In lieu of 9/11...

There will be no blog posts today as a mark of respect.

Abiraterone and prostate cancer

One drug that has been tearing up the newsfeed this year is abiraterone, a novel drug in phase II trials for prostate cancer.

In February, data was presented at ASCO's Genito-urinary satellite meeting that looked promising. Dr D.C. Danila and researchers from Memorial Sloan Kettering reported a small phase II trial in castration resistant metastatic prostate cancer after failure of docetaxel therapy.

They looked at abiraterone acetate (AA), an oral and irreversible inhibitor of CYP17 that decreases testosterone and DHT levels to undetectable. The study sought to determine the proportion of patients achieving a PSA decline of >50% and to assess toxicity. It was a multicenter trial using abiraterone 1000mg orally daily and prednisone 5mg daily. Successful abiraterone activity was defined as a PSA decline >50% in >30% of patients. It was defined as not successful if the PSA decline occurred in <10%>50% PSA decline. Radiological assessment was possible in 26 men who had at least 3 cycles of treatment. No decreases in bone metastasis by bone scans were noted, but some had unchanged bone scans. The addition of prednisone reduced the frequency of adverse events. Circulating tumor cells (CTCs) was used as an additional means to asses response to treatment and did correlate with PSA changes.

A total of >5 CTCs prior to treatment that decreased to <3 (link) - including more details on the company developing the agent.

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New iPhone apps and Protein Drug Database

Image via Wikipedia One of coolest apps I've come across in the iTunes store is Molecules.

It allows you to select different drugs or molecules from the database and see them in 3 dimensions on the screen. You can even zoom in and see close up detail.

For example, the crystal structure of the C-Abl kinase domain in complex with STI-571 (Gleevec) for Philadelphia-positive Chronic Myeloid Leukemia (CML) is a beautiful sight.

You can also see more details behind the structure, such as the reference, authors, number of atoms, PDB code, sequence etc.

A very useful tool on the iPhone.

Improving survival in Liver Cancer - at what cost?

No effective therapy is available for advanced hepatocellular carcinoma (liver cancer), it's a terminal condition. Over 18,000 people typically die from it in the USA each year. It is much more common in Africa and East Asia where the risk of infection from Hepatitis B and C is much higher, which are associated with increased risk factors for the disease.

Image via Wikipedia

In this month's New England Journal of Medicine, a randomised trial involving 602 patients with advanced hepatocellular carcinoma was reported. Sorafenib, a multikinase inhibitor of Raf, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor, improved median survival by 3 months compared to placebo (10.7 vs. 7.9 months, P<0.001). Adverse events, including diarrhea and weight loss, were more frequent in patients receiving sorafenib.

Three months doesn't sound a lot, but improvements in cancer survival nearly always occur in small increments. The other side of the coin is at what cost?

An editorial by Dr Lewis Roberts in the same journal noted the following:

“The pharmacy price of sorafenib is approximately $5,400 per month in the United States, {euro}3,562 per month in France, $1,400 per month in Korea, and $7,300 per month in China. Even in industrial nations, the high cost of new drugs produces significant stresses on health system budgets. There are substantial ethical implications in having effective therapies available for life threatening diseases that are priced beyond the reach of the populations most in need of therapy.”

Would you pay $15,000 for an extra three months of life?

15 minutes of fame in oncology

Wow, my blog on abiraterone in advanced prostate cancer got picked up last night by TopUSAsites for prostate cancer.

It looks like the drug is going to be a hot topic for a while, but caution against the hype is advised until we see whether reduction in PSA and tumour shrinkage actually translates to what really matters to patients - improved survival and better quality of life.

What say you?

A cancer patient's inspiring story

A lady who was diagnosed with non-Hodgkin's lymphoma (NHL) and relapsed on chemotherapy, tells her story about how she overcame the odds with a promising new approach called radioimmunotherapy:

VIDEO

There is always hope around the corner with new treatments coming on the market.

