Long-Term T-VEC Results in Melanoma Provide Reassurance for Clinicians and Patients, Expert Says

Robert Andtbacka, MD

Robert Andtbacka, MD

According to long-term follow-up results from the pivotal phase III OPTiM study, talimogene laherparapvec (T-VEC; Imlygic) continues to demonstrate durable response rates in patients with unresectable stage IIIb, IIIc, and IVM1a melanoma.

Based on the initial results from OPTiM, the FDA approved T-VEC in 2015 for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery.

In an interview withTargeted Oncologyat the 7th European Post-Chicago Melanoma/Skin Cancer Meeting, lead OPTiM investigator Robert Andtbacka, MD, an associate professor in the Division of Surgical Oncology, Department of Surgery at the University of Utah School of Medicine, discussed the long-term results for T-VEC in melanoma and the remaining challenges with the oncolytic immunotherapy.

TARGETED ONCOLOGY:Can you please provide an overview of the study?

Andtbacka:The OPTiM trial was a phase III randomized clinical trial for patients with unresectable stage IIIb, IIIc, and IV melanoma that had at least 1 dermal subcutaneous or lymph node metastases. These patients were randomized to receive intralesional talimogene laherparepvec, also known as T-VEC, or to receive subcutaneous GM-CSF. 

The primary endpoint of this study was durable response rate and we reported previously that this study met its primary endpoint. Patients receiving T-VEC had a significantly greater durable response compared to patients receiving GM-CSF.

A key secondary endpoint of this study was overall survival (OS). We had previously reported on the primary OS, which was improved by 4.4 months in patients receiving T-VEC compared to GM-CSF, at 23.3 months versus 18.9 months, respectively.

We also reported this with slightly earlier disease, such as in patients with stage IIIb, IIIc, and stage IVM1a. This is how the drug was approved in Europe. In this group, we showed that there is a significant improvement in OS in patients receiving T-VEC compared to GM-CSF. We’re almost doubling survival at just over 40 months of patients receiving T-VEC compared to 21.1 months in patients receiving GM-CSF.

Also, we were reporting on the final OS, which again has shown an improvement in patients receiving T-VEC versus GM-CSF, both with the intent to treat patient population, as well as patients with earlier stage of disease.

Once the OPTiM study was finished, patients who participated in the study could go onto a follow-up study to investigate the long-term survival outcomes. There were 105 patients in the T-VEC arm who were not reported as dead at the end of the OPTiM study. Out of these patients, 31 went onto that study, whereas the remaining 74 patients did not for various reasons, mainly the patients may have been lost to follow-up and may not have had contact information.

When we saw the follow-up data, we discovered that the patients who received T-VEC had very durable response rates. It appeared that no patients beyond 3 years died. Over 46% of the patients with stage IIIb, IIIc, and IVM1a [disease] lived beyond 3 years and did not die. I think this is good long-term data to have and demonstrates that if a patient has a complete response and makes it up to 3 years without recurring, the likelihood of recurring is exceedingly low. This provides reassurance for both the clinicians and the patients.

TARGETED ONCOLOGY:What are the next steps following this research?

Andtbacka:An issue that remains is not all the 105 patients who participated in the OPTiM study were still alive to join the follow-up study. Also, patients who were treated with T-VEC who went on to the follow-up study tended to have slightly better performance and received T-VEC as a first-line therapy. I think that these are potential biases in this reporting that may overestimate the survival slightly, although not very much.

The next step is that we need to think about T-VEC not only as a monotherapy, but also in combination therapies. We have reported on different combinations with T-VEC, specifically with ipilimumab (Yervoy), which saw an improvement in response compared to ipilimumab alone. The same also appeared to be true with pembrolizumab (Keytruda) in a phase Ib study we reported on previously. There was an improvement in the response rate by adding T-VEC to pembrolizumab compared to T-VEC or pembrolizumab alone.

We’re also investigating T-VEC in the neoadjuvant setting. We have completed a phase II study in patients with resectable stage IIIb, IIIc, and IVM1a melanoma. These patients received surgery upfront which is a standard of care versus receiving T-VEC for 3 months and then having surgery. The primary endpoint for this study is recurrence-free survival. The results are not yet available, but we’ve completed enrollment of this international multicenter study and the initial results should be coming up within the next year or so.

TARGETED ONCOLOGY:What other challenges remain with T-VEC?

Andtbacka:One of the challenges with many of these oncolytic immunotherapies is that we don’t fully know the mechanism of action. There is a biomarker study that has been completed with T-VEC and those results will be coming out within the year.

Additionally, one of the questions with T-VEC is the risk of transformation into herpes simplex 1 virus. We recently reported on a study that demonstrated no such transformation. This appears to be a very safe treatment for patients.

We’re also looking at T-VEC from the perspective of trying to change the tumor microenvironment, specifically in patients who have been on a PD-1 inhibitor or other checkpoint inhibitors. Many of these patients don’t respond to the checkpoint inhibitors. One of the reasons behind that is the tumor microenvironment is not conducive to have a response or a tumor infiltrating lymphocyte may not be available inside the tumor.

We’re also looking to understand the mechanisms of T-VEC and other oncolytic immunotherapies to potentially be able to change the tumor microenvironment and make nonresponders into responders. This is an active field of research and we have many reports that have come out. It is encouraging that these oncolytic immunotherapies can not only be used as single-agent immunotherapy for treatment, but also in combination. They also may be used in the neoadjuvant setting and in patients who are failing other therapies, such as checkpoint inhibitors. We may be able to rescue some of those patients where this treatment is failing and be able to change the tumor microenvironment to make the tumors more responsive to checkpoint inhibitors.

TARGETED ONCOLOGY:What are the key points that you would like community oncologists to take away?

Andtbacka:The key point from this talk is that the long-term follow-up with T-VEC indicates that the treatment is well tolerated. There are no new added safety concerns.

Secondly, patients who respond to T-VEC and have not succumbed to their disease by 3 years tend to be long-term survivors.

Reference:

Andtbacka HIR, Collichio F, Harrington K, et al. Long-term follow-up (LTFU) of overall survival (OS) data from the phase 3 OPTiM study of talimogene laherparepvec (T-VEC) for metastatic melanoma. 7th European Post-Chicago Melanoma/Skin Cancer Meeting; June 29-30, 2017; Munich, Germany.