Therapeutic Focus – Avastin provides glimmer in glioblastoma but progress still slow

Data last week from a phase III trial of Avastin showing an increase in progression-free survival in advanced brain cancer patients was an encouraging sign for an area with few drugs in late-stage development. Glioblastoma is thankfully a rare disease but its aggressive nature means it is very hard to treat; consequently drug developers are trying many different approaches and the pipeline, particularly in phase II, exhibits a broad array of approaches (see tables).

With a mean survival rate of just 14.6 months after diagnosis any drug therapy has to act quickly to have an impact. A common first-line therapy is Merck & Co’s Temodar, usually administered in combination with radiotherapy after patients have undergone aggressive surgery to remove the tumour. The chemotherapy agent was approved in 2010 after showing a 10 week improvement in overall survival when added to radiotherapy. No agent has yet managed to improve on that; the jury remains out on whether Avastin will succeed when Roche reveals final data from the trial next year.

Late-stage glioblastoma pipeline
Product Generic Name Company Pharmacological Class Trial ID
CDX-110 rindopepimut Celldex Therapeutics EGFr cancer vaccine NCT01480479 
Avastin bevacizumab Chugai Anti-VEGF MAb NCT00943826
Immuncell-LC activated T-lymphocyte Innocell Immunostimulant NCT00807027
Cilengitide cilengitide Merck KGaA Integrin inhibitor NCT00689221
DCVax-L - Northwest Biotherapeutics Cancer vaccine NCT00045968 

Aside from Roche’s antibody, Merck KGaA’s cilengitide is one of the most closely watched phase III products being studied in glioblastoma. The Centric trial, assessing the integrin inhibitor in combination with Temodar and radiation versus Temodar and radiation alone in newly diagnosed glioblastoma patients, is due to report in March 2013.

Before that, though, data from a phase III study of Immuncell-LC, an activated T lymphocyte developed by Innocell, should emerge. The primary endpoint of the Korean firm’s trial in is progression-free rather than overall survival; however, suggesting that further trials will be needed after this one reports in November. Little information on the project has been released recently so this remains a wild card in the phase III pipeline.

Celldex Therapeutics is testing rindopepimut or CDX-110, an EGFR cancer vaccine, in combination with Temodar, but this time after radiation – in newly-diagnosed patients whose tumours express the EGFRvIII protein. No biomarkers for glioblastoma have yet been validated, so industry watchers will be keen to see whether this strategy pans out when data is released, probably not until 2016. Pfizer returned rights to this programme two years ago, stating a change in priorities (Celldex reeling from Pfizer break up, September 6, 2010).

Northwest Biotherapeutics is conducting a phase III trial in patients with newly diagnosed patients with its cancer vaccine DCVax-L, aka DCVax-Brain. But the firm is on its uppers, having reported cash reserves of less than half a million dollars at the end of June. How it will fund the study until its reporting date next June remains to be seen.

Avastin is already marketed for the disease but only under a conditional approval in the US; European regulators have refused to grant a license to date. It was granted accelerated approval by the FDA in 2009 as a treatment for glioblastoma in patients who had failed to respond to at least one other drug, based solely on an objective response rate. The confirmative pivotal study, Avaglio, is being run in in newly-diagnosed glioblastoma. Roche said little last week other than that the trial met its co-primary endpoint of a significant improvement in progression-free survival.

Other efforts

Beyond the efforts in these tables, a number of agents are being studied by academic or government funded groups in mid- and late-stage studies.

Perhaps of most interest will be the outcome of the Radiation Therapy Oncology Group’s phase III trial of Avastin, which has completed recruiting more than 900 patients and should report sometime next year. The trial is similar in design to Roche’s Avaglio study, although patients who received placebo rather than Avastin are allowed to receive the antibody if their disease progresses. This will make it harder to draw conclusions about the drug’s impact on survival generally, but should show whether there is any benefit to giving the drug once progression has occurred.

