase II trial of VGX-3100 in women with biopsy-proven cervical intraepithelial neoplasia 2/3 (CIN2/3) associated with human papillomavirus (HPV) types 16 or 18.

Treatment with VGX-3100, Inovio's HPV16/18-specific immunotherapy, resulted in histopathological regression of CIN2/3 to CIN1 or no disease, meeting the study's primary endpoint, the company said.

In addition, the trial demonstrated clearance of HPV in conjunction with regression of cervical lesions. Robust T-cell activity was detected in subjects who received VGX-3100 compared to those who received placebo.

"This is a significant step toward providing women and their physicians a non-surgical approach to the treatment of precancerous lesions by stimulating their immune system to eliminate high risk HPV infection and induce regression of a cervical intraepithelial neoplastic process," Dr. Mark Bagarazzi, Chief Medical Officer, Inovio Pharmaceuticals, said in a news release.

"This proof of concept trial will guide the advancement of VGX-3100 for precancerous dysplasias as well as HPV-associated cervical, head and neck, and anogenital cancers," he added.

For the trial, treatment was randomized 3:1 between the VGX-3100 and placebo groups, and was stratified by age and severity of CIN. The primary endpoint, histologic regression, was evaluated 36 weeks after the first treatment.

In the per protocol analysis, CIN2/3 resolved to CIN1 or no disease in 53 of 107 (49.5%) women treated with VGX-3100 compared to 11 of 36 (30.6%) who received placebo (p<0 .025="" p="">

Virological clearance of HPV 16 or 18 from the cervix in conjunction with histopathological regression of cervical dysplasia to CIN1 or no disease, a secondary endpoint of the trial, was observed in 43 of 107 (40.2%) VGX-3100 recipients compared to 5 of 35 (14.3%) placebo recipients (p<0 .025="" p="">

As in the phase I study, VGX-3100 elicited robust HPV-specific T cell responses in the majority of treated subjects. A comprehensive analysis of T cell responses is ongoing, the company said.

The treatment was generally well-tolerated, with only administration site redness occurring significantly more frequently in the VGX-3100 group compared to the placebo group in the 7- and 28-day periods following treatment.

ROBOTIC CYSTECTOMY SHOWS NO ADVANTAGE

NEW YORK (Reuters Health) - Using robotic techniques to remove a cancerous bladder doesn't reduce the risk of complications compared with conventional open surgery, according to a new comparison of 118 patients conducted by surgeons at the Memorial Sloan Kettering Cancer Center in New York.

The study, detailed online July 23 in the New England Journal of Medicine, marks the first ongoing comparison of the risks and benefits of the two techniques. Past studies concluded that the robotic technique meant less time in the hospital and fewer complications but they were done by looking back at the records of already-treated patients.

"There's been a lot of hype surrounding robots and it's been hard to gain perspective," said Dr. Vincent Laudone, one of the coauthors.

Dr. Jennifer Yates, director of minimally invasive urology at the University of Massachusetts Medical School, who was not involved in the test, told Reuters Health that the findings will give surgeons pause because they're going to be surprised by the results.

Robots have shown to be so valuable for prostate removal, many surgeons were convinced that a similar benefit would appear when they were used for bladder removal, she said. "They're going to say, 'Hey, I'm kinda surprised by this.' They're also going to be encouraged that the complication rate was comparable."

"Bottom line: It looks like it was pretty much a wash," Laudone told Reuters Health. For patients, it means "if you're going to a surgeon who is experienced in traditional surgery and recommends traditional surgery, that's a reasonable recommendation."

He estimated that perhaps 25% of radical cystectomies are currently done with robots.

The study also found that patients who underwent conventional surgery spent about 28% less time in the operating room. They experienced more blood loss - about 5 ounces more - but "with that amount, we wouldn't expect to see any significant side effect," Laudone said.

"These results highlight the need for randomized trials to inform the benefits and risks of new surgical technologies before widespread implementation," he and his colleagues concluded.

About 67,000 bladder tumors are discovered in the U.S. each year and one quarter of them require bladder removal.

The new study involved patients who needed both the bladder and nearby lymph nodes extracted. The men also lost their prostate and the women lost their ovaries, fallopian tubes, uterus and related organs. Even when a $2 million robot was used, conventional surgery was employed to redirect urine to the intestine.

With robot-assisted surgery, 22% of the 60 patients had at least one serious complication within the first 90 days. A complication was regarded as serious if it required further surgery, intubation or major rehabilitation. The rate was essentially the same - 21% - with traditional surgery.

When the researchers included lesser complications, such as those requiring intravenous medicine or blood transfusion, the risk was 62% with robot-assisted surgery versus 66% with open surgery.

The average length of hospital stay was eight days for both groups.

But the patients in the robot group spent two hours longer in the operating room. The average time was 5 hours 29 minutes with conventional surgery and 7 hours 36 minutes with robotic assistance.

Both Laudone and Yates said that time difference is expected to shrink as doctors become more adept at working with robots.

