Pivotal T-VEC Data Published Ahead of FDA Approval Decision

Howard L. Kaufman, MD

At a recent FDA joint advisory committee meeting, members voted 22-1 to recommend approval of the oncolytic immunotherapy talimogene laherparepvec (T-VEC) as a treatment for patients with advanced melanoma. The FDA is scheduled to make a final approval decision by late October and in the meantime, data from the pivotal phase III OPTiM trial have now been published in the Journal of Clinical Oncology.

The OPTiM study met its primary endpoint, with T-VEC significantly extending the durable response rate (DRR) compared with GM-CSF. The immunotherapy also extended overall survival (OS) by 4.4 months; however, the difference was not statistically significant (P = .051).

“These data are significant because this is the first randomized trial of an oncolytic virus in patients with cancer and suggests that talimogene laherparepvec treatment is safe and can result in durable clinical responses with a trend toward improved survival,” lead author Howard L. Kaufman, MD, associate director for Clinical Science and chief surgical officer at Rutgers Cancer Institute of New Jersey, said in a press release.

The international OPTiM study included 436 patients with unresected stage IIIB/C and IV melanoma. Patients were randomized in a 2:1 ratio to receive intralesional T-VEC (n = 295) or subcutaneous GM-CSF (n = 141). The median age of patients in the study was 63 years. T-VEC was administered initially at ≤ 4 mL x10⁶ PFU/mL for 3 weeks followed by ≤ 4 mL x10⁸ PFU/mL every 2 weeks. GM-CSF was administered daily at 125 µg/m² every 14 days in a 28-day cycle.

The median duration of treatment in the T-VEC and GM-CSF arms was 23 weeks (range, 0.1-78.9 weeks) and 10 weeks (range, 0.6-72.0 weeks), respectively. Median potential follow-up (time from random assignment to analysis) was 44.4 months (range, 32.4-58.7 months) at the primary OS analysis.

DRR was 16.3% with T-VEC and 2.1% with GM-CSF (odds ratio, 8.9; P <.001). Overall response rates were 26.4% and 5.7% (P <.001) in the T-VEC and control arms, respectively. Median OS was 23.3 months (95% CI, 19.5-29.6) with T-VEC and 18.9 months (95% CI, 16.0-23.7) with GM-CSF (HR = 0.79; 95% CI, 0.62-1.00; P = 051).

The difference in DRR between the T-VEC and GM-CSF arms was more pronounced in patients with stage IIIB or IIIC (33% vs 0%, respectively) and IVM1a disease (16% vs 2%) than in patients with stageIVM1b (3% vs 4%) and IVM1c disease (7% vs 3%). Differences were also more pronounced in patients with treatment-naive metastatic melanoma (24% vs 0%) than in those receiving treatment as second-line or greater therapy (10% vs 4%).

The most common all-grade adverse events (AEs) with T-VEC were fatigue (50.3%), chills (48.6%), and pyrexia (42.8%). The only grade 3/4 AE occurring in ≥2% of T-VEC—treated patients was cellulitis (2.1%). No fatal treatment-related AEs occurred.

T-VEC is an oncolytic virus designed to selectively replicate within tumors and produce granulocyte macrophage GM-CSF to enhance systemic antitumor immune responses. It is the first oncolytic virus based on a modified herpes simplex virus (HSV) type 1 designed to selectively replicate in and lyse tumor cells while promoting regional and systemic antitumor immunity.

T-VEC is modified through deletion of two nonessential viral genes. Functional deletion of the herpes virus neurovirulence factor gene (ICP34.5) attenuates viral pathogenicity and enhances tumor-selective replication. T-VEC is further modified by deletion of the ICP47 gene to reduce virally mediated suppression of antigen presentation and increase the expression of the HSV US11 gene. Insertion and expression of the gene encoding GM-CSF results in local GM-CSF production to recruit and activate antigen-presenting cells with subsequent induction of tumor-specific T-cell responses.

T-VEC is currently being studied as both a single agent and as part of combination therapies.

“The results with T-VEC provide a new class of immunotherapy agent, with an acceptable safety profile, which may benefit patients who do not respond to other treatments and T-VEC may be especially useful in combination with other agents,” said Kaufman.

Andtbacka RHI, Kaufman HL, Collichio F, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma [published online May 26, 2015]. J Clin. Oncol. doi: 10.1200/JCO.2014.58.3377.