Karen Midthun, MD
The FDA has approved the first-in-class oncolytic immunotherapy talimogene laherparepvec (T-VEC; Imlygic) for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery, based on results from the phase III OPTiM study.
In the pivotal trial, 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
Based on the OPTiM data, members of the FDA’s ODAC and CTGTAC 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 PS 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 (HR, 0.79; 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.
In the subgroup analysis, those with stage IIIb/c or IVM1a melanoma experienced a 43% reduction in the risk of death with T-VEC (HR, 0.57; 95% CI, 0.40-0.80; P
<.001). 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 (HR, 0.50; 95% CI, 0.35-0.73; P
<.001). The median OS with T-VEC (n = 138) was 33.1 months compared with 17 months for GM-CSF (n = 65).
"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."
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.
"Imlygic is the first clinical and regulatory validation of an oncolytic virus as a therapy, which Amgen is proud to bring to patients with a serious form of skin cancer,” Sean E. Harper, MD, executive vice president of Research and Development at Amgen, said in a statement. “Not all melanoma patients currently benefit from available therapies, and Imlygic represents an important new option that can provide meaningful durable responses for patients with this aggressive and complex disease."
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).
"Immunotherapy is an exciting area for cancer research, and we are currently studying Imlygic in combination with other immunotherapies in advanced melanoma and other solid tumors," said Harper.
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