"It's an evolving technology and we're evolving in our learning to use the robot," Laudone said. "We're getting better as robotic surgeons, so operating time is diminishing. With prostate surgery, the same thing was true. Now, in some cases, doing it with the robot is faster. So the time difference is something I think will disappear with more experience."

Yates cautioned that "this was a small study and I think it needs to be fleshed out with larger numbers. And you have to remember that Sloan Kettering is one of the more prominent high-volume institutions in the country. Whether this is generalizable to other institutions remains to be seen."

SOURCE: http://bit.ly/1wN4FCQ

N Engl J Med 2014.

IBRUTINIB AND IDELALISIB SOON IN EUROPE

Two novel targeted agents that look to change the whole paradigm of treatment for chronic lymphocytic leukemia (CLL) look like they will be available in Europe soon.

Ibrutinib (Imbruvica, Janssen) and idelalisib (Zydelig, Gilead) have both been recommended for approval by the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) at its July meeting.

Both drugs are recommended for use in treatment of adult patients with CLL who have received at least 1 prior treatment, as well as a first-line treatment for patients with a specific genetic mutation that makes them unsuitable for chemoimmunotherapy.

They are also both recommended for use in certain lymphomas, although the indication is different for each drug.

Ibrutinib is also recommended for use in the treatment of adult patients with mantle cell lymphoma that has relapsed after previous treatments or is not responding to other treatments. Ibrutinib has orphan drug designation for this indication; mantle cell lymphoma is a very rare cancer, affecting around 15,000 people in the European Union. There is no standard-of-care treatment for this cancer when it relapses and is not responding to previous treatments, the EMA notes.

Idelalisib is also recommended for use for adult patients with follicular lymphoma that has not responded to 2 previous treatments.

The indications are similar to those in the United States, where ibrutinib was approved for CLL in February and for use in mantle cell lymphoma in November 2013, and idelalisib was approved for bothCLL and lymphoma just a few days ago.

Both drugs have generated considered excitement among experts who treat hematological malignancies, and there is hope that these oral targeted agents will eventually replace chemotherapy for the treatment of CLL. Although they are at present being used in patients who have progressed after chemotherapy (i.e., as second-line), their efficacy and tolerability have so impressed clinicians involved in their clinical trials that there is great enthusiasm to try these agents as front-line therapy, and those trials are now underway.

The EMA commented that ibrutinib and idelalisib "have the potential to bring new treatment options for patients suffering from these rare cancers, especially in cases where previous treatments have stopped working, as they act in different ways to previously authorized medicines."

Ibrutinib acts through a novel mechanism against the abnormal B-cells by blocking the action of an enzyme known as Bruton's tyrosine kinase, which is important for the growth, migration, and survival of B-cells. Idelalisib blocks the effects of another enzyme called PI3K-delta, which plays a role in the growth, migration, and survival of white blood cells.

The EMA also notes that today's announcement is "an intermediary step" on the drug's path to patient access. The CHMP recommendation will now be sent to the European Commission for the adoption of a decision on European Union–wide marketing authorizations. Once marketing authorizations have been granted, decisions about price and reimbursement will then take place at the level of each European Union member state considering the potential role/use of these medicines in the context of the national health system of that country.

T-DM1 SAFETY DATA

The antibody-drug conjugate ado-trastuzumab emtansine (Kadcyla) is currently indicated in the United States for treatment of patients with HER2-positive metastatic breast cancer who previously received trastuzumab (Herceptin) and a taxane and who have either received prior therapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy. As presented in the Journal of Clinical Oncology, Diéras et al have performed an integrated safety analysis of the use of single-agent ado-trastuzumab emtansine in patients with HER2-positive metastatic breast cancer.

The analysis included a total of 884 patients in six studies who received ado-trastuzumab emtansine 3.6 mg/kg every 3 weeks and included follow-up data from patients in an extension study. Patients received a median of 10 doses and had a median treatment duration of 6.3 months, with 28% having treatment for >1 year.

Averse Event Profile

The most common adverse events of any grade were fatigue (46%), nausea (43%), thrombocytopenia (32%), headache (29%), constipation (27%), and epistaxis (25%). The most common grade 3 or 4 adverse events were thrombocytopenia (11.9%, 2.4% grade 4), increased AST (4.3%), hypokalemia (3.3%), fatigue (3.3%), and increased ALT (3.1%). Peripheral neuropathy (including all relevant preferred terms) of any grade occurred in 29% of patients. Serious adverse events occurred in 19.8% of patients. Adverse events resulted in dose reduction in 17.2% of patients and to treatment discontinuation in 7.0%.

Adverse events on study or within 30 days of the last ado-trastuzumab emtansine dose led to death in 12 patients (1.4%). Of these events, seven were suspected to be related to ado-trastuzumab emtansine treatment, including hepatic failure, hepatic failure and encephalopathy (in one patient), hepatic function abnormal, bacterial sepsis, neutropenic sepsis, and metabolic encephalopathy.

