It's a Virus, It's a Therapy, It Improves Melanoma Survival

Nick Mulcahy

November 20, 2013

Injecting a herpes virus into a malignant skin lesion to treat advanced melanoma might sound a bit like medieval alchemy. But it's not.

It is the highly modern concept of oncolytic immunotherapy, and seems to work in the form of the experimental agent talimogene laherparepvec (Amgen), also known as T-VEC, according to an interim analysis of the phase 3 Oncovex (GM-CSF) Pivotal Trial in Melanoma (OPTiM).

Advanced melanoma patients treated with T-VEC lived about 4 months longer than those in the control group, who were treated with granulocyte-macrophage colony-stimulating factor (GM-CSF), according to results presented this week at the 2013 Society for Melanoma Research Congress in Philadelphia.

Median overall survival was 23.3 months in the T-VEC group and 19.0 months in the control group (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.61 - 1.02; = .0746).

"The interim overall survival analysis showed a trend in favor of T-VEC," the study authors write in their meeting abstract.

"Viruses have an attraction to cancer cells," said lead author Howard Kaufman, MD, professor and director of surgical oncology at the Rush University Medical Center in Chicago. Oncolytic viruses specifically target cancer cells and exploit the same cellular defects that promote tumor growth, he told Medscape Medical News.

In the case of T-VEC, a modified herpes simplex virus (HSV) type 1 has been engineered to selectively replicate in tumors and cause cancer cell destruction (lysis) and death. "It's an attenuated virus; 2 of the viral genes were removed," he explained.

Oncolytic virus research is finally arriving in clinical trials after years of early research. This T-VEC study is the first-ever phase 3 randomized controlled trial of an oncolytic virus, Dr. Kaufman noted.

The oncolytic coxsackievirus, which is best known for causing hand, foot, and mouth disease, is currently the subject of a phase 2 melanoma trial in Australia.

"This represents a new strategy; that's the excitement," said Steven Wang, MD, director of dermatologic surgery and dermatology at the Memorial Sloan-Kettering Cancer Center at Basking Ridge, New Jersey, who was not involved in the study.

"Perhaps this will be another class of agents for melanoma," said Dr. Wang, who was asked by Medscape Medical News to comment on the findings. "This specific agent could eventually be another tool in our treatment armamentarium," and T-VEC or other oncolytic viruses could eventually be used in combination with approved agents such as ipilimumab or BRAF inhibitors.

However, such talk is premature because the results with T-VEC are from an interim analysis. "The full potential is not yet known," said Dr. Wang, who is also the author of Beating Melanoma: A 5-Step Survival Guide.

Dr. Kaufman agrees that any conclusion about the efficacy of T-VEC is premature, but added the survival trend is "very clear." The 4-month overall survival benefit seen in the interim analysis is "aligned with ipilimumab," he added, referring to the survival benefit seen in the pivotal trial of the now-approved drug for advanced melanoma.

"I think it's going to have a role to play," said Dr. Kaufman about T-VEC in melanoma. T-VEC is not only an oncolytic virus with a direct, local effect. It has a "dual mechanism of action," he noted.

T-VEC is also engineered express human GM-CSF to achieve a systemic immune response and related antitumor effects. Hence, it is described as an oncolytic immunotherapy.

Safety Profile

The OPTiM phase 3 trial involved 436 patients with unresected stage IIIB, IIIC, or IV melanoma. Patients were randomized to receive intralesional T-VEC every 2 weeks (n = 295) or subcutaneous GM-CSF for the first 14 days of each 28-day cycle (n = 141). Treatment could last for up to 18 months.

The investigators highlight that fact that the differences in survival rates between the treatment groups were more pronounced in 2 subsets of patients: those with stage IIIB, IIIC, or IV M1a disease (HR, 0.56; 95% CI, 0.38 - 0.81), and those who received T-VEC as first-line treatment (HR, 0.49; 95% CI, 0.33 - 0.74).

The favorable trend in overall survival "was pronounced in patients with stage III and IV M1a disease, where an important clinical need exists for patients whose disease has not yet spread to distant organs," Dr. Kaufman said in a press statement.

"I look forward to seeing the final results next year," he added.

The formal primary overall survival analysis will be conducted when about 290 events have been observed, according to Amgen.

In the interim analysis, overall survival was similar when the 2 groups were matched for sex, baseline anti-HSV antibody, and BRAF status. There were no deaths from treatment-related adverse events, the investigators report.

According to the company press statement, the most frequently observed adverse events were fatigue, chills, and pyrexia. Serious adverse events were more common in the T-VEC than in the control group (26% vs 13%). The most common serious adverse events in the T-VEC group were cellulitis and pyrexia. Immune-mediated events were reported infrequently.

Dr. Kaufman described T-VEC as having an "excellent safety profile." He also explained the treatment can be administered in an office setting, and that many patients will be "back to work the next day." He commonly prescribes acetaminophen for pyrexia.

The study was sponsored by Amgen. Dr. Kaufman reports financial ties to Amgen. Dr. Wang has disclosed no relevant financial relationships.

2013 Society for Melanoma Research (SMR) Congress: Presented November 18, 2013.

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