First Oncolytic Immunotherapy Approved for Advanced Melanoma

October 28, 2015
Jason M. Broderick

The FDA has approved the first-in-class oncolytic viral therapy Imlygic (T-VEC; talimogene laherparepvec) for the local treatment of unresectable lesions of the skin and lymph nodes in patients with melanoma that recurred after initial surgery.

Tim Turnham, PhD

The FDA has approved the first-in-class oncolytic viral therapy Imlygic (T-VEC; talimogene laherparepvec) for the local treatment of unresectable lesions of the skin and lymph nodes in patients with melanoma that recurred after initial surgery.

“T-VEC represents a new approach to treating melanoma, a cancer that is increasing in incidence at an alarming rate,” Tim Turnham, PhD, executive director of Melanoma Research Foundation, said in a statement. “Unlike previously approved drugs that are given intravenously or by pill, this therapy is injected directly into the tumor and is the first intralesional therapy approved by the FDA for the treatment of cancer. T-VEC also represents an important milestone in using viruses as the vehicle to stimulate immune response and fight cancer.”

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

Based on the OPTiM data, members of two FDA advisory panels voted 22-1 to recommend approval of T-VEC following a joint committee meeting in late April.

“Melanoma is a serious disease that can advance and spread to other parts of the body, where it becomes difficult to treat,” Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research, said in a statement. “This approval provides patients and healthcare providers with a novel treatment for melanoma.”

OPTiM randomized 436 patients with unresected stage IIIB/C and IV melanoma in a 2:1 ratio to receive intralesional 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.

The median age of patients in the study was 63 years. In the T-VEC arm, 45% of patients had stage IVb/c melanoma compared with 39% in the GM-CSF group. Additionally, 28% of patients had an ECOG performance status of 1 in the T-VEC arm compared with 23% with GM-CSF.

DRR was 16.3% with T-VEC compared with 2.1% for GM-CSF. The objective response rate was 26.4% versus 5.7% and the complete response rate was 11% compared with 1%, for T-VEC and GM-CSF, respectively.

In a subgroup analysis, differences in DRR were more pronounced in patients with stage IIIb/c melanoma (33% vs 0%). In the stage IVM1a group, the DRR was 16% with T-VEC versus 2% with GM-CSF. The differences were less pronounced in the more advanced groups (IVM1b, 3% vs 4%; IVM1c, 7% vs 3%).

In the first-line setting, the DRR with T-VEC was 24% versus 0% with GM-CSF. In the second-line or beyond, the DRR with T-VEC was 10% compared with 4% for GM-CSF.

At the primary survival analysis, the median OS was 23.3 months with T-VEC compared with 18.9 months for GM-CSF. In the subgroup analysis, those with stage IIIb/c or IVM1a melanoma experienced a 43% reduction in the risk of death with T-VEC. For this group, the median OS with T-VEC (n = 163) was 41.1 versus 21.5 months with GM-CSF (n = 86). For those with previously untreated melanoma, T-VEC showed a 50% reduction in the risk of death. The median OS with T-VEC (n = 138) was 33.1 months compared with 17 months for GM-CSF (n = 65).

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.

"Advanced melanoma remains a complex disease to treat, requiring the use of several modalities over the course of a patient's therapeutic journey," OPTiM study lead investigator Howard L. Kaufman, MD, associate director for Clinical Science at the Rutgers Cancer Institute of New Jersey and president of the Society for Immunotherapy of Cancer, said in a statement. "As an oncolytic viral therapy, Imlygic has a unique approach, and provides another option for treating eligible patients with unresectable disease that has recurred after initial surgery."

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.

Multiple clinical trials are currently assessing T-VEC in combination with immune checkpoint inhibitors. A phase I/II study is assessing T-VEC with ipilimumab for unresected melanoma (NCT01740297). Additionally, a phase III study is currently exploring T-VEC with pembrolizumab for unresected melanoma (NCT02263508).

“With seven new drugs approved for metastatic melanoma since 2011, we are optimistic that we are seeing the progress patients need to make this a chronic, manageable condition,” Turnham said. “The best way to ensure that the progress continues is to explore using these drugs, including T-VEC, in combinations.”

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