August 30, 2012 10:00 pm
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Amgen’s (NASDAQ:AMGN) therapeutic vaccine, TVEC, shows promise in controlling regional melanoma, experts told BioPharm Insight. However, they questioned whether the injectable therapy would be effective in treating distal tumors in the liver, brain, and lungs.
TVEC (talimogene laherparepvec) is a treatment that leverages a patient’s own immune system. It has a dual mechanism of action, utilizing an attenuated herpes simplex virus (HSV) and a GM-CSF cytokine to stimulate the immune system. The virus is thought to potentiate local anti-tumor effects and the cytokine to potentiate systemic effects. GM-CSF stimulates T cells to kill melanoma cells at sites not infected with the HSV virus.
Immunotherapy has proven useful in treating melanoma, including traditional therapies such as interleukin-2 and interferon and more recently Bristol-Myers Squibb’s (NYSE:BMY) Yervoy, which was approved last year. Cancer therapeutic vaccines are thought to provide a more benign side-effect profile compared to chemotherapies and biologics.
Amgen obtained TVEC in March 2011 when it acquired privately held BioVex in a deal worth up to USD 1bn. On 29 July 2011, the company terminated a Phase III trial testing TVEC in patients with head and neck cancer. The Phase III study for the treatment of malignant melanoma is ongoing.
A complete analysis of the Phase III trial is expected in 2013, according to company guidance. The study’s primary endpoint is a statistically significant improvement in durable response rate, defined as the rate of complete response or partial response lasting continuously for six or more months, according to ClinicalTrials.gov. The secondary endpoint is overall survival (OS).
Amgen has said it does not plan on reporting study data until study completion in 2013.
The company did not provide further comment.
Limited patient population
Since TVEC is injected directly into a tumor mass, it is only useful for patients when there is an injectable lesion, explained Dr Robert Kaufman, director of the Rush University Cancer Center at Rush University Medical Center, Illinois. Generally, there are three locations that are amenable to injection: melanoma on the surface of the skin, in the soft tissue just below the skin (usually felt as small bumps under the skin) and the lymph nodes, he noted. Only one-third of advanced melanoma patients have some skin, soft tissue or nodal disease that is amenable to TVEC injection.
An important area of further research is whether TVEC can be injected into visceral lesions such as those in the liver or lungs, said Kaufman. Since these regions are more difficult to access, injecting the therapy into these regions will also be higher risk, he added.
Dr John Fruehauf, associate professor of Clinical Medicine, Biomedical Engineering and Biological Chemistry, University of California, Irvine, expressed skepticism that a vaccine therapy could have an impact on unresectable disease since previously, GM-CSF has only been shown effective in completely resected melanoma.
With an intra-lesional therapy like TVEC, there is always skepticism from clinicians about its effectiveness in treating metastatic disease, said Tim Turnham, director, Melanoma Research Foundation. OS will not be attained by only killing lesions on the skin, said Turnham, as the metastatic disease in the liver, brain and lungs are ultimately fatal.
One issue with an injected therapy is that it relies on the local environment to cause a systemic response that will kill tumors throughout the body. While it is one thing for an injected tumor to shrink, it is quite another for a distant tumor to shrink, Turnham explained.
A melanoma expert also expressed skepticism melanoma lesions that have not been injected with TVEC would show regression. The chance of regression for a metastatic liver lesion is not that high, he said.
Still, the same expert noted, it is challenging to interpret results from intra-lesional therapies. The lesions are typically quite small when treated, around 1 cm. Using response scoring is difficult in practice, particularly if a patient has many lesions, which all need to be assessed, he said. Grading partial responses, as opposed to complete disappearance of lesions, can be quite challenging, he noted.
Atypical trial design
A second trial investigator also questioned the Phase III trial design, noting that GM-CSF as a comparator is atypical. Dacarbazine is typically the comparator arm in melanoma trials, he noted.
No one would treat anyone with stage IV metastatic melanoma with GM-CSF, but it was chosen to show that any benefit was not just due to GM-CSF, the second investigator said.
The second investigator reported he found the trial difficult to enroll for this reason.
Safety profile deemed acceptable
Although TVEC is genetically engineered with the herpes simplex virus, there are “no qualms” about potential safety concerns, said investigator Dr Lee Cranmer, a former herpes virologist and director, melanoma/sarcoma program, University of Arizona Cancer Center. Genetically engineered therapies present a hypothetical concern that the alteration can have longer-term, unintended consequences that cannot be controlled.
Per study protocol, a predefined volume of TVEC can be injected into multiple tumor lesions. The multiple injections appear to be an acceptable tradeoff, as the side effects seem to be well tolerated, said Kaufman. The injections are done in a physician office with local anesthetic if needed, he said. Some patients have reported the anesthetic hurting more than the TVEC injection, Kaufman added. He reported patients having fever and injection-site reactions, with the fever mild and manageable with Tylenol. Cranmer also reported TVEC to be well tolerated and having an acceptable side-effect profile.
While 2011 saw the approval of new melanoma therapies from BMS and Roche (VTX:ROG) with Zelboraf , these have only shown benefit in smaller populations of patients with advanced disease. The US National Cancer Institute estimates that 76,250 individuals in the US will be diagnosed with melanoma in 2012, with 9,180 (12%) of those patients expected to die of the disease. Amgen has a current market cap of USD 64.83bn.
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