Novel Treatment Strategy in Melanoma Misses End Point

Nick Mulcahy

April 07, 2014

A novel treatment approach for melanoma, which involves injecting a virus directly into the lesions of patients with advanced disease, does not significantly improve overall survival.

The final clinical trial results for this melanoma "vaccine," talimogene laherparepvec (known as T-VEC), were announced by Amgen, the manufacturer.

The vaccine represents a new strategy in the treatment of melanoma, which employs a herpes virus and results in tumor cells being killed and the immune system being stimulated.

A trend toward improved survival was seen last year in an interim analysis of the phase 3 Oncovex (GM-CSF) Pivotal Trial in Melanoma (OPTiM), as reported by Medscape Medical News. However, the trend did not achieve statistical significance.

Patients with advanced melanoma who were treated with T-VEC lived longer than those in the control group, who were treated with granulocyte-macrophage colony-stimulating factor (GM-CSF).

But, in the newly announced final results, the secondary end point of overall survival was never met, despite "a strong trend" in favor of T-VEC (= .051).

The primary end point of a durable response rate was met in the study, as the company previously reported.

The vaccine's failure to significantly improve overall survival could affect its chances for approval and limit its commercial opportunity as a single therapy, according to a financial analyst quoted in a press report after the announcement.

However, T-VEC is also being tested in advanced melanoma in combination with the approved melanoma drug ipilimumab (Yervoy, Bristol-Myers Squibb); that clinical trial is ongoing.

"We remain encouraged that the study met its primary end point of achieving durable responses in patients with metastatic melanoma," said Sean E. Harper, MD, executive vice president of research and development at Amgen, in a statement. "We missed statistical significance on the secondary end point of overall survival, but the strong trend in survival benefit supports further research of talimogene laherparepvec to better understand its role in melanoma, both as a single agent and in combination with other therapies."

Long Time Coming

T-VEC is an investigational "oncolytic immunotherapy" designed to selectively replicate in tumors and to initiate an immune response to target cancer that has metastasized.

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

Viruses have an attraction to cancer cells.

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

In the case of T-VEC, modified herpes simplex virus 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 noted.

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

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.


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