Adverse Events of Special Interest

Among patients with grade 3 or 4 thrombocytopenia, 44% experienced grade 1 bleeding (primarily epistaxis), 4% grade 2 bleeding (primarily epistaxis), and 5% grade 3 to 4 bleeding. Four patients (0.5%) had a postbaseline left-ventricular ejection fraction < 40% and 1.8% had an left-ventricular ejection fraction decline of ≥ 15 percentage points to < 50%. Four patients (0.5%) discontinued ado-trastuzumab emtansine due to cardiac disorders (atrial fibrillation, left ventricular dysfunction, decreased ejection fraction in two). Pneumonitis-related adverse events occurred in 1.1% of patients (grade 3, 4, and 5 in one patient each). Infusion-related reactions and hypersensitivity (1.4%) occurred in 6.9% of patients. Eye disorders occurred in 9% of patients (87% grade 1).

The incidence of grade ≥ 3 adverse events was higher in patients aged ≥ 65 years vs < 65 years (52% vs 44%) and in Asian vs white patients (64% vs 42%), with the higher incidence in Asian patients largely reflecting a higher incidence of grade ≥ 3 thrombocytopenia (44% vs 11%).

The investigators concluded, “In this analysis of 884 [ado-trastuzumab emtansine]–exposed patients, grade 3 or greater [adverse events] were infrequent and typically asymptomatic and manageable. This favorable safety profile makes [ado-trastuzumab emtansine] treatment suitable for exploration in other breast cancer settings.”

Véronique Diéras, MD, of the Institut Curie Paris, is the corresponding author for the Journal of Clinical Oncology article.

The data reported in the Journal of Clinical Oncology article are from studies sponsored by Genentech and F. Hoffmann-La Roche. For full disclosures of the study authors, visit jco.ascopubs.org.

DRUG TO AVOID WHEN YOU ARE ON TKIs

With the rapid and widespread uptake of tyrosine kinase inhibitors (TKIs) in oncology over the past several years, serious drug–drug interactions are an "increasing risk," according a new report.

To guarantee the safe use of TKIs, "a drugs review for each patient is needed," write Frank G.A. Jansman, PharmD, PhD, from Deventer Hospital in the Netherlands, and colleagues in areview published in the July issue of the Lancet Oncology.

The review provides a comprehensive overview of known and suspected interactions between TKIs and conventional prescribed drugs, over-the-counter drugs, and herbal medicines.

All 15 TKIs approved to date by the US Food and Drug Administration or the European Medicines Agency are evaluated.

They are axitinib (Inlyta, Pfizer), crizotinib (Xalkori, Pfizer), dasatinib (Sprycel, Bristol-Myers Squibb and Otsuka America), erlotinib (Tarceva, Osi Pharmaceuticals), gefitinib (Iressa, AstraZeneca), imatinib (Gleevec, Novartis), lapatinib (Tykerb, GlaxoSmithKline), nilotinib (Tasigna, Novartis), pazopanib (Votrient, GlaxoSmithKline), regorafenib (Stivarga, Bayer), ruxolitinib (Jakafi, Incyte), sorafenib (Nexavar, Bayer), sunitinib (Sutent, Pfizer), vandetanib (Caprelsa, AstraZeneca), and vemurafenib (Zelboraf, Roche).

The authors offer specific recommendations to guide oncologists, hematologists, and clinical pharmacists in managing drug–drug interactions during treatment with TKIs in daily clinical practice.

They note that a number of "clinically relevant" drug interactions with TKIs have been identified. Most involve altered bioavailability related to altered stomach pH from acid-suppressive drugs, metabolism by cytochrome P450 isoenzymes, and prolongation of the QTc interval.

Interaction With Acid-Suppressive Drugs

Acid-suppressive drugs such as proton-pump inhibitors, H₂ antagonists, and antacids can profoundly alter the absorption of most TKIs. TKIs are weakly basic, and in the stomach they exists in both ionized and nonionized forms. An acid-suppressive drug will raise the stomach pH from about 1 to 4, which can shift the equilibrium between the 2 forms of TKIs toward the less soluble nonionized form; the result is that less drug is absorbed, leading to reduced concentrations in the blood.

This interaction between TKIs and acid-suppressive drugs is particularly important for crizotinib, dasatinib, erlotinib, gefitinib, lapatinib, and pazopanib. The concomitant use of these agents can result in a substantial alteration in the oral absorption of the TKI, the authors note. Therefore, if possible, the concomitant use of these TKIs with a proton-pump inhibitor, H₂ antagonist, or antacid "should be avoided, or the time of drug intake should be separated by several hours at least," the authors advise.

There is less interaction between acid-suppressive drugs and other TKIs. The authors note that proton-pump inhibitors, H₂ antagonists, and antacids can be used concomitantly with imatinib, axitinib, ruxolitinib, sorafenib, sunitinib, vandetanib, and vemurafenib.

However, they single out nilotinib, and advise that the concomitant use of proton-pump inhibitors is fine, but an H₂ antagonist should be taken 10 hours before or 2 hours after nilotinib, and an antacid should be taken 2 hours before or after nilotinibThey also note that there are no data available on potential interactions between regorafenib and acid-suppressive drugs.

Dose Adjustments Recommended

The authors move on to highlight potential interactions between TKIs and drugs that are metabolized by cytochrome P450 isoenzymes.

