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Puzanov Provides Perspective on T-VEC in Melanoma

Caroline Seymour
Published: Friday, Oct 19, 2018

Igor Puzanov, MD, MSCI, FACP
Igor Puzanov, MD, MSCI, FACP
In 2015, talimogene laherparepvec (T-VEC; Imlygic) became the first in-class oncolytic immunotherapy to be FDA approved for the treatment of advanced-stage unresectable melanoma, but its path forward may be in combination with checkpoint inhibitors, explained Igor Puzanov, MD, MSCI, FACP.

In the phase III OPTiM trial, which was the basis for the FDA approval of T-VEC, the therapy significantly extended durable response rates versus subcutaneous GM-CSF.

In a separate phase II study, patients who received the combination of T-VEC and the CTLA-4 inhibitor ipilimumab (Yervoy) experienced a doubling in objective response rate compared with ipilimumab alone (38.7% vs 18.0%; odds ratio [OR], 2.9; 95% CI, 1.5-5.5; P = .002).

Moreover, an ongoing phase III trial (NCT02263508) is examining T-VEC in combination with pembrolizumab (Keytruda). If the study is positive, Puzanov noted, it will further validate oncolytic viruses as a viable therapy in oncology.

In an interview with OncLive, Puzanov, director of the Early Phase Clinical Trials Program, chief of Melanoma, co-leader, CCSG Experimental Therapeutics Program, professor of oncology, Department of Medicine, Roswell Park Comprehensive Cancer Center, discussed the current and potential future utility of T-VEC in patients with advanced-stage melanoma.

OncLive®: What is T-VEC and how does it differ from other immunotherapies?

Puzanov: T-VEC is a drug dear to my heart; I helped develop it since 2009. T-VEC is an oncolytic virus. The basis of T-VEC is the herpes simplex virus, which is a virus that everybody is exposed to. The researchers modified it, so it cannot infect healthy cells; it can only infect the tumor cells of not just melanoma, but other [malignant cells].

It's weakened, so it cannot spread around. You have to inject it into the tumor and it kind of stays there, infects the cells in the tumor, and multiplies. It also releases GM-CSF, which is a protein our bodies make to stimulate the immune system. Once the tumor is visible to the immune system, the immune system can come in [and kill the tumor]. It kills the tumor that was injected, but it also looks around for others in your body and kills them, as well.

It's a locally administered immunotherapy unlike the other therapies people are used to, like nivolumab (Opdivo), pembrolizumab, ipilimumab, or avelumab (Bavencio). It has to be injected into the tumor, but it doesn't only work in the tumor. Through this mechanism I described, it spreads the immune surveillance and recognition so that it works elsewhere in the body.

T-VEC was FDA approved for patients with stage IIIb, IIIc, and IVa melanoma. These are patients who may have melanoma and metastases in their arms, legs, scalp, and lymph nodes, even in their soft lung tissue. It was approved as a single agent, but we are now testing it in combination with ipilimumab. In a publication in the Journal of Clinical Oncology, we showed that when you combine it with ipilimumab, it's a lot more efficacious than either drug alone. When you give T-VEC with ipilimumab, T-VEC doubles the rate of response.

Now we have a registrational trial with T-VEC plus pembrolizumab. The initial experience with the first phase Ib trial…showed that [over half] of patients [responded]—which is a lot more than you would expect with either drug alone.

We now have phase III trials for never-treated patients, regardless of BRAF mutation, so anybody can receive an injectable by itself—a CT scan- or ultrasound-guided injection. Half of patients will get pembrolizumab, which is the standard of care, and half of them will get pembrolizumab and T-VEC. We should have some results by spring 2019.

Which patients are eligible for T-VEC?

For single-agent T-VEC, patient selection is clear based on the label, which indicates unresectable stage IIIb, IIIc, and IVa melanoma. Let’s say a patient comes in with [involved] lymph nodes—in transit or satellite metastases. You know you can cut them out, but you will leave a patient very debilitated. They’ll have a lot of defects, and will be potentially missing muscle, fat, or other things that will make your patient’s life miserable.

The data from the phase III OPTiM trial showed that you can have 11% of patients with complete disappearance of their tumors if you inject their tumors. You don't have to inject all of them because the other tumors may die by approximation. Another 15% will have shrinkage and stabilization, so we use it for a lot for elderly patients where you worry about the side effects of systemically delivered immunotherapies, such as pembrolizumab or nivolumab.

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