Cediranib (AZD2171) in Glioblastoma and brain cancer

The investigational drug AZD2171 (cediranib) from Astra-Zeneca may help shrink tumours and prolong survival of patients with a relatively common, aggressive type of brain cancer. In a phase II study of 31 patients with recurrent glioblastoma, researchers observed that daily treatment with cediranib decreased tumour volume by more than half in 56 percent of patients. These results were reported at the recent AACR meeting.

Nearly 26 percent of patients were alive and their cancer had not progressed six months into treatment. On average, patients experienced a progression-free survival of 117 days and overall survival of 221 days. Cediranib was also found to alleviate brain swelling, a major cause of morbidity among these patients.

Cediranib is a selective signaling inhibitor for vascular endothelial growth factor (VEGF), which promotes formation of new blood vessels that tumours need for nourishment and growth. The drug targets all three receptors for VEGF, one of which is expressed on the endothelial cells in glioblastoma.

Two of the 31 patients were removed from the current study because of toxicity (fatigue). Dose reductions, ie short breaks from the drug, were required for most patients, usually due to hypertension, diarrhea and fatigue.

By analyzing blood samples from patients, the researchers found that the biomarkers FGF (fibroblast growth factor) and Tie-2 were associated with tumour progression and could be used to predict treatment failure in this study population. FGF is a protein tied to new blood vessel growth; Tie-2 is a receptor that binds to and is activated by the angiopoietins - protein growth factors required for the formation of blood vessels.

New treatment option for patients with liver cancer

Treatment with sunitinib (Sutent) slows tumour growth and reduces the risk of metastasis in patients with hepatocellular carcinoma, an aggressive cancer of the liver.

Hepatocellular carcinoma is a cancer that relies heavily on blood vessels for growth; sunitinib controls the growth of blood vessels and could therefore potentially play an important role for treatment.

Image via Wikipedia
Patients with this type of liver cancer have a very poor prognosis and the only currently available therapy is sorafenib. This study shows that it may be possible to effectively use sunitinib with manageable side effects, thereby providing patients with an alternative treatment option. Sunitinib (Sutent) is a small molecule tyrosine kinase inhibitor that targets multiple receptors, including VEGFR2, c-Kit and FLT3. These receptors may be present in cancer cells as well as in endothelial and immune cells.

Researchers enrolled 34 patients with advanced liver cancer and gave them 37.5 mg sunitinib daily on a standard four weeks on, two weeks off regimen. By 12 weeks, one patient had a partial response and 17 patients had stable disease. The median progression-free survival was four months and the median overall survival was 10 months.

Source:

AACR

Cervical cancer vaccines

The UK has recently approved a second vaccine that protects against HPV called Cervarix from GSK, in addition to Gardasil from Merck. Both vaccines protect against HPV, but Gardasil also protects against gentical warts, which Cervarix does not.

Male with genital warts - image courtesy of Wikipedia

The wholesale price for the two is exactly the same, £80.50, and the formal list price is also comparable at £240 per vaccination. Other European countries appear to have chosen Gardasil, for it's extra protective effects. Genital warts are, of course, far more common than cervical cancer in Western Europe. Most women over 40 receive a regular annual Pap smear to screen for HPV and cervical cancer, hence the low rates compared to Latin America and Africa, where the smear test is considerably less common.

Guess which vaccine the NHS chose in it's wisdom? Yes, Cervarix. Any parent wanting to innoculate their daughter with Gardasil will therefore have to get it on private health plans at a much greater cost.

Meanwhile, although a small number of boys were included in the trial, there were insufficent numbers to gain approval for use in the male population. If you are going to reduce the spread of genital warts and HPV in the population, it makes sense to innoculate both surely?

Are Her2 inhibitors an alternative to chemo in breast cancer?

