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CHICAGO -- Intralesional injection of an oncolytic therapy significantly increased the durable response rate in advanced melanoma compared with a control therapy, according to results of a randomized trial.

Patients treated with the virus-derived talimogene laherparepvec (T-VEC) had a 16.3% rate of durable responses, defined as partial or complete response maintained for at least 6 months. That compared with 2% of patients treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) who had durable responses.

Subgroup analysis showed durable responses in 33% of patients with IIIB-C (nonvisceral) disease and in 24% of patients who received T-VEC as first-line therapy, Howard L. Kaufman, MD, of Rush University Medical Center in Chicago, reported at the American Society of Clinical Oncology meeting.

"T-VEC is the first oncolytic immunotherapy to demonstrate therapeutic benefit against melanoma in a phase III trial," said Kaufman. "The only grade 3/4 adverse event that occurred in more than 2% of patients was cellulitis. We observed a trend toward improved overall survival with T-VEC at interim analysis."

Despite recent advances in the treatment of melanoma, patients with stage IIIB/C disease have a 5-year disease-free survival of 30% to 35%. Survival in stage IV melanoma is less than 15%.

Immunotherapeutic agents, such as interleukin-2 and ipilimumab (Yervoy), have demonstrated efficacy in metastatic melanoma, providing a rationale for continued investigation of immunology-based treatment strategies.

T-VEC consists of an attenuated herpes simplex virus, resulting from deletion of the viral neurovirulence gene and replacement of ICP47 with the human GM-CSF gene, said Kaufman. After direct injection into a melanoma lesion, T-VEC causes lysis of tumor cells and induces local and systemic immune responses that are enhanced by expression of GM-CSF.

Kaufman reported results from a trial involving 436 patients with unresectable stage IIIB/C and IV melanoma. Investigators at 64 sites in four countries randomized the patients 2:1 to intralesional T-VEC administered every 2 weeks or to subcutaneous GM-CSF.

T-VEC was injected into cutaneous, subcutaneous, or nodal lesions but not visceral lesions, said Kaufman. The volume injected depended on the size of the lesion, but any number of lesions could be treated in a single visit. At each treatment session, new lesions had treatment precedence, followed by larger lesions.

The primary endpoint was durable response. Secondary endpoints included overall survival, objective response rate, time to treatment failure (TTF), and safety.

About 30% of the patients had stage IIIB/C, and another 30% had stage IV M1a. T-VEC was administered as first-line therapy in 47% of the patients.

Analysis of the primary outcome showed a durable response rate of 16.3% with T-VEC and 2.1% with GM-CSF, which translated into an unadjusted odds ratio of 8.9 (P<0.0001). The overall response rates were 26.4% with T-VEC (10.8% complete responses) and 5.7% with GM-CSF (0.7% CR rate).

T-VEC consistently led to higher rates of the primary endpoint, regardless of prior treatment, performance status, sex, and HSV status.

The median TTF was 8.2 months with T-VEC and 2.9 months with GM-CSF (P<0.0001). An interim analysis of overall survival showed a trend in favor of T-VEC (23.3 months versus 19.0 months, HR 0.79, P=0.07). According to Kaufman, the final analysis of overall survival will occur in about 6 months.

The most common adverse events (all grades) with T-VEC were fatigue (50.3%), chills (48.6%), pyrexia (42.8%), nausea (35.6%), influenza-like illness (30.5%), injection-site pain (27.7%), and vomiting (21.2%). The most frequent grade 3/4 adverse event was cellulitis (2.1%).

The next step in evaluation of T-VEC will be directed toward building on the activity demonstrated in the trial, said principal investigator Robert Hans Ingemar Andtbacka, MD, of the University of Utah in Salt Lake City.

"Moving forward, the question is whether we can improve the response by combining talimogene laherparepvec with other immunotherapies and other agents," Andtbacka told 番茄社区app. "There is a study ongoing where talimogene laherparepvec is being combined with ipilimumab (Yervoy) to try to activate the immune system from two different mechanisms."

The favorable adverse event profile demonstrated thus far makes T-VEC a good candidate to combine with other therapies in patients with advanced and metastatic melanoma, he added.

Better understanding of the molecular mechanisms of melanoma has led to a boom in the development of targeted agents and immunotherapies for the disease, said Gary Schwartz, MD, of Memorial Sloan-Kettering Cancer Center in New York. The challenge for local therapies, such as T-VEC, will be to achieve adequate systemic activity that can match or exceed those seen with other new agents.

"I haven't really been convinced that this approach will lead to better responses or survival, and we already have other new therapies that activate immunity specifically against particular targets," Schwartz, who was not involved in the T-VEC study, told 番茄社区app. "I think we might have moved beyond this with current immunotherapy."

T-VEC could have potential as part of combination therapy, he added. Adding the agent to other therapies that have different or complementary mechanisms of action could lead to enhanced activity in melanoma.

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