Oncolytic Immunotherapies Show Benefit in Combinations and as Single Agents in Melanoma

Robert Andtbacka, MD

Oncolytic immunotherapies are proving to be powerful agents for the treatment of melanoma, both as monotherapies and in combination with checkpoint inhibitors.

In October 2015, the FDA approved talimogene laherparepvec (T-VEC; Imlygic) for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. The approval was the first of its kind for the treatment of melanoma and was based on the phase III OPTiM study, which compared T-VEC to GM-CSF.

In the study, a durable response rate of 16.3% was seen with T-VEC compared with 2.1% for GM-CSF. The objective response rate (ORR) was 26.4% versus 5.7% and the complete response rate was 11% compared with 1% for T-VEC and GM-CSF, respectively.

T-VEC has also shown potential in combination with pembrolizumab (Keytruda), as well as in combination with ipilimumab (Yervoy).

Results from a phase Ib trial that were recently presented at the 2015 Society for Melanoma Research Congress showed that the ORR was 56.3% with the combination of pembrolizumab and T-VEC. Based on these findings, Merck and Amgen, the developers of T-VEC, are planning a phase III study for the combination in patients with regionally or distantly metastatic melanoma.

T-VEC given in combination with ipilimumab for patients with previously untreated, unresectable melanoma also shows promise. In a phase Ib study, the ORR for ipilimumab plus T-VEC was 56%, with 33% of patients experiencing a complete response. The disease control rate was 72%.

In addition to T-VEC, additional oncolytic immunotherapies are currently being investigated in combination with checkpoint inhibitors. HF10, a replication-competent HSV-1 oncolytic virus, is being given in combination with ipilimumab in patients with stage IIIb, IIIc, or IV unresectable or metastatic malignant melanoma in an ongoing phase II study.

Another ongoing phase Ib study is investigating the use of coxsackievirus A21 (CAVATAK), a causative agent of the common cold, in combination with pembrolizumab in patients with advanced melanoma for whom pembrolizumab would be considered standard of care.

OncLive: What role do oncolytic immunotherapies currently play in the treatment of melanoma?

The role of oncolytic immunotherapies continues to evolve in melanoma, says Robert Andtbacka, MD, an associate professor in the Division of Surgical Oncology, Department of Surgery at the University of Utah School of Medicine. OncLive spoke with Andtbacka for a better understanding of what is on the horizon for the novel therapeutics.Andtbacka: The past few years have been very exciting for the use of oncolytic immunotherapies. We have a number of clinical trials that have been completed and others that are currently ongoing. Some of these studies are examining how we are using these oncolytic immunotherapies. Often, we are injecting directly into the tumor to activate the immune system. We are using them as both monotherapies and as combinations.

What role can oncolytic immunotherapies play in combating resistance?

Also, we are transitioning into using these in the neoadjuvant setting. Previously, it has really been with patients who primarily have had unresectable disease. However, it is now being studied in the neoadjuvant setting in patients who have resectable disease, but whom we know after surgery will have a very high risk of recurrence.Over the past year or so, we have really been able to show that oncolytic immunotherapies can change the tumor microenvironment. Many of our patients with melanoma who go on other therapies, specifically checkpoint inhibitors, do not always respond to those therapies. We often ask the question, “Why is this?” When we do biopsies in those patients who do not respond, we often find that they do not have tumor-infiltrating lymphocytes. Those lymphocytes need to be there in order for them to have a response to the checkpoint inhibitors. We have been able to inject into the lesions and show that we have a very robust change in the tumor microenvironment.

What would be the benefit of using a checkpoint inhibitor combined with an oncolytic immunotherapy?

How have oncolytic immunotherapies evolved in recent years?

Specifically, there appears to be an influx of both CD8 cells as well as an upregulation of PD-L1 expression. We are now starting to ask the question, “When we change this tumor microenvironment, can we add back those checkpoint inhibitors that the patients did not respond to and then get a response?” We are in the beginning of evaluating this, with ongoing clinical trials where we try and change the tumor microenvironment and then add back in the checkpoint inhibitor.Many of these oncolytic immunotherapies are very good at eliciting a response in the injected lesion as well as in lesions that are in the vicinity. They may not be as good at causing a response at distant sites. By combining them with a checkpoint inhibitor, we have shown a much better response at those distant sites. We also know that there are patients who don’t respond at distant sites, so we are really trying to understand how to sequence checkpoint inhibitors and the oncolytic immunotherapies in order to get the best response for patients.Traditionally, oncolytic immunotherapies had to be directly injected into the tumor. However, some of them can now be used intravenously. We have been interested in looking to see if those intravenous immunotherapies actually hone and seek out tumors. We have been able to show that they do that.

What specific oncolytic virus do you see potential for in combination with checkpoint inhibitors?

Now, we are starting to ask the question, “Can we then deliver some of these oncolytic immunotherapies intravenously and combine them with checkpoint inhibitors and get a response greater than what we would otherwise see?” We are looking specifically at patients who are already progressing on checkpoint inhibitors. All of these studies are still in the infancy and many of them are being planned, while others have just started. The next few years are going to be very interesting to see how we can modulate the immune system to get a better response from checkpoint inhibitors.In combination studies, we are looking at T-VEC with both ipilimumab as well as pembrolizumab. We have shown that, with that combination, there is no added toxicity. We have a bit more data on combining T-VEC with ipilimumab, and we have been able to show that the response rate is at least primarily better than with either ipilimumab or T-VEC alone. The response rate in our phase Ib study looking at this combination was 50%, which is greater than each agent alone.

We also recently presented data on the response rate of combining T-VEC with pembrolizumab. We found that with the combination, the response rate was just over 50%. It was a small group of patients, but it is very encouraging that we saw such a robust response rate. We should wait for the planned phase III study, in which we are comparing pembrolizumab alone to T-VEC plus pembrolizumab, to get a true idea of the responses in a larger set of patients.

We have also used other agents in combination. Specifically we are using coxsackievirus a21 with ipilimumab, and we are planning studies using coxsackievirus a21 with pembrolizumab. This agent is different than any of the other oncolytic viruses because it uses an ICON-1 protein on the cell surface to gain access into the cell. Melanoma cells express a lot of ICON-1. We can actually use this intravenously. We are looking to see if we can get a better response with the two drugs combined versus either one alone.

Another agent that we are looking at in combination with ipilimumab is HF10, which is also a herpes simplex virus, but it is a non-genetically modified virus. We presented preliminary data on this, which showed there was no added toxicity. Moreover, we saw a very good response rate in patients who received the combination. These data will mature over the next year and we will really start to see the effect of these combination studies. They will also guide us moving forward so we can try and design the best combination study possible with the least amount of side effects.