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.
OncLive: What is the evolution of T-VEC since its 2015 FDA approval?
: 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.