FDA Panels Support Approval of T-VEC in Melanoma

In a combined decision, members of the FDA’s Oncologic Drugs Advisory Committee (ODAC) and Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) voted 22-1 to recommend approval of the oncolytic immunotherapy talimogene laherparepvec (T-VEC) as a treatment for patients with advanced melanoma. A final approval decision from the FDA is scheduled by October 27, 2015.

By voting in favor of approval, the committees were specifically asserting that the benefits of T-VEC outweigh the risks for use in patients with injectable regionally or distantly metastatic melanoma. "The bulk of the data suggest there is clearly a favorable benefit/risk ratio for this particular therapy. It represents an important new tool for patients," said CTGTAC member Leisha Emens, MD, PhD, associate director of Oncology at Johns Hopkins University School of Medicine.

The vote followed a joint meeting of the ODAC and CTGTAC panels, which the FDA scheduled to discuss the biologics license application (BLA) for T-VEC. Prior to announcing the meeting, the FDA had extended the review period for T-VEC by 3 months to allow time for Amgen, the developer of the drug, to submit additional information.

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. The treatment is among a new class of agents known as oncolytic immunotherapies. At this point, a therapy in this class is not yet available and, if approved, T-VEC would become the first virus-based immunotherapy.

The BLA for T-VEC was based on findings from the phase III OPTiM study, which demonstrated a significant extension in durable response rates (DRR) with the immunotherapy compared with GM-CSF. DRR was the primary endpoint of the OPTiM study, with overall survival (OS) as a secondary endpoint. In the final analysis for OS, a 4.4-month extension was noted; however, this was not deemed statistically significant (P = .051).

In the OPTiM study, 436 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). 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 primary endpoint of 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 received similar therapies, between the two arms. However, more patients with advanced disease were randomized to the T-VEC arm compared with GM-CSF, lead investigator Robert H. I. Andtbacka, MD, CM, said in an interview with OncLive when the data were presented at the 2014 ASCO Annual Meeting.

"Clinically, I think that the 4.4-month difference [in survival] is important for our patients," Andtbacka, a surgeon and investigator with Huntsman Cancer Institute at the University of Utah, explained. "However, I think it's also important to recognize that this is a secondary endpoint, and the study clearly was not powered to look at a small difference, such as this. For me though, clinically, I look at more of what the median survival was for these patients and I also look at the durability of that response."

The primary safety analysis for the BLA 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.

An additional safety concern with T-VEC discussed at the hearing involved viral shedding and the potential for transmission of T-VEC to close contacts, including healthcare providers. There are limited available shedding data for T-VEC. Amgen has an active clinical protocol examining shedding and T-VEC that is expected to have results by the end of 2015. Additionally, Amgen has proposed measures to collect postmarketing safety data for T-VEC, as well as the implementation of a Risk Evaluation and Mitigation Strategy (REMS) and a Medication Guide, should the treatment gain approval.

Although the current review is for single-agent use, multiple clinical trials are currently assessing T-VEC in combination with immune checkpoint inhibitors. A phase II randomized study is ongoing that will evaluate the safety and efficacy of T-VEC in combination with ipilimumab versus ipilimumab alone. Additionally, other ongoing clinical trials will investigate T-VEC in combination with immune checkpoint inhibiting antibodies, such as those targeting PD-1.

In explaining his "yes" vote for the current assessment of T-VEC as a monotherapy, ODAC panel member Brian Rini, MD, associate professor of Medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University said, "I thought the totality of the evidence was that there was a benefit, and it seems to be beneficial even [given] the evolving current landscape [in melanoma]."