In phase II a number of big pharma-owned drugs, some of which are already on the market, are being studied by research groups. The kinase inhibitors in particular are of interest, with trials ongoing with agents including Caprelsa, Vargatef and Sprycel, made by AstraZeneca, Boehringer Ingelheim and Bristol-Myers Squibb. Sprycel for example is in two fairly large phase II studies being run by the North Central Cancer Treatment group in collaboration with the NCI. Recruiting up to 400 patients in total, one of the trials is testing Sprycel in combination with Avastin. Results should emerge in 2014.

Earlier stage

The table below contains products that are the primary focus of a commercial company, and some are looking promising.

One such is ImmunoCellular Therapeutics’s ICT-107, another cancer vaccine. Intended for newly-diagnosed glioblastoma, the drug is given immediately after radiation and chemotherapy.

“The idea is to induce a T-cell immune response against the tumour by teaching the immune system the targets or antigens on the tumour that we want the immune system to recognise and go after,” says Dr John Yu, director of surgical neuro-oncology at Cedars-Sinai Medical Center and scientific founder of ImmunoCellular. The vaccine targets cancer stem cells, which ImmunoCellular contends are the root cause of cancer as they are the only cells with the capacity for unlimited growth.

The company hopes to show a greater survival advantage than Temodar's 10 week benefit. “We’ve demonstrated that cancer stem cells are resistant to chemotherapy as well as radiation therapy. This vaccine is designed to go after the cells of the tumour which are resistant to chemotherapy and radiation and which tend to regrow within six months after it has been treated,” says Dr Yu.

Biomarker research

Biomarkers remain crucial to the success of cancer drugs, but little progress has been made in brain cancer.

“All kinds of biomarkers have been identified in brain cancers,” says Dr Yu. “So far none of them have led to significant improvements in responses to drugs, but it’s certainly an area of significant research effort. There’s no blood test for brain cancer that’s robust at this point.” He explains that the only technique that could be used to screen the population for glioblastoma is MRI – far from cost-effective in such a rare disorder.

In fact one of the few drugs for which a biomarker has been found is Temodar itself. In order to be enrolled in the Centric trial of cilengitide, patients must have a methylated promoter of the methylguanine-DNA methyltransferase (MGMT) gene in the tumour tissue – those with the methylated promoter are more likely to benefit from Temodar.

Roche says that biomarker data from Avaglio are being evaluated and these data will be submitted for presentation at an upcoming medical meeting.

The future

Another promising mid-stage agent is Apogenix’s APG101, which reported encouraging progression free survival last month, raising the company’s hopes of finding a partner (EP Vantage Interview – Apogenix closes in on deal for glioblastoma candidate, July 31, 2012). Again, crucial overall survival data is awaited.

Other active phase II programmes include another attempt by Roche, testing MetMab or onartuzumab alone or in combination with Avastin. Meanwhile Spectrum is seeking to recruit 140 patients into a trial testing lucanthone in combination with Temodar and radiation.

The challenges that brain cancer presents means that many of the agents below are likely to fail. But with options so limited it will not take much of an advance on Temodar's 10 week benefit to win a product approval.

Mid-stage glioblastoma pipeline
Product Company Pharmacological Class Trial ID
APG101 Apogenix CD95L blocker NCT01071837
ARC 100 Archer Biosciences Microtubule/tubulin inhibitor NCT01113463
PLX3397 Daiichi Sankyo FMS, c-kit & Flt-3 kinase inhibitor NCT01349036
VAL-083 Del Mar Pharmaceuticals Alkylating agent NCT01478178 
ICT-107 ImmunoCellular Therapeutics Cancer vaccine NCT01280552 
PX-866 Oncothyreon PI3K inhibitor NCT01259869 
RG3638 Roche Anti-cMet MAb NCT01632228
Lucanthone Spectrum Pharmaceuticals Topoisomerase II inhibitor NCT01587144 
Cotara Peregrine Pharmaceuticals Anti-cancer MAb-iodine 131 conjugate Phase III planned
Toca 511 & Toca FC Tocagen Cytosine deaminase gene therapy & pyrimidine analogue NCT01156584 

To contact the writer of this story email Elizabeth Cairns in London at [email protected]

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