There are several drugs to watch out for. In particular, drugs that act as CYP3A4 inhibitors (such as ketoconazole, itraconazole, and voriconazole) or CYP3A4 inducers (such as rifampicin and enzalutamide) can have a large effect on the blood concentration of any TKI, with the exception of sorafenib and vandetanib.

In many cases, the result of this interaction is increased blood concentrations of the TKI, with resultant increased toxicity. The action required is either to avoid concomitant administration or to reduce the dose of the TKI. However, in other cases, the result of the interaction is a decrease in blood concentrations of the TKI, so an increased in dose is needed.

The dose adjustment can be a 50% increase or decrease. The authors provide detailed recommendations for each TKI.

Concomitant use of the following combinations should be avoided: crizotinib plus ketoconazole, gefitinib plus itraconazole, vandetanib plus rifampicin, regorafenib plus rifampicin, and regorafenib plus ketoconazole.

The dose of the TKI should be reduced when the following drugs are used in combination with ketoconazole: axitinib, dasatinib, erlotinib, lapatinib, nilotinib, pazopanib, ruxolitinib, and sunitinib.

The dose of the TKI might need to be increased when rifampicin is used in combination with axitinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, nilotinib, ruxolitinib, or sunitinib. The dose of TKI might need to be decreased with the combinations of carbamazepine plus lapatinib, carbamazepine plus pazopanib, and phenytoin plus pazopanib.

The authors note that the following combinations "can be used safely": sorafenib plus rifampicin, sorafenib plus ketoconazole, and vandetanib plus itraconazole.

Another substance that can interfere with the P450 system is grapefruit, which acts as a CYP3A4 inhibitor. Grapefruit has been shown to increase the area under the curve (denoting higher blood concentrations) of sunitinib by 11% (Cancer Chemother Pharmacol. 2011;67:695-703) and of nilotinib by 29% (J Clin Pharmacol. 2010;50:188-194). Thus, the authors recommend that grapefruit juice be avoided with sunitinib and nilotinib, and discourage it's consumption with other TKIs.

The authors highlight potential interactions that can occur at the point of drug absorption, when the p-glycoprotein efflux transporter is involved. Some TKIs (such as pazopanib, lapatinib, and gefitinib) act as inhibitors of this p-glycoprotein, and can therefore increase the bioavailability of other drugs that act as p-glycoprotein substrates (such as digoxin, irinotecan, and paclitaxel). The authors recommend extensive therapeutic drug monitoring when p-glycoprotein substrates with a narrow therapeutic window (such as digoxin, ciclosporin, and tacrolimus) are used in combination with TKIs that inhibit p-glycoprotein.

Rare Interaction, But Potentially Fatal

A rare but potentially fatal interaction is QTc prolongation and the subsequent development of Torsades de pointes.

The TKIs with demonstrated QTc prolongation are crizotinib, gefitinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib, vandetanib, and vemurafenib.

Medical oncologists need to be "better informed" about the risk when coadministrating drugs that prolong the QTc interval and TKIs, the authors state.

Pharmacists need to routinely check for the concomitant use of such prolonging drugs and CYP3A4 inhibitors, they add. "Special attention should given to QTc interval-prolonging 5HT₃ antagonists, antibiotics, antifungals, and over-the-counter drugs (e.g., domperidone), because these drugs are frequently used by patients with cancer concomitantly with TKIs," they note.

"Unless absolutely necessary," the concomitant use of QTc interval-prolonging TKIs and other such drugs "should be avoided. If indicated, an ECG should be obtained 24 to 48 hours before and 1 week after initiating the concomitant therapy," the authors advise.

Other Possible Interactions

The authors note that there have been case reports describing pharmacodynamic interactions between TKIs and other drugs. For example, imatinib can increase methotrexate toxicity by causing fluid retention, and sunitinib and imatinib can antagonize levothyroxine treatment by interfering with thyroid hormones at the pituitary level.

In addition, the concomitant use of antibiotics that affect the flora of the gastrointestinal tract might interfere with the enterohepatic circulation of regorafenib and might decrease regorafenib absorption.

To improve the safety of TKIs in oncology, a thorough assessment of coprescribed drugs, herbal supplements, lifestyle food and drinks (e.g., grapefruit juice), cardiac risk factors, and physical examination" is needed, the authors conclude.

To do this, close collaboration between oncologists, hematologists, clinical pharmacists, family doctors, and cardiologists is imperative, they say.

"In case of a suspected interaction, and if pharmacokinetic data are not available, physicians and pharmacists should balance the available evidence, if possible, extrapolate available pharmacokinetic data for an individual patient, and monitor closely for toxic effects and response," they conclude.

The authors have disclosed no relevant financial relationships.

Lancet Oncol. 2014;15:e315-e326. Abstract

2 of 2

FIRST DATA ON ALS PREVALENCE

The first national prevalence data on amyotrophic lateral sclerosis (ALS) was reported today from the National ALS Registry, using administrative data to ascertain cases of ALS in the United States.

