T-VEC Injection for Melanoma Recommended for FDA Approval

Zosia Chustecka

April 30, 2015

An experimental treatment for melanoma that is injected directly into the lesion has been recommended for approval in the United States.

The product, talimogene laherparepavec (T-VEC, Amgen Inc), described by the company as the first oncolytic immunotherapy, is destined for use in patients with "injectable regionally or distantly metastatic melanoma lesions."

It contains a genetically modified version of the herpes simplex virus that has been engineered to selectively replicate in the tumor and cause cancer cell destruction and death. The product also contains a gene for granulocyte-macrophage colony stimulating factor (GM-CSF), which is expressed locally in the tumor. The rupture of the cancer cells releases tumor-derived antigens, and together with the released GM-CSF, these can stimulate a system-wide immune response, the company explains.

The recommendation for FDA approval, with a vote of 22 to 1 in favor, came from a meeting of two advisory panels, the Oncologic Drugs Advisory Committee and the Cellular, Tissue and Gene Therapies Advisory Committee.

The outcome was somewhat a surprise, inasmuch as the FDA briefing document released prior to the meeting had many queries and said it was unclear whether the product offers an acceptable benefit-risk profile in a therapeutic field in which many new therapies have recently been launched.

Melanoma has seen a host of new product launches in recent years, including checkpoint inhibitor immunotherapies and a genetic mutation inhibitor (targeting BRAK and MEK), and all of these new drugs have shown a statistically significant improvement in overall survival over standard therapy, as previously reported by Medscape Medical News.

In the clinical trial data presented at the meeting for talimogene laherparepvec, the data for overall survival (which was a secondary endpoint) just missed statistical significance, and the benefit that was significant was seen on a composite endpoint, the meaningfulness of which was "unclear," the FDA reviewers commented in the briefing document.

The FDA is expected to make a final decision on approval of talimogene laherparepavec before the end of October 2015.

Pivotal Clinical Trial

The clinical data considered for approval come mostly from a phase 3 pivotal trial known as OPTiM (or study 005/05), according to the briefing documents.

This study involved 436 patients with malignant melanoma that was not surgically resectable who were randomly assigned in a 2:1 ratio to receive talimogene laherparepavec or control (GM-CSF). The treatment was injected directly into all reasonably injectable skin lesions.

The initial dose of talimogene laherparepvec was up to 4 mL total, at a concentration of 106 PFU/mL. Subsequent doses began 3 weeks after the first dose and consisted of talimogene laherparepvec up to 4 mL total, at a concentration of 108 PFU/mL, every 2 weeks.

The control (GM-CSF) was administered at a dose of 125 μg/m2/day subcutaneously on an every-4-week schedule, consisting of daily doses for 14 days followed by a 14-day rest period.

The primary endpoint was durable response rate (DRR), which was defined as the rate of patients who experienced an overall complete or partial response (CR or PR) that began at any point within 12 months after initiating therapy and was maintained for at least 6 months. These results show a significant benefit for the product, with a DRR of 16.3% with talimogene laherparepvec arm compared with 2.1% for control (P < .0001).

Overall survival was a secondary endpoint. There were 189/295 (64%) confirmed deaths in the talimogene laherparepvec arm, and 101/141 (72%) confirmed deaths in the control arm (P = .051). The estimates of median OS were 23.3 months for the talimogene laherparepvec arm and 18.9 months for the control arm (hazard ratio, 0.79).

The most common treatment-emergent adverse events with talimogene laherparepvec were fatigue, chills, pyrexia, nausea, influenzalike illness, and injection site pain, according to the FDA briefing documents. Flulike symptoms were reported by 90% of patients.

Cellulitis at the site of the injection is an important adverse event, owing to the intratumoral injection route of administration of talimogene laherparepvec, the documents note. In the talimogene laherparepvec arm, 18 patients (6.2%) developed cellulitis; 7 events (2.4%) were categorized as serious, requiring hospitalization. One patient developed a wound that became resistant to medical therapy; the patient required a below-the-knee amputation, but the relationship of this event to the administration of talimogene laherparepvec is unclear, the FDA reviewers commented.

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