Talimogene laherparepvec (T-VEC; Imlygic) was approved by the FDA in October 2015, for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with recurrent melanoma after initial surgery, based on results from the phase III OPTiM study.
In the study, which compared T-VEC to GM-CSF, patients who received T-VEC experienced a durable response rate (DRR) of 16.3% compared with 2.1% for GM-CSF. The objective response rate (ORR) was 26.4% versus 5.7%, and the complete response rate (CRR) was 11% compared with 1% for T-VEC and GM-CSF, respectively.
Since then, the first-in-class oncolytic immunotherapy has continued to show promise, both as a single agent and in combination trials.
In the phase Ib portion of a phase Ib/II multicenter trial of T-VEC and ipilimumab (Yervoy) with previously untreated, unresected stage IIIB/IV melanoma, the ORR was 56% (33% CRR), and the DRR was 44% in 18 evaluable patients who received the combination.2
Median time to response was 5.3 months (range, 2.6-5.7) and median progression-free survival (PFS) was 10.6 months (2.6-19.3+). Median overall survival (OS) was not reached; 12-month and 18-month survival rates were 72.2% and 67%, respectively.
Grade 3/4 adverse events (AEs) occurred in 32% of patients and grade 3/4 immune-related AEs occurred in 2 patients. There were no treatment-related deaths.
Despite these advancements, there is still much to be understood about T-VEC, says Howard L. Kaufman, MD, chief surgical officer and associate director for Clinical Science at Rutgers Cancer Institute of New Jersey.
In an interview with OncLive
, Kaufman discusses remaining questions regarding T-VEC, the impact of the FDA approval, and its future potential.
OncLive: What impact has T-VEC’s approval made in the treatment of patients with melanoma?
: I think the real importance of T-VEC’s FDA approval is that it brings an entirely new class of drugs to patients with this cancer. Since T-VEC is a first-in-class agent, I think we really need to understand exactly how it is working. It will open up the field to other viruses, as well as other manipulations of the virus to improve responses.
It is going to be an excellent agent for combination studies. I think that T-VEC can really help to bring more lymphocytes to the tumor microenvironment, and that is half the battle. Making sure lymphocytes are activated and understanding which T cells are mediating tumor regression—whether it’s with T-VEC or with other agents—is going to be a very important area for future research.
Can you describe the trial that led to T-VEC’s approval?
The pivotal phase III trial with T-VEC randomized 436 patients with advanced melanoma. Two-thirds of the patients received T-VEC and one-third received a control, which, in this case, was recombinant GM-CSF.
This was selected as our control, because GM-CSF is actually part of T-VEC and, at the time that this trial was initiated in 2008, there was some evidence that GM-CSF might have some activity in both stage III and stage IV melanoma. The study was designed to look at DRR, which meant that patients needed to achieve an objective response and then that response had to be maintained for 6 months or longer.
What were the most significant findings?
The study met its primary endpoint, demonstrating an improved durable response. We also saw an improvement in ORR, PFS, and a trend toward improved OS. This was not reached in the trial, but it wasn’t necessarily powered for an OS endpoint. The results did show that there is a clinical benefit to patients.
The current approval really focused on skin and lymph node melanomas that one can actually access for treatment, but I think the future will encompass combinations. If we really understand the mechanism of this, we may find ways to improve the therapeutic potential of this agent.
Which agents have the most potential to be paired with T-VEC?
The most logical thing would be to start with other types of immunotherapy agents to try to enhance the immune response rates. In the early phase II studies, we did biopsy some of the T-VEC injected lesions. We saw evidence that there were melanoma-specific CD8 T cells, and we saw a decrease in regulatory T cells and myeloid-derived suppressor cells.
This suggests that there was a local immune response. To try and expand that, it might make sense to use agents with T-VEC that have a primary target of the T cell. The early studies that are combining T-VEC with ipilimumab look very promising.
Data from a phase Ib study was recently reported showing an over 40% response rate with the combination. This is much higher than either agent alone. A more complete randomized phase II study looking at the combination is nearly at completion.
Are there any toxicity concerns with the combination of T-VEC and ipilimumab?
I think we are always concerned about toxicity when we add 2 drugs together. Interestingly, with immunotherapy, we haven’t always thought that to be the case. In the early phase Ib study of ipilimumab plus T-VEC, we haven’t seen any unexpected toxicities outside of what we would expect with either agent alone.
What was interesting is that, in an ipilimumab and GM-CSF trial, it was actually suggested there might even be a little less gastrointestinal toxicity with that combination. We have to conduct these trials to really understand what the side effects will be, but I don’t think we are necessarily going to see added toxicities.
How far are we from finding a biomarker that will help identify which patients will benefit from T-VEC alone or in combination?
We have not identified a biomarker yet, but now that the drug has been approved there will be more focus on this area. We have to conduct clinical trials to really understand the full potential for clinical benefit with this agent as well as to identify biomarkers.
We do have a number of ancillary clinical trials in progress right now looking at viral shedding and the induction of the immune response with T-VEC. This will be really important. Unfortunately, these questions weren’t really included in the phase III study, so there is a lot of information that we still have to determine regarding this agent.
Andtbacka RHI, Kaufman HL, Collichio F, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33(25):2780-2788.
Puzanov I, Milhem M, Hans R, et al. Survival, safety, and response patterns in a phase 1b multicenter trial of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma. J Clin Oncol. 33, 2015 (suppl; abstr 9063).