In 2009, the federal Agency for Toxic Substances and Disease Registry (ATSDR), a sister agency to the Centers for Disease Control and Prevention (CDC), implemented the National ALS Registry to collect and analyze data regarding persons with ALS, which is a non-notifiable disease in the United States (except in Massachusetts). The main goals of the Registry, as defined by the 2008 ALS Registry Act, are to describe the incidence and prevalence of ALS better, examine risk factors such as environmental and occupational exposures, and characterize the demographic characteristics of those living with ALS.

In their first report, researchers estimate the overall prevalence of ALS is 3.9 per 100,000 people in the United States, with the highest prevalence (17.0 per 100,000) among those aged 70 to 79 years. Men have a higher prevalence than women (4.8 vs 3.0 per 100,000), and whites a higher rate than blacks (4.2 vs 2.0 per 100,000).

The new report is published online July 24 and appears in the July 25 issue of Morbidity and Mortality Weekly Report (MMWR).

Facilitating Research

ALS is a progressive and fatal neuromuscular disease. Most people with the condition die within 5 years of receiving the diagnosis. There's no known cause, but a hereditary form of the disease, familial ALS, occurs in 5% to 10% of cases.

There is no blood or other test for ALS; diagnosis is based on signs and symptoms and on neurophysiologic tests. There's also no cure, although riluzole (Rilutek, Sanofi-Aventis) has been shown to slow disease progression and has been approved in the United States to treat the condition.

The ATSDR is collecting data from 4 national databases, maintained by Medicare, Medicaid, the Veterans Health Administration, and the Veterans Benefits Administration. Researchers used an algorithm with variables such as international classification codes, a prescription for riluzole, and frequency of visits to a neurologist, to identify people with "definite ALS."

The algorithm, developed during previous pilot projects, was shown to have a sensitivity of 87% and specificity of 85%.

Researchers also used a secure Web portal to identify ALS cases. On this site, patients answer a series of validated screening questions that are very accurate, according to the report authors, led by Paul Mehta, MD, Division of Toxicology and Human Health Science, ATSDR, Atlanta, Georgia. Just over 93% of those who passed the screening questions were determined by a neurologist to have ALS/motor neuron disease.

A total of 12,187 people were identified as having "definitive ALS" across the 4 databases and through the Web portal.

The higher prevalence of ALS among men was observed across all age groups and data sources. The ratio of males to females (1:56) is consistent with other published data, said the authors.

EBOLA VIRUS ON THE RISE

FREETOWN (Reuters) - The head doctor fighting the deadly tropical virus Ebola in Sierra Leone has himself caught the disease, the government said.

The 39-year-old Sheik Umar Khan, hailed as a "national hero" by the health ministry, was leading the fight to control an outbreak that has killed 206 people in the West African country. Ebola kills up to 90% of those infected and there is no cure or vaccine.

Across Guinea, Liberia and Sierra Leone, more than 600 people have died from the illness, according to the World Health Organisation, placing great strain on the health systems of some of Africa's poorest countries.

Khan, a Sierra Leonean virologist credited with treating more than 100 Ebola victims, has been transferred to a treatment ward run by medical charity Medecins Sans Frontieres, according to the statement released late on Tuesday by the president's office.

Health Minister Miatta Kargbo called Khan a national hero and said she would "do anything and everything in my power to ensure he survives."

Khan told Reuters in late June that he was worried about contracting Ebola. "I am afraid for my life, I must say, because I cherish my life," he said in an interview, showing no signs of ill health at the time.

"Health workers are prone to the disease because we are the first port of call for somebody who is sickened by disease. Even with the full protective clothing you put on, you are at risk."

Three days ago, three nurses working in the same Ebola treatment center alongside Khan died from the disease.

The Ebola outbreak started in Guinea's remote southeast in February and has since spread across the region. Symptoms of the highly infectious disease are diarrhea, vomiting and internal and external bleeding.

TEST TO REDUCE REPEATED PROSTATE BIOPSIES

In men with previous histopathologically negative findings, the epigenetic ConfirmMDx (MDxHealth) assay for prostate cancer can lead to a 10-fold reduction in repeat biopsies, 2 new studies show.

Both confirm the utility of epigenetic profiling in helping to distinguish patients who have a true negative biopsy from those at risk for occult cancer, according to the researchers.

The commercially available assay assesses methylation markers of prostate cancer (GSTP1, APC, and RASSF1) to distinguish histologically benign biopsy cores from patients diagnosed with no cancer, low-volume cancer (a Gleason score of 6), or higher-volume cancer (a Gleason score of 7).

One of the studies, a clinical utility field study in which the assay was tested by practicing urologists working in community settings, was published in the May issue of American Health & Drug Benefits.

Assay a "Piece of the Puzzle"

Until ConfirmMDx, "we had no reliable tool to tell us whether or not a patient should have another biopsy," said investigator Jeffrey D. Small, MD, a practicing urologist from the Yale–New Haven Health System at Bridgeport Hospital in Connecticut.

"Although the test isn't perfect, it gives us something that we didn't have before," he told Medscape Medical News.

