Members of the FDAâ€™s Oncologic Drugs Advisory Committee (ODAC) and Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) voted 22-1 in a combined decision to recommend approval of the oncolytic immunotherapy talimogene laherparepvec (T-VEC) as a treatment for patients with advanced melanoma.
Robert H. I. Andtbacka, MD, CM
Members of the FDA’s Oncologic Drugs Advisory Committee (ODAC) and Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) voted 22-1 in a combined decision 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 US Food and Drug Administration (FDA) is scheduled by October 27, 2015.
“The benefit to risk ratio is favorable for patients with melanoma,” said ODAC panelist Patrick Hwu, MD, a professor in the department of Melanoma Medical Oncology at the University of Texas MD Anderson Cancer Center. The approval vote implies that the benefits of T-VEC outweigh the risks for use in patients with injectable regionally or distantly metastatic melanoma.
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 type 1 (HSV-1) to secrete the cytokine granulocyte-macrophage colony-stimulating factor (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 T-VEC would become the first virus-based immunotherapy if the FDA approves the agent.
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 phase III 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 x 106 PFU/mL for 3 weeks followed by ≤4 mL x 108 PFU/mL every 2 weeks. GM-CSF was administered daily at 125 µg/m2every 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 (ORR) 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 aPvalue 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 the GM-CSF arm, lead investigator Robert H. I. Andtbacka, MD, CM, said in an interview with Targeted Oncology 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 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 in the primary OPTiM study (n = 10) and an extension of the study (n = 2). 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 in each of the primary and extension analyses.
An additional safety concern with T-VEC discussed at the hearing involved viral shedding and the potential for transmission 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 Risk Evaluation and Mitigation Strategy (REMS) and a medication guide.