Omid Hamid, MD, discusses the mechanism by which talimogene laherparepvec operates, the trials that served as the basis for its approval, and the impact of oncolytic viruses on the field of oncology overall.
Omid Hamid, MD
Talimogene laherparepvec (T-VEC; Imlygic) was approved by the FDA in 2015 for the treatment of patients with locally advanced, unresectable melanoma and has since continued to show durable responses and minimal toxicity as a single agent and in combination with checkpoint inhibitors, making it a worthwhile treatment strategy to explore further, explained Omid Hamid, MD.
“Oncolytic viruses have already been approved in China for head and neck cancer. They’re a great way to prime the immune system,” said Hamid, director of Research and Immuno-Oncology at The Angeles Clinic. “They're not checkpoint inhibitors, so you can prime with the virus and boost with a checkpoint [inhibitor]. They've shown very little toxicity. Oncolytic viruses show a significant benefit that warrant future study.”
The approval of T-VEC was based on results from the phase III OPTiM trial, in which patients with unresectable stage IIIb, IIIc, and stage IV melanoma were randomized 2:1 to receive intralesional T-VEC or subcutaneous GM-CSF. Results showed an objective response rate of 26% (95% CI, 21%-32%) in the T-VEC arm compared with 6% (95% CI, 2%-10%) in the GM-CSF arm; durable response rates were 16% (95% CI, 12%-21%) and 2% (95% CI, 0%-5%) with T-VEC and GM-CSF, respectively (P <.0001).1
Moreover, a subsequent phase II trial reported a doubling in objective response rate in patients who received the combination of T-VEC and the CTLA-4 inhibitor ipilimumab (Yervoy) versus ipilimumab alone (38.7% vs 18.0%; odds ratio, 2.9; 95% CI, 1.5-5.5; P = .002).2
Pembrolizumab (Keytruda) is the latest checkpoint inhibitor to be tested in combination with the oncolytic virus (NCT02263508), added Hamid, with results anticipated in mid-2022.
In an interview with OncLive, Hamid discussed the mechanism by which T-VEC operates, the trials that served as the basis for its approval, and the impact of oncolytic viruses on the field of oncology overall.Hamid: T-VEC is an oncolytic virus; it’s part of a novel drug class where modified viruses are used for the treatment of [patients with] cancer. These viruses work by 2 separate mechanisms. Firstly, they replicate within cells; they grow and lyse the tumor, causing that tumor cell to break apart and die. Then the release of those viral particles allows continued infection. Those new viruses may go next door and take a seat in the next cell, which causes the local oncolytic effect. Secondly, the virus causes locoregional activation of the innate immune system. Then, [the dying tumor cell’s release of antigens] creates a priming environment for the immune system. Once it’s primed, the thought is that the immune system can go to distant and uninjected sites and cause the same thing.
This is a type 1 attenuated herpes simplex virus; it’s a genetically modified herpes simplex virus and it expresses GM-CSF. The virus only affects malignant cells. Based on this, and the trials done to date, T-VEC became the first oncolytic virus to receive regulatory approval in the United States. [As a result of the herpes simplex virus, we may see] cold sores and fever blisters. However, the virus is engineered to delete a gene that blocks antigen presentation, so patients don't [typically] get fever blisters.A couple of trials have been done. OPTiM was published in the Journal of Clinical Oncology by Robert Andtbacka, MD; this was a phase III trial of T-VEC versus subcutaneous GM-CSF for patients with unresectable stage IIIb, IIIc, and stage IV melanoma. The trial showed that T-VEC demonstrated a statistically significant improvement in durable responses over GM-CSF. There was a trend towards overall survival (OS) advantage, although it was not significant. T-VEC was very well tolerated. Some of the most common adverse events were fatigue, chills, and fevers.
The second trial [evaluated T-VEC] in combination with ipilimumab. [Those results were] presented by Jason Chesney, MD, PhD, of the University of Louisville. The trial showed that the combination was safe; it showed that T-VEC can induce a T-cell specific response, somewhat like a priming and then a boosting. The open-label phase II study was published by Dr Chesney in the Journal of Clinical Oncology and randomized 198 patients to receive either T-VEC plus ipilimumab or ipilimumab alone. Those who received the combination had a 39% response rate compared with 18% in those given single-agent ipilimumab; that was significant, and responses were not limited to injected lesions.
Fifty-two percent of patients in the combination arm experienced visceral lesion decreases as well as 23% of patients in the ipilimumab arm. The adverse events were fairly common and manageable. Patients experienced fatigue and diarrhea, although there was not a significant increase in toxicity.
There was also [a study that evaluated] a combination of T-VEC with pembrolizumab. The phase Ib study showed that the combination was well tolerated. Patients experienced fatigue, fever, and chills, although there were no dose-limiting toxicities. The objective response rate was 62% with a complete response rate of 33% by immune-related response criteria. The combination therapy saw an increase in CD8-positive T cells, elevated PD-L1 expression, and an interferon-gamma gene expression. This led to a randomized trial of pembrolizumab plus placebo versus pembrolizumab plus T-VEC, which has yet to be presented.Absolutely. They would make a lot of sense with any injectable disease, such as head and neck cancer, breast cancer, cutaneous lesions, squamous cell carcinoma, and Merkle cell carcinoma. The next step [is to look at] visceral injections. We’re currently looking at T-VEC for intrahepatic injections.We work in an academic center, which is a private clinic without a lot of ancillary support. Still, we’re able to give T-VEC every day. It's absolutely part of the future of care. If we can prove that a visceral injection shows efficacy, the next step would be to look at this in any solid tumor, including lung and other cancers. It has a bright future. Additionally, it has a good failsafe. If we get into trouble, we can give acyclovir (Zovirax) and turn off the virus. Unlike other immunotherapies that can have toxicities that are hard to take care of, we can render the virus harmless by giving acyclovir.