With the assay, changes in DNA methylation that occur during oncogenesis can be assessed in the biopsy tissue, indicating whether a repeat biopsy is necessary. "I use the test as a piece of the puzzle; it is not the whole answer. There are other things that would determine each individual's risk," Dr. Small explained.

"The goal is to minimize the number of biopsies in patients who otherwise might have routinely undergone repeat biopsy. In this era of managed care and Accountable Care Organizations, where we are looking at costs, if we have a test that can minimize the number of repeat biopsies without missing cancer, then everybody wins," he said.

"I now use the test routinely in my practice," he added.

The ConfirmMDx assay has a negative predictive value of 90%; however, the positive predictive value is only 28%.

In their study, Dr. Small and his colleagues assessed the impact of a negative ConfirmMDx result on a urologist's decision to conduct a repeat prostate biopsy.

They evaluated urologists from 5 practices that had ordered ConfirmMDx on at least 40 patients with previous biopsies negative for cancer during the previous 18 months.

The analysis involved 138 patients from these practices. Mean age in the cohort was 63 years, and median serum prostate-specific antigen (PSA) level was 4.7 ng/mL.

There was 10-fold reduction in repeat biopsies with the assay. Only 6 of the patients (4.3%) with a negative result underwent repeat biopsy. Previous research has shown the rate of repeat prostate biopsy to be above 40.0% (BJU Int. 2007;99:775-779).

More Validation From DOCUMENT

The second study, the multicenter Detection of Cancer Using Methylated Events in Negative Tissue (DOCUMENT) validation study, was published online April 16 in the Journal of Urology.

ONCE WEEKLY GLP-1 AGONIST FOR DIABETES

The investigational once-weekly dulaglutide (Eli Lilly) is noninferior to once-daily liraglutide (Victoza, Novo Nordisk), providing similar glycated hemoglobin (HbA1c) reductions, in adults with type 2 diabetes poorly controlled with metformin, a new study finds. In addition, the glucagon-like peptide-1 receptor (GLP-1) agonists showed similar tolerability.

Kathleen M. Dungan, MD, MPH, associate professor of medicine and director of the clinical endocrine trials unit at Ohio State University, Columbus, and colleagues published the results from the phase 3, randomized, open-label, head-to-head AWARD-6 online July 11 in The Lancet.

In the 62-site, 9-country study, 269 patients in each group completed treatment with once-weekly dulaglutide or once-daily liraglutide. At 26 weeks, HbA1c dropped 1.42% with dulaglutide and 1.36% with liraglutide. The 0.06% difference met the prespecified 0.4% noninferiority margin.

"From both a patient and physician perspective, having that robust HbA1c lowering with only a once-weekly therapy seems quite attractive," Dr. Dungan told Medscape Medical News. "We do have to consider other potential issues, such as tolerability. About 20% of patients in both groups had some nausea. Ultimately, we are all going to be thinking about cost, and that remains to be seen. This presents another attractive option for treating hyperglycemia in patients with type 2 diabetes."

In an accompanying editorial, André J. Scheen, MD, of the University of Liège, Belgium, writes that the new findings may help inform the decision of which incretin-based drug is preferred as a second- or third-line agent when patients don't achieve target HbA1c with metformin alone or in combination with other agents, although questions remain.

With regard to the GLP-1 agonist class, Dr. Scheen writes, "The obvious advantage of a once-weekly versus a once-daily injection concerns patients' acceptance and possibly compliance. However, compliance might be different in clinical trials, in which it is strictly controlled and regularly reinforced, as compared with everyday practice. Therefore, prediction of how short-term differences in compliance, balanced by potential improvement in patients' acceptance and compliance with the once-weekly medication, would affect glycemic control in daily life is difficult and needs further study."

Adverse Event Rates Similar

At baseline, patients had an average HbA1c of 8.1%, even with metformin treatment. Dulaglutide was started at 1.5 mg once-weekly and continued at that dose for the 26-week treatment period. Liraglutide was initiated according to labeling, and started at 0.6 mg/day in Week 1 and titrated up to 1.8 mg/day in Week 3.

Despite the differences in dosing, gastrointestinal adverse-event rates were similar in the 2 groups. The most common were nausea (20% with dulaglutide and 18% with liraglutide), diarrhea (12% in both groups), dyspepsia (8% and 6%, respectively), and vomiting (7% and 8%, respectively).

"Nausea peaked in both groups around 2 weeks and then declined to about 5% in both groups by 12 weeks... The curves are almost superimposable. You reach a steady stay in 2 to 3 weeks," Dr. Dungan said.

Both groups experienced significant weight loss: 3.61 kg for liraglutide compared with 2.90 kg for dulaglutide (P = .011). "The difference was statistically significant, but we don't how clinically significant that would be," she noted.

Hypoglycemia rates were 0.34 and 0.52 events/patient/year, with no severe episodes reported.

The authors note that they had originally wanted the trial to be blinded, but had to conduct it open-label because they could not obtain a liraglutide placebo pen.

Which Incretin-Based Drug Is Best?

Incretin mimetics, such as GLP-1 agonists, and incretin enhancers, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, are increasingly being used as second-line treatment after failure of metformin monotherapy, or later in triple combinations, according to Dr. Scheen.

