Robert Andtbacka, MD, discusses the current use of talimogene laherparepvec in melanoma and future directions with this type of treatment.
Robert Andtbacka, MD
Although the oncolytic immunotherapy talimogene laherparepvec (T-VEC; Imlygic) is approved for patients with advanced-stage unresectable melanoma, Robert Andtbacka, MD, explained that it holds promise beyond its current indication as a potential neoadjuvant therapy and in combination with PD-1 inhibitors.
“These oncolytic viruses have multiple roles to play as monotherapy in patients with more limited disease, as combination therapies in the first-line setting, and also in the second-line setting in patients who may not be responding to PD-1 inhibitors,” said Andtbacka.
In an interview with OncLive, Andtbacka, an associate professor in the Division of Surgical Oncology, Department of Surgery at the University of Utah School of Medicine, discussed the current use of T-VEC in melanoma and future directions with this type of treatment.Andtbacka: T-VEC was approved as monotherapy for patients in the United States with metastatic unresectable melanoma—stage III/IV melanoma. It's been used in that setting, but mostly in patients who have earlier disease. These are patients with unresectable stage III disease and some stage IV N1a disease. I don't think T-VEC is being used much in patients with lung and liver metastases. When T-VEC was approved, there were institutions around the country who were using it as monotherapy, but also in combination with PD-1 inhibitors and other therapies, as well.
Responses can be quite dramatic in the first-line setting and also in patients who have failed other therapies. There are 3 larger clinical trials that have been conducted in patients with unresectable metastatic melanoma. There is Amgen’s randomized phase II trial with ipilimumab (Yervoy), of which Jason A. Chesney, MD, is the first author. It was published in the Journal of Clinical Oncology about 1 year ago. We showed that when we combined T-VEC with ipilimumab, there was no substantial added toxicity, but rather a dramatic improvement in response rates. We went from about a 19% response rate with ipilimumab alone to a 39% response rate when we added T-VEC.
We have also combined T-VEC with pembrolizumab (Keytruda) in a phase Ib study. We reported on that in June 2018 and showed that the response rate, albeit in 21 patients, was 62%. There's a larger randomized phase III study that has been completed. In that study, T-VEC was combined with pembrolizumab and patients were randomized to a placebo injection with pembrolizumab versus T-VEC plus pembrolizumab. The safety data should be coming out later this year. That has sort of dramatically shifted the use of the therapy.
Then in the neoadjuvant setting, we take patients who have resectable disease—–stage IIIb, former stage IIIb, IIIc, and stage IV N1a. The question is whether we can decrease the risk of recurrence by using T-VEC in the neoadjuvant setting; it appears to be safe. We studied this in a phase II multinational study. Patients were randomized to upfront surgery, which is the standard of care, or T-VEC for 12 weeks followed by surgery. We don't have that data yet, but some of it should be available at the end of 2019. In that trial, we showed a 21% complete response (CR) rate by using T-VEC for 12 weeks before surgery; that’s quite dramatic to see a pathologic CR (pCR) in those patients. Time will tell whether that will result in a decreased risk of recurrence.
In terms of its practical use, it’s being used in the community in the first-line setting for patients who have stage IIIb or IIIc disease, and now the new stage IIIb patients who are deemed unresectable. It is also being used for stage IV N1a patients. T-VEC is also being used in combination with PD-1 inhibitors for an off-label use. Data have been published on that, as well, showing that these combinations can have dramatic effects in real-world situations.
T-VEC is also being used for patients who have been on PD-1 inhibitors but have failed them. In that setting, we believe patients fail PD-1 inhibitors because they don't have the correct immune cells inside the tumor. T-VEC is being used to try to re-educate the tumor microenvironment and make those nonresponding tumors into responsive tumors. I have used T-VEC in that setting, as a bridge to add the PD-1 inhibitor back in.
Broadly, T-VEC is going to be used in unresectable, stage III patients as monotherapy, in combination for patients with more advanced disease, off-label as a neoadjuvant therapy for patients with resectable disease, and in patients with an injectable lesion who are failing other therapies to try to re-educate the immune system. We know that T-VEC is a herpes simplex virus; it's a double-stranded DNA virus that has been genetically modified so that it has a very good lytic ability. It does not appear to give patients herpetic infections, due to deletions of certain genes with the virus. When we inject T-VEC, it only replicates in tumor cells, not normal cells. The reason being is that the tumor cells have proteins that the virus requires to replicate. Those proteins are produced by the tumor cells, whereas normal cells don't necessarily produce those proteins. T-VEC also produces GM-CSF, which is believed to activate the dendritic cell and then the immune system.
