T-VEC Promotes Tumor Shrinkage in Unresectable Melanoma

Howard L. Kaufman, MD

The oncolytic immunotherapeutic vaccine talimogene laherparepvec (T-VEC) promoted tumor shrinkage in 64% of patients with advanced melanoma, including a marked reduction in the size of uninjected metastatic lesions, according to a retrospective analysis presented at the 67th Society of Surgical Oncology Annual Cancer Symposium.

The new analysis was conducted on data from the phase III OPTiM trial that was initially presented at the 2013 ASCO Annual Meeting. In this analysis, treatment with T-VEC was shown to produce a durable response rate (DRR) of 16.3% compared with 2.1% for those receiving granulocyte-macrophage colony-stimulating factor (GM-CSF). The objective response rate (ORR) was 26.4% compared with 5.7% and the complete response rate was 10.8% versus 0.7% for T-VEC and GM-CSF, respectively.

In an analysis presented in November at the 2013 Society for Melanoma Research meeting, the median overall survival with T-VEC was 23.3 months compared with 19.0 months with GM-CSF (HR = 0.79, 95% CI: 0.61-1.02; P = 0.0746).

"A favorable trend in overall survival was observed in patients who received talimogene laherparepvec, and the trend 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," Howard Kaufman, MD, professor and director of the section of surgical oncology in the Department of General Surgery, Rush University Medical Center, said in a statement in November. "I look forward to seeing the final results [in 2014]."

T-VEC is engineered through the genetic alteration of the herpes simplex 1 virus. In this process, the gene involved with anti-host response, ICP34.5, is deleted and replaced with the coding sequence for the cytokine GM-CSF, to promote an antitumor immune response following virus replication. Additionally, to accelerate virus replication and release of GM-CSF, deletions are made in ICP47, which enhances US11 expressions.

Patients with unresected stage IIIB/C and IV melanoma were randomized in a 2:1 ratio to receive intralesional T-VEC (n = 295) or subcutaneous GM-CSF (n = 141). T-VEC was administered at ≤ 4 mL x10⁶ pfu/mL for 3 weeks followed by ≤ 4 mL x10⁸ pfu/mL every 2 weeks. GM-CSF was administered at 125 µg/m² for 14 days every 28 days.

Bidimensional measurements were recorded for 286 patients (97%) within the T-VEC arm every 4 to 6 weeks, representing 3219 total lesions (11.3 mean lesions per patient). A greater than 50% reduction in tumor size was seen in 64% of the 2043 lesions that were injected with T-VEC, 32% of the 1022 uninjected nonvisceral metastatic lesions, and in 16% of the 154 uninjected visceral metastatic lesions.

A total of 6 patients converted from unresectable to resectable melanoma, following the administration of T-VEC. In total, 37 surgeries were performed during the course of the trial: 15 resulted in no evidence of disease and 3 showed a pathologic complete response.

The most frequently reported all grade adverse events for the T-VEC arm were fatigue (50.3%), chills (48.6%), and pyrexia (42.8%). Grade 3/4 adverse events were limited, with cellulitis affecting 2.1% of patients in the T-VEC arm.

"Over the last 30 years, the incidence of metastatic melanoma has increased by over 200%, so there is a need for new treatment options," Robert Andtbacka, MD, assistant professor at the University of Utah Huntsman Cancer Institute, and the OPTiM study author, said in a release issued during the ASCO meeting. "The results of this study are encouraging in a disease as devastating as metastatic melanoma."

T-VEC is one of many drugs being explored as a treatment for melanoma that harnesses the immune system. In March 2011, the CTLA-4 inhibitor ipilimumab became the first approved immune checkpoint inhibitor for the treatment of advanced melanoma, setting off a chain reaction focused on the exploration of immune-targeted antibodies. More recently, the anti-PD-1 antibodies nivolumab and MK-3475 have also demonstrated promising results in early clinical trials for patients with melanoma.

Ongoing clinical trials are planned that will investigate T-VEC in combination with these immune checkpoint inhibiting antibodies. One such study, recently announced by Merck, will examine the combination of T-VEC with MK-3475 in previously untreated advanced melanoma. Additionally, a phase I/II trial is examining the combination of T-VEC and ipilimumab in unresected melanoma (NCT01740297).