Therapeutic focus - cancer vaccines to come under scrutiny

Despite a surge in optimism prompted by positive phase III results from Dendreon’s Provenge, the world of therapeutic cancer vaccines is still viewed as extremely high risk; for every Provenge there have been several failures.

Further insights into the field will be gleaned at the Annual Society of Clinical Oncology (Asco) meeting, which starts this Friday, with a host of data becoming available on the many candidates in late-stage development (see table below). Top of the schedule will be full phase III results from Accentia’s BiovaxID, which have been held back to be presented in a plenary session.

The patient-specific therapeutic vaccine has been designed to kill cancerous B-cells that might remain in the body after chemotherapy, with the initial indication of follicular Non-Hodgkin’s lymphoma. Top-line data released last October suggested significantly improved cancer free survival, and the study was stopped early. Given the financially perilous position of Accentia, further good news is needed.

Although a handful of cancer vaccines have already made it to market, none pursue the personalised, therapeutic approach of BiovaxID and Provenge. Few are actually on the main markets of the US or Europe, other than the bladder cancer products. None of their owners disclose sales.

The handful of bladder cancer products are based on the BCG vaccine, and work by promoting an inflammatory reaction in the bladder which clears superficial cancerous lesions. The treatments are fairly successful and widely used.

The rest are slightly more opaque. For example, Chugai’s Picibanil is only available in Japan, where it is indicated for use as an immunomodulator in cancer therapies, mainly alimentary tract cancer, lung cancer, head & neck cancer, & thyroid cancer. The drug is a lyophilised biological preparation containing streptococcus pyogenes, inactivated by heating with penicillin.

GlaxoSmithKline’s Melacine, which it gained through the acquisition of Corixa, is only on the market in Canada, although whether this is still the case is unclear. Efforts to bring the drug to the US market were abandoned in 2003, after FDA said it required trials that could take up to ten years to complete.

Bioven, a privately owned Malaysian group, makes the table with an EGFr cancer vaccine that won approval in Cuba and Peru in June last year, to treat advanced non-small cell lung cancer.

In the pipeline

The R&D pipeline is mostly comprised of therapeutic cancer vaccines, that work by programming the body’s immune system to recognise the tumour and attack. Progress, however, has been patchy.

Antigenics has got the furthest with its candidate, Oncophage. The product utilises a heat shock protein based technology aimed at stimulating the host immune system to specifically attack invading organisms or tumour cells. However, two phase III trials in non-metastatic renal cell carcinoma (RCC) and metastatic melanoma failed to reach their endpoint, even though a subset of patients appeared to respond. On this basis, approval was granted in Russia in April 2008 as an adjuvant treatment for intermediate risk kidney cancer. Reimbursement is being sought and launch could happen in 2009.

Conditional approval in this setting has been sought in Europe, with a decision anticipated later this year. Both US and European regulators have given the product orphan drug designation in glioma; the FDA has also granted orphan status in kidney cancer and metastatic melanoma. At Asco the group will present an update on survival data from the phase III RCC trial; the abstract stated that a favourable trend in the active arm has been noted.

Antigenics also has a stake in another one of the most promising pipeline candidates, Glaxo’s MAGE-A3, in phase III trials for melanoma and non-small cell lung cancer, although no data at Asco is due to be presented. The shot contains Antigenics' QS-21 immunostimulant, which is licensed to several other big partners including Elan and Wyeth, where it is being used in an Alzheimer’s vaccine programme, and Sanofi-Aventis; in fact there are 16 different clinical trials ongoing using the compound.

Another candidate close to market, but which will not feature at Asco, is OncoVAX. The shot has been filed for approval in Switzerland as a treatment for colorectal cancer and a decision is expected this year. The aim is for the vaccine to be used rather than chemotherapy after surgery, to prevent recurrence. Phase III results showed the treatment halved the death rate at five years after surgery in stage II colon cancer, with fewer side effects. The shot incorporates the patient's own surgically removed tumour, which is enzymatically treated, frozen, and irradiated to render the cells non-tumourogenic. Phase III trials are due to start in the US, and the company has targeted 2013/2014 for approval.

Encouraging long term safety of Stimuvax, formerly known as BLP25 liposome vaccine, in the treatment of NSCLC will also be presented at Asco. The data was gathered from patients taking part in a phase IIb trial, which produced encouraging results, and who continued treatment for more than two years. The results lead to a phase III trial in unresectable stage III NSCLC, called the Start study, which commenced in January 2007, with results anticipated at the end of 2010.

A couple of studies on Pfizer’s CDX-110 will be presented, although hopes for this product have faded since an ongoing phase III last year reverted to a single arm phase II trial because too many patients withdrew from the control arm.

Trovax will also be the subject of a couple of presentations, although the abrupt end to a phase III trial last year after the study missed its endpoint means hopes here have also dimmed. Oxford Biomedica is now waiting for a crucial ruling from the FDA at the end of June, to determine the drug’s fate (Event – FDA to decide fate of Oxford Biomedica’s Trovax, May 5, 2009).

Pharmexa will present results from a disappointing phase III trial of GV1001, which failed to show a survival benefit in non-resectable pancreatic cancer. A larger trial of the shot in combination with chemotherapy is continuing, with results due in 2011.

Meanwhile, phase II results from a study with Lucanix in lung cancer, examining immune responses, will be presented; an international, multicentre, randomised and double-blind phase III trial in 700 patients started in August last year, in the same setting.

The late-stage cancer vaccine pipeline is clearly full, unfortunately the list of abandoned products is even longer. In the last year phase III hopes including Favrille's SpecifId and Cell Genesys' GVAX hit the R&D dustbin, and given the mixed results from the current crop, many are likely to join them. Still, with several candidates getting close, the first approval for a therapeutic cancer vaccine in a major market might not be too far away.