CHMP Recommends T-VEC Approval for Melanoma

Sean E. Harper, MD

The first-in-class oncolytic immunotherapy talimogene laherparepvec (T-VEC; Imlygic) has received a positive recommendation from the Committee for Medicinal Products for Human Use (CHMP), which suggests that the treatment should gain European approval for patients with advanced melanoma. The company developing the intralesional injection, Amgen, expects a decision from the European Commission on the Marketing Authorization Application within the coming months.

In the phase III OPTiM study, which was the basis for the CHMP opinion, T-VEC significantly extended the primary endpoint of durable response rates (DRR) compared with GM-CSF. In the final analysis of the secondary endpoint of overall survival (OS), a 4.4-month extension with T-VEC was observed; however, this was not deemed to be statistically significant (P = .051).

"We are pleased that Imlygic has received a positive opinion from the CHMP, and if approved by the European Commission, we look forward to continuing to work with European regulatory authorities to bring this innovative therapy to patients," Sean E. Harper, MD, executive vice president of Research and Development at Amgen.

OPTiM randomized 436 patients with unresected stage IIIB/C and IV melanoma in a 2:1 ratio to receive T-VEC (n = 295) or subcutaneous GM-CSF (n = 141). 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.

DRR was 16% with T-VEC compared with 2% for GM-CSF. The objective response rate was 26% versus 6% and the complete response rate was 11% compared with 1%, for T-VEC and GM-CSF, respectively. At the primary survival analysis, the median OS was 23.3 months with T-VEC compared with 18.9 months for GM-CSF (HR, 0.787; 95% CI, 0.62-1.00; P = .051). This examination occurred after 290 events and was powered to detect an HR of 0.67, with a P value of .05 representing significance.

Following progression on the trial, patients in the two arms received similar therapies. However, more patients with advanced disease were randomized to the T-VEC arm compared with GM-CSF.

"Metastatic melanoma continues to be one of the most difficult-to-treat cancers, often requiring the use of multiple treatment modalities," said Harper. "Despite recent advances, the five-year survival rate for patients who cannot be cured with surgery remains unacceptably low, demonstrating the critical need for additional approaches to control this disease."

The primary safety analysis for the approval was based on findings from 292 patients in the T-VEC arm and 127 patients in the GM-CSF arm of the OPTiM study. The median treatment duration in the treatment versus control arms was 23 versus 10 weeks, respectively.

Incidence of all-grade adverse events (AEs) was 99.3% versus 95.3% in the two arms. The most frequently occurring all-grade AEs for patients receiving T-VEC included fatigue (50.3% vs 36.2% with GM-CSF), chills (48.6% vs 8.7%), pyrexia (42.8% vs 8.7%), nausea (35.6% vs 19.7%), influenza-like illness (30.5% vs 15%), and injection site pain (27.7% vs 6.3%).

Serious AEs occurred in 25.7% and 13.4% of the T-VEC and GM-CSF arms, respectively. Disease progression (3.1% vs 1.6%) and cellulitis (2.4% vs 0.8%) were the most commonly reported serious AEs in the treatment versus the control arm. Six immune-mediated AEs occurred in the T-VEC group compared with three in the GM-CSF group.

There were 12 patient deaths within 30 days of the last dose of T-VEC, including 10 in the primary OPTiM study and 2 in an extension of the study. Nine of the deaths were associated with progressive disease, with the remaining three attributed to myocardial infarction, cardiac arrest, and sepsis. There were four patient deaths in the GM-CSF arms, two each in the primary and extension analyses.

T-VEC is engineered through the genetic alteration of the herpes simplex 1 virus to secrete the cytokine GM-CSF within the tumor, causing cell lysis. Although the current CHMP opinion is for single-agent use, several ongoing clinical trials are assessing T-VEC in combination with immune checkpoint inhibitors, including ipilimumab and anti­­­—PD-1 agents.

In the United States, the FDA is currently evaluating an application for T-VEC for patients with advanced melanoma. The decision deadline for this application is October 27, 2015. Earlier in the year, members of the FDA’s Oncologic Drugs Advisory Committee and Cellular, Tissue and Gene Therapies Advisory Committee voted 22-1 to recommend approval of the oncolytic immunotherapy.