Image via WikipediaSeveral studies exploring the use of lapatinib (Tykerb, GlaxoSmithKline) in metastatic breast cancer have suggested that it may offer an alternative to chemotherapy in this setting, both as monotherapy, and in combination with other targeted therapies.

One study explored the use of lapatinib alone, whereas others investigated combinations with trastuzumab (Herceptin, Genentech/Roche), with bevacizumab (Avastin, Genentech/Roche), and with the investigational agent pazopanib (under development by GlaxoSmithKline).

Studies presented at American Society of Clinical Oncology opened up an interesting debate regarding whether biological therapy without chemotherapy for metastatic breast cancer is feasible.

The efficacy of these targeted agents is higher when they are combined with chemotherapy, and the toxicity of these agents in combination needs to be explored further. Hence, the preferred front-line choice for metastatic breast cancer is presently trastuzumab with chemotherapy, and the evidence suggests that continuation of trastuzumab is the best option for patients who progress. Combining drugs that have different targets is also a promising option.

Lapatinib is currently approved in the US for a very narrow indication in combination with capecitabine (Xeloda, Roche) for advanced metastatic HER2+ breast cancer in women who have received previous chemotherapy, including an anthracycline, a taxane, and trastuzumab. A similar approval in Europe is pending with the EMEA.

The largest of the new trials presented was a phase 3 study of lapatinib monotherapy compared with a combination of lapatinib and trastuzumab (EGF104900). Both of these drugs target HER2+ breast cancer, but trastuzumab (a monoclonal antibody) is a large-protein molecule that targets the part of the HER2 protein on the outside of the cell; lapatinib (an oral drug) is a smaller molecule that enters the cell and blocks the function of this and other proteins intracellularly. The combination effectively attacks HER2 from multiple angles.

The trial involved 269 patients with HER2+ breast cancer who had documented progression on trastuzumab in the metastatic setting. The combination of lapatinib plus trastuzumab showed a significant increase in progression-free survival, compared with lapatinib alone (12 weeks vs 8.1 weeks). This translates into a 27% reduction in the risk for disease progression (hazard ratio [HR], 0.73; P = .008). The overall clinical-benefit rate (the response rate and the rate of durable stable disease) for the combination was double that for monotherapy (24.7% vs 12.4%; P = .01). There was a trend toward improved overall survival.

More data on the role of combined HER2+ therapy in combination with chemotherapy will be available soon from the ongoing ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) study. ALTTO is being conducted in less-heavily pretreated patients with early-stage disease.

A trial of lapatinib plus bevacizumab was reported in a small phase 2 single-group study, conducted in 32 patients who had received a median of 5 previous metastatic breast cancer therapies. 28 of these 32 patients had received prior treatment with trastuzumab.

The combination resulted in a 34.4% clinical-benefit rate (defined as complete response plus partial response plus stable disease at 24 weeks or more), and 62.5% of patients were progression free at week 12.

The most common adverse events were diarrhea (81%), rash (66%), nausea (56%), fatigue (56%), and vomiting (46%). There were 2 grade 2 asymptomatic LVEF decreases, 1 grade 3 gastrointestinal hemorrhage, and 1 grade 3 hypertensive event.

Overall, blocking both the HER2 and the VEGF pathways led to anticancer activity for even heavily pretreated patients with metastatic breast cancer that could potentially advance the treatment of this high-risk disease.

A combination study of lapatinib plus pazopanib, where both drugs were taken orally once daily, suggested that they might provide a potential future treatment option for HER2+ breast cancer. It involved 141 patients and compared the combination with lapatinib monotherapy.

The results confirmed the efficacy of lapatinib monotherapy and showed a trend toward better outcomes with the combination. At 12 weeks, 36.2% of patients taking the combination and 38.9% taking the monotherapy experienced disease progression (P=.37). The response rate was 44.9% with the combination and 28.8% with the monotherapy according to investigator assessment, and 36.2% vs 22.2%, respectively, according to independent assessment.