In comparing the drug classes, he notes that GLP-1 agonists are better at lowering glucose than DPP-4 inhibitors, and GLP-1 agonists promote weight loss. But they are expensive, cause nausea and vomiting, and must be injected. By comparison, DPP-4 inhibitors have the advantages of oral administration, lower cost, and better gastrointestinal tolerability. On the downside, they do not lower glucose levels as well and do not promote weight loss.

There are an increasing number of GLP-1 options from which to choose. Although they all share the same mechanism of action, data suggest that their effects differ, especially regarding gastric emptying, resulting in different effects on postprandial versus fasting plasma glucose, Dr. Scheen writes.

But most data about the differences among the agents come from indirect comparisons between short- and long-acting GLP-1 agonists rather than head-to-head trials, and that is also the case for several large, long-term prospective trials currently underway.

Dr. Scheen concludes, "Although none of these trials will provide head-to-head comparisons, the data they will offer to the medical community should help physicians in the best choice of incretin-based therapies for management of type 2 diabetes."

Dr. Dungan and colleagues presented the trial results earlier this year at the American Diabetes Association (ADA) 2014 Scientific Sessions.

This trial was sponsored by Eli Lilly . Dr. Dungan reports consulting and advisory board activities with Eli Lilly, and research support from Novo Nordisk. Her coauthors have also received honoraria, speaker fees, or advisory fees from Eli Lilly, and 3 coauthors are Eli Lilly employees. Dr. Scheen has received lecture, adviser’s, or investigator’s fees from AstraZeneca/Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, sanofi-aventis, and Takeda.

The Lancet. Published online July 11, 2014. Abstract Editorial extract

LOSS OF FBP1 METABOLIC ENZYME IMPORTANT IN KIDNEY CANCER

In an analysis of metabolites in human kidney tissue, a research team from thePerelman School of Medicine at the University of Pennsylvania identified an enzyme key to applying the brakes on tumor growth. The new study, published inNature by Simon et al, demonstrated that an enzyme called FBP1, which is essential for regulating metabolism, binds to a transcription factor in the nucleus of certain kidney cells and restrains energy production in the cell body.

The researchers determined that this enzyme is missing from all kidney tumor tissue analyzed. When FBP1 is working properly, out-of-control cell growth is kept in check, but without the enzyme, tumor cells produce energy at a much faster rate than their noncancer cell counterparts.

A Personalized Approach for Kidney Cancer?

Clear cell renal cell carcinoma, the most frequent form of kidney cancer, is characterized by elevated glycogen and fat deposits in affected kidney cells. In the past decade, clear cell renal cell carcinomas have been on the rise worldwide. However, if tumors are removed early, a patient’s prognosis for 5-year survival is relatively good. If expression of the FBP1 gene is lost, patients have a worse prognosis.

“This study is the first stop in this line of research for coming up with a personalized approach for people with clear cell renal cell carcinoma–related mutations,” said Celeste Simon, PhD, Professor of Cell and Developmental Biology, Scientific Director for the Abramson Family Cancer Research Institute, and investigator with the Howard Hughes Medical Institute.

Renal cancer cells are associated with changes in two important intracellular proteins: elevated expression of hypoxia inducible factors (HIFs) and mutations in the von Hippel-Lindau (VHL) encoded protein, pVHL. In fact, mutations in pVHL occur in 90% of clear cell renal cell carcinoma tumors. pVHL regulates HIFs, which in turn affect activity of the Kreb’s cycle.

Study Details

Recent large-scale sequencing analyses have revealed the loss of several epigenetic enzymes in certain types of clear cell renal cell carcinomas, suggesting that changes within the nucleus also account for kidney tumor progression.

To complement genetic studies revealing a role for epigenetic enzymes, the investigators evaluated metabolic enzymes in the 600-plus tumors they analyzed. The expression of FBP1 was lost in all kidney cancer tissue samples examined. They found FBP1 protein in the cytoplasm of normal cells, where it would be expected to be active in glucose metabolism. But, they also found FBP1 in the nucleus of these normal cells, where it binds to HIF to modulate its effects on tumor growth. In cells without FBPI, the team observed the Warburg effect, a phenomenon in which malignant, rapidly growing tumor cells go into overdrive, producing energy up to 200 times faster than their non–cancer cell counterparts.

This unique dual function of FBP1 explains its ubiquitous loss in clear cell renal cell carcinoma, distinguishing FBP1 from previously identified tumor suppressors that are not consistently inhibited in all tumors. “And since FBP1 activity is also lost in liver cancer, which is quite prevalent, FBP1 depletion may be generally applicable to a number of human cancers,” noted Dr. Simon.

According to the researchers, the next steps will be to identify other metabolic pathways to target, measure the abundance of metabolites in kidney and liver cancer cells to determine FBP1’s role in each, and develop a better mouse model for preclinical studies.

Dr. Simon is the corresponding author for the Nature article.