Once the virus is injected into the tumor, it's taken up and replicates; that leads to lysis of those cells and exposes tumor-derived antigens to the immune system. As we know, melanomas and other cancers are very good at evading the immune system through multiple mechanisms. By injecting this, we have lysis of those cells and then exposure of those tumor-derived antigens to the immune system. It's believed that the GM-CSF that further activates the immune system activates those antigens. Whether that's true or not we don't know, but that's the mechanism we believe occurs.
The dendritic cells then take up the proteins and become antigen presenting cells to T cells—–the CD8-positive T cells. Then, those CD8-positive T cells are educated to recognize those proteins, go out and seek them elsewhere in the body, and then kill them. It's important to recognize that T-VEC is not competing with nivolumab (Opdivo) or ipilimumab. It's an additional modality of treating patients with metastatic melanoma. We know that patients with stage III disease tend to respond better to T-VEC. In the OPTiM study, the response rates in injected lesions was 64%. About two-thirds of those injected tumors will respond to T-VEC, and the majority of patients will have a CR. We also know that the response rate in regional tumors is about 34%. At distant sites in the lung or liver, the response rate is about 15%.
Overall response in patients with stage III unresectable metastatic melanoma, at least in the OPTiM study, was 52%. The question becomes, “How does that compare with PD-1 inhibitors and anti—CTLA-4 therapy with nivolumab and ipilimumab?” We've never compared them in a head-to-head study. However, in a phase II study, we know that the response rates to ipilimumab in patients with stage III disease was about 19%. The response rate for T-VEC in stage III patients is 52%, which is better.
With PD-1 inhibitors, whether it’s nivolumab or pembrolizumab, the response rate in stage III patients is around 35%. In the KEYNOTE-006 study, response rates were less than that; it was about 27%. T-VEC works favorably in that setting for those patients. With that in mind, T-VEC is best suited as monotherapy for those patients. That is also the [indication] in Europe—in unresectable stage III patients and stage IV and N1a patients. It's not approved for patients as a monotherapy with lung, liver, and other metastases. It's extremely well tolerated. The most common adverse events (AEs) are shakes, chills, and a bit of redness at the injection site. Grade 3 and greater toxicities are very low. In the OPTiM study, the most common AE was cellulitis. It's important to recognize that cellulitis may not be bacterial cellulitis, but just redness at the injection site—which is more from immune infiltration rather than bacteria cellulitis. We can't clearly discern this on the data though. In those patients, the grade 3 and greater toxicity for that cellulitis was 2.1%.
In terms of logistics, it's important to recognize that T-VEC does not have a biosafety label by the FDA. Institutions handle this differently. We've learned a lot about safety of T-VEC. We know for instance that the risk of healthcare providers’ and patients’ families being affected by the virus is virtually nonexistent. In most settings right now, T-VEC is given in the clinic. We don't have any special precautions in terms of the environment between treating one patient with T-VEC and then having another patient come in. For most healthcare providers, we use gloves and a gown, but this varies by institution. It’s not challenging to acquire it. One of the misconceptions is that it’s difficult to give this drug. In terms of time, it doesn't take up more time. At my institution, we measure a patient’s lesions to determine how much T-VEC is needed. We would give the pharmacy a call, let the patient go for breakfast. They come back 1 hour later, and we administer the drug. It's a little bit more in terms of the patients having to come back [for follow-up]. In terms of the clinic flow, it can be organized quite easily. It's not as much of a problem as people think it is. It may be a little different for clinics that aren’t used to giving the drug, but timing and all of those things can be overcome.
The other thing is the safety of T-VEC. People believe that it is sort of dangerous to the healthcare providers and the family members. There really are no data for that. There's also the understanding of responses. In the correct patients, T-VEC can be very effective at treating their metastatic melanoma and perhaps more effective than many of the therapies out there.
What needs to be emphasized is that in the patients who respond to T-VEC, the responses tend to be extremely durable. In patients who responded to T-VEC in the OPTiM study, 65% of patients had a response that lasted 12 months or longer. In patients who had a CR, 72% of those patients were still in CR at 3 years. If patients have not recurred before 3 years, the risk of recurrence beyond that is extremely low. That's very similar to what we see with some of the other therapies, such as ipilimumab.They have transformed the field. We recognize that we can use these viruses to activate the immune system against melanoma. We can use these oncolytic viruses to try to re-educate the immune system to make nonresponsive tumors into responsive ones by changing the tumor microenvironment.
They also have an important role in the neoadjuvant setting. I mentioned the randomized, phase II, neoadjuvant study of T-VEC in patients with resectable metastatic melanoma. We have also conducted other studies. We have done studies with another herpes simplex virus combined with nivolumab in the neoadjuvant setting. We've shown pCRs in almost all patients who were treated with this. Though it was a small study, it shows that we can have dramatic pCRs in the neoadjuvant setting. That's what the future holds for many of these viruses.