Puzanov Provides Perspective on T-VEC in Melanoma

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.

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

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.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.

Which patients are eligible for T-VEC?

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.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.

A patient may have multiple leg nodules, [so we’ll say], “Okay, you are 90 years old. Why don't we start with T-VEC and see what we get.” A lot of times, patients can be managed and controlled with these pretty simple injections every 2 weeks. We usually do it for 6 months or so until everything disappears, or a patient has real progression. By 6 months, you usually know if a patient is going to respond or progress. Sometimes patients respond even later than that.

There is a good rate of pseudoprogression with the injections, in which some tumors seem to be getting bigger. It's actually not growth of the tumor; it's inflammation. People have to be aware of that. Before the tumors disappear, they may actually appear bigger. It's no need to panic. We published a paper on that, in which the rate of pseudoprogression was 54%. Therefore, 54% of patients who eventually responded had some initial increase in their tumor size.

Do patients tolerate T-VEC well?

Could T-VEC have a neoadjuvant role?

You have to look at the whole patient. If a patient is feeling more pain, losing weight, and not feeling good, that is probably a real progression. If a patient is feeling great, they just have a red and inflamed tumor; that may be a patient who just needs more time to get to that response.Yes; that's why we do it. Of course, a patient who has stage IVb/IVc disease, with a lot of disease in the lung, liver, or spleen and high symptomatic lactate dehydrogenase, is the kind of patient who needs systemic therapy. They would not be considered for single-agent T-VEC. These would be patients to consider a combination therapy in.It could, but you have to do the trials. There's a movement for neoadjuvant therapy, especially in early-stage disease. Other drugs, like TLR9 agonists for example, look promising. There are some ongoing trials in Europe, and we have consortia with The University of Texas MD Anderson Cancer Center and others where we will be discussing these things.

Although we say that the risk of stage I/II melanoma is really low, there are thousands and thousands more patients with stage I/II melanoma than stage III/IV at diagnosis. If I have 100,000 patients with stage I melanoma, and say 5% will proceed to stage IV and die, that's 5000 patients. That’s still a lot of patients.

How have oncolytic viruses impacted the field of oncology?

What are the remaining challenges with this therapy?

The problem is I have to treat 100,000 to get to these 5000 and then make a difference for at least some of them. Of course, you worry that you will be treating 95,000 patients for no good reason because they were cured with surgery. If you can just inject the small melanoma before taking it out and lower the death rate, that would be good. T-VEC, or some other injectable agent, would be ideal. There are multiple agents now in development.The oncolytic viruses are a little different because they are administered locally. Their major role seems to be to raise awareness that there is a tumor somewhere in the lymph node, skin, or organ. [T-VEC colors the tumors], so the immune system knows to pick up the pieces and look for other pieces like that to finish the clean-up job.We have to see how the phase III data look with pembrolizumab. If it's positive, then it will raise the profile of T-VEC as well as oncolytic viruses and other injectables. The challenge is whether you can [inject] it into the organs. Additionally, what about resistant cell types?

Is there anything else you want to emphasize about T-VEC?

Can you engineer something better than T-VEC? A lot of people are trying to add—besides the GM-CSF—CTLA-4 or PD-1 into the virus so that the virus delivers 2 punches. It's a growing and exciting field of oncology. The beauty is that despite being invasive, it may actually have fewer side effects because it is injected directly into the tumor.When you are trained properly in the application and logistics of how to give the oncolytic virus, it can be incorporated into the office as long as that office sees a reasonable number of these patients. It wouldn't make any sense to organize your office [for T-VEC delivery] if you only see 1 patient in a blue moon.

However, if you specialize in melanoma like us here at Roswell Park Comprehensive Cancer Center, then you have the volume to justify any adjustments. When you do, it's a very natural and flowing type of treatment with no logistical issues. It's quite simple. The challenges are at the beginning when you are setting everything up.

Chesney J, Puzanov, Ross M, et al. Combination of talimogene laherparepvec and ipilimumab versus ipilimumab alone in unresected stage IIIB-IV melanoma: primary results from a randomized (1:1), open-label phase 2 study. Presented at: 7th European Post-Chicago Melanoma/Skin Cancer Meeting; June 29-30, 2017; Munich, Germany.