This work was supported by the Howard Hughes Medical Institute, and the National Cancer Institute.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®

BEVACIZUMAB-LOMUSTINE COMBINATION FOR RECURRENT GLIOBLASTOMA

Bevacizumab (Avastin) is frequently used in patients with recurrent glioblastoma, although it is unclear whether responses observed with such treatment result in improved overall survival. In the phase II Dutch BELOB study reported in The Lancet Oncology, Taal et al found that overall survival results supported phase III evaluation of the combination of bevacizumab and lomustine (CeeNU) but not bevacizumab monotherapy.  

Study Details

In this open-label trial, 153 adult patients from 14 Dutch hospitals with a first recurrence of glioblastoma after temozolomide chemoradiotherapy were randomly assigned between December 2009 and November 2011 to receive oral lomustine at 110 mg/m2 once every 6 weeks, intravenous bevacizumab at 10 mg/kg once every 2 weeks, or combination treatment at the same doses. The primary endpoint outcome was overall survival at 9 months in the intent-to-treat population.

A preplanned safety analysis after eight patients had received the combination regimen showed that three had grade 3 and two had grade 4 thrombocytopenia, with these toxicities requiring a reduction in bevacizumab dose intensity. The lomustine dose in the combination group was subsequently reduced to 90 mg/m2. In addition to the eight combination recipients getting the higher lomustine dose, 51 received bevacizumab alone, 47 received lomustine alone, and 47 received bevacizumab plus lomustine at 90 mg/m2.

9-Month Overall Survival

The 9-month overall survival rate was 43% (95% confidence interval [CI] = 29%–57%) in the lomustine group, 38% (95% CI = 25%–51%) in the bevacizumab group, 59% (95% CI = 43%–72%) in the bevacizumab/lomustine 90 mg/m2 group, 87% (95% CI = 39%–98%) in the bevacizumab/lomustine 110 mg/m2 group, and 63% (95% CI = 49%–75%) in the two bevacizumab/lomustine groups combined.

Toxicity

Combination treatment was well tolerated after the lomustine dose reduction. The most common grade 3 or higher adverse events were hypertension, which occurred in 26% of the bevacizumab group, 7% of the lomustine group, and 25% of the bevacizumab/lomustine 90 mg/m2 group, fatigue (4%, 9%, and 18%), and infection (6%, 4%, and 11%).

The investigators concluded, “The combination of bevacizumab and lomustine met prespecified criteria for assessment of this treatment in further phase 3 studies. However, the results in the bevacizumab alone group do not justify further studies of this treatment.”

Martin J. van den Bent, MD, of Erasmus MC Cancer Center, Rotterdam, is the corresponding author for The Lancet Oncology article.

The study was funded by Roche Nederland and KWF Kankerbestrijding. For full disclosures of the study authors, visit www.thelancet.com.

BEVACIZUMAB NEAR APPROVAL FOR PLATINUM RESISTANT OVARIAN CANCER

The U.S. Food and Drug Administration (FDA) has accepted Genentech’s supplemental Biologics License Application and granted Priority Review for bevacizumab (Avastin) plus chemotherapy for the treatment of women with recurrent platinum-resistant ovarian cancer.

“The majority of women with ovarian cancer will become resistant to platinum therapy, and a quarter of women will have platinum-resistant disease at the time of a first recurrence. New treatment options are needed,” said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development.

The designation of Priority Review status is granted to medicines that the FDA believes have the potential to provide “significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.” The supplemental Biologics License Application for bevacizumab plus chemotherapy for recurrent platinum-resistant ovarian cancer is based on data from the phase III AURELIA trial.

AURELIA Study

AURELIA is a company-sponsored, multicenter, randomized, open-label, phase III study in 361 women with platinum-resistant recurrent epithelial ovarian, primary peritoneal or fallopian tube cancer who had received no more than two anticancer regimens prior to enrollment in the trial. Participants were randomly assigned to one of six treatment arms (paclitaxel, topotecan, or liposomal doxorubicin with or without bevacizumab).

The study met its primary endpoint and showed that bevacizumab plus chemotherapy reduced the risk of disease progression by 52% compared to chemotherapy alone; the median progression-free survival was 6.7 months for bevacizumab plus chemotherapy vs 3.4 months for chemotherapy alone (hazard ratio [HR] = 0.48, P < .001). No statistically significant difference was seen in the secondary endpoint of overall survival (P < .174).

Women in the bevacizumab-plus-paclitaxel arm (n = 60) experienced a 54% improvement in progression-free survival (10.4 vs 3.9 months; HR = 0.46, 95% confidence interval [CI] = 0.30–0.71) and a 35% improvement in overall survival (22.4 vs 13.2 months; HR = 0.65, 95% CI = 0.42–1.02).

The study showed women who received bevacizumab plus chemotherapy had a significantly higher objective response rate compared to chemotherapy alone when evaluated by the RECIST criteria (27.3% vs 11.8%, respectively; P = .001).

Grade 3 to 5 adverse events occurring at a higher incidence in women receiving bevacizumab plus chemotherapy compared to women receiving chemotherapy alone were hypertension (7% vs 1%), proteinuria (2% vs 0 %) and gastrointestinal perforations (2% vs 0%).