Therapeutic focus - Sutent liver cancer failure leaves thin late-stage pipeline

The failure of Sutent to demonstrate any advantages over Nexavar in a head-to-head study in hepatocellular carcinoma (HCC) probably says as much about the challenges of treating this type of liver cancer as it does about the relative effectiveness of these two drugs.

Often discovered when in the very late stage, five year survival for a patient diagnosed with HCC is under 10%. Nexavar is the only targeted therapy approved to treat the illness and only prolongs life on average by a couple of months, and carries some nasty side effects. However, given the bare late stage pipeline it is likely to be the only targeted drug therapy available for some time (see table below).

Endemic disease

HCC accounts for most liver cancers and is most commonly caused by cirrhosis or hepatitis B and C. These viral infections are endemic in certain parts of Asia which is why HCC is more common in this region; in the western world the cancer is very rare and mostly occurs as a result of cirrhosis.

Surgery is sometimes possible to remove large tumours, and chemotherapy and radiotherapy are also used, but are rarely effective. Liver transplants are another radical approach.

Nexavar, a multi-kinase inhibitor, was approved in 2007 on the basis of median survival of 10.7 months, versus 7.9 months for patients given a placebo.

Pfizer announced last week that the head-to-head trial was discontinued because of more serious adverse events in the Sutent arm and the fact that the drug failed to establish either superiority or non-inferiority to Nexavar in prolonging survival. Although results have not been released, it seems probable that Sutent failed to generate survival in this 10.7 month ball park.

Effective delivery

Many products in development for HCC represent attempts to deliver chemotherapy more effectively, such as the DC Bead, a drug eluting bead that contains the chemotherapy agent anthracycline. SciClone has filed in China, reflecting the global prevalence of this disease, and the company expects to receive approval from the country’s regulatory bodies by the end of this year. Eisai has licensed the product for the Japanese market.

Aptocine, a light-activated approach that uses singlet oxygen to kill the tumour cells, could yield results in the next couple of months (EP Vantage Interview - LSO seeing the light on data and a deal, January 22, 2010).

Interestingly, Light Sciences Oncology has found evidence that this seemingly local approach could be having a systemic effect, by prompting the body to launch an immune response. If further evidence is seen of this in the pivotal trial, this could represent a big breakthrough for HCC.

Targeted therapies

In terms of the targeted therapies, many of the kinase inhibitors are being trialled in combination in the quest to find a breakthrough. For example, Bayer is running a large trial called Search examining whether Tarceva, an EGFR kinase antagonist, in combination with Nexavar is better than Nexavar alone. Approximately 700 advanced HCC patients will be recruited with results due later this year.

Other than this study, late stage data is some time away.

Bristol-Myers Squib is running a large phase III programme with its FGFR and VEGF kinase inhibitor, brivanib. Four studies are underway, looking at overall survival versus Nexavar, comparing the drug’s performance against a type of chemotherapy therapy called Trans-Arterial Chemo-Embolization (TACE), while two studies are seeking to determine whether brivanib is an effective treatment for liver cancer patients who have failed or could not take Nexavar; one study will be conducted only in Asians.

The data is due to emerge over the next couple of years.

Roche and Abbott are also trialling a multi-kinase inhibitor linifanib, which they are jointly developing. A head-to-head study against Nexavar will report mid-2012.

Therefore although Nexavar has provided doctors with another treatment option for HCC, there is certainly huge room for improvement with regard to targeted therapies. However, should the Tarceva study due to report later this year go the way of the Sutent study, a lot of faith will be lost in the kinase inhibitor approach to HCC.

Late-stage HCC pipeline
Status Product Generic Name Pharmacological Class Proprietary Level 2 Company
Filed DC Bead doxorubicin hydrochloride Anthracycline NDA (ex. USA Only) SciClone Pharmaceuticals
Phase III Precision Bead doxorubicin Anthracycline NDA (ex. USA Only) Eisai
ThermoDox doxorubicin (liposomal) Anthracycline NME (ex. USA Only) Yakult Honsha
Aptocine talaporfin sodium Anti-cancer agent NME (Patented Compound) Light Sciences Oncology
Tarceva erlotinib hydrochloride EGFr antagonist NME (Patented Compound) Roche/OSI Pharmaceuticals
BMS-582664 brivanib FGFR & VEGFr kinase inhibitor NME (Patented Compound) Bristol-Myers Squibb
Immunecell-LC activated T-lymphocyte Immunomodulator NME (Patented Compound) Innocell
ABT-869/RG3635 linifanib Multi-kinase inhibitor NME (Patented Compound) Abbott Laboratories
Sutent sunitinib malate Multi-kinase inhibitor NME (Patented Compound) Pfizer

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