ASCO unveils latest treatment strategies

The ASCO​ conference, which took place in Orlando, Florida between May 13-17, took the opportunity to present the best of clinical and translational cancer research. Many drug companies presented new drug candidates at the show as DrugResearcher.com presents a round up of the latest research presented at the meeting.

Just ahead of the start of ASCO, OncoGenex Technologies​ announced results from a second Phase 1 study of OGX-011, the company's lead product candidate. OGX-011 is a second-generation antisense inhibitor of clusterin, a cell-survival protein that is over-expressed in many cancers and is associated with treatment resistance and poor clinical outcome.

At the 2004 ASCO meeting, OncoGenex and Isis reported that OGX-011, in a dose-dependent fashion, achieved effective drug concentration in prostate cancer tissue and produced up to a 91 per cent dose-dependent decrease in clusterin expression.

Results from the Phase 1 clinical trial also demonstrated that the inhibition of clusterin was associated with the predicted pharmacological outcome, the death of prostate cancer cells.

A second Phase 1 study, also featured at this year's ASCO annual meeting, was designed to determine recommended dose of OGX-011 in combination with Taxotere in various solid tumours. In preclinical animal studies, OGX-011 improved the potency of traditional chemotherapies by more than 10-fold in prostate cancer with no increase in toxicity. OncoGenex plans to initiate Phase 2 clinical trials of OGX-011 in patients with lung, breast and prostate cancers this year.

New data presented by Pfizer​ suggests that its investigational new drug Sutent/SU11248 (sunitinib malate) extends overall survival in gastrointestinal stromal tumours (GIST). Sutent is a highly selective, multi-targeted tyrosine kinase inhibitor that starves tumours of blood and nutrients needed for growth and simultaneously kills cancer cells that make up tumours.

Long-term follow-up data from the Phase I/II GIST study that served as the basis for the larger Phase III trial demonstrated that Sutent extended overall survival to nearly 20 months in patients whose cancer had progressed despite treatment with other standard therapies. In addition, the median time to tumour progression in this study was 7.8 months for all patients, with some specific subtypes of patients benefiting even more dramatically than would be expected with Gleevec.

Results from a double-blind Phase III study of more than 300 GIST patients resistant to or intolerant of the standard treatment Gleevec (imatinib mesylate) showed Sutent significantly prolonged the time to tumour progression (6.3 months on Sutent vs 1.5 months for controls) and reduced the risk of death by approximately 50 per cent compared to placebo.

"These results substantiate the concept that multi-targeted molecular therapy can overcome resistance to other targeted drugs in cancer,"​ said Dr George Demetri of Harvard University's Dana-Farber Cancer Institute in Boston, the lead investigator on the Sutent trial for GIST.

"We think that Sutent may have a broad spectrum of activity for many different forms of cancer beyond what we have seen in patients with GIST. We believe that Sutent is an important step forward in cancer therapy,"​ he added.

According to DataMonitor​, the oncology market is the third largest pharmaceutical market, behind the cardiovascular and CNS therapy areas, worth an estimated $40 billion (€32 billion) in 2004. Datamonitor projects the sector to grow to $53 billion by 2008, yielding a compound annual growth rate (CAGR) greater than 10 per cent over this period.

In 2004, the top 20 cancer drugs in each of the seven major pharmaceutical markets generated combined sales exceeding $27 billion, with the US accounting for 67 per cent of this total, Japan 12 per cent and the five EU countries 21 per cent (Midas, IMS Health, April 2004). Collective sales in these markets represent approximately 70 per cent of global oncology revenues.

Over the next 10 years, Datamonitor predicts that of the cancer drugs that currently hold a top 20 position in one or more of the seven markets, only those in the innovative and supportive care classes will maintain a positive CAGR. Conversely, cytotoxics and antihormonals are expected to experience declining sales.

US bioscience company, Kosan Biosciences​, presented favourable interim data from two Phase Ib clinical trials evaluating KOS-862 (Epothilone D) in combination with carboplatin (Paraplatin) and gemcitabine (Gemzar) in patients with advanced solid tumours. Both trials were open-label, dose-escalation, two-centre studies designed to determine the maximum tolerated dose, toxicity profile, pharmacokinetics, and recommended Phase II dose of the combination therapies.

In the trial investigating KOS-862, the twelve patients that were treated with the KOS-862/carboplatin combination therapy, one patient with ovarian cancer experienced a complete response, and one patient with hepatocellular carcinoma demonstrated a 41 per cent decrease in aFP (alpha feto-protein) and stable disease for 21 weeks, Pharmacokinetic data revealed no apparent drug-drug interactions between the two agents.

In the trial investigating KOS-862 and gemcitabine, out of the fourteen patients that were treated with the KOS-862/gemcitabine combination therapy, one patient was observed to have a partial response, and two patients had disease stabilisation for more than three months, suggesting evidence of anti-cancer activity. Pharmacokinetic data revealed no apparent drug-drug interactions between the two agents.

KOS-862 is a polyketide that inhibits cancer cell growth in vitro by a mechanism similar to paclitaxel, and pre-clinical models have shown the compound to be effective against paclitaxel-resistant tumours. KOS-862 continues to be evaluated in Phase II monotherapy trials in breast and prostate cancer, as well as Phase Ib combination trials with Gemzar, Paraplatin and Herceptin.

It wasn’t just cancer drug trials that featured in the meeting. The ASCO conference took the opportunity to inform a worldwide audience about new techniques and methods that could be used to prevent cancer development or reduce the number of incidences.

A new study suggested that detecting a genetic deletion during the initial evaluation of children with neuroblastoma might indicate to physicians that they should recommend a more aggressive regimen of chemotherapy to fight the cancer. It is generally accepted that when certain genes are deleted on a particular section of chromosome 11, the result is an aggressive form of the childhood cancer neuroblastoma.

Edward Attiyeh, a paediatric oncology fellow at The Children's Hospital of Philadelphia​, reported on a study of 915 patients that an abnormal increase in the number of copies, of a cancer-causing gene called MYCN heralds a high-risk, aggressive cancer. However, a significant number of neuroblastomas are aggressive without having amplified MYCN.

"The deletion of genetic material on chromosome 11 may account for a significant percentage of these high-risk neuroblastomas,"​ said Dr Attiyeh.

It is unknown what causes the deletion of genes on chromosome 11, at a location designated chromosome 11q23. However, the loss of material at that site apparently removes the protective effect of a tumour suppressor gene, and thereby allows the tumour to grow. Patients in the study with the chromosome deletion had a three-year overall survival rate of 66 per cent, compared to 83 per cent for patients without the deletion.

Neuroblastoma, which accounts for 10 per cent of all paediatric cancers, often occurs as a solid tumour in a child's abdomen or chest. Some cases of neuroblastoma are low risk, and resolve after surgeons remove the tumour. Other cases are more aggressive, and are more likely to resist initial treatment, or to cause a relapse. Identifying the correct risk level allows doctors to treat aggressive cancers appropriately, while not subjecting children with low-risk cancer to overtreatment.