The approval was based on results from the phase 3 OPTiM study in which Imlygic significantly extended durable response rates compared with GM-CSF.
The FDA has approved the first-in-class oncolytic immunotherapy Imlygic (talimogene laherparepvec; T-VEC) for the treatment of patients with advanced melanoma, based on results from the phase 3 OPTiM study.
Imlygic is engineered through the genetic alteration of the herpes simplex 1 virus to secrete the cytokine GM-CSF within the tumor, causing cell lysis.
In the pivotal OPTiM trial, Imlygic significantly extended durable response rates (DRR) compared with granulocyte-macrophage colony-stimulating factor (GM-CSF). Durable response rate was the primary endpoint, with overall survival (OS) as a secondary endpoint. In the final overall survival analysis, a 4.4-month extension with Imlygic was observed; however, this was not deemed to be statistically significant.
Based on the OPTiM data, members of the FDA’s Oncologic Drugs Advisory Committee and Cellular, Tissue, and Gene Therapies Advisory Committee panels voted 22 to 1 to recommend approval of Imlygic following a joint committee meeting in late April.
"[Imlygic] represents a new approach to treating melanoma, a cancer that is increasing in incidence at an alarming rate," Tim Turnham, executive director, 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."
"[Imlygic] also represents an important milestone in using viruses as the vehicle to stimulate immune response and fight cancer."
OPTiM randomized 436 patients with unresected stage 3B/C and 4 melanoma in a two-to-one ratio to receive intralesional Imlygic (295 patients) or subcutaneous GM-CSF (141 patients). The median age of patients in the study was 63 years. Imlygic was administered initially at less than or equal to 4 mL x106 PFU/mL for three weeks followed by less than or equal to 4 mL x108 PFU/mL every two weeks. GM-CSF was administered daily at 125 µg/m2 every 14 days in a 28-day cycle.
Durable response rate was 16 percent with Imlygic compared with 2 percent for GM-CSF. The objective response rate was 26 percent versus 6 percent and the complete response rate was 11 percent compared with 1 percent, for Imlygic and GM-CSF, respectively.
At the primary survival analysis, the median overall survival was 23.3 months with Imlygic compared with 18.9 months for GM-CSF. This examination occurred after 290 events and was statistically significant.
Following progression on the trial, patients in the two arms received similar therapies. However, more patients with advanced disease were randomized to the Imlygic arm compared with GM-CSF, lead investigator Robert H. I. Andtbacka, said in an interview with CURE when the data were presented at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of nearly 30,000 oncology professionals.
“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 approval was based on findings from 292 patients in the Imlygic 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 was 99.3 percent versus 95.3 percent in the two arms. The most frequently occurring all-grade adverse events for patients receiving Imlygic included fatigue (50.3 percent vs 36.2 percent with GM-CSF), chills (48.6 percent vs 8.7 percent), pyrexia (42.8 percent vs 8.7 percent), nausea (35.6 percent vs 19.7 percent), influenza-like illness (30.5 percent vs 15 percent) and injection site pain (27.7 percent vs 6.3 percent).
Serious adverse events occurred in 25.7 percent and 13.4 percent of the Imlygic and GM-CSF arms, respectively. Disease progression (3.1 percent vs 1.6 percent) and cellulitis (2.4 percent vs 0.8 percent) were the most commonly reported serious adverse events in the treatment versus the control arm. Six immune-mediated adverse events occurred in the Imlygic group compared with three in the GM-CSF group.
There were 12 patient deaths within 30 days of the last dose of Imlygic, including 10 in the primary OPTiM study and two 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.
Although the current review is for single-agent use, several ongoing clinical trials are assessing Imlygic in combination with immune checkpoint inhibitors, including Yervoy (ipilimumab) and anti­­­—PD-1 agents.